Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:9]1[C:17]2[C:12](=[C:13]([CH3:29])[C:14]([CH2:26][CH2:27]Cl)=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1OCCOCCOCCOCCOCCOC1.C[C:49]#[N:50]>>[CH2:1]([N:9]1[C:17]2[C:12](=[C:13]([CH3:29])[C:14]([CH2:26][CH2:27][C:49]#[N:50])=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC#N
Reactant: CCCCCCCCN1CCc2c(C)c(CCCl)c(C)c(NC(=O)C(C)(C)C)c21
Agent: C1COCCOCCOCCOCCOCCO1
Product: CCCCCCCCN1CCc2c(C)c(CCC#N)c(C)c(NC(=O)C(C)(C)C)c21

Procedure:
N-(1-Octyl-5-chloroethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (3.0 g) was dissolved in CH3CN (30 ml), and NaCH (3.7 g) and 18-crown-6 (0.1 g) were added, which was followed by refluxing for 17 hr under a nitrogen atmosphere. CH3CN was evaporated under reduced pressure, and water (100 ml) was added to the obtained residue. The mixture was extracted twice with AcOEt (100 ml). The AcOEt layer was washed with saturated brine (100 ml) and dried over anhydrous sodium sulfate, and AcOEt was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: AcOEt/benzene=1/10−1/5) to give 1.14 g of N-(1-octyl-5-cyanoethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
Reaction SMILES: [OH-].[Na+].O.[NH2:4][CH2:5][C:6]([OH:8])=[O:7].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18](Cl)=[O:19])=[CH:12][CH:11]=1>O1CCOCC1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]([NH:4][CH2:5][C:6]([OH:8])=[O:7])=[O:19])=[CH:14][CH:15]=1
Reactant: NCC(=O)O
Reactant: O=C(Cl)CCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CNC(=O)CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of 26 mmol sodium hydroxide in 7 ml water 8.7 mmol of glycine were added. The mixture was cooled in an ice-bath and a solution of 8.7 mmol 3-(4-chloro-phenyl)-propionyl chloride (CA [52085-96-8]) in 10 ml dioxane was slowly added over a period of 20 minutes. After stirring overnight at room temperature, the mixture was extracted with diethyl ether. The aqueous phase was acidified by addition of diluted hydrochloric acid and filtered. Trituration of the solid in diethyl ether yielded the title compound as a colorless solid. Yield=42%.
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20]([C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[Cl:30])=O)(=O)OC.O.[NH2:32][NH2:33]>>[Cl:30][C:23]1[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=1[C:20]1[CH:19]=[C:4]2[C:3]([C@:2]3([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]2[CH2:6][CH2:7]3)=[N:33][N:32]=1
Reactant: NN
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Reactant: COP(=O)(CC(=O)c1cc(F)c(F)cc1Cl)OC
Solvent: O
Product: CC1(C)[C@H]2CC[C@]1(C)c1nnc(-c3cc(F)c(F)cc3Cl)cc12

Procedure:
yellow oil. MS (EI): 334.1 (M+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, [2-(2-Chloro-4,5-difluoro-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:15][CH:16]=1
Reactant: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.47 g (12.5 mmol) of 1-(tert-butyloxycarbonyl)-4-(5-methylpyridin-2-yl)piperazine is dissolved in 10 ml of dioxane and mixed with 31 ml (125 mmol) of hydrogen chloride in dioxane (4 mol). It is allowed to stir for 2 hours at room temperature. Then, it is concentrated by evaporation, the residue is alkalized with 1 M sodium hydroxide solution, and it is extracted several times with dichloromethane. The combined organic phases are dried on sodium sulfate, concentrated by evaporation, and dried in a vacuum.
Reaction SMILES: [N+:1]1([O-:10])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH3:9].C([O-])([O-])=O.[K+].[K+].[Br:17]Br.CCOC(C)=O>C(Cl)(Cl)(Cl)Cl.CO.CCOC(C)=O>[Br:17][C:4]1[C:5]([CH3:7])=[CH:6][N+:1]([O-:10])=[C:2]([CH3:9])[C:3]=1[CH3:8]
Reactant: Cc1cc(C)c(C)[n+]([O-])c1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1c[n+]([O-])c(C)c(C)c1Br
Yield: 48.6 %

Procedure:
2,3,5-collidine-N-oxide (1.3 g, 10 mmol) and K2CO3 (2.9 g, 20 mmol) were suspended in 10 mL of CCl4. Bromine (1 mL, 20 mmol) was added dropwise, and the reaction mixture was heated to reflux for 2 h. Work-up (EtOAc) and flash chromatography (10% MeOH/EtOAc) afforded the title compound as a solid (1.05 g, 51% yield). R.t.: 5.24 min. 1H-NMR (CDCl3): δ 8.06 (s, 1H), 2.56 (s, 3H), 2.43 (s, 3H), 2.31 (s, 3H). m/z (%) 216.2 (M+1, 100%), 218.2 (M+3, 100%). Rf (20% MeOH/EtOAc): 0.45.
Reaction SMILES: [Li]CCCC.[N+:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([O-:8])=[O:7].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>C1COCC1.C(Cl)Cl>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([CH:22]([OH:23])[CH:9]([N+:6]([O-:8])=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:24][CH:25]=1)([O-:17])=[O:16]
Reactant: CCCCCC[N+](=O)[O-]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCC(C(O)c1ccc([N+](=O)[O-])cc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
n-BuLi (1.6 M in hexane, 6.24 mL) was added dropwise with stirring to a solution of nitrohexane (1.4 mL, 10 mmol) in THF (12 mL) at -78° C. After 15 minutes a solution of TiCl3 (OPriso) (5 mmol) in THF (2 mL) and CH2Cl2 (3 mL) solution was added. After a further 15 minutes 4-nitrobenzaldehyde (0.75 mL, 5 mmol) in CH2Cl2 (3 mL) was added and the mixture allowed to warm up to room temperature (18 30 min.). Stirring was continued for a further 3.5 hours at room temperature and the mixture was quenched with an aqueous slurry of disodium EDTA (1.86 g, 5 mmol) and extracted with Et2O (3×75 mL), aqueous sodium bicarbonate (75 mL) and water (75 mL), dried and evaporated in vacuo. Flash column chromatography [SiO2, hexane:Et2O, 4:1 v/v] gave 1-(4-nitrophenyl)2 -nitro-heptan-1-ol (1.13 g, 81% Erythro:threo ratio 3.9:1
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=4)[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl.C(N(CC)CC)C.[CH3:39][C:40]1([CH3:47])[C:44]([CH3:46])([CH3:45])[O:43][BH:42][O:41]1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=4)[CH:18]=[C:13]3[C:12]([B:42]3[O:43][C:44]([CH3:46])([CH3:45])[C:40]([CH3:47])([CH3:39])[O:41]3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)OBOC1(C)C
Reactant: CN(C)c1ccc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)c1ccc(-c2cnc3c(c2)c(B2OC(C)(C)C(C)(C)O2)cn3S(=O)(=O)c2ccccc2)cc1
Yield: 115.6 %

Procedure:
A mixture of 3 (0.50 g, 0.99 mmol), [1,1′-bis(diphenylphosphino) ferrocene dichloropalladium(II).dichloromethane complex [PdCl2(dppf)2.CH2Cl2] (24.3 mg, 0.0298 mmol), triethylamine (415 μL, 2.98 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (221 μL, 1.52 mmol) in dioxane (5.0 mL) was microwaved at 120° C. for 0.5 h. The reaction mixture was cooled, poured onto water (100 mL), extracted with ethyl acetate (4×30 mL), the combined organic extracts washed with brine (30 mL), dried (MgSO4) and concentrated. This gave the product 16 as a brown foam (576 mg, 113%) which was used in the next step without further purification; 1H NMR (400 MHz, CDCl3) δ 1.38 (s, 12H), 3.02 (s, 6H), 6.86 (d, J=8.8 Hz, 2H), 7.65-7.45 (m, 5H), 8.16 (s, 1H), 8.26 (d, J=7.4 Hz, 2H), 8.30 (d, J=2.2 Hz, 1H), 8.63 (d, J=2.2 Hz, 1H).
Reaction SMILES: Cl.[C:2]([CH:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:17]1[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:18]=1.C(N(CC)CC)C.O>O1CCCC1>[C:2]([CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:17]2[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[N:18]=2)[CH2:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(c1ccccc1)C1CCCNC1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCCC(C(=O)c3ccccc3)C2)nc(-c2ccncc2)cc1=O
Yield: 121.5 %

Procedure:
A solution of 3-benzoylpiperidine hydrochloride (109 mg, 0.60 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (118 mg, 0.40 mmol) and triethylamine (0.50 ml, 4.00 mmol) in tetrahydrofuran (6 ml) was stirred at room temperature for several hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and evaporated in vacuo. Purification of the residue by silica gel column chromatography (ethyl acetate) gave the title compound (182 mg, 61%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[C:3]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12].[OH:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:17]=2)[C:3]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: COC(=O)Cc1c(C)nc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc(Cl)nc1Oc1cccc(-c2ccccc2)c1

Procedure:
Methyl α-[6-methyl-2,4-dichloro-5-pyrimidinyl]-acetate (4 g, 18 mmol), 3-hydroxybiphenyl (3 g, 18 mmol) and potassium carbonate (11 g, 80 mmol) in dimethylformamide (50 ml) are stiffed at +80° C. for 2 hours. Workup as for example 1a) gives pure methyl α-[6-methyl-2-chloro-4-(3-phenylphenoxy)-5-pyrimidinyl]-acetate.
Reaction SMILES: CS([O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14](=[O:30])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:17][CH:16]=3)=[C:12]([C:31]3[CH:36]=[CH:35][C:34]([O:37]S(C)(=O)=O)=[CH:33][CH:32]=3)[S:11][C:10]=2[CH:42]=1)(=O)=O.O1CCCC1.[OH-].[Na+]>CO>[OH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14](=[O:30])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)=[CH:19][CH:20]=3)=[C:12]([C:31]3[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=3)[S:11][C:10]=2[CH:42]=1
Reactant: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 3.6 g. portion of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene was dissolved in 100 ml. of tetrahydrofuran and 40 ml. of methanol, and 10 ml. of 5 N sodium hydroxide was added. The mixture was stirred for 16 hours at ambient temperature, and was then worked up by the procedure of Example 3 above to obtain 3.5 g. of a yellow solid. The impure product was purified by column chromatography on silica gel, eluting with a gradient solvent from 5% methanol in chloroform to 30% methanol in chloroform. The product-containing fractions were evaporated to obtain 1.85 g. of oily product, which was recrystallized from acetone to obtain 1.25 g. of purified product, m.p. 141°-144° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([O:22]C)=[O:21])=[CH:13][C:12]=3[CH:24]=2)=[CH:4][CH:3]=1.[OH-].[Na+].CO>C(OCC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([OH:22])=[O:21])=[CH:13][C:12]=3[CH:24]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(C)cc3)ccc2S(=O)(=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
To methyl 7-(4-methylphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (1.6 g) was added 1N sodium hydroxide solution (50 ml), methanol (200 ml) and diethylether (100 ml), and the mixture was stirred overnight, concentrated and extracted with water. The aqueous layer was washed with ethyl acetate, made acidic with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-(4-methylphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (1.5 g; purity about 70%) as colorless powder.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][NH:9][C:8]2=[N:13][N+:14]([O-:16])=[O:15])[CH2:2]1.[H-].[Na+].[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21]>C(#N)C>[CH:20]([C:19]([N:9]1[CH2:10][CH2:11][CH2:12][N:7]([CH2:6][CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)[C:8]1=[N:13][N+:14]([O-:16])=[O:15])=[O:23])([CH3:22])[CH3:21]
Reactant: O=[N+]([O-])N=C1NCCCN1CC1CCOC1
Reactant: CC(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)C(=O)N1CCCN(CC2CCOC2)C1=N[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
A mixture of 2.2 g of 1-[(tetrahydro-3-furanyl) methyl]-2-(nitroimino)hexahydropyrimidine, 0.58 g of sodium hydride (60%) and 100 ml of acetonitrile was stirred at 50° C. for 30 minutes. After this mixture was cooled on ice, 1.58 g of isobutanoyl chloride was added dropwise thereto over 30 minutes, and the mixture was then stirred at room temperature for 2 hours. After the completion of reaction, insolubles were removed by filtration, and concentration was then carried out under a reduced pressure. The resultant residue was purified by silica gel column chromatography (2:1 ethyl acetate/acetone) to obtain 1.30 g of 1-(isopropylcarbonyl)-2-(nitroimino)-3-[(tetrahydro-3-furanyl)methyl]hexahydropyrimidine
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=O)=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2].[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][O:39][C:40]2[CH:41]=[C:42]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=2)[NH2:43])[CH2:33][CH2:32]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>N1C=CC=CC=1.CC(=O)OCC>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:43][C:42]3[CH:44]=[C:45]([C:47]([F:49])([F:50])[F:48])[CH:46]=[C:40]([O:39][CH2:38][CH2:37][N:34]4[CH2:33][CH2:32][O:31][CH2:36][CH2:35]4)[CH:41]=3)=[O:29])=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2]
Reactant: Nc1cc(OCCN2CCOCC2)cc(C(F)(F)F)c1
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(OCCN4CCOCC4)cc(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a mixture of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (70.9 mg, 0.172 mmol) and 3-(2-morpholinoethoxy)-5-(trifluoromethyl)aniline (50 mg, 0.172 mmol) in pyridine (5 mL) was added T3P® (50% in EA, 0.3 mL) dropwise and the mixture was stirred at 25° C. for 1 h. The mixture was quenched with cold water (20 mL), extracted with DCM/MeOH (10:1, v/v, 20 mL×3). The organic layer was dried over Na2SO4 and concentrated to give an off white solid of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(2-morpholinoethoxy)-5-(trifluoromethyl)phenyl)acetamide (80 mg, 0.111 mmol, 64.5% yield): 1H NMR (400 MHz, CD3OD): δ 7.94 (d, J=1.8 Hz, 1H), 7.54 (s, 1H), 7.48 (s, 1H), 7.45-7.35 (m, 6H), 6.95-6.88 (m, 3H), 5.35 (s, 2H), 4.20-4.10 (m, 4H), 3.80 (s, 2H), 3.78 (s, 3H), 3.73-3.66 (m, 4H), 2.81 (t, J=5.4 Hz, 2H), 2.59 (d, J=4.2 Hz, 4H), 1.41 (t, J=6.8 Hz, 3H). ES-LCMS m/z: 684 (M+H).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C[C:6]1[CH:7]=[CH:8][N:9]2[C:14]=1[CH:13]=[CH:12][CH:11]=[CH:10]2.[C:15]1(C)C=CC=CC=1>>[CH3:15][C:7]1[CH:6]=[C:14]2[N:9]([C:8]=1[C:1]([Cl:4])=[O:2])[CH:10]=[CH:11][CH:12]=[CH:13]2
Reactant: Cc1ccn2ccccc12
Reactant: Cc1ccccc1
Reactant: O=C(Cl)Cl
Product: Cc1cc2ccccn2c1C(=O)Cl
Reaction time: 8 h

Procedure:
A solution of 99 g of phosgene (1 mole) in 800 ml of anhydrous toluene was cooled beneath 15° C. While the reaction mixture was cooled and stirred a solution of 131 g of methylindolizine (1 mole) in 475 ml of anhydrous toluene was added dropwise. The reaction mixture was kept overnight and the residue formed was sucked off.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[S:22][N:21]=[C:20]([CH3:23])[N:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[S:22][N:21]=[C:20]([CH3:23])[N:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nsc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nsc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.2 %

Procedure:
To a solution of N-tert-butyl-2-(3-methyl-1,2,4-thiadiazol-5-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (128 mg, 277 μmol) in dichloromethane (4.3 mL) was added trifluoroacetic acid (632 mg, 427 μL, 5.55 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated then re-dissolved in dichloromethane (4 mL), methanol (2 mL) and ammonium hydroxide (0.6 mL) and the mixture stirred at room temperature for 1 h. The mixture was concentrated in vacuo then triturated with water and filtered. The solid obtained was washed with ether then dried to give N-tert-butyl-2-(3-methyl-1,2,4-thiadiazol-5-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (90 mg, 272 μmol, 98%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.80 (s, 1H), 12.57 (s, 1H), 8.35 (s, 1H), 8.34 (s, 1H), 7.34 (s, 1H), 2.53 (s, 3H), 1.62 (s, 9H); MS (EI/CI) m/z: 332.1 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O-:11])=O)[CH:5]=[CH:6][CH:7]=1.CCN=C=NCCCN(C)C.Cl.[O:24]([CH2:31][CH2:32][NH2:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>ClCCl>[O:24]([CH2:31][CH2:32][NH:33][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCCOc1ccccc1
Reactant: O=C([O-])Cc1cccc(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1cccc(O)c1)NCCOc1ccccc1

Procedure:
3-Hydroxyphenylacetate (1.5 g, 9.88 mmol) was dissolved in dichloromethane. WSC.HCl (2.82 g, 14.76 mmol) and 2-phenoxyethylamine (1.5 g, 10.95 mmol) were added thereto, and then the resultant mixture was stirred for 4 hours at room temperature. After completion of reaction, water was added to the reaction mixture. The resultant mixture was extracted with chloroform, followed by washing with brine. The resultant mixture was subjected to drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification by chromatography, whereby 2.85 g, a stoichiometric amount, of the target compound was obtained as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=O)[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:28]=1.C(N(CC)CC)C.[CH3:36][C:37]([NH2:40])([CH3:39])[CH3:38].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>ClCCl>[C:37]([NH:40][C:25]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:8]1[O:9][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:28][C:6]=3[CH:7]=1)[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18]2)=[O:27])([CH3:39])([CH3:38])[CH3:36]
Reactant: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(F)ccc2o1
Reactant: CC(C)(C)N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(C)c1nc2cc(C(=O)NC(C)(C)C)ccc2nc1-c1cc2cc(F)ccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(5-fluorobenzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylic acid (486 mg, 1.28 mmol) in dichloromethane (30 ml) was added triethylamine (366 mg, 3.62 mmol), 2-methylpropan-2-amine (212 mg, 2.90 mmol) and T3P (610 mg, 1.92 mmol), and the resulting mixture was stirred for 1 h at room temperature. The reaction mixture was then quenched with water (120 ml), extracted with dichloromethane (4×60 ml), and the organic layers combined and concentrated in vacuo to afford N-tert-butyl-2-(5-fluorobenzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxamide as a yellow solid (600 mg, crude), which was used to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.[C:24](C1NC=CN=1)(C1NC=CN=1)=[O:25]>O1CCCC1>[CH2:12]([N:9]1[CH2:10][CH2:11][CH:6]([N:5]2[CH2:4][C:3]3[C:2](=[C:22]([F:23])[CH:21]=[CH:20][CH:19]=3)[NH:1][C:24]2=[O:25])[CH2:7][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1c(F)cccc1CNC1CCN(Cc2ccccc2)CC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: O=C1Nc2c(F)cccc2CN1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-(2-amino-3-fluorobenzyl)-1-benzylpiperidin-4-amine (36.3 g, 116 mmol) in tetrahydrofuran (600 mL) at room temperature was added carbonyl diimidazole (20.7 g, 1.10 equiv.) in one portion. The reaction was stirred at room temperature for 3 h, heated at reflux for 30 min, and concentrated. The resulting solid was dissolved in 1:1 diethyl ether/ethyl acetate, washed with water (3×), then brine, dried over magnesium sulfate, and concentrated to give the crude product as a wet, yellow solid. The solid was triturated with diethyl ether and filtered to give 30.0 g (76%) as a white powder. 1H-NMR (CDCl3, 500 MHz) δ 1.68 (m, 2H), 1.86 (dddd, J=11.9, 11.9, 11.9, 3.4, 2H), 2.14 (dd, J=11.6, 10.1, 2H), 2.98 (d, J=11.6, 2H), 3.51 (s, 2H), 4.34–4.44 (m, 3H), 6.71 (bs, 1H), 6.79–6.89 (m, 2H), 6.94 (dd, J=9.2, 9.2, 1H), 7.21–7.34 (m, 5H). Mass spec.: 340.30 (MH)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:10]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:11]2)[CH:6]=[CH:7][C:8]=1[OH:9])#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C@@H:28]([CH3:31])[CH2:29][CH3:30].O>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([N:10]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:11]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:27][C@@H:28]([CH3:31])[CH2:29][CH3:30])#[N:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(O)c(C#N)c2)c1
Reactant: CC[C@H](C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(-c2ccc(OC[C@@H](C)CC)c(C#N)c2)c1
Temperature: 90 °C
Yield: 89.1 %

Procedure:
To a solution (10 ml) of ethyl 1-(3-cyano-4-hydroxyphenyl)pyrazole-4-carboxylate (1.5 g) in dimethylformamide were added potassium carbonate (0.91 g) and (S)-(+)-1-bromo-2-methylbutane (1 g) with stirring, and the mixture was heated at 90° C. for 2 hours. After the completion of the reaction, the reaction mixture was poured into water and the mixture was acted with ethyl acetate, washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from isopropyl ether to give 1.7 g of ethyl 1-(3-cyano-4-((S)-2-methylbutoxy)phenyl)pyrazole-4-carboxylate, melting point 105-106° C.