Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(CC)CC.[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[N+:14]([O-:16])[CH:15]=1)[CH3:9].O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:15]1[N:14]=[C:13]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[CH:11][C:10]=1[CH2:8][CH3:9].[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[N+:14]([O-:16])[CH:15]=1)[CH3:9]
Reactant: O=P(Cl)(Cl)Cl
Agent: CCc1ccc(NC(=O)C(C)(C)C)[n+]([O-])c1
Solvent: CCN(CC)CC
Product: CCc1ccc(NC(=O)C(C)(C)C)nc1Cl
Yield: 5 %

Procedure:
Et3N (123 mL, 93.6 mmol) was added to a solution of 5-ethyl-2-pivalamidopyridine 1-oxide (16.0 g, 72.0 mmol) in POCl3 (250 mL) and the reaction mixture was heated at reflux for 3 days. Excess POCl3 was distilled off and the residue was poured into water. The mixture was neutralized with aqueous NaOH to pH 9. The aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO4 and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (10% EtOAc in petroleum ether) to afford N-(6-chloro-5-ethylpyridin-2-yl)pivalamide (900 mg, 5%) and unreacted 5-ethyl-2-pivalamidopyridine 1-oxide (4.8 g). 1H NMR (CDCl3, 300 MHz) δ 8.12 (d, J=8.7, 1H), 7.94 (br s, 1H), 7.56 (d, J=8.7, 1H), 2.70 (q, J=7.5, 2H), 1.30 (s, 9 H), 1.23 (t, J=7.5, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=2)[C:3]=1[C:14]([NH2:16])=[O:15].C(N(CC)C(C)C)(C)C.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32]>C(Cl)Cl>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][CH:36]=[C:28]([C:27]([F:26])([F:37])[F:38])[CH:29]=3)[CH:8]=2)[C:3]=1[C:14]([NH2:16])=[O:15]
Reactant: NC(=O)c1c(-c2cccc(N)c2)nsc1N
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1c(-c2cccc(NC(=O)c3cccc(C(F)(F)F)c3)c2)nsc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a mixture of 5-amino-3-(3-aminophenyl)isothiazole-4-carboxamide (13 mg, 0.056 mmol) and N,N-diisopropylethylamine (0.029 mL, 0.17 mmol) in 1.0 mL CH2Cl2 at room temperature was added 3-(trifluoromethyl)benzoyl chloride (0.008 mL, 0.056 mmol) and the reaction stirred at room temperature. After 1 hour, additional 3-(trifluoromethyl)benzoyl chloride (0.0015 mL) was added, then again at 2 hours (0.002 mL) and 3 hours (0.0015 mL). After 4 hours the reaction was evaporated, and then treated to an aqueous Na2CO3 and EtOAc workup to yield a light yellow solid. The solid was precipitated from EtOAc/hexane to give the title compound as an off-white solid (16 mg, 68%).
Reaction SMILES: [NH2:1][C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][C:4]1[CH:11]=[C:9]([I:10])[C:8]([O:12][C:13]2[CH:20]=[C:18]([I:19])[C:17]([OH:21])=[C:15]([I:16])[CH:14]=2)=[C:6]([I:7])[CH:5]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].O>C1COCC1.CN(C)C1C=CN=CC=1>[C:25]([O:23][C:22](=[O:24])[C@H:2]([CH2:3][C:4]1[CH:5]=[C:6]([I:7])[C:8]([O:12][C:13]2[CH:14]=[C:15]([I:16])[C:17]([OH:21])=[C:18]([I:19])[CH:20]=2)=[C:9]([I:10])[CH:11]=1)[NH2:1])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OC(=O)[C@@H](N)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Reaction time: 0.75 h
Yield: 115.5 %

Procedure:
The N-FMOC protected L-Thyroxine (26.3 g, 23.2 mmol) was dissolved in 150 mL THF, 3.28 mL (34.8 mmol) of acetic anhydride added, 283 mg (2.32 mmol) of 4-dimethylaminopyridine added, and reaction stirred under N2 for 45 minutes, then poured into 400 mL H2O and extracted with CHCl3 (3×400 mL). The CHCl3 extracts were combined, dried over Na2SO4, and solvent removed in vacuo. The residue was then purified by silica gel column chromatography, eluting with CH2Cl2 /MeOH/HOAc (90/10/0.4, v/v), to yield 21.95 g (91%) of the desired O-acetyl thyroxine as a beige solid; 1H NMR (300 MHz, DMSO-D6) d 7.12-7.91 (m, 12H), 4.07-4.31 (m, 4H), 3.07-3.19 (m, 1H), 2.82 (t, 1H), 2.29-2.40 (m, 3H); mass spec (FAB) (M+H)+ 1042.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:7]=[CH:6][NH:5][C:4]=1[C:8]([NH:10][CH3:11])=[O:9].[C:12]([CH2:15][C:16](=O)[CH3:17])(=O)[CH3:13].[ClH:19]>CO>[Cl-:19].[CH3:1][N+:2]1[C:3]2[N:7]([CH:6]=[N:5][C:4]=2[C:8]([NH:10][CH3:11])=[O:9])[C:12]([CH3:13])=[CH:15][C:16]=1[CH3:17]
Reactant: CNC(=O)c1[nH]cnc1NC
Reactant: Cl
Reactant: CC(=O)CC(C)=O
Solvent: CO
Product: CNC(=O)c1ncn2c(C)cc(C)[n+](C)c12
Product: [Cl-]

Procedure:
Theophyllidine (hydrochloride), 27.0 g (0.142 mol), from step 1, was heated in 1400 ml methanol under reflux for 5 hours with acetylacetone, 28.7 g (0.284 mol), and 20 g concentrated hydrochloric acid. The solvent was then removed on the rotary evaporator and the yellow residue was purified by recrystallization from ethanol/diethyl ether.
Reaction SMILES: [O:1]1[CH2:4][C:3]2([CH2:9][CH:8]3[CH:6]([CH:7]3[C:10]([OH:12])=O)[CH2:5]2)[CH2:2]1.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.[CH3:26][NH:27][O:28][CH3:29]>ClCCl>[CH3:29][O:28][N:27]([CH3:26])[C:10]([CH:7]1[CH:6]2[CH:8]1[CH2:9][C:3]1([CH2:5]2)[CH2:2][O:1][CH2:4]1)=[O:12]
Reactant: O=C(O)C1C2CC3(COC3)CC21
Reactant: CNOC
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: CON(C)C(=O)C1C2CC3(COC3)CC21
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
To a solution of spiro[bicyclo[3.1.0]hexane-3,3′-oxetane]-6-carboxylic acid (0.70 g, 4.2 mmol) in dichloromethane (21 mL) was added carbonyl diimidazole (1.35 g, 8.33 mmol) at 15° C. After 30 min, N,O-dimethylhydroxylamine hydrochloride (487 mg, 4.99 mmol) was added in one portion. After 16 h, the reaction mixture was diluted with dichloromethane (50 mL), and the resulting mixture was washed with saturated aqueous sodium chloride solution (2×20 mL). The collected organic was concentrated, and the resulting residue was purified by flash column chromatography (30% ethyl acetate in petroleum ether) to afford product as a white solid (0.30 g, 34% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][C@H:9]1[C:20](O)=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].CSC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][C@H:9]1[CH2:20][OH:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccccc2)C[C@H]1C(=O)O
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccccc2)C[C@H]1CO
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 124.3 %

Procedure:
To a stirred solution of (2S,4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidinylcarboxylic acid (2.39 g, 7.76 mmol) in THF (50 ml) was added BH3.DMS (1.55 ml, 15.5 mmol) at 0° C. After 10 min. stirring at the same temperature, the mixture was allowed to room temperature and then heated at 50° C. for 2 h. After cooling to room temperature, the mixture was concentrated in vacuo and quenched by the addition of water at 0° C. The mixture was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was chromatographed on silica gel [60 g, CHCl3/MeOH (50/1)] to give (2S,4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidinylmethanol (2.83 g, 100%) as a colorless oil. 1H-NMR (CDCl3) δ1.47 (s, 9H), 1.95 (br, 1H), 2.36 (m, 1H), 3.56-3.74 (m, 3H), 3.89-4.52 (m, 3H), 4.85 (br, 1H), 6.84 (dd, J=8.8, 1.2 Hz, 2H), 6.97 (t, J=7.2 Hz, 1H), 7.29 (t, 2H, J=7.8 Hz).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:6]=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][CH3:26])=[O:24])=[CH:18][CH:17]=2)[N:4]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:26][NH:25][C:23](=[O:24])[NH:22][C:19]1[CH:20]=[CH:21][C:16]([C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]3[CH3:15])[CH:8]=[C:3]([CH2:2][O:1][S:35]([CH3:34])(=[O:37])=[O:36])[N:4]=2)=[CH:17][CH:18]=1
Reactant: CNC(=O)Nc1ccc(-c2nc(CO)cc(N3CCOC[C@@H]3C)n2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1ccc(-c2nc(COS(C)(=O)=O)cc(N3CCOC[C@@H]3C)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-[4-[4-(Hydroxymethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-methyl-urea (1.24 g) was partially dissolved in DCM (30 mL) and triethylamine (0.724 mL) and the solution was cooled to 0° C. Methane sulfonyl chloride was added (0.405 mL) and the reaction was stirred for 15 minutes at RT then concentrated in vacuo to give the desired material.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[NH2:11])=[O:4].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:11][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=1)=[O:4]
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)[C@@H]1CCCC[C@@H]1N
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@@H]1CCCC[C@@H]1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.9 %

Procedure:
(1R,2S)-2-Amino-cyclohexanecarboxylic acid methyl ester (1 g, 6.4 mmol) was dissolved in methanol (70 mL). 4-Fluoro-benzaldehyde (0.794 g, 6.4 mmol) was added followed by acetic acid (1 mL). The solution was stirred at 25° C. for 10 min. Sodium cyanoborohydride (1 g, 16 mmol) was added and the mixture was stirred at 25° C. for 16 h. The mixture was poured into 1/2 saturated aqueous sodium bicarbonate solution (150 mL). The aqueous layer was extracted with ethyl acetate (2×150 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1R,2S)-2-(4-fluoro-benzylamino)-cyclohexanecarboxylic acid methyl ester (0.8 g, 3 mmol, 47%), as a light yellow oil. LC-MS (ESI) calcd for C15H20FNO2 265.15, found 266.2 [M+H+].
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:6]2[S:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([CH3:19])[C:7]=2[N:8]=1.[C:26](O)(=[O:30])[CH:27]([CH3:29])[OH:28]>>[Cl:2][C:3]1[N:4]=[C:5]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:6]2[S:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:26](=[O:30])[C@@H:27]([OH:28])[CH3:29])[CH2:15][CH2:14]3)=[C:9]([CH3:19])[C:7]=2[N:8]=1
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC(O)C(=O)O
Agent: Cl
Product: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12

Procedure:
Tert-butyl 44(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate (777 mg) was subjected to General Procedure E to give the HCl salt of 2-chloro-7-methyl-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine. The HCl salt of 2-chloro-7-methyl-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (590 mg) was reacted with lactic acid via General Procedure B-2 to give (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[C:20]([C:21]([F:24])([F:23])[F:22])=[C:19]([C:25]([OH:27])=O)[CH:18]=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:50][CH2:51][C:52]([N:54]1[CH2:59][CH2:58][N:57]([C:60](=[O:72])[C:61]2[CH:66]=[C:65]([F:67])[CH:64]=[CH:63][C:62]=2[C:68]([F:71])([F:70])[F:69])[CH2:56][CH2:55]1)=[O:53]>CN(C=O)C.O>[F:67][C:65]1[CH:64]=[CH:63][C:62]([C:68]([F:70])([F:69])[F:71])=[C:61]([CH:66]=1)[C:60]([N:57]1[CH2:58][CH2:59][N:54]([C:52](=[O:53])[CH2:51][NH:50][C:25]([C:19]2[CH:18]=[N:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:20]=2[C:21]([F:22])([F:23])[F:24])=[O:27])[CH2:55][CH2:56]1)=[O:72]
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Reactant: O=C(O)c1cnn(-c2ccccc2)c1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1cnn(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 27.9 %

Procedure:
DIPEA (141 mg, 0.19 mL, 1.1 mmol) was added to a stirred solution of 1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (70 mg, 0.27 mmol) in DMF (5 mL). HOBT (40 mg, 0.29 mmol) and EDCI (131 mg, 0.68 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (111 mg, 0.3 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using 60-120 silica gel and 70% EtOAC in hexane as eluent) to afford 43 mg (27.56% yield) of 1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LCMS Purity: 86.39%. 1H NMR (CDCl3): δ 8.0 (s, 1H), 7.8 (t, 1H), 7.56-7.4 (m, 5H), 7.26 (s, 1H), 7.1 (d, 2H), 4.36-4.2 (m, 2H), 4.06-3.84 (m, 1H), 3.8-3.64 (m, 2H), 3.62-3.48 (m, 2H), 3.44 (t, 1H), 3.3-3.2 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([C:18](=[O:22])[C:19](Cl)=[O:20])=[CH:12][NH:13]2.[C:23]1([C:29]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[C:30]([C:33]#[N:34])[C:31]#[N:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([C:18](=[O:22])[C:19]([N:38]1[CH2:37][CH2:36][N:35]([C:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:30]([C:33]#[N:34])[C:31]#[N:32])[CH2:40][CH2:39]1)=[O:20])=[CH:12][NH:13]2
Reactant: N#CC(C#N)=C(c1ccccc1)N1CCNCC1
Reactant: O=C(Cl)C(=O)c1c[nH]c2cccc(F)c12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CC(C#N)=C(c1ccccc1)N1CCN(C(=O)C(=O)c2c[nH]c3cccc(F)c23)CC1
Reaction time: 16 h

Procedure:
Triethyl amine (2 ml) was added into a solution of 2-(4-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride (284 mg) and 2-(phenyl(piperazin-1-yl)methylene)malononitrile (300 mg) in dry THF (20 ml). After 16 hours, the reaction mixture was partitioned between saturated NaHCO3 (20 ml) and EtOAc (20 ml), and the aqueous phase was extracted with EtOAc (3×20 ml). Then the combined organic layer was dried over MgSO4 and concentrated to offer a residue which was purified using Shimadzu automated preparative HPLC System to afford 2-((4-(2-(4-fluoro-1H-indol-3-yl)-2-oxoacetyl)piperazin-1-yl)(phenyl)methylene)malononitrile.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:27])[CH2:10][N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[N:13]=[C:12]1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)C.[OH-].[K+:30]>C(O)C>[OH2:3].[K+:30].[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:12]2[N:11]([CH2:10][C:9]([NH:8][CH2:7][CH2:6][CH2:5][C:4]([O-:28])=[O:3])=[O:27])[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[N:13]=2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)CCCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O
Product: O=C([O-])CCCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 69.9 %

Procedure:
A mixture of 4-[[[2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridin-3-yl]acetyl]amino]butanoic acid ethyl ester (3.3 g, 0.008 mole), potassium hydroxide (0.5 g, 0.009 mole), and 80 ml of 95% ethyl alcohol was heated at reflux for 13/4hours. The hot reaction mixture was filtered, washed with absolute ethanol, and the filtrate was evaporated to a solid residue. The solid was triturated with acetone and filtered. The solid was dissolved in hot tert-butanol and allowed to cool with seeding. The crystalline precipitate was collected by filtration, washed with tert-butyl alcohol and dried under high vacuum at 50° C. overnight to give 1.2 g (35%) of title compound, mp 263°-264° C.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>CCCCCC>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(F)c(F)c1F
Solvent: CCCCCC
Product: O=C(Cl)c1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Yield: 98.6 %

Procedure:
In a 1000 ml three-neck flask with thermometer, reflux condenser, 50 ml dropping funnel, mechanical stirrer, bubble counter, exhaust pipe and oil bath 0.5 ml of dimethylformamide were added with stirring to a suspension of 97.05 g of 2,3,4,5-tetrafluorbenzoic acid (8; 0.5 mol) in 100 ml of n-hexane. In the course of 10 min. 44 ml of thionyl chloride (0.61 mol) were added, and the reaction mixture was heated for 17 hours at reflux temperature. After cooling to room temperature, the n-hexane was evaporated off at 55° C. and increasing vacuum for 30 min. (at the end 3 min. at 55° C./40 torr). 104.8 g of 2,3,4,5-tetrafluoro-benzoic acid chloride (9) were obtained as a yellow, clear liquid, which was directly used in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:3](OS(C(F)(F)F)(=O)=O)=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:23]([O:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1B(O)O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.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>[CH2:23]([O:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[C:3]1[C:2]([CH3:1])=[CH:11][C:10]([N+:12]([O-:14])=[O:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C)c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(F)cc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cc([N+](=O)[O-])cc(C)c1-c1ccc(F)cc1OCc1ccccc1
Yield: 70 %

Procedure:
A mixture of methyl 3-methyl-5-nitro-2-trifluoromethylsulfonyloxybenzoate (Reference Compound No. 1-4-(3), 13.26 g, 38.6 mmol), 2-benzyloxy-4-fluorophenylboronic acid (14.3 g, 58.1 mmol), potassium phosphate (21.3 g, 100 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.23 g, 2.80 mmol) was suspended in anhydrous 1,4-dioxane (200 mL), and then the mixture was refluxed for 3 days. After cooling down, ethyl acetate (500 mL) was added thereto, and then the whole was washed with water (500 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (10.7 g) as a pale brown solid. (Yield 70%)
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40](N)=[N:41][CH:42]=2)O1.[C:45]([O-])([O-])=[O:46].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:6]3[CH2:5][C:4]4[S:3][C:2]([C:37]5[CH:42]=[N:41][C:40]([O:46][CH3:45])=[CH:39][CH:38]=5)=[CH:9][C:8]=4[C:7]=3[N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[N:11]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(OC)nc4)cc2-3)cc1
Temperature: 100 °C
Yield: 60 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.5 g, 0.1 mmol), 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (0.4 g, 1.7 mmol), Na2CO3 (2 M, 2.7 mL), and Pd(PPh3)2Cl2 (100 mg, 0.09 mmol) in toluene/ethanol (1:1, 10 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 6-(4-Methoxy-phenyl)-2-(6-methoxy-pyridin-3-yl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as orange solid in 60% yield.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Br:30])[CH:25]=2)[CH:19]=[CH:18][C:17]=1[S:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1>>[Br:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][O:22][C:20]1[CH:19]=[CH:18][C:17]([S:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:21]=1
Reactant: Nc1cc(OCc2cccc(Br)c2)ccc1Sc1ccc(O)cc1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Product: CCCc1ccc2c(Nc3cc(OCc4cccc(Br)c4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 2g (62 mg, 0.30 mmol) was reacted with 4-[2-Amino-4-(3-bromo-benzyloxy)-phenylsulfanyl]-phenol (120 mg, 0.30 mmol) for 48 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (86 mg, 41%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.73 Hz, 3H) 1.85 (dt, J=7.73 Hz, 2H) 3.00 (dd, J=7.72 Hz, 2H) 5.15 (s, 2H) 6.27 (d, J=7.35 Hz, 1H) 6.66 (d, J=8.82 Hz, 2H) 7.07-7.69 (m, 7H) 7.65 (s, 1H) 7.83 (d, J=8.82 Hz, 1H) 8.41 (d, J=6.99 Hz, 1H) 9.03 (d, J=8.82 Hz, 1H) 9.81 (s, 1H) 11.05 (br s, 1H) 14.43 (br s, 1H); MS (ESI+) m/z 572, 574 (M+H−TFA)+; (ESI−) m/z 570-572 (M−H−TFA)−.
Reaction SMILES: Cl.[NH2:2][C:3](=[NH:15])[C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1.O.[NH2:17]N.[C:19]([NH:22][CH:23]([CH2:31][CH3:32])[C:24](=O)[C:25](OCC)=[O:26])(=[O:21])[CH3:20]>C(O)C>[C:19]([NH:22][CH:23]([C:24]1[C:25](=[O:26])[NH:15][C:3]([C:4]2[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=2)=[N:2][N:17]=1)[CH2:31][CH3:32])(=[O:21])[CH3:20]
Reactant: CCOC(=O)c1ccc(C(=N)N)cc1
Reactant: CCOC(=O)C(=O)C(CC)NC(C)=O
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(-c2nnc(C(CC)NC(C)=O)c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.98 g (8.66 mmol) ethyl 4-[amino(imino)methyl]benzoate hydrochloride are suspended in 50 ml of ethanol and 1.47 g (10.2 mmol, 1.2 equiv.) hydrazine hydrate are added. After stirring at room temperature for 1 hour, 2.59 g (13 mmol, 1.5 equiv.) of the compound of Example 2A, dissolved in 10 ml of ethanol, are added. The reaction mixture is stirred at 80° C. (bath temperature) for 4 hours and then at room temperature over night. The mixture is evaporated to dryness in vacuo and the product is purified by chromatography (flash or column chromatography or preparative HPLC).