Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:32][C:33]1[CH:34]=[C:35]2[C:39](=[C:40]([C:42]([OH:44])=O)[CH:41]=1)[NH:38][CH:37]=[CH:36]2.[C:45]([C:49]1[CH:68]=[CH:67][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:66])([F:65])[F:64])[CH:58]=2)=[C:51]([Cl:69])[CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:68]=[CH:67][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:66])([F:65])[F:64])[CH:58]=2)[C:42]([C:40]2[CH:41]=[C:33]([Cl:32])[CH:34]=[C:35]3[C:39]=2[NH:38][CH:37]=[CH:36]3)=[O:44])=[C:51]([Cl:69])[CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)c(Cl)c1
Temperature: 25 °C
Yield: 83 %

Procedure:
91 mg (0.9 mmol) of N-methyl morpholine and then 170 mg (0.45 mmol) of HBTU were added to 59 mg (0.30 mol) of 5-chloro-1H-indol-7-carboxylic acid and 122 mg (0.33 mmol) of (4-tert-butyl-2-chloro-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine dissolved in 3 ml DMF at rt under nitrogen. The reaction mixture was stirred at rt over night. Water was added and the reaction mixture was extracted twice with EtOAc. The combined organic layers were washed once with 1N aqueous HCl solution, once with saturated aqueous NaHCO3 solution and once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (20 g silica gel; heptane/EtOAc 4:1) to yield 150 mg (91%) product as a yellow viscous oil. MS (ISP) 547.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[NH:5][C:4](=[O:14])[C:3]=1[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OCC)(=O)C>CC(C)=O>[CH2:30]([O:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[NH:5][C:4](=[O:14])[C:3]=1[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CON1CCC2(CC1)NC(=O)C(c1c(C)cc(C)cc1C)=C2O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CON1CCC2(CC1)NC(=O)C(c1c(C)cc(C)cc1C)=C2OCc1ccccc1
Yield: 64.8 %

Procedure:
To a suspension of 4-hydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one [prepared according to WO09/049,851] (67.0 g, 211.7 mmol) in acetone (900 ml) was added potassium carbonate (35.1 g, 254.1 mmol), followed by benzyl bromide (35.3 ml, 50.7 g, 296.4 mmol) dropewise. The suspension was stirred at reflux for one hour, then poured on ice water and ethyl acetate. The resulting precipitate was filtered off, dissolved in methylene chloride, dried over sodium sulfate, concentrated and dried over phosphorus pentoxide under vacuum at 50° C. overnight to afford a first crop of product as a white solid (55.8 g). The layers of the mother liquor were separated, the aqueous phase extracted with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulfate and concentrated. The residue was suspended in diethyl ether, filtered and dried to further deliver 22.6 g of product. Yield: 78.4 g of 4-benzyloxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P3.4) as a solid, mp 184-186° C.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Br:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1>N1C=CC=CC=1>[C:1]([O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([Br:8])[CH:10]=1)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Oc1cccc(Br)c1
Reactant: CCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCC(=O)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pentanoyl chloride (12.7 g) was added dropwise to 3-bromophenol (9.0 g) in pyridine (50 ml), and the reaction mixture was stirred at room temperature for 1 hour. Work-up as described in Example 12 gave 3-bromophenyl pentanoate.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:25]=[CH:24][C:8]([C:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH:17]3[CH2:22][CH2:21][CH2:20][NH:19][C:18]3=[O:23])[CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:6]=1.Cl[CH2:27][C:28]1[NH:29][C:30](=[O:38])[C:31]2[CH2:37][O:36][CH2:35][CH2:34][C:32]=2[N:33]=1>C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([CH2:27][C:28]4[NH:29][C:30](=[O:38])[C:31]5[CH2:37][O:36][CH2:35][CH2:34][C:32]=5[N:33]=4)[C:18]3=[O:23])[CH2:13][CH2:12]2)=[O:10])=[CH:24][CH:25]=1
Reactant: COc1ccc(C(=O)C2CCN(C3CCCNC3=O)CC2)cc1
Reactant: O=c1[nH]c(CCl)nc2c1COCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCN(C3CCCN(Cc4nc5c(c(=O)[nH]4)COCC5)C3=O)CC2)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
To a stirred solution of NaH (23.8 mg, 0.942 mmol, 2.1 eq) in THF (10 mL) were added 4-(4-methoxy-benzoyl)-[1,3′]bipiperidinyl-2′-one (142 mg, 0.449 mmol, 1.0 eq) and 2-chloromethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (90 mg, 0.449 mmol, 1.0 eq). The reaction was let to stir at 70° C. for 3 h. The solid precipitate was filtered off and washed with CH2Cl2. The solvent of the mother liquor was evaporated and the residue purified by flash chromatography on silica gel (0-15% MeOH/CH2Cl2) to afford the title compound as an off-white powder (60 mg, 0.139 mmol, 31.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.34 (br s, 1H) 7.94 (d, J=8.59 Hz, 2H) 7.03 (d, J=8.59 Hz, 2H) 4.14-4.54 (m, 5H) 4.06-4.10 (m, 1H) 3.45 (br s, 1H) 3.18 (d, J=5.05 Hz, 3H) 3.03 (br s, 1H) 2.85 (br s, 2H) 2.30-2.65 (m, 5H) 1.30-2.05 (m, 9H). HR-MS (m/z, MH+): 481.2461, 482.2471. HPLC retention time: 2.78 min (Agilent column 3.0×100 mm 3 um C18 column; flow rate of 1.0 mL/min with gradient from 5% to 95% acetonitrile in 10 min, 0.1% FA)
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]2[O:18][N:17]=[C:16]([CH3:19])[N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C.B(Br)(Br)Br.C(O)C>C(Cl)Cl>[CH3:19][C:16]1[N:15]=[C:14]([C:5]2[CH:4]=[C:3]([OH:2])[C:8]([OH:9])=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[O:18][N:17]=1
Reactant: COc1cc(-c2nc(C)no2)cc([N+](=O)[O-])c1OC
Agent: BrB(Br)Br
Solvent: CCO
Solvent: ClCCl
Product: Cc1noc(-c2cc(O)c(O)c([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.5 g of 5-(3,4-dimethoxy-5-nitrophenyl)-3-methyl-1,2,4-oxadiazole are dissolved in 70 ml of methylene chloride. After cooling to -60° there is added dropwise thereto within 20 minutes while stirring a solution of 23.62 g of boron tribromide in 50 ml of methylene chloride, whereupon the mixture is held at the reflux temperature for 48 hours. After cooling to -60°, the mixture is treated with 60 ml of ethanol and subsequently stirred at room temperature for 30 minutes. The yellow solution is evaporated to dryness, whereupon the residue is treated three times with 100 ml of toluene/ethanol (1:1) each time and the solvent is distilled each time. After crystallization from ethanol, there is obtained 5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-nitropyrocatechol in the form of yellow crystals of m.p. 201°-202°.
Reaction SMILES: Cl.Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH2:27][CH2:28][C@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].C=O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH2:27][CH2:28][C@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][N:30]2[CH3:37])=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nnc(OCC[C@H]2CCCCN2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: C=O
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nnc(OCC[C@H]2CCCCN2C)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 12 h
Yield: 68.1 %

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-((R)-2-piperidin-2-yl-ethoxy)-pyridazine dihydrochloride (0.065 mmol, 0.033 g) and aqueous formaldehyde (37%, 0.323 mmol, 0.03 mL) in dry DCM (2 mL) was added macroporous resin-bound triacetoxyborohydride (loading 2.36 mmol/gram, 0.39 mmol, 0.165 g). The mixture was shaken for 12 hours. The reaction was filtered and the resin was washed with DCM (5 mL). The solvent was removed under reduced pressure. The crude product was purified on a 4 g SiO2 cartridge with 4-6% (2N NH3 in MeOH) in DCM to give 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-[2-((R)-1-methyl-piperidin-2-yl)-ethoxy]-pyridazine (0.02 g, 73%). The neutral amine was treated with 2N HCl in diethyl ether (1 mL) and DCM (1 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.025 g). LCMS: m/z 453 [M+1]. 1H NMR (400 MHz, CD3OD) δ 6.97-7.45 (5H, m), 4.55-4.72 (2H, m), 4.35-4.46 (1H, m), 3.46-3.82 (1H, m), 3.05-3.19 (1H, m), 2.79-3.06 (5H, m), 2.44-2.74 (2H, m), 2.10-2.36 (2H, m), 1.74-2.06 (9H, m), 0.79 (3H, t).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5](C(O)=O)=[N:6][N:7]([C:9]2[C:19]([F:20])=[CH:18][C:12]3[O:13][C:14]([F:17])([F:16])[O:15][C:11]=3[CH:10]=2)[CH:8]=1.C1C=CC(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(CC)CC.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:39][C:5]1[C:4](=[O:24])[C:3]([O:2][CH3:1])=[CH:8][N:7]([C:9]2[C:19]([F:20])=[CH:18][C:12]3[O:13][C:14]([F:17])([F:16])[O:15][C:11]=3[CH:10]=2)[N:6]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1cn(-c2cc3c(cc2F)OC(F)(F)O3)nc(C(=O)O)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cn(-c2cc3c(cc2F)OC(F)(F)O3)nc(N)c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
A mixture of 5-methoxy-4-oxo-1-(2,2,6-trifluoro-1,3-benzodioxol-5-yl)-1,4-dihydropyridazine-3-carboxylic acid (1.18 g, 3.42 mmol), DPPA (1.10 mL, 5.13 mmol) and Et3N (0.715 mL, 5.13 mmol) in toluene (12 mL) was heated to 100° C. for 1 h. To the mixture was added 8 M NaOH aqueous solution (4.3 mL) at 0° C. The mixture was stirred at room temperature for 1 h, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on basic silica gel (hexane/EtOAc=50/50 to 0/100) and recrystallized with EtOAc/hexane to yield the title compound (704 mg, 65% yield) as a white solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 173 (3H, s), 6.21 (2H, s), 7.85 (1H, d, J=9.4 Hz), 7.90 (1H, d, J=6.4 Hz), 8.33 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:7][C@H:6]1[C:8]([O:10]C)=[O:9])=[O:4].Cl>P([O-])([O-])([O-])=O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:7][C@H:6]1[C:8]([OH:10])=[O:9])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H]1C(=O)OC
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Product: COC(=O)[C@@H]1C[C@H]1C(=O)O
Reaction time: 0.08 h
Yield: 93.2 %

Procedure:
Suspend trans-cyclopropane-1,2-dicarboxylic acid dimethylester (59.8 g, 0.378 mol) is suspended in 1.0N phosphate buffer (1.5 L, pH=7) add pig liver esterase (2.25 mL, 7500 units), and monitor NaOH consumption with a pH meter to control the reaction. After 3 h the consumption of 189 mL of 2N NaOH indicates the complete hydrolysis of the diester to the monomethylester. Acidified the clear solution by the addition of 5N HCl to a pH=1. Separate the enzyme by addition of dichloromethane (500 mL) and diatomaceous earth (25 g). Stir for 5 min, and then filter the mixture. Saturate the filtrate with NaCl, and extract with ethyl acetate (5 times). Combine the extracts, dry (Na2SO4) and evaporate to obtain 50.8 g (93%) of solid, mp 46-47° C., m/z=145 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([OH:22])=[CH:7][C:8]([C:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1.[BrH:33].[S:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][C:43](O)=[O:44])[CH2:36][CH2:35]1.C1(N=C=NC2CCCCC2)CCCCC1>>[BrH:33].[CH3:32][C:2]1([CH3:1])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([O:22][C:43](=[O:44])[CH2:42][CH2:41][CH2:40][N:37]3[CH2:36][CH2:35][S:34][CH2:39][CH2:38]3)=[CH:7][C:8]([C:10]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCSCC1
Reactant: C#CCN1CCC2=C(C1)c1c(O)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: C#CCN1CCC2=C(C1)c1c(OC(=O)CCCN3CCSCC3)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C

Procedure:
Equimolar amounts of 5,5-dimethyl-10-hydroxy-8-(4-fluorophenyl-1-methylbutyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5H[1]benzopyrano[3,4-d]pyridine, γ-thiomorpholinobutyric acid hydrobromide and dicyclohexylcarbodiimide are reacted to form the desired product.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1B(O)O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Br)o1
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc(-c2cccs2)o1
Reaction time: 26 h
Yield: 90.8 %

Procedure:
Methyl 5-bromofuran-2-carboxylate (150 mg, 0.73 mmol), Pd(PPh3)4 (42 mg, 0.04 mmol), 2M Na2CO3 (0.73 ml, 1.46 mmol) and thiophen-2-ylboronic acid (121 mg, 0.95 mmol) in 1,4-dioxanes (7 ml) and was warmed to 90° C. The solution was then held at this temperature for 26 hours then cooled and washed with 1M HCl (2×20 mL), brine (2×20 mL) then dried (MgSO4) followed by filtration and evaporation to dryness. The resulting residue was then purified by flash column chromatography (5% EtOAc/hexanes) to obtain methyl 5-(thiophen-2-yl)furan-2-carboxylate (138 mg, 91%) as a yellow oil. 1H NMR (500 MHz, DMSO-d6) δ 7.69 (dt, J=5.0, 0.9 Hz, 1H), 7.59 (dt, J=3.6, 0.8 Hz, 1H), 7.40 (dd, J=3.7, 0.6 Hz, 1H), 7.23-7.15 (m, 1H), 6.99 (d, J=3.7 Hz, 1H), 3.83 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 158.1, 152.5, 142.3, 131.2, 128.5, 127.7, 125.8, 120.7, 107.5, 51.8; HRMS (ESI) calcd for [C10H8O3S+H]+209.0267. found 209.0272. Method D with methyl 5-(thiophen-2-yl)furan-2-carboxylate (100 mg, 0.48 mmol) afforded 5-(thiophen-2-yl)furan-2-carboxylic acid (92 mg, 99%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 13.16 (bs, 1H), 7.68 (dd, J=5.0, 1.1 Hz, 1H), 7.56 (dd, J=3.6, 1.1 Hz, 1H), 7.30 (d, J=3.6 Hz, 1H), 7.18 (dd, J=5.0, 3.7 Hz, 1H), 6.95 (d, J=3.6 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 159.1, 152.0, 143.5, 131.5, 128.5, 127.4, 125.5, 120.0, 107.4; HRMS (ESI) calcd for [C9H6O3S+H]+195.0110. found 195.0112. Method B with 5-(thiophen-2-yl)furan-2-carboxylic acid (75 mg, 0.39 mmol) afforded the title compound VPC16b1145 (46 mg, 37%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.69 (bs, 1H), 8.72 (s, 1H), 7.81 (d, J=3.8 Hz, 1H), 7.73 (t, J=4.4 Hz, 2H), 7.22 (dd, J=4.9, 3.7 Hz, 1H), 7.07 (d, J=3.8 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 162.2, 156.0, 153.2, 143.2, 142.5, 141.9, 131.1, 128.4, 128.1, 126.5, 120.7, 107.8; HRMS (ESI) calcd for [C12H7N3O4S2+H]+321.9951. found 321.9963.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[OH:15][CH2:16][CH2:17][S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([S:18]([CH2:17][CH2:16][OH:15])(=[O:20])=[O:19])=[CH:29][CH:28]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)CCO)cc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)CCO)cc1

Procedure:
5 g of 4-fluorobenzonitrile was used in Procedure Q with 2-mercaptoethanol to afford 4-(2-hydroxyethylthio)benzonitrile. 900 mg of 4-(2-hydroxyethylthio)benzonitrile was reacted via Procedure T to give 4-(2-hydroxyethylthio)benzoic acid. 1.0 g of 4-(2-hydroxyethylthio)benzoic acid was reacted via Procedure R to give 4-(2-hydroxyethylsulfonyl)benzoic acid. 80 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-hydroxyethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxyethylsulfonyl)benzamide. MS (Q1) 417.0 (M)+.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[O:6][CH:7]=[CH:8][C:9]=1[SH:10].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CO.Cl.CCCCCC>[CH2:11]([S:10][C:9]1[CH:8]=[CH:7][O:6][C:5]=1[CH3:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1occc1S
Reactant: BrCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCCCCC
Product: Cc1occc1SCc1ccccc1
Temperature: 25 °C

Procedure:
Into a 25 ml round bottom flask equpped with magnetic stirrer, thermometer, reflux condenser and heating mantle is placed a solution containing 0.27 g (0.005 moles) of sodium methoxide in 3 ml of absolute methanol. With stirring and while maintaining the temperature at 25° C-30° C, 0.57 g (0.005 moles) of 2-methyl-3-furan thiol in 3 ml absolute methanol is added. The reaction mass is stirred for a period of 10 minutes. 0.86 g of benzyl bromide dissolved in 2 ml absolute methanol is then added to the reaction mass with stirring at 25° C. The reaction mass is heated to reflux (50° C-60° C) and maintained at this temperature with stirring for a period of 4 hours. The reaction mass is then allowed to cool down to room temperature and is admixed with 10 ml of water with stirring. The reaction mass is neutralized to a pH of 5-6 with one drop of 10% hydrochloric acid and 5 ml hexane is added with stirring. The mass is then transferred to a separatory funnel and the organic and aqueous phases are separated. The aqueous phase is diluted with 5 ml water and extracted with 7 ml of n-hexne. The hexane extracts are combined, washed with 5 ml saturated sodium chloride, dried over anhydrous sodium sulfate, and gravity filtered. The resulting solution is then concentrated to an amber oil using rotary evaporation under a water aspirator vacuum. NMR, IR and Mass Spectral analyses confirm that the major product isolated by GLC trapping has the structure: ##STR32##
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:5]=[C:6]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].[Cl:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=1)[CH:22]=[CH:23][C:24](O)=[O:25].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:24]([NH:1][C@H:2]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:5]=2)[CH3:3])=[O:25])[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)C=Cc1cccc(Cl)c1
Reactant: C[C@H](N)c1cccc(NCc2cccnc2)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)C=Cc1cccc(Cl)c1)c1cccc(NCc2cccnc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.1 %

Procedure:
A mixture of (s)-[3-(1-amino-ethyl)-phenyl]-pyridin-3-ylmethyl-amine (0.2 mmol), 3-chlorocinnamic acid (0.2 mmol), EDACeHCl (0.4 mmol), DMAP (0.2 mmol), triethylamine (0.6 mmol) in dichloromethane (4 mL) was stirred at 5 room temperature for 12 h. The reaction mixture was purified by flash chromatography eluting with 5% methnol in ethyl acetate to provide the desired title compound (51 mg) as a solid.
Reaction SMILES: CC1N=CC=CC=1C(N)=O.[C:11]([C:15]1[N:20]=[C:19]([O:21][CH3:22])[C:18]([CH:23]([NH2:25])[CH3:24])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[C:26]([C:28]1[C:33]2[N:34]([CH2:37][C:38](O)=[O:39])[CH:35]=[N:36][C:32]=2[CH:31]=[CH:30][CH:29]=1)#[N:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:11]([C:15]1[N:20]=[C:19]([O:21][CH3:22])[C:18]([CH:23]([NH:25][C:38](=[O:39])[CH2:37][N:34]2[C:33]3[C:28]([C:26]#[N:27])=[CH:29][CH:30]=[CH:31][C:32]=3[N:36]=[CH:35]2)[CH3:24])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Reactant: COc1nc(C(C)(C)C)ccc1C(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ncccc1C(N)=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(C(C)(C)C)ccc1C(C)NC(=O)Cn1cnc2cccc(C#N)c21

Procedure:
The title compound was synthesized according to the procedure described for the synthesis of 2-methylnicotinamide, starting from [1-(6-tert-butyl-2-methoxypyridin-3-yl)ethyl]amine (intermediate 27) (85 mg, 0.48 mmol), 7-cyanobenzimidazole-1-acetic acid (96 mg 0.48 mmol) HATU (173 mg, 0.5 mmol) and DIPEA (209 μl, 1.20 mmol). The product was recovered by filtration following precipitation induced by the addition of water. (Yield 27 mg, 46%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.27 (s, 9 H), 1.32 (d, J=6.84 Hz, 3 H), 3.86 (s, 3 H), 5.02 (t, J=7.03 Hz, 1 H), 5.25 (d, J=4.69 Hz, 2 H), 6.91 (d, J=7.62 Hz, 1 H), 7.31-7.37 (m, 1 H), 7.62 (dd, J=7.62, 0.39 Hz, 1 H), 7.71 (dd, J=7.71, 1.07 Hz, 1 H), 8.01 (dd, J=8.20, 0.98 Hz, 1 H), 8.34 (s, 1 H), 8.78-8.83 (m, J=7.81 Hz, 1 H). MS [MH+] cal. 392.2086 found 392.3.
Reaction SMILES: C1(=O)CCC([C:7]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)CC1.[C:27]([NH:29][C:30]([NH2:32])=[NH:31])#[N:28]>C(OCCOCCO)C>[NH2:31][C:30]1[N:29]=[C:27]([NH2:28])[C:8]2[CH2:9][CH:10]([CH:17]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([F:16])([F:15])[F:14])[CH:7]=3)[CH2:11][CH2:12][C:7]=2[N:32]=1
Reactant: N#CNC(=N)N
Reactant: O=C1CCC(c2c(COCc3ccccc3)cccc2C(F)(F)F)CC1
Solvent: CCOCCOCCO
Product: Nc1nc(N)c2c(n1)CCC(C(OCc1ccccc1)c1cccc(C(F)(F)F)c1)C2

Procedure:
This compound is prepared in a manner analogous to that of Example 1, using 4.7 grams (0.013 mole) of phenylmethyl [(cyclohexanon-4-yl)(3-trifluoromethylphenyl)]methyl ether and 1.2 grams (0.014 mole) of cyanoguanidine in 2-(2-ethoxyethoxy)ethanol, yielding 2,4-diamino-6-[(phenylmethoxy)(3-trifluoromethylphenyl)methyl]-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH:10]=2)=[CH:4][CH:3]=1.[CH:28]([Mg]Cl)([CH3:30])[CH3:29].O>O1CCCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH:28]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:20])[CH3:21])[CH:10]=2)=[CH:4][CH:3]=1)([CH3:30])[CH3:29]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(Cl)nc2)c2cccnc21
Reactant: CC(C)[Mg]Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ccc(Cc2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)cn1
Temperature: 20 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
To 3-(6-Chloro-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (6, 54.0 mg, 0.000135 mol, prepared as described in Example 2) in Tetrahydrofuran (4.0 mL) were added [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (23.0 mg) and Isopropylmagnesium Chloride (0.15 mL, 2.0 M in Tetrahydrofuran). The reaction was stirred at 20° C. under an atmosphere of Nitrogen for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 10% methanol in dichloromethane to give compound 39 (38 mg, 70.4%).