Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18]C)=[O:17])[CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].CO.O1CCOCC1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([OH:18])=[O:17])[CH3:13])(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1ccccc1N(C)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CN(c1ccccc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-(3,4-dichloro-N-methylphenylsulfonamido)benzoate (21.0 g, 56.1 mmol) was dissolved in a mixture of methanol/dioxane/4 M NaOH (15/4/1, 420 ml, 84 mmol NaOH, 1.5 eq.), and further 4 M NaOH (63 ml, 252 mmol, 4.5 eq.) was added. The solution was stirred overnight at room temperature and then concentrated using a rotary evaporator. Ethyl acetate (800 ml) was added to the residue, and the mixture was washed with 0.5 M KHSO4 (1000 ml). The aqueous phase was then extracted three times with ethyl acetate (350 ml each time), and the combined organic phases were washed with saturated NaCl solution (500 ml). The organic phase was dried (sodium sulfate) and concentrated in vacuo.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:5]2[C:10]3[CH:11]=[CH:12][N:13](S(C4C=CC(C)=CC=4)(=O)=O)[C:9]=3[N:8]=[CH:7][C:6]=12.C(Cl)Cl.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O.CCOC(C)=O.[Cl-].[Na+].O.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]>[CH:24]1([C:4]2[N:5]3[C:10]4[CH:11]=[CH:12][NH:13][C:9]=4[N:8]=[CH:7][C:6]3=[C:2]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:3]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(Br)nc(C4CCCCC4)n23)cc1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: c1ccc(-c2nc(C3CCCCC3)n3c2cnc2[nH]ccc23)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 28.2 %

Procedure:
To a solution of 3-bromo-1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.27 g, 0.056 mmol) and PdCl2(dppf).DCM (0.0046 g, 0.0056 mmol) in THF (1 mL) was added a solution of phenylboronic acid (0.12 g, 0.098 mmol) and Na2CO3 (0.009 g, 0.084 mmol) in water (0.25 mL). The mixture was heated to about 60° C. After about 6 h, the mixture was cooled to rt and was diluted with EtOAc (5 mL) and brine (5 mL). The organic layer was separated and concentrated in vacuo. The residue was dissolved in 1,4-dioxane (5 mL) and aqueous NaOH (2 N, 1 mL) was added. The mixture was heated to about 65° C. After about 15 h, the mixture was cooled to rt and aqueous HCl (1 N, 3 mL) and EtOAc (5 mL) were added. The organic layer was separated, concentrated in vacuo, and the residue was purified by chromatography on silica gel (12 g) eluting with 20 to 80% EtOAc in DCM to provide 1-cyclohexyl-3-phenyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.005 g, 28%): LC/MS (Table 2, Method a) Rf=2.75 min; MS m/z: 317 (M+H)+. Syk IC50=C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[Br:12]N1C(C)(C)C(=O)N(Br)C1=O.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1.C(O)(=O)C>C1(Cl)C=CC=CC=1>[Br:12][CH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: CC(=O)O
Solvent: Clc1ccccc1
Product: O=[N+]([O-])c1ccc(F)cc1CBr
Yield: 27.3 %

Procedure:
5-Fluoro-2-nitrotoluene (9.3 g, 60 mmol), 1,3-dibromo-5,5-dimethylhydantoin (20 g, 70 mmol), and 1,1′-azobis(cyclohexanecarbonitrile) (VAZO 88, 600 mg, 2.5 mmol) were combined in C6H5Cl (600 ml) and stirred. Acetic acid (300 ul, 5.24 mmol) was added to the solution and the solution was stirred at 40° C. for 96 h. The crude reaction mixture was washed three times with hot NaHCO3 solution (200 ml, 80° C.), dried over magnesium sulfate, filtered and the solvent removed. The resulting crude red-orange solid was filtered through silica to yield a mixture that was about 1:1 brominated product and unbrominated starting material. The material was carried onto the next step without further purification. Pure material could be obtained from flash chromatography on silica (6:1 hexanes/EtOAc) to give a brown oil (3.84 g, 27%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:25])=[C:22]([OH:24])[CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:25])=[C:22]([CH:23]=1)[O:24][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(F)cc1O
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(F)cc1OCc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 90 °C
Yield: 69 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 5-fluoro-2-methylphenol (20 μL. 0.18 mmoL) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(5-fluoro-2-methyl-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (24 mg, 69%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.38 (br. s., 1H), 8.01 (br. s., 1H), 7.93 (d, J=8.2 Hz, 2H), 7.52-7.65 (m, 3H), 7.16 (t, J=7.5 Hz, 1H), 6.92 (dd, J=11.3, 2.6 Hz, 1H), 6.67 (td, J=8.5, 2.7 Hz, 1H), 5.20 (s, 2H), 2.16 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:15])([CH3:14])[C:10]([O:12]C)=[O:11])[CH:6]=[CH:7][CH:8]=1>C1COCC1.CO.[Li+].[OH-]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:15])([CH3:14])[C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C(C)(C)c1cccc(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(C(C)(C)C(=O)O)c1
Temperature: 60 °C

Procedure:
To methyl 2-(3-methoxyphenyl)-2-methylpropanoate (800 mg, 4 mmol) in THF (10 ml) and MeOH (10 ml), aqueous LiOH (excess) was added and the reaction mixture was heated at 60° C. for 7 h. Then volatiles were removed in vacuum and the aqueous layer was extracted with ether. Ether layer was discarded. Then the aqueous layer was acidified and extracted with ethyl acetate. Organic layer was dried with sodium sulfate and volatiles removed under vacuum to yield 2-(3-methoxyphenyl)-2-methylpropanoic acid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:15])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH3:2][O:3][C:4]([C:6]1([NH:15][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([O:17][CH3:16])=[C:19]([N+:27]([O-:29])=[O:28])[CH:20]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5]
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2ccc(OC)c([N+](=O)[O-])c2)Cc2ccccc2C1
Temperature: 60 °C
Yield: 65.6 %

Procedure:
To 2-amino-indane-2-carboxylic acid methyl ester hydrochloride (0.40 g, 1.77 mmol) and 4-methoxy-3-nitrobenzoic acid (0.35 g, 1.77 mmol) in 4 ml of DMF were added NMM (0.59 ml, 5.32 mmol), HOBT (0.31 g, 2.31 mmol) and EDC (0.44 g, 2.31 mmol). The mixture was stirred at 60° C. until LC/MS analysis showed complete conversion. The crude product was purified by silica gel chromatography (HEP/EA gradient) to give 0.43 g of the title compound.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH3:27])=[CH:6][CH:5]=1.[NH2:29][NH2:30]>CO.O>[CH3:27][C:13]1[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=2)[S:16][C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:29][NH2:30])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1
Reactant: NN
Solvent: O
Solvent: CO
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C(=O)NN)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 66.5 %

Procedure:
To a suspension of 4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzoic acid methyl ester (Example 6, 364 mg, 1 mmol) in methanol (10 mL) add anhydrous hydrazine (128 ml, 4 mmol). Warm the resulting mixture to 60° C. and stir at this temperature for 18 hrs. Cool the resulting solution to room temperature, and add 3 drops of water. Concentrate the solution under vacuum and purify the residue by flash chromatography (elute with 5% methanol in dichloromethane) to give the title compound (271 mg).
Reaction SMILES: C(O[C:4]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)=[O:5])C.[H-].[Na+].[C:13](#[N:15])[CH3:14]>C1(C)C=CC=CC=1>[S:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:4]([CH2:14][C:13]#[N:15])=[O:5]
Reactant: CCOC(=O)c1cccs1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CCC(=O)c1cccs1
Yield: 92.6 %

Procedure:
78.1 grams (0.5 mole) of thiophene-2-carboxylic acid ethyl ester and 30 grams (1 mole) of sodium hydride (80% suspension in white oil) were reacted with 41.5 grams (1 mole) of acetonitrile in 500 ml of dry toluene. There were obtained 70.0 grams (92.6% of theory) of 2-thiophenoylacetonitrile having a melting point of 110° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH+:9]([O-:25])[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCc1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[NH+]([O-])CCc1ccncc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
tert-Butyl 2-(4-pyridyl)ethylcarbamate (6.9 g, 31 mmol) and 3-chloroperbenzoic acid (77%, 9.1 g, 40 mmol) were dissolved in ethyl acetate (100 ml), and the mixture was stirred at room temperature for 3 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with methanol-ethyl acetate (1:3, v/v) were collected and concentrated to give the titled compound (7.4 g, 99%).
Reaction SMILES: Br[CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]([O:23][CH3:24])=[O:22].[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([NH2:35])=[N:27][CH:26]=1.C(N(CC)C(C)C)(C)C.[H-].[Na+]>O.C1COCC1.ClCCl>[CH3:24][O:23][C:21]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:35][C:28]1[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:25]=[CH:26][N:27]=1)=[CH:10][CH:9]=[C:8]([Cl:14])[CH:7]=2)=[O:22]
Reactant: COC(=O)c1c(CBr)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: Nc1ncnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(CNc2ncnc3ccccc23)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 10 mL round-bottomed flask, methyl 3-(bromomethyl)-7-chloro-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxylate (50 mg, 0.123 mmol) was combined with dichloromethane (5 mL) to give a colorless solution. Quinazolin-4-ylamine (17.8 mg, 0.123 mmol) and N,N-diisopropylethylamine (19.1 mg, 0.148 mmol) were added. The reaction mixture was stirred at room temperature overnight. TLC showed only starting material present after this time. Sodium hydride (60% suspension) (9.8 mg, 0.264 mmol) and 2 mL of THF were added. The reaction mixture was stirred at room temperature. The reaction mixture was poured into 25 mL H2O and extracted with ethyl acetate (1×25 mL). The organic layer was washed with 1 M HCl (1×10 mL), sat aqueous NaHCO3 (1×10 mL), and H2O (1×10 mL). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 30% to 100% ethyl acetate in hexanes) to yield 7-chloro-4-oxo-1-phenyl-3-(quinazolin-4-ylaminomethyl)-1,4-dihydro-quinoline-2-carboxylic acid methyl ester. MS calcd. for C26H19ClN4O3 [(M+H)+] 471.1, obsd. 471.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.O.O.[Cl-].[Ca+2].[Cl-].CCO>[Zn].O>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1ccc(CNc2ccc([N+](=O)[O-])cc2OC)cc1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: COc1ccc(CNc2ccc(N)cc2OC)cc1
Yield: 71.6 %

Procedure:
This compound was prepared by General Method 10 (EXAMPLE 19) from (2-methoxy-4-nitrophenyl)-(4-methoxybenzyl)amine (1.92 g, 6.65 mmol), zinc dust (1.87 g, 28.6 mmol), and calcium chloride dihydrate (2.10 g, 14.3 mmol) in 350 mL 95:5 EtOH:water to afford 1.23 g (70%) of (4-amino-2-methoxyphenyl)-(4-methoxybenzyl)amine, a light purple solid, after flash chromatography (CH2Cl2:MeOH 19:1). Data for (4-amino-2-methoxyphenyl)-(4-methoxybenzyl)amine: Rf 0.80 (19:1 CH2Cl2:MeOH); 1H NMR (400 MHz, CDCl3) δ 7.30 (d, 2H, J=8.6), 6.87 (d, 2H, J=8.6), 6.47 (d, 1H, J=8.1), 6.28 (d, 1H, J=2.4), 6.23 (dd, 1H, J=8.1, 2.4), 4.20 (s, 2H), 4.10 (v broad s, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.31 (broad s, 2H).
Reaction SMILES: N1CCC(C2C=C(NC(=O)CC)C=CC=2)CC1.[CH:18]1([C:21]([NH:23][C:24]2[CH:25]=[C:26]([CH:30]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]3)[CH:27]=[CH:28][CH:29]=2)=[O:22])[CH2:20][CH2:19]1>>[NH:33]1[CH2:34][CH2:35][CH:30]([C:26]2[CH:25]=[C:24]([NH:23][C:21]([CH:18]3[CH2:19][CH2:20]3)=[O:22])[CH:29]=[CH:28][CH:27]=2)[CH2:31][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Agent: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Yield: 99.5 %

Procedure:
According to the procedure used for the synthesis of N-[3-(4-piperidinyl)phenyl]propanamide, tert-butyl 4-{3-[(cyclopropylcarbonyl)amino]phenyl}-1-piperidinecarboxylate (18.9 g, 0.0543 mol) provided N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide (13.2 g, 100%). 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.36–7.22 (m, 3H), 7.23 (d, 1H, J=6.9 Hz), 3.17 (d, 2H, J=11.9 Hz), 2.72 (dt, 2H, J=2.6, 12.2 Hz), 2.65–2.55 (m, 1H), 1.82 (d, 2H, J=13.9 Hz), 1.63 (dt, 3H, J=4.1, 12.5 Hz), 1.53–1.45 (m, 1H), 1.11–1.06 (m, 2H), 0.87–0.81 (m, 2H); ESMS m/e: 245.03 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:11])[CH2:7][CH2:8][CH2:9]Br)(C)(C)C.[C:12]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:24])[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C=O)C.CCOC(C)=O>[C:6]([CH2:7][CH2:8][CH2:9][CH:13]([C:12]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([OH:11])=[O:5]
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)CCCC(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Yield: 54 %

Procedure:
tert-Butyl-4-bromobutyrate (10 mmol) in DMF (100 mL) was treated with dibenzyl malonate (20 mmol) and potassium carbonate (30 mmol) at 40° C. overnight. EtOAc (200 mL) and saturated aqueous ammonium chloride (100 mL) were added and the separated organic layer was washed with 1N HCl (50 mL), saturated aqueous ammonium chloride (100 mL), brine (100 mL), and water (100 mL). After removal of the solvent in vacuo, the crude product was dissolved in dichloromethane (60 mL) and treated at room temperature with trifluoroacetic acid (15 mL) for 2 h. Removal of the solvent in vacuo afforded the crude product, which was purified by reverse phase preparative HPLC using 0.05% TFA/CH3CN/H2O as the mobile phase. The title compound (37) (2 g) was obtained as a colorless oil. 1H NMR (CD3OD, 400 MHz): δ 7.3 (m, 10H), 5.1 (q, 4H), 3.5 (t, 1H), 2.3 (t, 2H), 1.9 (q, 2H), 1.6 (m, 2H). MS (ESI) m/z 370.4 (M+H)+.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[C:17]1([CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Li].IC1C=CC=CC=1C>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH3:24])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: [Li]c1ccccc1C
Agent: Cc1ccccc1I
Product: CCSc1ncc(C(=O)c2ccccc2C)c(N)n1

Procedure:
The same procedure was used as described in Example 2, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (from Example 1) and a solution of 2-tolyllithium (−3 equiv, freshly prepared from 2-iodotoluene, as in Example 2A), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-o-tolyl-methanone as a white solid. MS (M+H)+: 274.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].Br[C:21]1[CH:28]=[N:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH:23]([C:22]1[CH:21]=[CH:28][N:27]=[CH:26][C:25]=1[C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=1)=[O:24]
Reactant: O=Cc1ccncc1Br
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-c2cnccc2C=O)ccc1C#N
Yield: 71.4 %

Procedure:
A mixture of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (259 mg, 1 mmol), 3-bromoisonicotinaldehyde (186 mg, 1.000 mmol), a solution of sodium carbonate (2M in water, 1.000 ml, 2.000 mmol), bis(triphenylphosphine)palladium(11) chloride (17.55 mg, 0.025 mmol) in DMF (6 mL, dry) was heated to 120° C. for 3 hrs. After concentration, the residue was dissolved into CH2Cl2-MeOH and mixed with silica gel and concentrated. After flash column (MeOH—CH2Cl2, v/v, 0.5%-1%) yielded colorless solid (170 mg). 1H NMR (400.3 MHz, CDCl3): δ 3.99 (s, 3H), 6.98 (d, J=1.32 Hz, 1H), 7.05 (dd, J=1.48, 7.8 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.81 (d, J=5 Hz, 1H), 8.81 (s, 1H), 8.90 (d, J=5 Hz, 1H), 10.04 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]([NH:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])C#N)=[CH:4][CH:3]=1.FC(F)(F)S(O)(=O)=O.CN(C)C=O.Cl[C:32](=[CH2:37])[C:33]([O:35][CH3:36])=[O:34]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[NH:9][C:10]([C:11]([F:12])([F:13])[F:14])=[CH:37][C:32]=2[C:33]([O:35][CH3:36])=[O:34])=[CH:16][CH:17]=1
Reactant: C=C(Cl)C(=O)OC
Reactant: N#CC(NC(=O)C(F)(F)F)c1ccc(Cl)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
A slurry of N-(p-chloro-α-cyanobenzyl)-2,2,2-trifluoroacetamide (10.5 g, 0.04 mol) in toluene under a nitrogen atmosphere is cooled to 10° C., treated with trifluoromethanesulfonic acid (12.0 g, 0.08 mol) over 10-15 minutes, allowed to warm to room temperature and stirred for 3 hours. The reaction is monitored by 19F NMR (DMSO-d6) analysis to show completion of the intermediate salt formation. When formation is complete, the mixture is cooled to 10° C., treated with dimethylformamide, treated with methyl 2-chloroacrylate (7.2 g, 0.06 mol), allowed to warm to room temperature, stirred for 18 hours, and diluted with water and ethyl acetate. The phases are separated and the organic phase is washed with water and concentrated to give a waxy solid residue. Flash column chromatography of the residue on silica gel, packed and eluted with 20% ethyl acetate in heptane gives the title product as a white crystalline solid, 7.6 g (62% yield), mp 123°-125° C. identified by 1H and 19F NMR analyses.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[CH:10]([Br:13])(Br)[Br:11].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:11][C:10]1([Br:13])[CH2:1][C:2]1([CH3:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrC(Br)Br
Reactant: C=C(C)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CC1(c2ccccc2)CC1(Br)Br
Yield: 86.3 %

Procedure:
To a solution of 12.5 ml (0.0963 mol) of α-methylstyrene in 30.4 ml (0.348 mol) of bromoform and 1.34 g (0.00416 mol) of tetrabutylammonium bromide was added slowly via addition funnel 20.9 ml (0.400 mol) of 50% aqueous sodium hydroxide. After heating to 55° C. for 1 hour 20.9 ml (0.400 mol) of 50% aqueous sodium hydroxide was added. After 2 additional hours of heating, the reaction was cooled to room temperature when hexanes and water were added. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo. The product was isolated by vacuum distillation to yield 24.1 g of 2,2-dibromo-1-methyl-1-phenylcyclopropane as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH:33]=[CH:34][C:35]=1[N+:36]([O-:38])=[O:37])[C:15]([C:17]1[N:21]2[CH:22]=[C:23]([C:26]([O:28]C(C)(C)C)=[O:27])[CH:24]=[CH:25][C:20]2=[CH:19][N:18]=1)=[O:16])=[O:11]>ClCCl.CC(C)=O>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH:33]=[CH:34][C:35]=1[N+:36]([O-:38])=[O:37])[C:15]([C:17]1[N:21]2[CH:22]=[C:23]([C:26]([OH:28])=[O:27])[CH:24]=[CH:25][C:20]2=[CH:19][N:18]=1)=[O:16])=[O:11]
Reactant: COC(=O)c1cc(C(=O)c2ncc3ccc(C(=O)OC(C)(C)C)cn23)ccc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)c2ncc3ccc(C(=O)O)cn23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.2 %

Procedure:
2.13 ml (28.68 mmol) of trifluoroacetic acid are added to 610 mg (1.43 mmol) of tert-butyl 3-[3-(methoxycarbonyl)-4-nitrobenzoyl]imidazo[1,5-a]pyridine-6-carboxylate in 2 ml of dichloromethane and the mixture is stirred at ambient temperature for 5 hours. The reaction medium is concentrated under reduced pressure and then the residue obtained is taken up in acetone. The precipitate formed is filtered off, washed with acetone and dried. 450 mg of a yellow powder are obtained. Melting point: 290° C.; 1H NMR (d6-DMSO): 3.90 (3H, s), 7.78 (1H, d), 8.04 (1H, s), 8.12 (1H, d), 8.26 (1H, d), 8.68 (1H, d), 8.75 (1H, s), 10.26 (1H, s)
Reaction SMILES: C(OC([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([CH3:17])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O)C.[OH-].[Na+].Cl>O>[CH3:17][C:11]1[N:10]=[C:9]2[C:14]([C:15]([OH:16])=[CH:6][CH:7]=[N:8]2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1c[nH]c2nc(C)ccc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(O)ccnc2n1
Temperature: 25 °C
Yield: 83 %

Procedure:
A solution of the product from Example 7b (1.30 g, 5.59 mmol) and NaOH (233 mg, 5.82 mmol) in 20 mL of water was heated in a sealed metal reactor at 180° C. for 16 h. Cooled to room temperature and adjusted to pH 6 with 1N HCl. The resulting precipitates was filtered and dried under vacuum giving the title compound as a black solid (743 mg, 82%).