Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10].[CH3:20][N:21]([CH:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1)[C:22]1[O:23][C:24]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:25]=2[N:26]=1.N1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[CH2:7]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([NH:31][C:28]2[CH:29]=[CH:30][C:24]3[O:23][C:22]([N:21]([CH3:20])[CH:32]4[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]4)=[N:26][C:25]=3[CH:27]=2)=[O:17])=[CH:18][CH:19]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1ccc(C(=O)O)cc1
Reactant: CN1CCC(N(C)c2nc3cc(N)ccc3o2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1ccc(C(=O)Nc2ccc3oc(N(C)C4CCN(C)CC4)nc3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
Add oxalyl chloride (0.16 mL, 1.82 mmol) and 3 drops of DMF to a stirring suspension of 4-butyl-benzoic acid (0.162 g, 0.910 mmol) in CH2Cl2 (2.0 mL). Stir the reaction mixture at room temperature for 2 h. Concentrate the mixture in vacuo, add n-hexane, re-concentrate, and re-dissolve in CH2Cl2. Add the resultant 4-butyl-benzoyl chloride solution to a mixture of rac-N2-methyl-N2-(1-methyl-piperidin-4-yl)-benzooxazole-2,5-diamine (0.158 g, 0.607 mmol) and pyridine (0.05 mL) in CH2Cl2 (10 mL). Shake the reaction mixture overnight at room temperature. Wash the mixture with saturated NaHCO3 (aq) (2×20 mL), dry the organic phase over Na2SO4, filter, and concentrate the mixture in vacuo. Subject the residue to silica gel flash column chromatography (3×4 g columns, eluting with 5% 2N NH3 in MeOH/CH2Cl2) to yield the desired product as an oil (0.098 g, 35%). mass spectrum (m/e): 421.0 (M+1). 1H NMR (400 MHz, CDCl3): δ 7.84-7.78 (m, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.48 (d, J=1.9 Hz, 1H), 7.35 (dd, J 8.8, 1.8 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 4.21-4.11 (m, 1H), 3.07 (s, 3H), 2.97 (d, J=11.2 Hz, 2H), 2.66 (t, J=8.0 Hz, 2H), 2.32 (s, 3H), 2.17 (t, J=11.6 Hz, 2H), 2.01-1.87 (m, 2H), 1.83-1.75 (m, 2H), 1.65-1.56 (m, 2H), 1.40-1.30 (m, 2H), 0.92 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:34])[CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[NH:23][C:22](=[O:27])[C:21]4[NH:28][CH:29]=[C:30]([C:31]([OH:33])=[O:32])[C:20]=4[C:19]=3[CH:18]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OS(OCCC)(=O)=O)CC>>[C:1]([O:5][C:6]([N:8]([CH3:34])[CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[NH:23][C:22](=[O:27])[C:21]4[NH:28][CH:29]=[CH:30][C:20]=4[C:19]=3[CH:18]=2)(=[O:15])=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([C:31]([O-:33])=[O:32])[CH2:20][CH3:19]
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(S(=O)(=O)c2ccc3[nH]c(=O)c4[nH]cc(C(=O)O)c4c3c2)C1
Agent: CCCOS(=O)(=O)OCCC
Solvent: CCN(CC)CC
Product: CCCC(=O)[O-]
Product: CN(C(=O)OC(C)(C)C)C1CCN(S(=O)(=O)c2ccc3[nH]c(=O)c4[nH]ccc4c3c2)C1

Procedure:
This compound was prepared according to general method of esterification C from 294 mg (0.6 mmol) of 8-[3-(tert-butoxycarbonyl-methyl-amino)-pyrrolidine-1-sulfonyl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid, 836 μL (6 mmol) of triethylamine and 492 μL (3 mmol) of di-n-propylsulfate to give, after purification by chromatography on silica (eluent dichloromethane/methanol 98/2), 155 mg (50%) of 8-[3-(tert-butoxycarbonyl-methyl-amino)-pyrrolidine-1-sulfonyl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-propyl carboxylate in the form of a brown solid.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.C1(P(=[CH:29][C:30]([O:32][CH3:33])=[O:31])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:9][C:1]1[CH:2]=[C:3]([CH:4]=[CH:5][CH:6]=1)[CH:7]=[CH:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cccc(C=O)c1
Solvent: C1CCOC1
Product: COC(=O)C=Cc1cccc(C)c1

Procedure:
A mixture of 6.0 g (49.9 mmol) of m-tolualdehyde and 18.37 g (54.93 mmol) of methyl (triphenylphosphoranylidene)acetate in 50 ml of THF was stirred at reflux for 4 hours. The THF was evaporated and the residue was stirred with 200 ml of petroleum ether (bp=30°-60° C.) and filtered. The filtrate was evaporated to give the title compound as a light yellow liquid which was distilled bulb-to-bulb at 90° C./0.4 mm of Hg.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[NH2:17][C:18]1[C:19]([Cl:36])=[C:20]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:21][NH:22][C:23](=[O:31])[C:24]([CH3:30])([C:26]([F:29])([F:28])[F:27])[CH3:25]>O.O1CCOCC1>[Cl:36][C:19]1[C:18]([N:17]=[C:1]=[S:2])=[C:34]([Cl:35])[CH:33]=[CH:32][C:20]=1[CH2:21][NH:22][C:23](=[O:31])[C:24]([CH3:30])([C:26]([F:27])([F:28])[F:29])[CH3:25]
Reactant: CC(C)(C(=O)NCc1ccc(Cl)c(N)c1Cl)C(F)(F)F
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl)C(F)(F)F

Procedure:
1,1′-Thiocarbonyldi-2-pyridone (3.12 g, 13 mmol) is added to a mixture of N-(3-amino-2,4-dichloro-benzyl)-2-methyl-2-trifluoromethyl-propionamide (3.90 g, 11.8 mmol) and dioxane (135 mL) and stirred at reflux overnight. The mixture is diluted with water, most of the dioxane is removed under reduced pressure and the resulting precipitate is filtered, washed with water and dried.
Reaction SMILES: [H-].[Na+].[CH:3]1([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4]1.CN(C=O)C.F[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)=[CH:23][N:22]=1>O>[CH:3]1([N:8]2[CH2:9][CH2:10][CH:11]([O:14][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=4)=[CH:23][N:22]=3)[CH2:12][CH2:13]2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: N#Cc1ccc(-c2ccc(F)nc2)cc1
Reactant: OC1CCN(C2CCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(OC3CCN(C4CCCC4)CC3)nc2)cc1
Temperature: 130 °C
Reaction time: 7 h

Procedure:
60% sodium hydride (13 mg) and 1-cyclopentyl-4-hydroxypiperidine (60 mg) were added to a DMF solution (3 ml) of 2-fluoro-5-[4-cyanophenyl]pyridine (56 mg), and stirred at 130° C. for 7 hours. The reaction mixture was cooled to room temperature, and water was added thereto and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, chloroform:methanol=9:1) to obtain the entitled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[N:10]([CH3:22])[C:11](SC)=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]([NH2:35])[CH2:32][CH2:33][NH2:34]>>[NH2:35][CH:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[F:24])[CH2:32][CH2:33][NH:34][C:11]1[N:10]([CH3:22])[C:9](=[O:23])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:12]=1
Reactant: NCCC(N)c1ccccc1F
Reactant: CSc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c(=O)n1C
Product: Cn1c(NCCC(N)c2ccccc2F)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Reaction time: 3 h

Procedure:
2-34 2-((3-Amino-3-(2-fluorophenyl)propyl)-amino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone was prepared from 5-(4-fluorophenyl)-3-methyl-2-methylthio-6-(4-pyridyl)-4(3H)-pyrimidinone and 1-(2-fluorophenyl)-1,3-propanediamine according to the General Procedure. The reaction was done at 190° C. for 3 h. MS (m/z): 448.1 (M+H)+; C25H23F2N5O requir. 447.5 (free base).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([N:21]3[C:29]4[C:24](=[CH:25][C:26]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)[N:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:36]N(C=O)C.CI>[Cl-].[Na+].O.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([C:15]2[CH:20]=[C:19]([N:21]3[C:29]4[C:24](=[CH:25][C:26]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)[N:18]=[CH:17][N:16]=2)[CH3:36])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: ClCCl
Solvent: O
Product: CN(c1cc(N2CCc3cc(S(C)(=O)=O)ccc32)ncn1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6b (80 mg, 0.17 mmol), NaH (75 mg, 1.87 mmol) and DMF (1 mL) was stirred at room temperature for 30 minutes. Methyl iodide (0.025 mL, 0.4 mmol) was added and the mixture was heated at 90° C. in a sealed vial for 18 h. After cooling to room temperature, DCM (4 mL) and brine (4 mL) were added. The layers were separated and the aqueous layer was extracted with DCM (3×3 mL). The combined extracts were dried, filtered, evaporated and purified by preparative HPLC to give 16-1, LCMS 488.4 (MH+).
Reaction SMILES: CN(C)C=O.[N+:6]([C:9]1[N:10]=[C:11](S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[N:12]([CH2:14][C@:15]([OH:40])([CH3:39])[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH:27]=[CH:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[O:24])[CH2:19][CH2:18]2)[CH:13]=1)([O-:8])=[O:7].CC(C)([O-])C.[Na+].O>C(OCC)(=O)C>[CH3:39][C@@:15]1([CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH:27]=[CH:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:31][CH:30]=3)=[O:24])[CH2:19][CH2:18]2)[O:40][C:11]2=[N:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:13][N:12]2[CH2:14]1
Reactant: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@]1(CN2CCN(C(=O)OCC=Cc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reaction time: 0.5 h
Yield: 39.8 %

Procedure:
To N,N-dimethylformamide (0.5 ml) solution of 3-(4-trifluoromethylphenyl)-2-propenyl (S)-4-{3-[4-nitro-2-(4-nitrobenzenesulfonyl)imidazol-1-yl]-2-hydroxy-2-methylpropyl}piperazin-1-carboxylate (45 mg) was added sodium tert-butoxide (8 mg) at 0° C., and stirred at the same temperature for 30 minutes. To the reaction mixture was added water and ethyl acetate, the organic layer was taken by separation. The ethyl acetate layer was washed with an aqueous solution of 5%-potassium carbonate, water, and an aqueous solution being saturated with sodium chloride, then dried over anhydrous sodium sulfate. The residue obtained by removal of the solvent by distillation was purified by use of a thin layer chromatography (eluent: dichloromethane/ethyl acetate/methanol=15/15/1), there was obtained 3-(4-trifluoromethylphenyl)-2-propenyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo-[2,1-b]oxazol-2-ylmethyl)piperazin-1-carboxylate (13 mg, yield: 39%) as pale yellow amorphous product.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]([F:19])[F:18])=[C:12]([O:20][CH:21]([F:23])[F:22])[CH:11]=2)[CH2:8][CH2:7]C(=O)[CH2:5][CH2:4]1)#[N:2].[CH:24]([O:29][CH3:30])([O:27][CH3:28])OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:30][O:29][C:24]1([O:27][CH3:28])[CH2:5][CH2:4][C:3]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]([F:18])[F:19])=[C:12]([O:20][CH:21]([F:22])[F:23])[CH:11]=2)([C:1]#[N:2])[CH2:8][CH2:7]1
Reactant: COC(OC)OC
Reactant: N#CC1(c2ccc(OC(F)F)c(OC(F)F)c2)CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC1(OC)CCC(C#N)(c2ccc(OC(F)F)c(OC(F)F)c2)CC1
Yield: 98.2 %

Procedure:
A mixture of 4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexan-1-one (1.34 g, 4.05 mmol), trimethyl orthoformate (0.53 mL, 4.85 mmol) and a catalytic amount of p-toluenesulfonic acid in methanol (40 mL) was heated gently under an argon atmosphere for 2 h. The mixture was cooled and then concentrated. The residue was partitioned between 5% aqueous sodium carbonate and ethyl acetate, was extracted twice with ethyl acetate, the organic extract was dried (potassium carbonate) and the solvent was removed in vacuo to provide an oil (1.5 g, 98%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:16]=2[O:17][CH3:18])[C:13]([C:19](=[O:28])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[N:12][CH:11]=[C:10]3[CH:29]=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.P([O-])(O)(O)=[O:33].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O.CCCCCC>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:16]=2[O:17][CH3:18])[C:13]([C:19](=[O:28])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[N:12][CH:11]=[C:10]3[C:29]([OH:33])=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=P([O-])(O)O
Reactant: COc1cccc(C(=O)c2ncc(C=O)c3cc(OC4CCCC4)c(OC)cc23)c1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CCCCCC
Product: COc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OC4CCCC4)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 58.1 %

Procedure:
To a stirred solution of afforded 6-cyclopentyloxy-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carbaldehyde (200 mg, 0.49 mmol) in t-butanol (2 mL) and water (2 mL) solution was added sodium dihydrogenphosphate monohydrate (184 mg, 1.33 mmol), 2-methyl-2-butene (0.226 mL, 2.00 mmol) and sodium chlorite (181 mg, 2.00 mmol) at room temperature. The reaction suspension was then stirred at room temperature for 14 hrs. The resulting two-phase mixture was partitioned between dichloromethane and water and acidified to pH=3 by addition of acetic acid. The aqueous phase was then extracted with dichloromethane (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a brown semi-solid oil. The crude product was recrystallized in ethyl acetate and hexane to afford 6-cyclopentyloxy-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (120 mg, 58% yield) as a yellow solid: HR-MS m/e calcd for C24H23N1O6 (M−H+) 421.1525, found 421.1526; 1H NMR (300 MHz) compatible.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][N:13]=2)[CH:10]=1)[NH2:4].[F:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([CH:23]=1)[C:20](O)=O.N>>[F:14][C:15]1[CH:23]=[C:19]([C:20]2[O:1][N:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]4[N:9]([CH:11]=[CH:12][N:13]=4)[CH:10]=3)[N:4]=2)[CH:18]=[N:17][CH:16]=1
Reactant: NC(=NO)c1ccc2nccn2c1
Reactant: O=C(O)c1cncc(F)c1
Agent: N
Product: Fc1cncc(-c2nc(-c3ccc4nccn4c3)no2)c1

Procedure:
The title compound was prepared according to method C using N′-hydroxyimidazo[1,2-a]pyridine-6-carboximidamide (Bionet) and 5-fluoronicotinic acid (Frontier). 1H NMR (300 MHz, DMSO-d6) δ 7.71 (d, J=1.4 Hz, 1 H), 7.74-7.88 (m, 2 H), 8.20 (s, 1 H), 8.51 (ddd, J=9.0, 2.9, 1.7 Hz, 1 H), 8.97 (d, J=3.1 Hz, 1 H), 9.24 (t, J=1.5 Hz, 1 H), 9.47 (t, J=1.4 Hz, 1 H) ppm; MS (DCI/NH3) m/z 282 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[C:7]([OH:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=1)=[N+]=[N-].Cl[C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:19]=[CH:18][N:17]=1.[H-].[Na+].CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O>[F:31][C:28]([F:29])([F:30])[C:25]1[CH:24]=[CH:23][C:22]([C:20]2[CH:21]=[CH:16][N:17]=[C:18]([O:14][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[N:5]=[C:4]([NH2:1])[CH:13]=[CH:12]4)[CH:19]=2)=[CH:27][CH:26]=1
Reactant: FC(F)(F)c1ccc(-c2ccnc(Cl)c2)cc1
Reactant: [N-]=[N+]=Nc1ccc2cccc(O)c2n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc2cccc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ccn3)c2n1
Temperature: 180 °C

Procedure:
A mixture of 2-azido-quinolin-8-ol (0.28 g, 1.5 mmol), 2-chloro-4-(4-trifluoromethyl-phenyl)-pyridine (Example 410 (c), 0.26 g, 1 mmol), and sodium hydride (64 mg, 1.6 mmol) in DMF (2 mL) was heated in a 180° C. oil bath for 48 h. The reaction mixture was then transferred to a 5-mL tube, and irradiated in the Microwave Smith Synthesizer at 250° C. for 10 min. EtOAc and brine were added, and the aqueous layer was extracted with EtOAc. Combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The compound was purified on a Biotage 40S column (98:2 dichloromethane: MeOH) followed by recrystallization from EtOAc/hexanes to give the title compound as a light-yellow shiny crystal. MS (ESI, pos. ion) m/z: 382 (M+1). Mp: 196.5-199.5° C. Anal. Calcd for C21H14F3N3O: C, 66.14; H, 3.70; N, 11.02. Found: C, 66.18; H, 3.69; N, 11.08.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[C:10]1(NN)[CH:15]=CC=[CH:12][CH:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:15]=[CH:10][C:11]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: NNc1ccccc1
Product: Cc1ccn(-c2ccc(Cl)cc2)n1

Procedure:
This compound was prepared by the same methodology described for EXAMPLE 8 with 4-chlorophenyl hydrazine · HCl substituted for phenyl hydrazine and 2-amino-5-(2-N-t-butylaminosulfonylphenyl)pyridine was used in the coupling step. There was obtained the title compound; HRMS (M+H)+ : calc. 468.089714; found 468.088873.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1C(=O)[N:5]1[C:15]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]4)=[CH:19][C:18]=3[O:32][CH3:33])=[N:14][C:13]3[N:34]([S:37]([C:40]4[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=4)(=[O:39])=[O:38])[CH:35]=[CH:36][C:12]=3[C:6]1=[N:7]2.[C:48](=[O:51])([O-])[O-:49].[K+].[K+].[CH3:54]O>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:7][C:6]2[C:12]3[CH:36]=[CH:35][N:34]([S:37]([C:40]4[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=4)(=[O:39])=[O:38])[C:13]=3[N:14]=[C:15]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]4)=[CH:19][C:18]=3[O:32][CH3:33])[N:5]=2)[C:3]=1[C:48]([O:49][CH3:54])=[O:51]
Reactant: CO
Reactant: COc1cc(N2CCN(C(C)C)CC2)ccc1Nc1nc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c2nc3cccc(Br)c3c(=O)n12
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1c(Br)cccc1Nc1nc(Nc2ccc(N3CCN(C(C)C)CC3)cc2OC)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Yield: 80 %

Procedure:
A solution of 8-bromo-5-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (120 mg, 0.167 mmol), and potassium carbonate (69.4 mg, 0.502 mmol) in methanol (25 ml) was stirred at room temperature. The reaction was filtered to remove the base, organic layer was filtered through a cotton plug, concentrated by rotary evaporation, adsorbed onto silica gel, and purified by silica gel chromatography (DCM to 10% MeOH/DCM) to give methyl 2-bromo-6-({2-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzoate (0.1 g, 80%). ESIMS (M+H)+=748.
Reaction SMILES: [CH:1](=[C:8]1[CH2:12][N:11]([C:13]([O:15]C(C)(C)C)=O)[C@H:10]([C:20]([OH:22])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)=C=O.[CH2:33]([NH:40][CH3:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([N:40]([CH3:41])[C:20]([C@@H:10]1[CH2:9][C:8](=[CH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][N:11]1[C:13]([NH:23][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)=[O:15])=[O:22])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CC(=Cc2ccccc2)C[C@H]1C(=O)O
Reactant: Cc1cccc(N=C=O)c1
Reactant: CNCc1ccccc1
Product: Cc1cccc(NC(=O)N2CC(=Cc3ccccc3)C[C@H]2C(=O)N(C)Cc2ccccc2)c1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 1-isocyanato-3-methylbenzene, and N-benzyl-N-methylamine the title compound was obtained in 68% purity by LC/MS. MS(ESI+): m/z=440.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][CH3:22])=[C:19]([C:23](O)=[O:24])[C:18]([CH2:26][CH3:27])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[CH3:46][N:47]1[CH2:52][CH2:51][CH:50]([CH2:53][N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:49][CH2:48]1>CC#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][CH3:22])=[C:19]([C:23]([N:57]4[CH2:56][CH2:55][N:54]([CH2:53][CH:50]5[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]5)[CH2:59][CH2:58]4)=[O:24])[C:18]([CH2:26][CH3:27])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: CCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(CC)c1C(=O)O
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(CC)c1C(=O)N1CCN(CC2CCN(C)CC2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 0.40 g (1.10 mmol) of 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-diethyl-1H-pyrazole-4-carboxylic acid (intermediate 1) and 0.18 g (1.1 mmol) of 2-chloro-4,6-dimethoxy-[1,3,5]triazine were dissolved in 10 ml of MeCN. The solution was then cooled down to 0° C. and 0.32 g=0.35 ml (3.2 mmol) of N-methylmorpholine was added drop by drop. After 2 hours stirring at 0° C., a solution of 0.21 g (1.1 mmol) 1-(1-methyl-piperidin-4-ylmethyl)-piperazine in 3 ml of MeCN was added drop by drop. Then, the mixture was warmed up to RT and stirring continued for 20 hours. Subsequently, it was poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0-7.5:2.5) to afford the title compound as colorless solid. MS: 560.2 (MH+, 1 Cl).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([O:13][CH3:14])[C:5](=[O:12])[C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH3:11].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]([O:13][CH3:14])[C:5](=[O:12])[C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH2:11][Br:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: CON=C(OC)C(=O)c1ncsc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CON=C(OC)C(=O)c1ncsc1CBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 106 g (0.5 mol) of the methylthiazol (cis-isomer from Example 3 c), 100 g (0.56 mol) of N-bromosuccinimide and 1 g of azobisisobutyronitrile in 1 l of carbon tetrachloride is refluxed for 3 hours. 20 g (0.11 mol) of N-bromosuccinimide are also added and heating is carried out for a further 2 hours. The reaction mixture is cooled to room temperature and the precipitated succinimide is filtered off under suction. The filtrate is extracted with water, dried over MgSO4 and evaporated down. The residue is purified by column chromatography using hexane/ethyl acetate mixtures. The products brominated in the nucleus and polybrominated products are obtained in the first fraction, followed by 58 g of the cis-isomer (about 90% purity; 0.18 mol, 36%) and 11 g of the trans-isomer (about 90% purity, 34 mmol, 7%) of the title compound as yellow oils.