Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[C:8]([O:11][C:12]3[CH:21]=[CH:20][N:19]=[C:18]4[C:13]=3[C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16](=[O:22])[NH:17]4)[CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[C:30]([C:37]([F:40])([F:39])[F:38])[CH:29]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([N:4]2[C:5]3[CH:10]=[CH:9][C:8]([O:11][C:12]4[CH:21]=[CH:20][N:19]=[C:18]5[C:13]=4[C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16](=[O:22])[NH:17]5)=[CH:7][C:6]=3[O:1][CH2:2][CH2:3]2)=[O:33])=[C:30]([C:37]([F:38])([F:39])[F:40])[CH:29]=1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: O=c1[nH]c2nccc(Oc3ccc4c(c3)OCCN4)c2c2ccccc12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(F)cc1C(F)(F)F)N1CCOc2cc(Oc3ccnc4[nH]c(=O)c5ccccc5c34)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.4 %

Procedure:
Compound 218 (50 mg, 0.14 mmol), 4-fluoro-2-trifluoromethyl-benzoyl chloride (49 mg, 0.22 mmol), and DIEA (0.07 mL, 0.43 mmol) were dissolved in dioxane (2 mL) and stirred for 1 h at room temperature. The reaction was quenched with H2O, diluted with EtOAc, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 100% EtOAc in hexanes to provide 219 (28 mg, 36% yield) as a tan solid. LC-MS (M+H=536, obsd.=536).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.O1CCCC1.[C].[Pd]>[CH2:31]([C:28]1[CH:29]=[CH:30][C:25]([O:24][CH2:23][CH2:22][CH2:21][N:16]2[C:17]([CH3:20])=[CH:18][CH:19]=[C:15]2[C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[CH:26][CH:27]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1CCCOc1ccc(Cc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(-c2ccc(O)cc2)n1CCCOc1ccc(Cc2ccccc2)cc1
Reaction time: 4 h
Yield: 98 %

Procedure:
To a solution of 2-(4-benzyloxyphenyl)-1-[3-(4-benzylphenoxy)propyl]-5-methyl-1H-pyrrole (1.15 g, 2.26 mmol) in ethanol (60 ml) and tetrahydrofuran (30 ml) was added 10% palladium carbon (200 mg) and the mixture was stirred for 4 hours under hydrogen atmosphere. The insoluble matter was filtered out and the filtrate was concentrated to give the object compound as an oily substance. 920 mg (yield: 98.0%)
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:30])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C@@H:13]1/[CH:18]=[CH:19]/[C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1.Cl>C(Cl)Cl.CO>[CH3:3][O:4][C:5](=[O:30])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C@@H:13]1/[CH:18]=[CH:19]/[CH:20]([OH:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1
Reactant: COC(=O)COCCCCN1C(=O)CC[C@@H]1/C=C/C(=O)Cc1cccc(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)COCCCCN1C(=O)CC[C@@H]1/C=C/C(O)Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
Sodium borohydride (4.3 mg, 0.11 mmol) was added to a solution of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-oxo-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-butoxy)-acetic acid methyl ester (42 mg, 0.10 mmol) in CH2Cl2 (1 mL) at 0° C. Methanol (3 drops) was added and the reaction was stirred at rt for 3 h. Aqueous HCl (0.5 M, 5 mL) was added and the mixture was extracted with CH2Cl2 (3×5 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (0%→5% MeOH/CH2Cl2) to afford 31 mg (73%) of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-hydroxy-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-butoxy)-acetic acid methyl ester.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[N:13](C2CCCCO2)[N:12]=[C:11]([C:20]([F:23])([F:22])[F:21])[C:10]=1[C:24]1[NH:25][C:26]2[C:32]3[CH:33]=[CH:34][N:35]=[CH:36][C:31]=3[NH:30][C:29]3[N:37]=[CH:38][CH:39]=[CH:40][C:28]=3[C:27]=2[N:41]=1.Cl>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[NH:13][N:12]=[C:11]([C:20]([F:23])([F:22])[F:21])[C:10]=1[C:24]1[NH:25][C:26]2[C:32]3[CH:33]=[CH:34][N:35]=[CH:36][C:31]=3[NH:30][C:29]3[N:37]=[CH:38][CH:39]=[CH:40][C:28]=3[C:27]=2[N:41]=1.[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: Cc1c(-c2nc3c([nH]2)-c2ccncc2Nc2ncccc2-3)c(C(F)(F)F)nn1C1CCCCO1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1[nH]nc(C(F)(F)F)c1-c1nc2c([nH]1)-c1ccncc1Nc1ncccc1-2
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[5-methyl-1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]-3,8-dihydroimidazo[4,5-d]dipyrido[2,3-b:4′,3′-f]azepine trifluoroacetate (715 mg, 1.23 mmol) in methanol (16 mL) was added 1.25 mL concentrated HCl and the reaction was stirred at 50° C. for 3 h. The reaction was reduced in vacuo and then purified by preparative LCMS to obtain the desired product as a bis-TFA salt (548 mg, 73%). 1H NMR (400 MHz, DMSO-d6): δ 13.8 (bs, 1H), 8.60 (bs, 1H), 8.10 (d, 1H), 8.01 (s, 1H), 7.94 (dd, 1H), 7.61 (m, 2H), 6.88 (dd, 1H), 2.35 (s, 3H). 19F NMR (400 MHz, DMSO-d6): δ-59.476 (3F), −74.791 (6F). MS (EI) m/z=384. (M+H).
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:4]=2[NH:3]1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:2]1=[N:3][C:4]2[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:5]=2[O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: COC(=O)c1ccc2c(c1)NC(=O)c1ccccc1O2
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(c1)N=C(Cl)c1ccccc1O2
Temperature: 100 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Compound 548 (1.00 g, 3.71 mmol)) was suspended in POCl3 (20 mL). The reaction mixture was stirred at 100° C. for 3 h. POCl3 was removed on rotovap. The crude product was dissolved in ethyl acetate and washed with 2M Na2CO3 solution then with NaHCO3 saturated solution and finally with brine. The organic layer was separated and dried with Na2SO4, filtered and concentrated via rotary evaporation to afford compound 549 (1.069 g, 100%) as a orange solid that was taken on without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:28][C:29](=[O:35])[CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C.[CH3:60][Si:61]([C:64]#[CH:65])([CH3:63])[CH3:62]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:23]([N:22]([CH2:25][CH3:26])[C:21]([CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([NH:28][C:29](=[O:35])[CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:3][C:2]=2[C:65]#[C:64][Si:61]([CH3:63])([CH3:62])[CH3:60])[CH2:9][CH2:10]1)=[O:27])[CH3:24]
Reactant: C#C[Si](C)(C)C
Reactant: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)N(CC)CC)c3ccccc3)CC2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)N(CC)CC)c3ccccc3)CC2)c(C#C[Si](C)(C)C)c1
Temperature: 120 °C
Yield: 15.6 %

Procedure:
To a solution of N-{3-bromo-4-[4-(diethylcarbamoyl-phenyl-methyl)-piperazin-1-yl]-phenyl}-2-ethyl-butyramide (66 mg, 0.12 mmol) in DMF (1.5 mL) was added CuI (1.3 mg, 0.01 mmol), triphenylphosphine (73 mg, 0.28 mmol), diethylamine (220 μL, 2.1 mmol), trimethylsilylacetylene (22 μL, 0.15 mmol) and dichlorobis(triphenylphosphine)palladium (II) (5.0 mg, 0.01 mmol). This solution was heated in a focused microwave reactor at 120° C. for 5 min, after which the solution was concentrated and purified by reverse phase HPLC to provide N-{4-[4-(diethylcarbamoyl-phenyl-methyl)-piperazin-1-yl]-3-trimethylsilanylethynyl-phenyl}-2-ethylbutyramide (10.5 mg, 16%). This compound (18 mg, 0.03 mmol) was dissolved in MeOH and treated with K2CO3 (9.0 mg, 0.06 mmol). After 1 h, the solids were filtered off, the filtrate concentrated, and the product purified by reverse phase HPLC to afford the title compound (10 mg, 63%). MS: 489.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13](O)[N:12]2[CH:16]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:18]=[C:11]2[CH:10]=1.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:13]1[N:12]2[CH:16]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:18]=[C:11]2[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:14]=1
Reactant: Oc1nc(-c2ccc(Cl)cc2Cl)cc2nc(CN3CCOCC3)cn12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc(-c2cc3nc(CN4CCOCC4)cn3c(Cl)n2)c(Cl)c1
Temperature: 0 °C

Procedure:
103 mg (0.267 mmol) of 7-(2,4-dichlorophenyl)-2-(morpholin-4-ylmethyl)imidazo[1,2-c]-pyrimidin-5-ol (Example 93A) are introduced in 5 ml (53.64 mmol) of phosphoryl chloride and heated at the reflux temperature for 3 h. The mixture is allowed to cool and is added cautiously to an ice/water mixture. The precipitate which separates out is filtered off. Drying under high vacuum results in 105 mg (99% of theory) of the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](O)=[O:10])=[CH:5][CH:4]=1.N1C=CC=CC=1.O=S(Cl)[Cl:22]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([Cl:22])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C=CC(=O)O)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc(C=CC(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.3 %

Procedure:
A first 3 L, 4 necked round bottomed flask (RBF) was equipped with a mechanical stirrer, thermowell, and a condenser with nitrogen adapter. The RBF was charged with 4-methoxycinnamic acid (175 g, 982 mmol) and 0.1 mL dry pyridine in 2 L dry toluene. The addition funnel was charged with 107.2 mL (1.473 mol) SOCl2 which was then added slowly to the reaction mixture at room temperature. The reaction mixture was heated to reflux and monitored by GC analysis (aliquots were withdrawn periodically, quenched with MeOH, and analyzed). After 5 hours, the GC analysis indicated that the reaction was complete and the reaction mixture was allowed to cool to room temperature. Excess SOCl2 and toluene were removed by rotary evaporation and the crude product was purified by distillation to give 182 g of 4-methoxycinnamoyl chloride (94% yield) with 98.9% purity by GC.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:21])[N:5]([CH2:18][CH2:19][OH:20])[CH2:6][C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH3:17])[CH3:2].C(O)C>[Pd]>[NH2:13][C:11]1[CH:10]=[CH:9][C:8]([O:16][CH3:17])=[C:7]([CH:12]=1)[CH2:6][N:5]([CH2:18][CH2:19][OH:20])[C:4]([NH:3][CH2:1][CH3:2])=[O:21]
Reactant: CCNC(=O)N(CCO)Cc1cc([N+](=O)[O-])ccc1OC
Agent: [Pd]
Solvent: CCO
Product: CCNC(=O)N(CCO)Cc1cc(N)ccc1OC
Yield: 106.9 %

Procedure:
3-Ethyl-1-(2-hydroxy-ethyl)-1-(2-methoxy-5-nitro-benzyl)-urea (0.43 g, 0.0014 mol) in Ethanol (50 mL, 0.8 mol) was hydrogenated with 10% Pd/C (10:90, Palladium:carbon black, 0.027 g) catalyst overnight. The reaction was filtered and the filtrate evaporated to give 1-(5-Amino-2-methoxy-benzyl)-3-ethyl-1-(2-hydroxy-ethyl)-urea as a yellow oil (0.40 g, 75%). 0.020 g was chromatographed on Alumina with DCM/IPA (20-1) giving 1-(5-Amino-2-methoxy-benzyl)-3-ethyl-1-(2-hydroxy-ethyl)-urea as an oil (0.010 g). LCMS (m/e) 268 (M+1); 1H-NMR (DMSO, 400 MHz) δ 6.68 (d, 1H, J=8.59 Hz),6.44-6.39 (d, 1H, J=9.6 Hz), 6.32 (s, 1H), 6.26-6.23 (t, 1H, J=5.30 Hz), 4.79-4.76 (t, 1H, J=5.06 Hz), 4.59 (s, 2H), 4.15 (s, 2H), 3.65 (s, 3H), 3.47-3.43 (q, 2H, J=5.30 Hz), 3.20-3.17 (t, 2H, J=6.06 Hz), 3.08-3.00 (q, 2H, J=5.81 Hz), 1.07-0.98 (t, 3H, J=7.07 Hz).
Reaction SMILES: [C:1]([C:3]1[C:4]([I:16])=[C:5]([CH2:14][OH:15])[C:6]([I:13])=[C:7]([C:11]=1[I:12])[C:8]([OH:10])=[O:9])#[N:2].[OH-:17].[Na+]>O>[C:1]([C:3]1[C:4]([I:16])=[C:5]([CH2:14][OH:15])[C:6]([I:13])=[C:7]([C:11]=1[I:12])[C:8]([OH:10])=[O:9])(=[O:17])[NH2:2]
Reactant: N#Cc1c(I)c(CO)c(I)c(C(=O)O)c1I
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: NC(=O)c1c(I)c(CO)c(I)c(C(=O)O)c1I
Reaction time: 3 h
Yield: 87.1 %

Procedure:
27.8 g of 5-cyano-3-hydroxymethyl-2,4,6-triiodobenzoic acid is suspended in 120 ml of water and dissolved by adding 10 g of sodium hydroxide. The batch is held at 60° C. for 3 hours and then precipitated into 50 ml of semiconcentrated sulfuric acid. After several hours of agitation in an ice bath, the precipitate is vacuum-filtered, washed with water, and dried at 50° C., thus obtaining 25 g of 5-carbamoyl-3-hydroxymethyl-2,4,6-triiodobenzoic acid as a white powder with a decomposition point above 280° C. Yield: 88% of theory.
Reaction SMILES: O=[C:2]1[C:6]2=[CH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:5]2[CH2:4][CH:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]>[Ni].C(O)C.O>[CH2:2]1[C:6]2=[CH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:5]2[CH2:4][CH:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C1Cn2c(cc3ccccc32)C1=O
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1Cc2cc3ccccc3n2C1
Reaction time: 5.5 h
Yield: 13.3 %

Procedure:
6 spoon spatula measures of Raney nickel were added to a solution of 5.08 g of ethyl 2,3-dihydro-1-oxo-1H-pyrrolo[1,2-a]indole-2-carboxylate in 180 ml of ethanol and 90 ml of water. The mixture was heated to reflux for 10 hours. Then, an additional 3 spoon spatula measures of Raney nickel were added. Heating was continued for 5.5 hours, whereupon the mixture was cooled and filtered. The filter residue was washed with ethyl acetate and dichloromethane. The combined filtrate and washings were evaporated and the residue was purified by chromatography on silica gel with diethyl ether/petroleum ether (1:2). Crystallization from methanol gave 635 mg of ethyl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-2-carboxylate of melting point 55°-57° C.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=2)[CH:6]=[CH:5][CH:4]=1.S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:18][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:14]=[C:13]([CH3:15])[NH:12][N:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cc(Nc2cccc(CO)n2)n[nH]1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(Nc2cccc(CCl)n2)n[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 114.9 %

Procedure:
68 mg (340 μmol) of 3-(6-hydroxymethylpyridin-2-yl)amino-5-methyl-1H-pyrazole was dissolved in 4 mL of a 6:1 mixed solvent of chloroform and dimethylformamide. Under cooling on an ice bath, 250 μL (3.4 mmol) of thionyl chloride was added thereto. After stirring at room temperature for 18 hours, the reaction solution was concentrated. The resulting residue was purified by a silica gel thin-layer chromatography to give 87 mg of a brown oil. This oil was used as it was for the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[O:38][C:37]([C:39]2([NH2:42])[CH2:41][CH2:40]2)=[N:36][CH:35]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:42][C:39]5([C:37]6[O:38][C:34]([CH3:33])=[CH:35][N:36]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1cnc(C2(N)CC2)o1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(C)o5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 0.46 mmol, 1 eq), 1-(5-methyloxazol-2-yl)cyclopropanamine (0.06 g, 0.46 mmol, 1.0 eq), HOBT (0.062 g, 0.46 mmol, 1.0 eq), EDC.HCl (0.08, 0.46 mmol, 1.0 eq), in DCM at ambient temperature and under a nitrogen atmosphere was added diisopropylehtylamine (0.19 ml, 1.3 mmol, 3.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by Combiflash column chromatography (4 g flash column, CV 4.8 ml, 18 ml/min, max pressure 200 psi) using 0.5% Methanol/DCM. Yield: 0.030 g (11.76%). 1H NMR (400 MHz, CD3OD): δ 1.43-1.46 (m, 2H), 1.61-1.65 (m, 2H), 2.29 (d, 3H, J=0.8 Hz), 2.37 (s, 3H), 2.96 (s, 3H), 4.06 (s, 3H), 6.69 (s, 1H,), 7.14 (s, 1H), 7.28 (apparent t, 2H), 7.34 (dd, 1H, J=1.6, 8.4 Hz), 7.59 (d, 1H, J=1.2 Hz), 7.64 (d, 1H, J=8.4 Hz), 7.88 (s, 1H), 7.96-8.00 (m, 2H). LCMS: (ES+) m/z=554.2 (M+H)+
Reaction SMILES: C[Si](C)(C)[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.C([Li])CCC.Br[CH2:16][C:17](=[O:24])[C:18]([CH2:22][F:23])([CH3:21])[CH2:19][F:20].[Cl-].[NH4+]>C(OCC)C>[F:20][CH2:19][C:18]([C:17]1([C:5]2[S:4][CH:3]=[N:7][CH:6]=2)[CH2:16][O:24]1)([CH3:21])[CH2:22][F:23]
Reactant: CC(CF)(CF)C(=O)CBr
Reactant: C[Si](C)(C)c1nccs1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(CF)(CF)C1(c2cncs2)CO1
Temperature: 25 °C

Procedure:
To 2.00 g (12.7 mmol) of 2-trimethylsilyl-1,3-thiazole dissolved in 20 ml of diethyl ether were added, at −78° C. under an argon atmosphere, 5.1 ml (2.5 M, 12.7 mmol) of n-butyllithium, and the reaction mixture was stirred at −78° C. for 20 min. Then 2.73 g (12.7 mmol) of 1-bromo-4-fluoro-3-(fluoromethyl)-3-methylbutan-2-one were added and the reaction mixture was gradually warmed to room temperature. After addition of saturated aqueous ammonium chloride solution, the phases were separated and the aqueous phase was extracted with diethyl ether. The combined organic phases were dried over sodium sulphate, filtered and concentrated. The crude product was then purified by column chromatography (5:1 cyclohexane/ethyl acetate). This gave 2.39 g (86%) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:29][C:30](=[O:31])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2[nH]c1=O
Reactant: O=C(CBr)c1ccccc1
Product: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2n(CC(=O)c2ccccc2)c1=O

Procedure:
This compound was prepared from 6-fluoro-2-oxo-4-[4-(furan-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (99) and 2-bromoacetophenone according to General Procedure B. Yield 242 mg (31%), MP 293° C.; 1H-NMR (DMSO-d6): δ 3.79 (m, 4H), 3.98 (m, 4H), 5.87 (s, 2H), 6.67 (dd, J=1.6, 3.2 Hz, 1H), 7.10 (d, J=3.6 Hz, 1H) 7.59 (m, 2H), 7.73 (m, 1H), 7.90 (d, J=1.6 Hz, 1H), 8.12 (m, 2H), 8.21 (dd, J=2.8, 9.2 Hz, 1H), 8.70 (d, J=2.8 Hz, 1H); EIMS: 486 (M+1). Anal. (C26H20FN5O4) C, H, N.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)[CH3:2].[O:8]1CCC[CH2:9]1.C([Li])CCC.CCCCCC>CN(C)C=O>[CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH:9]=[O:8])[CH3:2]
Reactant: CCn1ccnc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCn1ccnc1C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.2 %

Procedure:
Under nitrogen, a solution of 15.1 g (0.157 moles) N-ethylimidazole and 150 ml tetrahydrofuran was cooled to -40° C. Sixty-three ml 2.6M n-butyllithium in hexane (0.164 moles) was added via syringe. After fifteen minutes, 12.8 ml N,N-dimethylformamide was added and the reaction was allowed to warm to room temperature. After 18 hours the reaction was quenched with 5N hydrochloric acid. After stirring 15 minutes, the tetrahydrofuran was removed under reduced pressure. The remaining aqueous solution was basified with potassium carbonate solution and the product extracted into ethyl acetate (3×150 ml). After drying (anhydrous sodium sulfate) and concentration, 18.15 g (93.2%) of product was obtained as a pale tan oil, bp 90° C. at 12 mm.
Reaction SMILES: [ClH:1].Cl.[C:3]1([NH2:11])[C:4]([NH2:10])=[CH:5][C:6]([NH2:9])=[CH:7][CH:8]=1.[OH:12][C:13]1[CH:14]=[C:15]([C:19]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=O)=O)[CH:16]=[CH:17][CH:18]=1>O1CCOCC1.O>[ClH:1].[ClH:1].[OH:12][C:13]1[CH:14]=[C:15]([C:19]2[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=3)=[N:10][C:4]3[C:3](=[CH:8][CH:7]=[C:6]([NH2:9])[CH:5]=3)[N:11]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(N)c(N)c1
Reactant: O=C(C(=O)c1cccc(O)c1)c1cccc(O)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc2nc(-c3cccc(O)c3)c(-c3cccc(O)c3)nc2c1
Yield: 168.5 %

Procedure:
40.4 mg (0.206 mmol) of 1,2,4-benzenetriamine dihydrochloride and 50 mg (0.20 mmol) of 3,3′-dihydroxybenzil were dissolved in 2 mL of 1:1 mixture of dioxane-water. The reaction was refluxed for 3 hours. Then solvent was removed in vacuo. The residue was dissolved in 2 mL of methanol and this solution was added dropwise to 40 mL of diethyl ether. The formed dark-red precipitate was collected, washed with ether and dried in vacuo to give 69.8 mg (92.6% yield) of the product. 97.6% purity by LC/MS (230 DAD). Mass-spec [ES+]=330.8. 1H NMR (500 MHz, MeOH-d4) 6.81–6.87 (2H, m), 6.96–6.98 (4H, m), 7.10 (1H, m), 7.13–7.16 (1H, t), 7.28–7.31 (1H, t), 7.56–7.58 (1H, m), 8.04–8.06 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16](OCCOCC)=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:4]([F:27])[CH:3]=1.ClC1C(Cl)=CC(NC2C3C(=[CH:42][C:43]([O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59]CCO)=C([N+]([O-])=O)C=3)N=CN=2)=C(F)C=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:20])[CH:18]=3)[N:13]=[C:12]([O:59][CH2:58][CH2:57][O:56][CH2:55][CH2:54][O:53][CH2:52][CH2:51][O:50][CH2:43][CH3:42])[N:11]=2)=[C:4]([F:27])[CH:3]=1
Reactant: CCOCCOc1cc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2cc1N
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCOCCOCCO
Product: CCOCCOCCOCCOc1nc(Nc2cc(Cl)c(Cl)cc2F)c2cc(N)ccc2n1

Procedure:
Compound 41b is prepared as described hereinabove for Compound 41a, using Compound 29b a starting material.