Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[S:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[N:20][CH:21]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[N:20][CH:21]=2)=[O:14])[S:7][C:8]=1[CH:9]([CH3:10])[CH3:11])([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(C(=O)O)sc1C(C)C
Reactant: COC(=O)c1ccc(N)cn1
Product: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)s2)cn1
Yield: 67 %

Procedure:
In the same manner as that of Example 2, 4,5-diisopropylthiophene-2-carboxylic acid (102 mg, 0.481 mmol) was condensed with methyl 5-aminopyridine-2-carboxylate, and the resultant was purified by silica gel chromatography [benzene-ethyl acetate (2:1)] to obtain methyl 5-[(4,5-diisopropylthiophene-2-carbonyl)amino]pyridine-2-carboxylate (112 mg, 67%) as colorless needles.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH3:29][C:30]([CH3:41])=[CH:31]B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].N#N>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]=2[CH:29]=[C:30]([CH3:41])[CH3:31])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)=CB1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C(F)(F)F)c2I)Cc2ccccc2C1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C1(NC(=O)c2cccc(C(F)(F)F)c2C=C(C)C)Cc2ccccc2C1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 42-(2-Iodo-3-trifluoromethyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (A8) (500 mg, 1.10 mmol) and 2-methyl-1-propenyl boronic acid pinacol ester (400 mg, 2.20 mmol) in dioxane (20 mL) is added dichloro[1,1′-bis(diphenylphosphino)ferrocene]-palladium (II) DCM adduct (71.8 mg, 8.2% mmol) and 2M aqueous solution of K2CO3 (1.65 mL, 3.30 mmol). The resulting reaction mixture is filled in with N2, heated to 100° C. and stirred continuously overnight. Reaction mixture is filtered and concentrated in vacuo, and the resulting residue is purified by flash column chromatography (12 g silica gel, gradient elution: 0%-50% EtOAc in heptane) to give a pure product (396) as light brown oil (100 mg, 21%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([F:18])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][C:14]([CH3:16])([CH3:15])[CH3:17])[C:9]([F:18])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(F)c(C#CC(C)(C)C)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)C#Cc1cc(Cl)c(C(=O)O)cc1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
Methyl 2-chloro-5-fluoro-4-(3,3-dimethylbut-1-ynyl)benzoate (6.1 g, 22 mmol) was dissolved in MeOH (30 mL), sodium hydroxide (1.3 g, 33 mmol) (in 20 mL, water) was added and stirred at 60° C. overnight. Solvent was removed, residue was dissolved in water, neutralized by HCl till pH <2, extracted by EtOAc, washed by water, brine and dried over Na2SO4. Product was obtained as a beige solid (3.1 g, 52%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[CH3:25][O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:30]3[CH2:31][CH2:32][CH:27]([O:26][CH3:25])[CH2:28][CH2:29]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Solvent: O=C(O)C(F)(F)F
Product: COC1CCN(c2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)CC1

Procedure:
Prepared in analogy to Example A3(d) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 4-methoxy-piperidine trifluoroacetate. Yellow oil. MS (m/e): 333.3 ([M+H]+, 100%).
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([F:13])[CH:7]=1>CS(C)=O.O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:1]#[N:2])=[CH:7][C:8]=1[F:13]
Reactant: [C-]#N
Reactant: Fc1cc(CBr)ccc1Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1ccc(Cl)c(F)c1
Reaction time: 1 h
Yield: 61 %

Procedure:
KCN (1.25 g, 19.2 mmol) was added to a solution of 4-(bromomethyl)-1-chloro-2-fluorobenzene (3.90 g, 17.5 mmol) in DMSO (60 mL). Several milliliters of H2O were added to help dissolve the KCN. After 1 hour, the reaction mixture was diluted with H2O and extracted with EtOAc. The extracts were dried (Na2SO4), filtered, and concentrated. The crude product was flashed on silica (Biotage 40M, 9:1 to 4:1 hex:EtOAc) to give 2-(4-chloro-3-fluorophenyl)acetonitrile (1.81 g, 61.2% yield) as a yellow crystalline solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Br[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[C:17]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)=[O:11])=[N:26][CH:27]=1
Reactant: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Reactant: Clc1ccc(Br)nc1
Product: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(Cl)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(1H-pyrazol-1-yl)pyridin-2-yl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 425 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C1C(=O)N([Br:25])C(=O)C1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:25][C:10]1[C:2]([F:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5][CH2:4]2
Reactant: CC(C)(C)OC(=O)N1CCc2c(F)cccc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c1ccc(Br)c2F
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a solution of 1,1-dimethylethyl 4-fluoro-2,3-dihydro-1H-indole-1-carboxylate (0.866 g, 3.65 mmol) in Dichloromethane (DCM) (10 mL) was added a solution of NBS (0.650 g, 3.65 mmol) in Dichloromethane (DCM) (10 mL). The reaction was stirred overnight. The reaction mixture was poured into sodium bicarbonate (aq., sat., 50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (0-30% EtOAc in hexanes, 24-g silica gel column) to afford 1,1-dimethylethyl 5-bromo-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate (1 g, 87% yield) as a (4:1 LCMS, 10:1 by 1H NMR) mixture with the starting material. The mixture was used without further purification. LC-MS (ES) m/z=260, 262 [M+H-t-Bu]+. 1H NMR (400 MHz, DMSO-d6) δ 1.51 (s, 9H), 3.13 (t, J=8.72 Hz, 2H), 3.94-4.08 (m, 2H), 7.26-7.63 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:11](=[CH:12]2)[C:10]2([C:26]4[C:18]([C:19]5[C:24]([CH:25]=4)=[CH:23][CH:22]=[CH:21][CH:20]=5)=[CH:17][CH:16]=[CH:15]2)[C:9](Br)=[C:8](Br)[C:7]=3Br)=[C:4](Br)[C:3]=1Br.B(O)(O)[C:33]1[CH:34]=[CH:35][C:36]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:37][CH:38]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:36]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:35]=[CH:34][CH:33]=[CH:38][C:37]=1[C:2]1[CH:14]=[C:13]([C:12]2[CH:25]=[CH:26][CH:18]=[CH:17][C:11]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]2[C:6]3[C:15](=[CH:10][C:9]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=4[C:36]4[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=4)=[CH:8][CH:7]=3)[C:16]3([C:17]4[CH:18]=[C:26]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=5[C:36]5[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=5)[CH:25]=[C:24]([C:23]5[CH:22]=[CH:21][CH:20]=[CH:16][C:15]=5[C:10]5[CH:11]=[CH:6][CH:7]=[CH:8][CH:9]=5)[C:19]=4[C:42]4[C:41]3=[CH:40][C:39]([C:36]3[CH:37]=[CH:38][CH:33]=[CH:34][C:35]=3[C:13]3[CH:14]=[CH:2][CH:3]=[CH:4][CH:5]=3)=[CH:44][CH:43]=4)[C:4]=2[CH:3]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: BrC1=C2C(=Cc3cc(Br)c(Br)c(Br)c32)C2(C=CC=C3C2=Cc2ccccc23)C(Br)=C1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccccc2-c2ccc3c(c2)C2(c4cc(-c5ccccc5-c5ccccc5)ccc4-c4c(-c5ccccc5-c5ccccc5)cc(-c5ccccc5-c5ccccc5)cc42)c2cc(-c4ccccc4-c4ccccc4)cc(-c4ccccc4-c4ccccc4)c2-3)cc1

Procedure:
In a 250 ml two-necked flask fitted with reflux condenser and precision glass stirrer, 1.6 g of hexabromospirobifluorene and 3 g of biphenylboronic acid are slurried in a mixture of 50 ml of toluene and 50 ml of 1 M potassium carbonate solution. The mixture is refluxed under nitrogen and 115 mg of tetrakis(triphenylphosphine)palladium in 5 ml of toluene are added. The mixture is boiled under reflux for 7 hours while stirring. After the reaction is complete, the cooled solution is filtered and the filtrate is extracted twice by shaking with water (to improve the phase separation, chloroform is added). The organic phase is dried over sodium sulfate, filtered through a short column of silica gel and subsequently evaporated on a rotary evaporator. The product is further purified by recrystallization from dichloromethane/pentane. This gives 2 g (80%) of colorless crystals which fluoresce blue under UV illumination.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.S(Cl)([Cl:17])=O>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:17])=[O:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Product: COc1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Temperature: 75 °C

Procedure:
A mixture of 4-methoxy-2-nitrobenzoic acid 1 (1.0 g) and thionyl chloride (5 mL) was heated at 75° C. for overnight under nitrogen atmosphere. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was evaporated at 40° C. under vacuum to give 4-methoxy-2-nitrobenzoyl chloride as a yellow solid which was used in the next step without further purification. To a solution of 4-methoxy-2-nitrobenzoyl chloride (1.0 g) in 10 mL THF was added ammonium hydroxide (5 mL) drop-wise (exothermic). The resulting mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was evaporated to give 4-methoxy-2-nitrobenzamide 2 which was purified by triturating with methyl tert-butyl ether. Pink solid (1.05 g, 100%). 1H NMR (400 MHz, CDCl3): δ 3.89 (s, 3H); 5.87 (br s, 2H); 7.13-7.15 (m, 1H); 7.25-7.26 (m, 1H); 7.47-7.52 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][CH3:9])=[C:4](I)[CH:3]=1.[C:11]([O:15][C:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]1B(O)O)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]1[C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=1[O:8][CH3:9])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Reactant: COc1nnc(Cl)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COc1nnc(Cl)cc1-c1cc2ccccc2n1C(=O)OC(C)(C)C

Procedure:
Argon is passed for 30 min through a suspension of 135 mg 6-Chloro-4-iodo-3-methoxy-pyridazine, 130.5 mg 1-(tert-butoxycarbonyl)indole-2-boronic acid, 152 mg potassium carbonate, and 52.5 mg triphenylphosphine in 2.2 ml DME and 1.1 ml water. 11.2 mg palladium (II) acetate is added, and the mixture is stirred under reflux for 3 h. The product is isolated by extraction with ethyl acetate and purified by chromatography on silica gel yielding 80 mg 2-(6-Chloro-3-methoxy-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C([O:5][C:6](=[O:31])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[NH:17][S:16]2(=[O:22])=[O:21])=[C:11]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:10]=1)(C)(C)C.CO.[OH-].[Na+]>C1COCC1>[CH2:24]([O:23][C:11]1[CH:10]=[C:9](/[CH:8]=[CH:7]/[C:6]([OH:31])=[O:5])[CH:14]=[CH:13][C:12]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (E)-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acrylic acid tert-butyl ester (2.2 g, 5.18 mmol) in THF (14 mL)/MeOH (7 mL) is added 3.5 mL (20.7 mmol) of 6N NaOH solution and the mixture is stirred at RT for 18 h. The solvent is removed under reduced pressure and water is added to the residue. The mixture is acidified with 1N HCl and is extracted with methylene chloride. The organic phase is washed with water and brine then is dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound as a reddish solid: ): (M−1)−=387.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:36][CH2:37][CH2:38][CH2:39]I.Cl>CN(C)C=O>[Cl:36][CH2:37][CH2:38][CH2:39][N:16]1[C:17]2[C:12](=[N:11][CH:10]=[C:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:18]=2)[C:13]([OH:25])=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]1=[O:19]
Reactant: ClCCCI
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCCl)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (40 mg, 0.117 mmol) in N,N-dimethylformamide was added lithium bis(trimethylsilyl)amide (234 μL, 1.0 M in tetrahydrofuran, 0.234 mmol) dropwise. 1-Chloro-3-iodopropane (50 μL, 0.468 mmol) was added dropwise and stirred 4 hours at room temperature. The reaction mixture was acidified with cold 1 N aqueous hydrochloric acid and extracted with toluene. The organic layer was washed with water and brine, then dried over sodium sulfate. Filtration and concentration provided ethyl 1-(3-chloropropyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J=1.1 Hz, 1 H), 7.50 (s, 1 H), 7.18 (dd, J=8.6, 5.3 Hz, 2 H), 7.03 (t, J=8.6 Hz, 2 H), 4.50 (q, J=7.1 Hz, 2 H), 4.27 (t, J=7.6 Hz, 2 H), 4.13 (s, 2 H), 3.61 (t, J=5.9 Hz, 2 H), 2.09 (m, 2 H), 1.47 (t, J=7.3 Hz, 3 H); MS m/z 417 (M−H)−.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][CH2:38][NH:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][CH2:38][NH:39][C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: NCCNc1cccnc1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)NCCNc2cccnc2)cc1
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
4-geranyloxybenzoic acid(3.57 g) was dissolved in chloroform(60 ml) and triethylamine(3.60 ml), and then diphenylphosphinic chloride(2.48 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 3-(2-aminoethylamino)pyridine(2.24 g) added thereto, was stirred for 3 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=15:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 2.41 g of the aimed compound.
Reaction SMILES: COC1C=CC(C[N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH:11]=[CH:10][S:9]2(=[O:19])=[O:18])=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[CH:10][S:9]1(=[O:18])=[O:19]
Reactant: COc1ccc(CN2c3ccccc3C=CS2(=O)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S1(=O)C=Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The title compound was synthesized according to the method described in WO 2008/073956 A2. To a solution of 1-(4-methoxybenzyl)-1H-benzo[c][1,2]thiazine 2,2-dioxide (0.9 g, 3 mmol) in anhydrous methylene chloride was added trifluoroacetic acid (18 mL). The mixture was stirred at room temperature for 5 hours and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (25-70% ethyl acetate in hexanes) to give a white solid. (0.6 g, 72%). 1H NMR (CDCl3, 300 MHz) δ 7.43-7.38 (m, 2H), 7.29 (m, 1H), 7.20-7.14 (dt, 1H, J=1.2, 7.5 Hz), 7.02-6.99 (d, 1H, J=7.8 Hz), 6.78-6.75 (dd, 1H, J=2.4, 10.5 Hz).
Reaction SMILES: C([N:3]1[C:7]([CH2:8]CN)=[N:6][N:5]=[N:4]1)C.[CH3:11][C:12]1[N:13]=NNN=1.C(I)C.C(OC(=O)NCCBr)(C)(C)C>>[CH3:8][C:7]1[N:6]=[N:5][N:4]([CH2:11][CH2:12][NH2:13])[N:3]=1
Reactant: Cc1nn[nH]n1
Reactant: CCn1nnnc1CCN
Agent: CC(C)(C)OC(=O)NCCBr
Solvent: CCI
Product: Cc1nnn(CCN)n1

Procedure:
This compound is prepared by an analogous procedure to intermediate CI2 by replacing [2-(1H-Tetrazol-5-yl)-ethyl]-carbamic acid tert-butyl ester in step 1 with 5-Methyl-2H-tetrazole and by replacing ethyliodide with (2-Bromo-ethyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.[H-].[Na+].Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1ccc2cc(Br)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2c(=O)ccc3cc(Br)ccc32)cc1
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a stirred solution of 6-bromoquinolin-2(1H)-one (2 g, 8.92 mmol) in DMF (20 mL) was added NaH (0.26 g, 10.7 mmol) at 0° C. After stirring for 30 min, 1-(chloromethyl)-4-methoxybenzene (1.67 g, 10.7 mmol) was added and the resulting reaction mixture was stirred at RT overnight. The reaction mixture was diluted with water and the precipitate was filtered, washed with water and dried. The crude product was purified by flash chromatography on silica gel using hexane/ethyl acetate to give 6-bromo-1-(4-methoxybenzyl)quinolin-2(1H)-one as yellow solid (2.4 g, 80%). 1HNMR: 400 MHz, DMSO-d6: δ 3.70 (s, 3H), 5.43 (s, 2H), 6.78 (d, J=9.60 Hz, 1H), 6.87 (dd, J=2.00, 6.40 Hz, 2H), 7.14 (d, J=8.80 Hz, 2H), 7.38 (d, J=8.80 Hz, 1H), 7.66 (dd, J=2.40, 8.80 Hz, 1H), 7.94 (d, J=−8.40 Hz, 1H), 8.01 (d, J=2.40 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[CH:10]=2)[N:5]=[CH:4][N:3]=1.CO[CH:20]=[C:21]([C:26]([O:28][CH3:29])=[O:27])[C:22]([O:24][CH3:25])=[O:23].O>CN(C)C=O>[CH3:25][O:24][C:22](=[O:23])[C:21](=[CH:20][NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:17])[CH:14]([CH3:15])[CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:26]([O:28][CH3:29])=[O:27]
Reactant: CC(C)C(=O)Nc1ccc2ncnc(N)c2c1
Reactant: COC=C(C(=O)OC)C(=O)OC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(=CNc1ncnc2ccc(NC(=O)C(C)C)cc12)C(=O)OC
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 88.8 %

Procedure:
A mixture of 4-amino-6-(2-methylpropionamido)-quinazoline (6.2 g) and dimethyl methoxymethylenepropanedioate (7.01 g) in N,N-dimethylformamide (25 ml) was stirred at 100° C. for 1.5 hours and cooled to room temperature. Water was added to the reaction mixture. The resulting solid was separated by filtration, washed with water and dried to give dimethyl[[6-(2-methylpropionamido)-4-quinazolinylamino]methylene]propanedioate (8.9 g). Recrystallization from ethyl acetate gave pure crystals melting at 212°-214° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:23])=[C:4]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:3]=1[CH3:29].[C:30](OCC)(OCC)(OCC)[CH3:31]>>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:5]2[N:23]=[C:30]([CH3:31])[N:24]([C:25]([CH3:26])([CH3:28])[CH3:27])[C:4]=2[C:3]=1[CH3:29]
Reactant: Cc1c(Cl)nc(N(Cc2ccccc2)Cc2ccccc2)c(N)c1NC(C)(C)C
Reactant: CCOC(C)(OCC)OCC
Product: Cc1c(Cl)nc(N(Cc2ccccc2)Cc2ccccc2)c2nc(C)n(C(C)(C)C)c12
Reaction time: 2 h

Procedure:
6-Chloro-5-methyl-N4 -(1,1-dimethylethyl)-N2,N2 -bis(phenylmethyl)pyridine-2,3,4-triamine was combined with an excess of triethyl orthoacetate and heated first on a steam bath for about 16 hours and then in an oil bath at 130° C. for 2 hours. The excess triethylorthoacetate was distilled off under vacuum. The resulting residue was diluted with methylene chloride, washed with water and sodium bicarbonate solution, dried over magnesium sulfate then filtered through a layer of silica gel eluting with additional methylene chloride. The filtrate was concentrated under vacuum to provide a mixture which was carried on to thenext step.
Reaction SMILES: Cl[CH:2]([C:9]1[CH:10]=[C:11]([C:20]([CH3:24])([CH3:23])[C:21]#[N:22])[CH:12]=[C:13]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])[CH:14]=1)[C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1.C(N(CC)CC)C>[Pd].C(O)C>[N:5]1[CH:4]=[C:3]([CH2:2][C:9]2[CH:10]=[C:11]([C:20]([CH3:24])([CH3:23])[C:21]#[N:22])[CH:12]=[C:13]([C:15]([CH3:18])([CH3:19])[C:16]#[N:17])[CH:14]=2)[CH:8]=[N:7][CH:6]=1
Reactant: CC(C)(C#N)c1cc(C(Cl)c2cncnc2)cc(C(C)(C)C#N)c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C#N)c1cc(Cc2cncnc2)cc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2,2'-[5-(1-chloro-1-(pyrimidin-5-yl)methyl)-1,3-phenylene]di(2-methylpropiononitrile), (0.55 g), triethylamine (0.25 ml), 5% palladium-on-carbon (0.02 g) and ethanol (10 ml) was stirred under hydrogen at room temperature and atmospheric pressure for 10 minutes and then filtered. The filtrate was diluted with ethyl acetate (25 ml), and the solution washed with aqueous sodium hydrogen carbonate, dried and evaporated to dryness. The residue was purified by flash chromatography using 1% by volume of methanol in dichloromethane as eluant to give 2,2'-[5-(pyrimidin-5-ylmethyl)-1,3-phenylene]di(2-methylpropiononitrile), mp 132°-134°.