Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7]CC)=[O:6])=[C:2]=[O:3].Cl.O1CCOCC1.[CH3:17][C:18]1([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19]1.[OH-].[Na+]>ClCCl.CO>[CH3:17][C:18]1([O:23][C:2]([NH:1][CH2:4][C:5]([OH:7])=[O:6])=[O:3])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)CN=C=O
Reactant: CC1(O)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CC1(OC(=O)NCC(=O)O)CCCC1
Reaction time: 0.5 h

Procedure:
500 mg (3.87 mmol) of ethyl isocyanatoacetate was dissolved in 5 ml of dichloromethane. 0.05 ml of 4 N hydrochloric acid/1,4-dioxane solution was added to the obtained solution. 465 mg (4.64 mmol) of 1-methylcyclopentanol was added to the resultant mixture, and they were stirred for 3 hours 30 minutes. 10 ml of methanol and 12 ml of 1 N aqueous sodium hydroxide solution were added thereto and they were stirred for 15 minutes. The organic solvent was evaporated under reduced pressure. After extracting with dichloromethane twice, the aqueous layer was neutralized with 1 N aqueous hydrochloric acid solution. The product was extracted with dichloromethane 3 times and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound. The product was subjected to the next reaction without any purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH2:26][O:27][C:28]4[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:29]=4[CH:30]=3)(=[O:24])=[O:23])[CH2:18][C:17]2=[O:36])([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C.CO>[Cl:35][C:33]1[CH:32]=[CH:31][C:29]2[CH:30]=[C:25]([S:22]([N:19]3[CH2:20][CH2:21][N:16]([CH2:15][C:11]4([OH:14])[CH2:12][CH2:13][N:8]([C:11]5[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=5)[CH2:9][CH2:10]4)[C:17](=[O:36])[CH2:18]3)(=[O:23])=[O:24])[CH2:26][O:27][C:28]=2[CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CN(S(=O)(=O)C2=Cc3ccc(Cl)cc3OC2)CCN1CC1(O)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
To 1-[1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-ylmethyl]-4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-piperazinone (150 mg) were added 4N hydrochloric acid in ethyl acetate (8 ml) and methanol (4 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, and to the residue were added 4-chloropyridine hydrochloride (81 mg), triethylamine (81 mg) and ethanol (20 ml). The mixture was allowed to react in a sealed tube at 150° C. for 15 hours. The reaction solution was concentrated, and the residue was purified with silica gel column chromatography (dichloromethane:methanol containing 10% ammonia solution=10:1) to give colorless solid of the title compound (63 mg).
Reaction SMILES: [C:1]([CH2:4][C:5]1([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([N:19]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=3)[C:20]([C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)=[O:21])[CH2:15][CH2:14]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)(=O)[NH2:2].C(N(CC)CC)C.CS(Cl)(=O)=O.O>ClCCl>[C:1]([CH2:4][C:5]1([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([N:19]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=3)[C:20]([C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)=[O:21])[CH2:15][CH2:14]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)#[N:2]
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(N)=O)CCCCC3)CC2)nc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC#N)CCCCC3)CC2)nc1
Reaction time: 24 h
Yield: 89.9 %

Procedure:
To a solution of N-[1-[2-[1-(carbamoylmethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide (154 mg) dissolved in dichloromethane (3 mL) was added triethylamine (0.10 mL). Methanesulfonyl chloride (0.038 mL) was added to the solution under ice cooling. After allowing the temperature to rise to room temperature, the solution was stirred for 24 hours. Triethylamine (0.14 mL) and methanesulfonyl chloride (0.063 mL) were further added to the solution under ice cooling. The solution was stirred at room temperature for 24 hours. Water was added to he solution and it was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The resulting residue was purified by chromatography (silica gel, chloroform:methanol=20:1) to give the title compound (133 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:23])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][S:19][CH2:20][CH2:21]O)[CH2:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.CS([Cl:28])(=O)=O.N1C=CC=CC=1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:23])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][S:19][CH2:20][CH2:21][Cl:28])[CH2:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](CSCCO)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](CSCCCl)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 645 mg (corresponds to 1.65 mmol) of trans-[4-(2-Hydroxy-ethylsulfanylmethyl)-cyclohexyl]-methyl-carbamic acid 4-chloro-phenyl ester in 12 ml CH2Cl2 was treated at 0° C. with 0.14 ml (1.82 mmol) methanesulfonylchloride, 0.20 ml (2.45 mmol) pyridine and 202 mg (1.65 mmol) DMAP. The reaction mixture was warmed up over night to room temperature. Water (2 ml) was added and the reaction was stirred for 5 min. After extraction with aqueous 10% KHSO4/Et2O (3×), the organic phases were washed with aqueous saturated NaHCO3 (2×), aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 650 mg (quantitative) trans-[4-(2-Chloro-ethylsulfanylmethyl)-cyclohexyl]-methyl-carbamic acid 4-chloro-phenyl ester, MS: 376 (MH+, 2Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C@H:23]([N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)[CH3:24])[CH:19]=[N:20][C:21]=3[F:22])[CH:10]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:21]1[C:16]([C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:7][C:6]3[CH:47]=[CH:48][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:38][C:39]3[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=3)[CH:10]=2)=[CH:17][C:18]([C@H:23]([N:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]2)[CH3:24])=[CH:19][N:20]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)nc(C)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCNCC4)cnc3F)nc(C)n2)cc1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
A mixture of tert-butyl 4-((1R)-1-(5-(6-(bis(4-methoxybenzyl)amino)-2-methyl-4-pyrimidinyl)-6-fluoro-3-pyridinyl)ethyl)-1-piperazinecarboxylate (0.57 g, 0.87 mmol) in CH2Cl2 (4.3 mL) at 0° C. was treated with TFA (1.29 mL, 17.36 mmol). The reaction mixture was allowed to warm up to RT. After 90 minutes the reaction mixture was concentrated and the residue was dissolved in CH2Cl2 and saturated NaHCO3 (aq.). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give 6-(2-fluoro-5-((1R)-1-(1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.41 g, 0.74 mmol, 85% yield). m/z (ESI, +ve) 557.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.41 (dd, J=9.29, 2.45 Hz, 1H); 8.14-8.18 (m, 1H); 7.18 (d, J=7.43 Hz, 4H); 6.86 (d, J=8.61 Hz, 4H); 6.83 (br. s, 1H); 4.74 (br. s., 4H); 3.79 (s, 6H); 3.57 (q, J=6.78 Hz, 1H); 2.96 (m, 4H); 2.62 (s, 3H); 2.57 (br. s., 2H); 2.44-2.51 (m, 2H); 1.40 (d, J=6.85 Hz, 3H).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[N:10]=[C:11]3[CH:20]=[CH:19][C:18]4([CH2:24][CH:17]4[N:12]3[C:13](=[O:16])[C:14]=2[CH3:15])[C:21]([OH:23])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[C:27]([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[N:10]=[C:11]3[CH:20]=[CH:19][C:18]4([CH2:24][CH:17]4[N:12]3[C:13](=[O:16])[C:14]=2[CH3:15])[C:21]([O:23][CH3:27])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1c(/C=C/c2ccccc2)nc2n(c1=O)C1CC1(C(=O)O)C=C2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C12C=Cc3nc(/C=C/c4ccccc4)c(C)c(=O)n3C1C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
2-trans-(2-phenyl-ethenyl)-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid (0.8 g) was reacted with methyl iodide (0.55 g) and anhydrous K2CO3 (0.65 g) in dimethylformamide (7 ml) under stirring at room temperature for 4 hours. After dilution with ice water the precipitate was filtered off: crystallization from acetone gave 0.5 g of 2-trans-(2-phenyl-ethenyl)-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid, methyl ester, m.p. 164°-165° C.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([OH:15])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[CH3:39][NH:40][O:41][CH3:42].C(N(CC)CC)C>C(Cl)Cl>[CH3:42][O:41][N:40]([CH3:39])[C:13]([C@@H:10]1[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:9]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)O)C1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C

Procedure:
In a 500 mL round-bottomed flask under a positive pressure of nitrogen, was added a methylene chloride (125 mL) solution of (R)—N-Boc-pyrroldine-3-carboxylic acid (7.00 g, 0.0325 mol). This solution was cooled to 0° C. using an ice/water bath and treated sequentially with, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (7.48 g, 0.0390 mol) and 1-hydroxybenzotriazole (5.29 g, 0.0391 mol) in single portions. Following the addition of the coupling agents, the reaction mixture became cloudy, but upon further stirring a clear solution was obtained. The reaction mixture was stirred at 0° C. for 20 min then charged with N,O-dimethylhydroxylamine hydrochloride (4.78 g, 0.0490 mol) and triethylamine (13.5 mL, 0.0968 mol). The cooling bath was removed and the reaction mixture was allowed to warm to room temperature with stirring over a period of 1 h. The resulting solution was diluted with dichloromethane (600 mL) and 1 N HCl (1000 mL), mixed thoroughly and separated. The organic layer was washed with saturated aqueous sodium bicarbonate (300 mL) and saturated aqueous sodium chloride (300 mL), then dried over Na2SO4, filtered and concentrated to give tert-butyl (3R)-3-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate as a colorless oil (7.00 g; 83%). 1H NMR (400 MHz, CDCl3) δ 3.73 (s, 3H), 3.60-3.37 (m, 4H), 3.21 (s, 3H), 2.35-2.09 (m, 3H) 1.47 (s, 9H); ESI MS found for C12H22N2O4 m/z [159.1 (M+1-Boc)]
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[CH3:23])=[CH:9][C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)=[C:4]([CH3:24])[CH:3]=1.C([Li])CCC.[CH:30](OCC)=[O:31]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[CH3:23])=[C:9]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:30]=[O:31])=[C:4]([CH3:24])[CH:3]=1
Reactant: CCOC=O
Reactant: Cc1cc(F)ccc1C(=Cc1nnnn1C)c1ccc(F)cc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1C(=C(C=O)c1nnnn1C)c1ccc(F)cc1C
Reaction time: 0.25 h
Yield: 56.4 %

Procedure:
To a solution of 1,1-bis(4-fluoro-2-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene (1.6 g, 5.0 mmoles) in tetrahydrofuran at -70° C. was added butyl lithium (2.3 mL of 2.2 M solution, 5.0 mmoles). After stirring for 0.25 hour, ethyl formate (0.44 g, 6.0 mmoles) was added and the mixture stirred for 2 hours. The reaction was quenched with 1N hydrochloric acid and the mixture was extracted with methylene chloride. The extracts were dried and concentrated in vacuo to give 1.0 g of the title compound; m.p.=135°-136° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[O:11]([CH2:18][C:19]1[O:20][C:21]2[CH2:22][NH:23][CH2:24][CH2:25][C:26]=2[N:27]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:24][CH2:25][C:26]3[N:27]=[C:19]([CH2:18][O:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[O:20][C:21]=3[CH2:22]2)=[O:7])=[CH:4][CH:3]=1
Reactant: c1ccc(OCc2nc3c(o2)CNCC3)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)N1CCc2nc(COc3ccccc3)oc2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.2 %

Procedure:
4-Fluorobenzoyl chloride (0.25 mL, 2.12 mmol) was added dropwise to a stirred solution of 4,5,6,7-tetrahydro-2-(phenoxymethyl)-oxazolo[5,4-c]pyridine (0.37 g, 1.63 mmol) and TEA (0.34 mL, 2.44 mmol) in DCM (8.15 mL) at 0° C. The reaction mixture was stirred at room temperature for 15 minutes and then diluted with a saturated solution of NaHCO3. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 30/70). The desired fractions were collected and the solvents evaporated in vacuo. The crude product was triturated with heptane to yield 5-(4-fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-oxazolo[5,4-c]pyridine (0.38 g, 67% yield) as a white solid. C20H17FN2O3. 1H NMR (400 MHz, CDCl3) δ ppm 2.73 (br. s., 2 H), 3.69 (br. s., 1.4 H), 3.99 (br. s., 0.6 H), 4.57 (br. s., 0.6 H), 4.78 (br. s., 1.4 H), 5.12 (br. s., 2 H), 7.02 (d, J=7.4 Hz, 3 H), 7.14 (t, J=8.6 Hz, 2 H), 7.31 (t, J=7.7 Hz, 2 H), 7.43-7.51 (m, 2 H).
Reaction SMILES: S1C=CC(C2N3N=C(N)N=C3C=CC=2)=C1.Br[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([N:23]=[C:24]([NH:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]=2)[CH:22]=1.[OH:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>>[OH:35][C:36]1[CH:41]=[C:40]([C:17]2[CH:18]=[CH:19][C:20]3[N:21]([N:23]=[C:24]([NH:26][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:25]=3)[CH:22]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: O=C(Nc1nc2ccc(Br)cn2n1)c1ccccc1
Agent: Nc1nc2cccc(-c3ccsc3)n2n1
Product: O=C(Nc1nc2ccc(-c3cccc(O)c3)cn2n1)c1ccccc1
Yield: 12 %

Procedure:
The title compound was prepared following procedure described for intermediate A1, step a), but starting from N-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B5), 75 mg; 0.24 mmol; 1.0 eq.) and 3-hydroxyphenylboronic acid (65 mg; 0.47 mmol; 2.0 eq.). Purification by flash chromatography on silica (EtOAc/c-Hex, gradient from 50:50 to 100:0) gave the title compound as a brown solid (9.5 mg, 12%). HPLC, Rt: 2.59 min. (purity 91.6%). LC/MS, M+(ESI): 331.1, M−(ESI): 329.1.
Reaction SMILES: [O:1]([C:8]([CH2:10][CH:11]([NH:13][C:14]([NH2:16])=[O:15])[CH3:12])=[O:9])C1C=CC=CC=1.OCC[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O1CCO[CH2:30][CH2:29]1>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[CH:29]([C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][O:9][C:8]([CH2:10][CH:11]([NH:13][C:14]([NH2:16])=[O:15])[CH3:12])=[O:1])=[CH:27][CH:26]=1)=[CH2:30]
Reactant: OCCC=Cc1ccccc1
Reactant: C1COCCO1
Reactant: CC(CC(=O)Oc1ccccc1)NC(N)=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Product: C=Cc1ccc(CCOC(=O)CC(C)NC(N)=O)cc1
Yield: 40 %

Procedure:
Phenoxycarbonylpropyleneurea 8.2 g (37.3 mmol) and hydroxyethylstyrene 5 g (37.3 mmol) were dissolved into dioxane 90 ml by heating. Into the solution obtained was added dibutyltin dilaurate 0.5 g, and the mixture was heated for 6 hours with stirring. After the reaction the solution was concentrated to give a solid mass, which was then purified by column chromatography. The title compound 3.9 g (yield: 40%) was obtained, which was analyzed to:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:10][CH:11]=1)=[O:16]
Reactant: NCCc1cccs1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCc1cccs1)c1ccc(-c2ccccc2)cc1
Yield: 54.8 %

Procedure:
Reaction of 2-thiopheneethylamine (50 μL, 0.42 mmol) in THF (2.5 mL) with 4-biphenylcarbonyl chloride (120 mg, 0.55 mmol) in presence of triethylamine (78 μL, 0.55 mmol) according to method A gave biphenyl-4-carboxylic acid (2-thiophen-2-yl-ethyl)-amide (70 mg, 0.23 mmol, 55% yield) as a grey powder after crystallisation in hexane/EtOAc.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH:8]2[CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[CH2:9][N:10]([C:21](=[O:23])[CH3:22])[CH2:11]2)=[CH:12][CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: Brc1ccc(OCC2CNC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)N1CC(COc2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of 3-[(4-bromophenoxy)methyl]azetidine (220 mg, 0.91 mmol) in CH2Cl2 (10 mL) was added triethylamine (276 mg, 2.73 mmol) and acetic anhydride (186 mg, 1.82 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give a yellow oil. The crude product was diluted with ethyl acetate (20 ml), washed with 1N HCl followed by saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, and concentrated to give 1-{3-[(4-bromophenoxy)methyl]azetidin-1-yl}ethanone (233 mg, 100%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.38 (d, 2H), 6.78 (d, 2H), 4.28 (m, 1H), 4.24-4.00 (m, 4H), 3.87 (m, 1H), 3.07 (m, 1H), 1.90 (s, 3H)
Reaction SMILES: [S:1]1[C:5]2=[N:6][C:7]([C:14]([O:16]C)=[O:15])=[C:8]([C:10]([O:12]C)=[O:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[OH-].[K+].O>CO>[S:1]1[C:5]2=[N:6][C:7]([C:14]([OH:16])=[O:15])=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: COC(=O)c1cc2ccsc2nc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2ccsc2nc1C(=O)O

Procedure:
A solution containing dimethyl thieno[2,3-b]pyridine-5,6-dicarboxylate (27.75 g, 0.11 mol) and potassium hydroxide (30.98 g, 0.55 mol) in methanol (200 mL) under a N2 atmosphere is heated at reflux for two hours. The reaction mixture is cooled and sufficient water added to dissolve any solids present before evaporating the mixture to dryness. The resulting solid is dissolved in a minimum volume of water, cooled in an ice bath and acidified with concentrated H2SO4 to pH~1. Thieno[2,3-b]pyridine-5,6-dicarboxylic acid is filtered off and dried overnight to give 23.36 g mp 272°-275° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[NH4+].[OH-].[CH3:21]O>C1COCC1.O.ClCCl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:21])=[O:12])=[CH:6][CH:7]=1
Reactant: Nc1ccc(CCCC(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)CCCc1ccc(N)cc1
Temperature: 60 °C
Yield: 96 %

Procedure:
A 250-mL round bottom flask was charged with 4-(4-aminophenyl)butyric acid (2.00 g, 11.2 mmol) in methanol (50 mL) and treated with conc. sulfuric acid (1 mL). The resultant mixture was heated to reflux for 1.5 h. After this time, methanol (˜25 mL) was distilled off. The reaction was cooled to 60° C. and methyl tert-butyl ether was added. The mixture was allowed to slowly cool to room temperature, then diluted with hexanes (50 mL) to afford a white solid. The solid was dissolved in THF (6 mL)/water (4 mL) and treated with conc. NH4OH (6 mL). The mixture was diluted with dichloromethane (50 mL) and the layers separated. The organic layer was washed with saturated sodium chloride (5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (2.07 g, 96%) as a brown solid. MW=193.24. 1H NMR (DMSO-d6, 500 MHz) δ 6.83-6.79 (m, 2H), 6.50-6.46 (m, 2H), 4.81 (s, 2H), 3.57 (s, 3H), 2.39 (t, J=7.5 Hz, 2H), 2.25 (t, J=7.5 Hz, 2H), 1.73 (quin, J=7.5 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:24][S:25]([CH2:28][C:29](O)=[O:30])(=[O:27])=[O:26].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:24][S:25]([CH2:28][C:29]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1)=[O:30])(=[O:27])=[O:26]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: CS(=O)(=O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Yield: 62.7 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.323 mmol), (methylsulfonyl)acetic acid (67 mg, 0.485 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (99 mg, 0.517 mmol), 1-hydroxybenzotriazole (71 mg, 0.522 mmol), triethylamine (0.08 mL, 0.549 mmol) and N,N-dimethylformamide (4.0 mL), and by a reaction in the same manner as in Example 187, the title compound (87 mg, 63%) was obtained as pale-yellow crystals.
Reaction SMILES: [C:1]([N:4]([C:8]1[C:9]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:23][C:10]=2[O:11][C:12]=1[C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])C(=O)C)(=[O:3])[CH3:2].[OH-].[Na+].C(OCC)(=O)C.CCCCCC>C1COCC1.C(OCC)(=O)C>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:13]([C:12]1[O:11][C:10]2[CH:23]=[C:24]3[C:29](=[CH:30][C:9]=2[C:8]=1[NH:4][C:1](=[O:3])[CH3:2])[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:22]
Reactant: CC(=O)N(C(C)=O)c1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc3c(cc12)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc3c(cc12)CCCC3
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of N-acetyl-N-[2-(2,4-dichlorobenzoyl)-5,6,7,8-tetrahydronaphtho[2,3-b]furan-3-yl]-acetamide (40 mg, 0.09 mmol) in anhydrous THF (1.8 mL) was added 2N sodium hydroxide solution (1.8 mL), and the reaction mixture was stirred at 100° C. for 1 h. The reaction was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, water, and brine. The organic layer was then dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified on the MPLC (Biotage) eluted with 5% ethyl acetate-hexane to afford 24.5 mg (67.6%) as yellow foam. 1H-NMR (DMSO-d6) δ 10.22 (s, 1H), 7.79 (t, J=1.2 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J=0.9 Hz, 2H), 7.30 (s, 1H), 2.84 to 2.79 (m, 4H), 2.06 (s, 3H), 1.74 to 1.72 (m, 4H); LC-MS (ES MH+=402); Rf=0.68 (25% ethyl acetate-hexane).