Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([CH2:14][Cl:15])[C@H:11]2[O:16][C@@](OC)(C)[C@](OC)(C)[O:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]1[CH2:13][C@H:12]([CH2:14][Cl:15])[C@@H:11]([OH:16])[C@H:10]([OH:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(C)O[C@@H]2[C@@H](CCl)CN(Cc3ccccc3)C[C@H]2O[C@]1(C)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O[C@@H]1[C@@H](CCl)CN(Cc2ccccc2)C[C@H]1O

Procedure:
To a solution of (2S,3S,4aR,8S,8aR)-6-benzyl-8-(chloromethyl)-2,3-dimethoxy-2,3-dimethyloctahydro-[1,4]dioxino[2,3-c]pyridine (2) (2.2 g, 5.9 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (0.35 mol, 26 mL). Reaction mixture was heated at reflux for about 1 hour at which point reaction was judged complete by TLC. Excess solvent and TFA were evaporated in vacuo and the residue was chromatographed using silica gel (2-8% MeOH in CHCl3). Fractions were combined and evaporated to give (1.3 g, 87%) as the title compound. Product was characterized via HPLC/MS (MH+=255) and judged to be >95% pure.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)(Cl)Cl>[CH:28]1([NH:33][C:12]([C:9]2[C:8](=[O:15])[N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[N:11][CH:10]=2)=[O:14])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCCC1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc2ncc(C(=O)NC3CCCC3)c(=O)n12
Reaction time: 0.08 h
Yield: 65.9 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at -10° C. during 20 minutes. After stirring for 5 minutes, 7.49 g (0.088 mol) of cyclopentylamine dissolved in 80 ml of chloroform are dropped to the above solution at -15° C. during 30 minutes. The reaction mixture is stirred for 1 hour below -10° C., then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to yield 14.3 g (65.9%) of the named product as yellow crystals after recrystallization from ethanol, m.p.: 158°-160° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:31][CH3:32])=[CH:20][C:21]([CH:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[OH:24])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:33](Cl)(=[O:35])[CH3:34].C(N(CC)CC)C>ClCCl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:31][CH3:32])=[CH:20][C:21]([CH:23]([O:24][C:33](=[O:35])[CH3:34])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:22][C:12]=3[N:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(O)c3ccccc3)cc(OC)c21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(OC(C)=O)c3ccccc3)cc(OC)c21
Yield: 98.7 %

Procedure:
A solution of 136 mg (0.30 mmol) [2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-yl]-phenyl-methanol, 46 μl (0.66 mmol) acetyl chloride and 125 μl (0.90 mmol) triethylamine in 3 ml dichloromethane is stirred at room temperature for 1 h. The reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=1:1) to afford 140 mg of the title compound as a colorless oil.
Reaction SMILES: [N+](=C)=[N-].CN(N=O)S(C1C=CC(C)=CC=1)(=O)=O.[OH-].[K+].[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=1)[C:26](Cl)=[O:27]>CCOCC.O.C(O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[O:30][CH2:31][C:26](=[O:27])[C:25]=2[CH:29]=1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: C=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: O=C1COc2ccc(Cl)cc21
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
According to the procedure of M. E. Jung et al., J. Org. Chem., 53, 423 (1988), a solution of diazomethane in ether [prepared from N-methyl-N-nitroso-p-toluenesulfonamide (5.8 g, 0.026 mol) and potassium hydroxide (2.9 g, 0.052 mol) in H2O (7 mL), ethanol (10 mL), and ether (70 mL) utilizing a mini-Diazald® apparatus] was added to 5-chloro-2-methoxybenzoyl chloride (2.0 g, 0.010 mol). The resulting mixture was stirred for 30 minutes, concentrated, and acetic acid (20 mL) was added. After 15 minutes, the mixture was concentrated to give 1.6 g (97%) of the product as an orange solid.
Reaction SMILES: O.[NH2:2][C:3]1[N:8]=[C:7]([CH:9]2[CH2:11][CH2:10]2)[N:6]=[C:5]([C:12]([OH:14])=[O:13])[C:4]=1[Cl:15].S(Cl)(Cl)=O.[OH-].[Na+].Cl.[CH3:23]O>>[NH2:2][C:3]1[N:8]=[C:7]([CH:9]2[CH2:11][CH2:10]2)[N:6]=[C:5]([C:12]([O:14][CH3:23])=[O:13])[C:4]=1[Cl:15]
Reactant: CO
Reactant: Nc1nc(C2CC2)nc(C(=O)O)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1nc(C2CC2)nc(N)c1Cl
Temperature: 60 °C
Yield: 80 %

Procedure:
A 1-L flask equipped with a nitrogen bubbler connected to a trap and caustic-containing scrubber, an addition funnel, reflux condenser and thermocouple, was charged with 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylic acid monohydrate (144 g, 0.62 mol) and methanol (500 mL). Thionyl chloride (185 g, 115 mL, 1.58 mol) was added over about 30 minutes with cooling, and then the reaction mixture was heated at 60° C. for 12 h. The resulting mixture was concentrated at 40-45° C./6 kPa to remove excess methanol (about 300 mL), and the reaction mixture was diluted with water (580 mL). Phenolphthalein (5 mg) was added, and 50% aqueous NaOH (80 g, 1.0 mol) was added dropwise with cooling at 10-25° C. to bring the pH to about 9 as indicated by appearance of pink color. Then just enough 1 N aqueous hydrochloric acid was added to extinguish the pink color. The resulting slurry was cooled to 5° C. and filtered. The filtered wet cake was washed with water and dried to constant weight at 50° C./6 kPa to give 123 g (80% yield) of the title compound with 98% purity by HPLC analysis as a solid melting at 147-148° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][CH:12](N2CCOCC2)[C:13](O)=[O:14])=[CH:6][C:5]=1[O:23][CH3:24])[CH3:2].O.[NH2:26][NH2:27]>C(O)CCC>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13](=[O:14])[NH:26][N:27]=2)=[CH:6][C:5]=1[O:23][CH3:24])[CH3:2]
Reactant: NN
Reactant: CCOc1ccc(C(=O)CC(C(=O)O)N2CCOCC2)cc1OC
Solvent: O
Solvent: CCCCO
Product: CCOc1ccc(-c2ccc(=O)[nH]n2)cc1OC

Procedure:
4.5 g of 4-(4-ethoxy-3-methoxyphenyl)-2-morpholino-4-oxobutyric acid are boiled under reflux in 30 ml of 1-butanol with 6.7 g of 100% pure hydrazine hydrate for 8 hours. The reaction mixture is then evaporated in vacuo; the residue is boiled up in 100 ml of 2N hydrochloric acid, filtered off with suction and washed with water until free from acid. After drying, 2.1 g (65.6% of theory) of the title compound of m.p. 182°-184° are obtained; after recrystallization from ethanol/ethyl acetate, the product has a melting point of 186°.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[CH:3]=1.C([Li])CCC.[B:18](OC)([O:21]C)[O:19]C.Cl>CCCCCC.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([B:18]([OH:21])[OH:19])[CH:6]=[CH:5]2
Reactant: COB(OC)OC
Reactant: Brc1ccc2cc(Br)ccc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc2cc(Br)ccc2c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 35 %

Procedure:
First, 5.0 g of 2,6-dibromonaphthalene was placed into a 500-mL three-neck flask, and the air in the flask was replaced with nitrogen. To this compound was added 200 mL of tetrahydrofuran (THF), and this solution was stirred at −78° C. for 20 minutes. Then, 12 mL of a 1.7M hexane solution of n-butyllithium (n-BuLi) was dripped into this mixture solution, followed by stirring at −78° C. for 2 hours. After the predetermined time had elapsed, 3.5 mL of trimethyl borate was added to the mixture and this solution was stirred for 18 hours while the temperature was raised to room temperature. After the predetermined time had elapsed, 80 mL of 1.0M hydrochloric acid was poured into this solution, and the mixture was stirred for 1 hour. Then, the mixture solution was separated into an organic layer and an aqueous layer. Organic substances were extracted with ethyl acetate from the obtained aqueous layer. The solution of the extract was combined with the organic layer that had been first obtained, and the mixture was washed with saturated brine and dried by addition of anhydrous magnesium sulfate. Then, the filtrate obtained by gravity filtration was concentrated to give a white solid. The obtained white solid was washed with ethanol, whereby 6-bromonaphthalene-2-boronic acid was obtained (as a white powder in 35% yield). The synthesis scheme of Step 1 is illustrated in the following (a-4).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11]>>[Br:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1ccc(Br)c(C)c1
Reactant: O=[N+]([O-])O
Product: Cc1cc(C)c([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Bromo-2,4-dimethyl-benzene (9 g, 48.6 mmol) was added to HNO3 (100 mL, 60%) at rt. The mixture was stirred overnight at rt. The mixture was poured into ice-water and extracted with EtOAc. The organic phase was then dried over Na2SO4 and concentrated to give 1-bromo-2,4-dimethyl-5-nitro-benzene (6.5 g) which was used in the subsequent step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12](F)=[CH:13][C:14]=3[O:19][CH2:20][CH2:21][O:22][CH:23]([CH3:25])[CH3:24])[N:9]=2)[CH:5]=[C:4]([CH3:27])[N:3]=1.[CH3:28][O-:29].[Na+]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([O:29][CH3:28])=[CH:13][C:14]=3[O:19][CH2:20][CH2:21][O:22][CH:23]([CH3:25])[CH3:24])[N:9]=2)[CH:5]=[C:4]([CH3:27])[N:3]=1
Reactant: Cc1cc(-c2nc3cc(F)cc(OCCOC(C)C)c3c(=O)[nH]2)cc(C)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OCCOC(C)C)c2c(=O)[nH]c(-c3cc(C)nc(C)c3)nc2c1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
2-(2,6-Dimethyl-pyridin-4-yl)-7-fluoro-5-(2-isopropoxy-ethoxy)-3H-quinazolin-4-one (22) (960 mg, 2.58 mmol) was taken up in anhydrous DMF (10 mL). Sodium methoxide (25% solution in methanol, 12.9 mmol) was added. After the addition, the reaction mixture was stirred at 60° C. for 72 hours. The reaction mixture was cooled to room temperature, and quenched with saturated solution of NH4Cl. The product was extracted with ethyl acetate (3×200 mL). The combined organic layer was washed with water, brine, dried over Na2SO4, and evaporated to give crude product. The crude compound was purified by preparative HPLC, to give the title compound 23 as a white solid.
Reaction SMILES: O1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[C:7]1[C:19]2[N:18]3[CH:20]=[CH:21][N:22]=[C:17]3[C:16](=[O:23])[NH:15][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2.C1N2C3CC4C=CC=CC=4C=3NC(=O)C2=[N:26][CH:25]=1.[H-].[Na+].N1C=CC=C(C=O)C=1>CS(C)=O>[N:26]1[CH:5]=[CH:4][CH:3]=[C:2]([CH:6]=[C:7]2[C:19]3[N:18]4[CH:20]=[CH:21][N:22]=[C:17]4[C:16](=[O:23])[NH:15][C:14]=3[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)[CH:25]=1
Reactant: O=c1[nH]c2c3ccccc3c(=Cc3ccco3)c2n2ccnc12
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Agent: O=Cc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=c1[nH]c2c3ccccc3c(=Cc3cccnc3)c2n2ccnc12

Procedure:
The procedure is performed as in Example 17 for the preparation of 10-(2-furylmethylene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, but starting with 3 g of 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 60 ml of dimethyl sulphoxide, 0.96 g of sodium hydride and 1.6 g of 3-pyridinecarboxaldehyde. 1.38 g of 10-(3-pyridylmethylene)-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one are obtained, in the form of a yellow-orange solid melting above 260° C. (Analysis % calculated C: 73.07, H: 3.87, N: 17.94, O: 5.12, % found C: 73.1, H: 3.9, N: 17.9, O: 5.1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:2]1[O:4][CH2:3]1.O[C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:20]2[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=2)([CH3:19])[CH3:18])=[CH:13][CH:12]=1>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[OH:4][CH:2]([CH2:1][O:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:3][CH:2]([OH:4])[CH2:1][O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:22][CH:21]=2)([CH3:19])[CH3:18])=[CH:13][CH:12]=1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CCCCOCC1CO1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Product: CCCCOCC(O)Cc1ccc(C(C)(C)c2ccc(CC(O)COCCCC)cc2)cc1
Reaction time: 1 h

Procedure:
Butyl glycidyl ether (232.5 g), 2,2-bis(p-hydroxyphenyl)propane (171 g), and benzyltrimethylammonium chloride (4 g) were stirred and heated slowly to 100°. The mixture was kept at 100° for 1 hour, then at 110° for 2 hours, 120° for 1 hour, and 150° for 11/2 hours. The product had an epoxy value of 0.2 equiv./kg.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[N:8]=[C:7]2I.C([Mg]Cl)(C)C.[CH2:26]([Sn:30]([CH2:36][CH2:37][CH2:38][CH3:39])([CH2:32][CH2:33][CH2:34][CH3:35])Cl)[CH2:27][CH2:28][CH3:29]>C1COCC1>[F:1][CH:2]([F:20])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[N:8]=[C:7]2[Sn:30]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CN(C)CCCn1nc(I)c2cc(OC(F)F)ccc21
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(CCCN(C)C)c2ccc(OC(F)F)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a solution of 3-(5-(difluoromethoxy)-3-iodo-1H-indazol-1-yl)-N,N-dimethylpropan-1-amine (1.2 g, 2.78 mmol) in dry THF (25 mL) was added isopropylmagnesium chloride (1.5 mL, 2M in THF, 3 mmol) drop-wise at −16° C. under nitrogen atmosphere, stirred for 30 minutes, tributylchlorostannane (3.3 mL, 3.6 mmol) was added drop-wise at −16° C. under nitrogen, then the reaction mixture was warmed to room temperature slowly and stirred for 2 hours. Then the reaction mixture was quenched with a saturated solution of NH4Cl (40 mL) and extracted with EtOAc (3×30 mL), the combined organic layer were dried over Na2SO4, filtered and concentrated under reduced pressure to give 3-(5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazol-1-yl)-N,N-dimethylpropan-1-amine, (1.1 g, 71%) as an oil, used into the next step without purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH:14]1([CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:17][CH2:16][CH2:15]1>>[CH:14]1([CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=4[C:2]([F:1])([F:13])[F:12])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)c1ccccc1C(F)(F)F
Reactant: O=C(NCC1CCC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCC1CCC1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2-trifluoromethylbenzoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid cyclobutylmethylamide, the title compound was obtained as a white powder (45.0% yield). 1H NMR (CDCl3) δ 8.04, 7.83, 7.72, 7.64-7.51, 7.32, 7.00, 4.10-4.01, 3.90-3.66, 3.49-3.27, 2.63-2.47, 2.11-1.67. 13C NMR (CDCl3) δ 167.7, 162.9, 159.8, 145.4, 134.2, 132.4, 129.6, 127.4, 126.9, 126.8, 125.4, 121.8, 112.8, 46.4, 44.6, 41.2, 35.1, 25.7, 18.3. MS (ES+) m/z 448 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]([I:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH2:14][CH2:15][CH2:16][N:17]1[C:21]([CH3:23])([CH3:22])[C:20](=[O:24])[NH:19][C:18]1=[O:25].C(N(CC)CC)C>CC(O)C>[I:13][C:10]1[S:9][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:14][CH2:15][CH2:16][N:17]3[C:21]([CH3:22])([CH3:23])[C:20](=[O:24])[NH:19][C:18]3=[O:25])[N:7]=2)=[CH:12][CH:11]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCN
Reactant: Clc1nccc(-c2ccc(I)s2)n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2ccc(I)s2)n1

Procedure:
A solution of 205 mg (0.64 mmol) of 2-chloro-4-(5-iodothiophen-2-yl)pyrimidine, 186 mg (1.1 mmol) of 1-(2-aminoethyl)-5,5-dimethylimidazolidine-2,4-dione and 0.15 mL (1.1 mmol) of triethylamine in 5 mL of iPrOH was heated in a microwave to 180° C. for 10 min then concentrated in vacuo. The crude solid product was purified by flash chromatography eluting with a linear gradient of 40% EtOAc in hexane to 100% EtOAc to deliver the title compound. MS (M+H)+ 458.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([C:12]([O:14]C)=O)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][NH2:30]>C(O)(=O)C.C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:30][N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)[C:12](=[O:14])[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1
Reactant: NNc1ccccn1
Reactant: CCOC(=O)C(=O)c1c(C(=O)OC)n(C)c2cc(F)ccc12
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(-c2ccccn2)c(=O)c2c1c1ccc(F)cc1n2C

Procedure:
A solution of 0.40 g (1.36 mmol) of ethyl 6-fluoro-2-(methoxycarbonyl)-1-methyl-α-oxo-1H-indole-3-acetate (obtained in stage 1.4.), of 30 ml of absolute ethanol, of a few drops of glacial acetic acid and of 0.60 g (5.5 mmol) of 2-pyridinylhydrazine is brought to reflux for 17 h.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH:7]([OH:16])[CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)C(=O)CC1.C(O)C.[ClH:22]>>[ClH:22].[NH2:5][CH2:6][CH:7]([OH:16])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1CC(O)COc1ccccc1
Agent: Cl
Solvent: CCO
Product: NCC(O)COc1ccccc1
Yield: 69 %

Procedure:
1-Succinimido-3-phenoxy-2-propanol (16 gm, 0.06 mole) was dissolved in 100 mL conc. HCl and 100 mL ethanol and heated to reflux for 6 hours. After the reaction, the mixture was evaporated to a white residue which was thentaken up in 25 mL water and washed with 3×50 mL ether. The aqueous phase was then evaporated and the white-residue recrystallized from ethanol to provide 8.3 gm (69%) of white crystals: mp 226°-228°. The NMR spectrum was consistent with the assignedstructure and the elemental analysis was consistent with the molecular formula C9H14NO2Cl.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:38])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:32][C:33]3[NH:34][CH:35]=[CH:36][N:37]=3)[CH2:25][C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>N1C=CC=CC=1>[CH3:39][N:40]([CH3:44])[C:41]([N:37]1[CH:36]=[CH:35][N:34]=[C:33]1[CH2:32][N:24]([CH2:23][C:20]1[CH:19]=[CH:18][C:17]([C:16](=[O:38])[NH:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[CH:14][CH:13]=2)=[CH:22][CH:21]=1)[CH2:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=1)=[O:42]
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3nccn3C)cc2)cc1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3nccn3C)Cc3nccn3C(=O)N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 42 %

Procedure:
The compound (95.0 mg) obtained in Example 49-1, was dissolved in pyridine (5.0 ml) and added with N,N-dimethylcarbamoyl chloride (20.0 mg). After the solution had been stirred at room temperature for 15 hours, pyridine was distilled off and the residue was then added with a saturated aqueous sodium bicarbonate solution and extracted with chloroform. The extract was concentrated and purified through column chromatography (chloroform/methanol), thereby obtaining the subject compound (45.4 mg) as a white solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1([C:14](O)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.O.[OH-].[Na+]>CCOCC>[CH:7]1([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(O)C1CCCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCC1CCCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To an oven-dried, three-necked flask under an N2 atmosphere was added LiAlH4 (4.0 g, 0.11 mol) followed by anhydrous Et2O (100 ml). To the stirred suspension was added dropwise over 1 hour a solution of cycloheptane carboxylic acid (5.0 g, 0.035 mol) in anhydrous Et2O (50 ml). The reaction was stirred at room temperature for 2 hours and then cooled with an ice bath. H2O (4 ml) was added cautiously dropwise over 20 minutes, followed by cautious dropwise addition of NaOH (4 ml of a 15% aqueous solution) and then dropwise addition of further H2O (12 ml). The reaction was stirred vigorously for 5 minutes and the resultant white precipitate was removed by filtration and washed with copious Et2O. The combined filtrate and washings were evaporated to dryness under reduced pressure to yield the desired compound (3.74 g) as a colourless oil with no need for further purification.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[C-:18]#[N:19].[Na+]>CN(C=O)C>[C:18]([C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:19]
Reactant: CCOC(=O)c1cnn(-c2ccccn2)c1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2ccccn2)c1C#N
Temperature: 0 °C
Yield: 66.6 %

Procedure:
A solution of 7.36 g of 5-chloro-1-(2-pyridinyl)-1H-pyrazole-4-carboxylic acid, ethyl ester, 3.2 g of sodium cyanide and 25 ml of DMF was heated at approximately 100° C. for 3 hours. The reaction mixture was cooled and poured into 300 ml of ice water. The precipitated solid was collected by filtration to afford 5.79 of solid. This material was recrystallized from ethanol to provide 4.72 g of 5-cyano-1-(2-pyridinyl)-1H-pyrazole-4-carboxylic acid, ethyl ester. mp=112°-114° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C([Sn](CCCC)(CCCC)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)CCC>CN(C=O)C>[N:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccccn2)s1
Temperature: 80 °C

Procedure:
To methyl 5-bromo-thiophene-2-carboxylate (2 g), tri-2-furylphosphine (400 mg), and tris(dibenzylidineacetone)dipalladium(0) (400 mg) was added DMF (50 mL), 2-(tributylstannyl)pyridine (4 g) and TEA (1 mL) The mixture was heated at 80° C. for 7 hours, cooled and partitioned between ethyl acetate and brine. The aqueous phase was extracted with ethyl acetate, and the extract was dried, filtered and concentrated. The concentrate was flash chromatographed on silica gel with a 20-70% ethyl acetate in hexane.