Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl/[CH:2]=[CH:3]/[C:4]([CH:6]1[CH2:9][C:8]2([CH2:12][CH2:11][CH2:10]2)[CH2:7]1)=[O:5].[I-:13].[Na+]>CC(C)=O>[I:13]/[CH:2]=[CH:3]/[C:4]([CH:6]1[CH2:9][C:8]2([CH2:12][CH2:11][CH2:10]2)[CH2:7]1)=[O:5]
Reactant: [I-]
Reactant: O=C(/C=C/Cl)C1CC2(CCC2)C1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(/C=C/I)C1CC2(CCC2)C1
Reaction time: 8 h
Yield: 59.5 %

Procedure:
1-Chloro-3-(spiro[3.3]hept-2-yl)-1E-propen-3-one (7.3 g, 0.042 mole) was mixed with 25.2 g (0.168 mole) of sodium iodide and 45 ml of dry acetone (distilled from anhydrous potassium carbonate, b.p. 56° C). The mixture was refluxed with rapid stirring overnight. The mixture was cooled and the solvent was removed in vacuo. The solid residue was taken up in 75 ml of water and the products were extracted with 150 ml (3×50 ml) of ether. The organic material was washed with 50 ml of saturated sodium bicarbonate solution, 50 ml of aqueous sodium thiosulfate solution and 50 ml of saturated sodium chloride solution. The material was dried over anhydrous magnesium sulfate, filtered and the solvent was removed in vacuo to yield 6.9 g (62.2%) of crude 1-iodo-3-(spiro[3.3]hept-2-yl)-1E-propen-3-one.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][F:20])[N:13]=[N:12]1.[CH:21](I)([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:1][C:2]1[C:7]([O:8][CH:21]([CH3:23])[CH3:22])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][F:20])[N:13]=[N:12]1
Reactant: Nc1c(O)c(Cl)cc(F)c1-n1nnn(CCCF)c1=O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)Oc1c(Cl)cc(F)c(-n2nnn(CCCF)c2=O)c1N

Procedure:
The mixture of 1-(2-amino-4-chloro-6-fluoro-3-hydroxyphenyl)-4-(3-fluoropropyl)-1,4-dihydro-5-oxo-5H-tetrazole (0.30 g), isopropyl iodide (1.2 ml), and potassium carbonate (0.14 g) in acetonitrile (5 ml) was heated under reflux for 2 hours. The reaction mixture was evaporated and purified by a silica gel column, eluted with hexane-ethyl acetate (2:1) to give the desired product (0.29 g).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](Cl)=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:19][OH:20]>C(Cl)Cl>[CH3:19][O:20][C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][Br:1])=[CH:4][CH:5]=1)=[O:10]
Reactant: CO
Reactant: O=C(Cl)c1ccc(CBr)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 19.5 grams of alpha-bromo-p-toluoyl chloride in 100 ml of methylene chloride is added to a solution of 15.7 ml of triethylamine in 100 ml of methanol. The reaction mixture is stirred overnight at room temperature and then concentrated. The residue is dissolved in ether, washed with water and the ether evaporated to give the intermediate p-methoxycarbonylbenzyl bromide.
Reaction SMILES: [CH:1]1([CH:4]([NH2:6])[CH3:5])[CH2:3][CH2:2]1.[N+:7]([C:10]1[CH:11]=[C:12]2[C:19](=O)[O:18][C:16](=[O:17])[C:13]2=[N:14][CH:15]=1)([O-:9])=[O:8].S(Cl)(Cl)=O>ClCCCl.C(Cl)Cl>[CH:1]1([CH:4]([N:6]2[C:19](=[O:18])[C:12]3[C:13](=[N:14][CH:15]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=3)[C:16]2=[O:17])[CH3:5])[CH2:3][CH2:2]1
Reactant: O=C1OC(=O)c2ncc([N+](=O)[O-])cc21
Reactant: CC(N)C1CC1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C1CC1)N1C(=O)c2cc([N+](=O)[O-])cnc2C1=O
Temperature: 25 °C
Reaction time: 0.13 h

Procedure:
11.2 g (0.132 mol) of 1-cyclopropylethylamine were added to a mixture of 22.3 g (0.115 mol) of 5-nitropyridine-2,3-dicarboxylic anhydride in 150 ml of 1,2-dichloroethane at 25a° C with stirring in the course of 8 minutes and the mixture was stirred at 70° C. for 3 hours. After cooling to 25° C., 19.6 g (0.165 mol) of thionyl chloride were added with stirring in the course of 10 minutes and the mixture was stirred at 25° C. for 10 hours and at 70° C for 11/2 hours. The reaction mixture was diluted with 100 ml of methylene chloride and added with stirring to 500 ml of ice-water. The aqueous phase was extracted twice more with methylene chloride. The organic phase was then washed successively with water, saturated sodium hydrogencarbonate and sodium chloride solution and filtered off with suction over neutral alumina. After concentrating, 21.5 g (72% of theory) of the title compound of m.p. 96-99° C. were obtained (active compound Example 1.020).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([NH2:25])[NH:19][C:18]3=[O:26])[CH2:11][C:12]#[CH:13])=[CH:6][CH:5]=1)(=O)[CH3:2].[CH3:27][N:28]([CH3:30])[NH2:29]>CO>[NH2:25][C:20]1[NH:19][C:18](=[O:26])[C:17]2[C:22](=[CH:23][CH:24]=[C:15]([CH2:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([C:1](=[N:29][N:28]([CH3:30])[CH3:27])[CH3:2])=[CH:9][CH:8]=3)[CH2:11][C:12]#[CH:13])[CH:16]=2)[N:21]=1
Reactant: CN(C)N
Reactant: C#CCN(Cc1ccc2nc(N)[nH]c(=O)c2c1)c1ccc(C(C)=O)cc1
Solvent: CO
Product: C#CCN(Cc1ccc2nc(N)[nH]c(=O)c2c1)c1ccc(C(C)=NN(C)C)cc1

Procedure:
A suspension of 3.46 g (10 mmol) of 6-[[(4-acetylphenyl)-2-propynylamino]methyl]-2-amino-4(3H)-quinazolinone (see Example 2j) and 6.01 g (100 mmol) of 1,1-dimethylhydrazine in 250 ml of methanol is heated under reflux for eighteen hours. The solution is concentrated and the residue recrystallized from methanol to give the product.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][NH:4]1.[OH-].[Na+].[C:18](=[S:20])=[S:19].[C:21]1([CH2:26]Cl)[S:25][CH:24]=[CH:23][CH:22]=1>CO.C(O)C>[OH:1][CH2:2][C@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][N:4]1[C:18]([S:20][CH2:26][C:21]1[S:25][CH:24]=[CH:23][CH:22]=1)=[S:19]
Reactant: S=C=S
Reactant: ClCc1cccs1
Reactant: OC[C@H]1Cc2c([nH]c3ccccc23)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: OC[C@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1cccs1
Yield: 44.9 %

Procedure:
In the same manner as described in Example 8 by using (3R)-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline (2.02 g), 2N NaOH (12.5 ml), CS2 (1.9 g), 2-thenyl chloride (3.31 g) and 80% ethanol (50 ml), there is prepared the title compound (1.68 g, 45%) as white powder, [α]D20 -113.8° (c=1.0, methanol). NMR (CDCl3, δ): 4.83 (s, 2H, ##STR10## Mass m/e: 374 (M+), 244 (M+ -- ##STR11##
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:28]4[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=4)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C
Reactant: OB(O)c1ccncc1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3ccncc3)c2n1C
Temperature: 140 °C
Yield: 65.4 %

Procedure:
A mixture of 4-Amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile, (0.10 g, 0.26 mmol), 4-pyridyl boronic acid (0.041 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.01 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 minutes, then heated for 40 minutes at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH then concentrated in vacuo. The residue was purified by chromatography eluting with (SiO2, 0-10% (2M ammonia in methanol) in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water). The relevant fractions were concentrated to approximately ⅓ volume then partitioned between DCM (3×) and saturated aqueous NaHCO3. The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo to give 429 as a white solid (0.066 g, 66%). LCMS (Method K): RT 2.32 min [M+H]+ 389.1. 1H NMR (DMSO-d6, 400 MHz): δ 8.72 (2H, d, J=5.05 Hz), 8.03 (1H, s), 7.71-7.70 (2H, m), 7.53 (2H, d, J=13.97 Hz), 7.31 (2H, s), 7.18 (1H, dd, J=10.45, 8.79 Hz), 5.64 (1H, m), 3.21 (3H, s), 1.58 (3H, d, J=6.74 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[CH2:9]([SH:13])[C:10](O)=[O:11]>C1(C)C=CC=CC=1>[SH:13][CH2:9][C:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1)=[O:11]
Reactant: O=C(O)CS
Reactant: Cc1cccc(N)c1
Solvent: Cc1ccccc1
Product: Cc1cccc(NC(=O)CS)c1

Procedure:
Freshly distilled meta-toluidine (10.168 g) was dissolved in toluene (50 ml) and treated with thioglycollic acid (7 ml). The mixture was heated under reflux, and water collected in a Dean and Stark apparatus overnight. The reaction mixture was then cooled and poured into hexane (50 ml). The product separated as an oil and the solvents were removed under reduced pressure to give a white solid (17.975 g). Attempts at recrystallisation resulted in failure and the residue was chromatographed on silica gel. The product (14.84 g), still contaminated with meta toluidine, was taken up in ethyl acetate and washed with 2M hydrochloric acid. The title compound was then isolated in the usual manner as a white solid, yield 13.13 g, mp 58°-60° C.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][N:23]2C(=O)C3=CC=CC=C3C2=O)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][NH2:5]
Reactant: O=C1c2ccccc2C(=O)N1CCOCCOCCOCCOCCOCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCOCCOCCOCCOCCOCCN
Temperature: 100 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
A solution containing 60 g of 1,17-diphthalimido-3,6,9,12,15 - pentaoxaheptadecane (0.118 mol), 14.8 g of hydrazine hydrate (0.296 mol) and 500 ml of ethanol were heated with mechanical stirring in a 100° C. oil bath for 3 hours. The mixture was then allowed to cool and was then filtered. The filter cake was washed four times with 300 ml portions of ethanol. The combined filtrates were concentrated to give 32.35 g of a yellow opaque glassy oil. Evaporative distillation at 150°-200° C. (0.01 mm) gave 22.82 g of a light yellow oil (69% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C([Sn](CCCC)(CCCC)C1C=CC=CC=1[N+]([O-])=O)CCC.FC(F)(F)S(O[C:39]1[CH2:48][CH2:47][C:46]2[C:41](=[CH:42][CH:43]=[C:44]([O:49][CH3:50])[CH:45]=2)[CH:40]=1)(=O)=O>>[CH3:50][O:49][C:44]1[CH:45]=[C:46]2[C:41]([CH:40]=[C:39]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N+:8]([O-:10])=[O:9])[CH2:48][CH2:47]2)=[CH:42][CH:43]=1
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: COc1ccc2c(c1)CCC(OS(=O)(=O)C(F)(F)F)=C2
Agent: CCCC[Sn](CCCC)(CCCC)c1ccccc1[N+](=O)[O-]
Product: COc1ccc2c(c1)CCC(c1ccccc1[N+](=O)[O-])=C2

Procedure:
Synthesized from 1-bromo-2-nitrobenzene according to an analogous synthetic method to Preparation Example 76, tributyl(2-nitrophenyl)tin (7.3 g) and 6-methoxy-3,4-dihydronaphthalen-2-yl trifluoromethanesulfonate (2.2 g) were used according to an analogous synthetic method to Preparation Example 77 to provide the title compound (1.5 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])=[C:11]([O:23][CH3:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[C:11]([O:23][CH3:24])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OCc2ccccc2)ccc1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(OCc2ccccc2)ccc1CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl [4-(benzyloxy)-2-methoxyphenyl]acetate (2.2 g, 6.70 mmol) in DCM (10 ml) was treated with TFA (10.3 ml, 134 mmol) and the mixture stirred at RT for 30 min. The volatiles were removed in vacuo to afford the title compound. LC/MS (m/z): 273 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH:19][C:20]1[C:27]([CH3:28])=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[CH3:29]>>[OH:19][C:20]1[C:27]([CH3:28])=[CH:26][C:23]([CH:24]=[CH:15][C:14]([C:12]2[S:13][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[O:16])=[CH:22][C:21]=1[CH3:29]
Reactant: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: Cc1cc(C=O)cc(C)c1O
Product: Cc1cc(C=CC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc(C)c1O

Procedure:
3-(4-Hydroxy-3,5-dimethylphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)ethanone and 4-hydroxy-3,5-dimethylbenzaldehyde according to general procedure B. The evaporation residue is washed with dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].Cl[C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N+:29]([O-:31])=[O:30])=[CH:27][N:28]=2)[N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:20]3[CH:21]=[CH:22][C:23]4[N:24]([C:26]([N+:29]([O-:31])=[O:30])=[CH:27][N:28]=4)[N:25]=3)[CH:13]=2)=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C)c(Cl)c(NCc2cccc(O)c2)n1
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C)c(Cl)c(NCc2cccc(Oc3ccc4ncc([N+](=O)[O-])n4n3)c2)n1

Procedure:
In analogy to the method described in example 1, 7.9 g (30 mmol) of 3-[(5-chloro-2,6-dimethylpyrimidin-4-ylamino)methyl]phenol (from example B2), 6.08 g (30 mmol) of 6-chloro-3-nitroimidazo-[1,2-b]pyridazine and 20.9 g (150 mmol) of potassium carbonate are reacted in 125 ml of dimethylformamide. After chromatography on silica gel (mobile phase: gradient toluene/dioxane 5:1 to 2:1) and crystallization from methylene chloride/methanol and extraction with stirring from diisopropyl ether, 10.95 g (85%) of the title compound are isolated as a pale beige solid. m.p.: 222-223° C.
Reaction SMILES: CO[C:3]([CH:5]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([F:18])[CH:16]=2)[C:11]2[C:6]1=[CH:7][C:8]([F:20])=[CH:9][C:10]=2[CH3:19])=[O:4].[H-].[Na+].I[CH2:24][C:25]([NH2:27])=[O:26]>O1CCCC1>[F:18][C:15]1[CH:16]=[C:17]2[C:5]3([CH2:24][C:25](=[O:26])[NH:27][C:3]3=[O:4])[C:6]3[C:11](=[C:10]([CH3:19])[CH:9]=[C:8]([F:20])[CH:7]=3)[C:12]2=[N:13][CH:14]=1
Reactant: NC(=O)CI
Reactant: COC(=O)C1c2cc(F)cnc2-c2c(C)cc(F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(F)cc2c1-c1ncc(F)cc1C21CC(=O)NC1=O

Procedure:
Treatment of 3,7-difluoro-9-methyl-5H-indeno[1,2-b]pyridin-5-one with hydrazine in hot diethylene glycol provided 3,7-difluoro-9-methyl-5H-indeno[1,2-b]pyridine. Deprotonation using n-butyllithium in tetrahydrofuran followed by reaction with carbon dioxide and methanolic hydrogen chloride provided 3,7-difluoro-9-methyl-5H-indeno[1,2-b]pyridin-5-carboxylic acid methyl ester. The ester was then deprotonated using a slight excess of sodium hydride in tetrahydrofuran and treated with iodoacetamide to provide, after 18 hours at room temperature and 6 hours at reflux, the title compound.
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3]P(=O)(OC)OC.[H-].[Na+].[CH3:17][O:18][C:19](=[O:38])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[C:30](=[O:31])[CH2:29][CH:28]([O:32][C:33](=[O:35])[CH3:34])[CH:27]1[CH:36]=O>O1CCCC1>[CH3:17][O:18][C:19](=[O:38])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[C:30](=[O:31])[CH2:29][CH:28]([O:32][C:33](=[O:35])[CH3:34])[CH:27]1[CH:36]=[CH:3][C:2](=[O:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Reactant: COC(=O)CCCCCCC1C(=O)CC(OC(C)=O)C1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC(=O)C=CC1C(OC(C)=O)CC(=O)C1CCCCCCC(=O)OC

Procedure:
70 Mg. of dimethyl 2-oxoheptylphosphonate in 2 ml. of tetrahydrofuran is added to 12 mg. of 48% sodium hydride in 1 ml. of tetrahydrofuran, and the mixture stirred at 0°C. under nitrogen for 30 minutes. 70 Mg. of 3-acetoxy-2-formyl-5-oxocyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene ketal in 2 ml. of tetrahydrofuran is then added dropwise and the mixture allowed to warm to 20°-25°C. After 3 hours the mixture is chilled, added to cold saturated aqueous NaH2PO4, extracted with ethyl acetate, and the latter extract dried over Na2SO4 and concentrated to dryness. The residue is purified by silica gel chromatography (7.8 g. silica gel), eluting with 7% acetone in chloroform to give 3-acetoxy-2-(3-oxo-1-octenyl)-5-oxocyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal: ir (CHCl3) 5.78, 5.9, 6.0, 6.17, 8.00, 10.55 μ; ##EQU2##
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N:12]1([C:18]([S:20][CH3:21])=[S:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[CH2:22]=O>C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:6]=1)[CH2:22][N:15]1[CH2:16][CH2:17][N:12]([C:18]([S:20][CH3:21])=[S:19])[CH2:13][CH2:14]1)(=[O:3])[CH3:2]
Reactant: CSC(=S)N1CCNCC1
Reactant: C=O
Reactant: CC(=O)Oc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: CSC(=S)N1CCN(Cc2cc(OC(C)=O)ccc2O)CC1
Yield: 65.9 %

Procedure:
To 5 ml of chloroform were added 152 mg of 4-acetoxyphenol, 211 mg of methyl 1-piperazinecarbodithioate and 36 mg of paraformaldehyde. The resulting mixture was refluxed for 4 hours. The mixture was cooled, and tothis was added chloroform. The mixture was then washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and placed under reduced pressure to distill of the solvent. The residue was purified by siica gel column chromatography to yield an oil. The oil was crystallized by addition of ethanol. The obtained crystals were collected by filtration to give 224 mg of the desired compound as a white crystalline product, m.p. 124° C., yield 65.9%.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][NH:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:26][CH:25]=5)[S:23][C:16]=34)=[C:10]([F:36])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C([O:53]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O:73][CH2:74][CH3:75])(=O)C>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH2:32][CH2:33][O:34][CH3:35])[C:74](=[O:73])[CH2:75][OH:53])=[CH:26][CH:25]=5)[S:23][C:16]=34)=[C:10]([F:36])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: CCOC(C)=O
Reactant: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)cc1)C(=O)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
To a solution of 113 (168 mg, 0.332 mmol) in DMF (8 mL) at RT was added DIPEA (0.203 mL, 1.161 mmol), followed by HATU reagent (378 mg, 0.995 mmol). The reaction mixture was stirred overnight at RT. Ethyl acetate was added, the reaction mixture was washed with water, saturated ammonium chloride solution and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified via Biotage (0-50% MeOH/EtOAc; SNAP 50 g cartridge) to give an off-white solid which upon trituration with ether/acetone afforded title compound 115-A (20 mg, 11% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): contains 2 rotamers: 8.74 (s, 1H), 8.54 (d, 1H, J=5.5 Hz), 8.10, 8.07 (2s, 1H), 7.94, 7.89 (2d, 2H, J=8.2 Hz), 7.78 (dd, 1H, J1=2.4 Hz, J2=13.5 Hz), 7.44-7.38 (m, 3H), 7.25-7.22 (m, 1H), 6.63-6.61 (m, 2H), 4.73-4.61 (m, 3H), 4.28, 4.14 (2d, 2H, J=5.5 Hz), 3.51-3.40 (m, 4H), 3.27 (s, 3H), 2.60-2.56 (m, 1H), 0.71-0.67 (m, 2H), 0.48-0.44 (m, 2H). MS: 565.5 (MH+).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].N1C=CC=CC=1.C(N(CC)CC)C.[C:35](Cl)(=[O:43])[O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:35](=[O:43])[O:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
N1-Methyl-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (2.163 g, 7.66 mmol) synthesized in Production example 5-1 was dissolved in N,N-dimethylformamide (50 ml) under nitrogen atmosphere; pyridine (0.93 ml, 11.5 mmol), triethylamine (2.4 ml, 17.24 mmol) and phenyl chlorocarbonate (1.44 ml, 11.5 mmol) were sequentially added dropwise while cooled with an ice water bath; and the reaction mixture was heated to room temperature while stirred. After 1 hour, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and then the residue was purified by silica gel column chromatography (eluent; ethyl acetate), precipitated from ethyl acetate-hexane (1:10), filtered off, and dried under aeration to yield the title compound (2.731 g, 6.79 mmol, 88.6%) as white crystals.
Reaction SMILES: Br.Br[CH:3]([C:5]1[CH:6]=[C:7]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:8]=[C:9]2[C:14]=1[O:13][C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[CH:11][C:10]2=[O:21])[CH3:4].[F:27][C:28]1[CH:29]=[C:30]([CH:32]=[C:33]([F:35])[CH:34]=1)[NH2:31]>CN(C=O)C>[F:27][C:28]1[CH:29]=[C:30]([NH:31][CH:3]([C:5]2[CH:6]=[C:7]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:8]=[C:9]3[C:14]=2[O:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][C:10]3=[O:21])[CH3:4])[CH:32]=[C:33]([F:35])[CH:34]=1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: Nc1cc(F)cc(F)c1
Agent: Br
Solvent: CN(C)C=O
Product: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 50 °C
Reaction time: 5 h
Yield: 68.4 %

Procedure:
To a suspension of 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (3.63 g, 7.41 mmol, as described in Example 3.03) in DMF (35 mL) under nitrogen was added 3,5-difluoroaniline (3.82 g, 29.62 mmol). The resulting yellow solution was stirred at 50° C. for 5 hrs. The reaction mixture was concentrated to dryness, then purified by flash chromatography on silica gel eluting with 1 to 7% methanol in DCM. The solvent was evaporated to dryness to afford 8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (2.32 g, 68.5%) as a pale yellow solid. Mass Spectrum: M+H+ 458. NMR Spectrum: (DMSOd6) 1.52 (d, 3H), 2.74 (s, 3H), 2.95 (s, 3H), 3.50-3.64 (m, 4H), 3.70-3.79 (m, 4H), 4.97-5.05 (m, 1H), 5.60 (m, 1H), 6.15 (dd, 2H), 6.22 (tt, 1H), 6.96 (d, 1H), 7.54 (d, 1H), 7.81 (d, 1H).