Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:35])[CH2:21][CH2:20]2)=[O:18])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.C1(N=C=NC2CCCCC2)CCCCC1.FC1C(O)=C(F)C(F)=C(F)C=1F.[C:63](O)([CH3:66])([CH3:65])[CH3:64].C([Li])(CC)C.C1CCCCC1>CN(C)C=O.O1CCCC1>[C:63]([O:14][C:13](=[O:15])[CH:12]([NH:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][C:26]2=[O:35])[CH2:23][CH2:24]1)=[O:18])[CH2:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=1)[NH:9][N:8]=[CH:7]2)([CH3:66])([CH3:65])[CH3:64]
Reactant: CC(C)(C)O
Reactant: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc2cn[nH]c12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)OC(C)(C)C)cc2cn[nH]c12
Reaction time: 8 h

Procedure:
A solution of (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid (50 mg, 0.105 mmol) and dicyclohexylcarbodiimide (25 mg, 0.12 mmol) in dimethylformamide was stirred for 30 min at room temperature, and then pentafluorophenol (26 mg, 1.3 mmol) was added. Stirring was continued at room temperature overnight, and then the solvent was removed, the residue was dried under high vacuum for 4 h. The crude pentafluorophenyl ester was used without further purification in the next step. To a solution of tert-butyl alcohol (10 equiv.) in tetrahydrofuran at −78° C. under nitrogen was added 1.4M sec-butyllithium in cyclohexane (10 equiv.). After 10–15 min, a solution of pentafluorophenol ester (1 equiv.) in tetrahydrofuran was added. The reaction mixture was stirred at room temperature overnight. The solvents were removed in vacuo, and the residue was purified by preparative-HPLC to give the desired compound. 1H-NMR(CD3OD) δ 1.40 (s, 9H) 1.56 (m, 4H), 2.54 (s, 3H) 2.85 (m, 2H) 3.05 (m, 1H) 3.19 (m, 1H) 4.14 (m, 4H) 4.44 (m, 2H) 6.76 (d, J=7.68 Hz, 1H) 6.93 (t, J=7.5 Hz, 1H) 7.10 (m, 3H) 7.14 (s, 1H) 7.97 (s, 1H). LC/MS: tR=2.19 min, 533.36 (MH)+.
Reaction SMILES: [CH2:1]([C:3]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:7](=[O:16])[CH:6]=[CH:5][N:4]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:22]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O>[Br:22][CH:1]([C:3]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:7](=[O:16])[CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: BrBr
Reactant: CCc1nccc(=O)n1-c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(Br)c1nccc(=O)n1-c1ccc(F)cc1
Reaction time: 2 h
Yield: 95.6 %

Procedure:
A solution of the pyrimidinone (24) (150 mg, 0.69 mmol) and sodium acetate (140 mg) in glacial acetic acid (1.5 mL) was warmed to 40° C. and treated dropwise with a preformed bromine solution (0.7 mL bromine in 10 mL of glacial acetic acid) (0.55 mL, 0.69 mmol). After 2 h, water (20 mL) was added to the mixture which was subsequently basified with potassium carbonate, and extracted with dichloromethane (2×10 mL). The combined organic phases were washed with water (10 mL), dried (MgSO4), and concentrated to give the title bromide (25) (196 mg, 96%) as a pale brown oil:
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)O[C:2]2=[O:3].[CH3:13][NH2:14]>O1CCCC1.CO>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:14][CH3:13])=[O:3]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CN
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1N
Yield: 100 %

Procedure:
Isatoic anhydride (10.0 g) was suspended in tetrahydrofuran (200 ml) and treated dropwise with 40% solution of methylamine in methanol (10.0 ml) with stirring. After stirring at room temperature for 16 hours, the solvent was distilled off under reduced pressure to give the title compound (10.3 g, about 100%). Melting point: 78.0 to 79.0° C. (recrystallized from ethyl acetate-n-hexane).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([Br:9])=[CH2:8])[CH3:2].[CH:11]([Br:14])(Br)[Br:12].[Br-].[Br-].C([N+](C)(C)CC[N+](CC1C=CC=CC=1)(C)C)C1C=CC=CC=1.[OH-].[K+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]1([Br:9])[CH2:8][C:11]1([Br:14])[Br:12])[CH3:2]
Reactant: C=C(Br)CCC(=O)OCC
Reactant: BrC(Br)Br
Agent: C[N+](C)(CC[N+](C)(C)Cc1ccccc1)Cc1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)CCC1(Br)CC1(Br)Br
Reaction time: 96 h
Yield: 66.4 %

Procedure:
To a solution made of 12.12 g (58 mmol) of 4-bromo-pent4-enoic acid ethyl ester and 51 g (202 mmol) of bromoform and 100 g of methylene chloride was added 2.0 g of N,N′-dibenzyl-N,N,N′,N′-tetramethylethylenediammonium dibromide and 27.1 g (218 mmol) of 45% aqueous potassium hydroxide. The reaction mixture was stirred rapidly for 4 days. The resulting mixture was transferred to a separatory funnel and the phases were separated. The solvent was removed from the isolated organic layer in vacuo. This residue was extracted with hexanes from water. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo. This residue was purified by column chromatography with 10% diethyl ether/hexanes to yield 14.6 g (66.3% of theory) of 3-(1,2,2-tribromo-cyclopropyl)-propionic acid ethyl ester.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:8][CH2:7]2)[N:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4][NH:3]1.F[C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH3:36][O:35][C:33]([C:32]1[CH:37]=[CH:38][C:29]([N:3]2[C:2](=[O:1])[C:6]3([CH2:7][CH2:8][N:9]([C:12]([O:14][CH2:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[O:13])[CH2:10][CH2:11]3)[N:5]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:4]2)=[CH:30][CH:31]=1)=[O:34]
Reactant: COC(=O)c1ccc(F)cc1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)cc1
Yield: 99.4 %

Procedure:
Benzyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.50 g, 1.37 mmol), methyl 4-fluorobenzoate (0.21 g, 1.37 mmol), and potassium carbonate (0.38 g, 2.74 mmol) in dimethyl sulfoxide were stirred at 100° C. for 3 days. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by Biotage flash chromatography (gradient from 0 to 30% ethyl acetate/hexanes) to give product as an oil (0.68 g, 21%); 1H NMR (DMSO-d6); δ1.90 (d, 15.6 hz, 2H); 2.25-2.34 (m, 2H); 3.56 (m, 2H); 3.98-4.02 (m, 2H); 5.13 (m, 2H); 5.24 (s, 2H); 6.92 (t, J=8.4 hz, 1H); 6.98 (d, J=8.8 hz, 2H); 7.26-7.39 (m, 7H); 8.02 (dd, J=10 Hz and 17.6 Hz, 4H); MS for C29H29N3O5 m/z 500 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[N+:22]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-c2ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c2)cc1
Agent: [Ni]
Product: COc1ccc(-c2ccc(NC(=O)OC(C)(C)C)c(N)c2)cc1

Procedure:
Prepared from (4′-methoxy-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example B1) by catalytic hydrogenation with Raney-Ni according to the general procedure G (method a). Obtained as a white solid (77 mg).
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:27])[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[N:7]=[C:6]1[CH2:15][CH2:16][C:17]1[N:26]=[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[N:19]2[N:18]=1.[CH3:28][NH:29][CH3:30].CO>CS(C)=O>[CH3:28][N:29]([CH3:30])[CH2:2][C@H:3]([OH:27])[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[N:7]=[C:6]1[CH2:15][CH2:16][C:17]1[N:26]=[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[N:19]2[N:18]=1
Reactant: Cc1cccc2nc(CCc3nc(-c4cccs4)cn3C[C@@H](O)CCl)nn12
Reactant: CNC
Solvent: CO
Solvent: CS(C)=O
Product: Cc1cccc2nc(CCc3nc(-c4cccs4)cn3C[C@@H](O)CN(C)C)nn12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of (R)-1-Chloro-3-{2-[2-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-4-thiophen-2-yl-imidazol-1-yl}-propan-2-ol (2 mg, 0.005 mmol) in DMSO (0.5 mL) was added a 2M solution of dimethylamine in methanol (100 μL, 0.2 mmol), the reaction vessel was capped and stirred at 100° C. for 30 minutes. The volatiles were removed in vacuo and the residue purified by preparative LC-MS to yield the title compound. 100% yield, LC-MS: m/z=411.4 (MH+), tR=0.33 minutes, method B.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:6](O)=[O:7].C(Cl)(=O)C(Cl)=O.[CH2:29]([O:36][C:37]1[CH:38]=[CH:39][C:40]2[CH:44]=[C:43]([N:45]([CH3:47])[CH3:46])[S:42][C:41]=2[CH:48]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])(O)=O.[Na+]>ClC(Cl)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]([C:44]2[C:40]3[CH:39]=[CH:38][C:37]([O:36][CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:48][C:41]=3[S:42][C:43]=2[N:45]([CH3:46])[CH3:47])=[O:7])[CH:9]=[CH:10][C:11]=1[O:12][Si:13]([CH:17]([CH3:19])[CH3:18])([CH:20]([CH3:21])[CH3:22])[CH:14]([CH3:15])[CH3:16]
Reactant: COc1cc(C(=O)O)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Reactant: CN(C)c1cc2ccc(OCc3ccccc3)cc2s1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)c2c(N(C)C)sc3cc(OCc4ccccc4)ccc23)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A slurry of 3-methoxy-4-triisopropylsilyloxybenzoic acid (9.75 g, 30 mmol; Part A) in 300 mL of dichloroethane and 1 drop of DMF was treated with oxalyl chloride (13.1 mL, 150 mmol) and stirred overnight at ambient temperature. The reaction mixture was concentrated in vacuo and suspended in 300 mL of chlorobenzene. 6-Benzyloxy-2-(N,N-dimethylamino)benzo[b]thiophene (8.5 g, 30 mmol) was added, and the resulting mixture was heated at 105° C. for 5 h. After cooling to ambient temperature, the reaction mixture was poured into 500 mL of saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CHCl3 (3×150 mL). The combined organics were dried over K2CO3, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2; gradient of 5% to 10% EtOAc in hexanes) afforded 6.05 g (10.3 mmol; 34%) of the title compound.
Reaction SMILES: Cl[CH:2]=[CH:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:11][NH:12][CH3:13]>>[CH3:11][N:12]([CH3:13])[CH:2]=[CH:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CNC
Reactant: CCCCCC(=O)C=CCl
Product: CCCCCC(=O)C=CN(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of dimethylamine (560 ml, 40% aqueous) is cooled to 5° C. 1-Chloro-1-octen-3-one (192 g) is added and the mixture stirred at room temperature for 20 min. The solution is then saturated with potassium carbonate and extracted with ether. The organic layer is washed 3× with sat. sodium chloride solution, dried over sodium sulfate, concentrated and distilled to give the title compound, b.p. 94°-96° C./0.2 mm.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20]I.O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH3:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of 1-benzyloxycarbonyl-4-hydroxypiperidine (1.3 g) in dimethylformamide (10 mL) was added sodium hydride (360 mL) under ice cooling and the mixture was stirred at room temperature under nitrogen-gas atmosphere for 1 hours. To the reaction mixture was added methyl iodide (374 μL) under ice-cooling and the mixture was stirred at the same temperature for 1 hour and at room temperature for 2 hours. To the reaction mixture was added water and ethyl acetate and the mixture was stirred. The organic layer washed with a brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=88/12 to 70/30) to obtain 1-benzyloxycarbonyl-4-methoxypiperidine (622 mg, yield: 45%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[N:9]=2)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:52][C:53]([NH2:56])([CH3:55])[CH3:54]>CN(C=O)C.CO>[C:53]([NH:56][C:26]([C:23]1[CH:24]=[CH:25][C:20]([S:17]([N:10]2[C:11](=[O:16])[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9]2)(=[O:19])=[O:18])=[CH:21][CH:22]=1)=[O:27])([CH3:55])([CH3:54])[CH3:52]
Reactant: O=C(O)c1ccc(S(=O)(=O)n2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)cc1
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1ccc(S(=O)(=O)n2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
An amount of 50 mg (0.113 mmol) of the compound from Example 15A was introduced in 1 ml of DMF and admixed with 18 mg (0.136 mmol) of 1-hydroxy-1H-benzotriazole hydrate and with 28 mg (0.147 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride. After 10 minutes of stirring at RT, 2-methylpropan-2-amine (13.1 μl, 0.124 mmol) was added and the mixture was stirred further at room temperature overnight. Subsequently the reaction solution was diluted with methanol and purified by preparative HPLC [Method 5]. This gave 13 mg (24% of theory) of the target compound.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[CH3:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:4][CH2:3][CH2:2][N:9]1[CH2:10][CH2:11][N:6]([CH3:5])[CH2:7][CH2:8]1
Reactant: OCCBr
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1CCN(CCO)CC1
Yield: 46.4 %

Procedure:
2-Bromoethanol (2.36 g, 19 mmol) was added dropwise to a mixture of 1-methylpiperazine (1.26 g, 13 mmol) and potassium carbonate (5.0 g, 36 mmol) in absolute ethanol (150 ml) and the mixture heated at reflux for 18 hours. The mixture was allowed to cool and the precipitates were removed by filtration and the solvent volatiles were removed by evaporation. The residue was treated with acetone/methylene chloride, the insolubles were removed by filtration and the solvent was removed from the filtrate by evaporation to give 1-(2-hydroxyethyl)-4-methylpiperazine (870 mg, 48%) as a light brown oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1Br)[CH3:2].[CH:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)=[O:13].C(=O)([O-])[O-].[Na+].[Na+].O>C(OCC)(=O)C.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.C1(C)C=CC=CC=1.C(O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:12]=[O:13])[CH:19]=1)[CH3:2]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CCc1cccc(CC)c1Br
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+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cccc(CC)c1-c1cccc(C=O)c1
Yield: 80.2 %

Procedure:
A mixture of 1,3-diethyl-2-bromobenzene (3.87 g, 18.2 mmol), 3-formylphenylboronic acid (3.0 g, 20.0 mmol), tetrakistriphenylphosphinepalladium (0.84 g, 0.73 mmol), sodium carbonate (5.79 g, 54.6 mmol), water (20 mL), ethanol (20 mL) and toluene (200 mL) was heated under reflux overnight under an argon atmosphere. The reaction mixture was cooled, diluted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane/ethyl acetate=5/1) to give the title compound (3.48 g, yield 81%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=[S:23])[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[S:23])[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=S)CCCN(C(=O)OC(C)(C)C)C(N)=NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N=C(N)N(CCCC(O)=S)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a stirring solution of methyl [2-(N,N'-di-tert-butyloxycarbonylguanidino)ethyl]thioacetate (1.24 g, 3.17 mmol) in ethanol (15 mL) at room temperature (15 mL) was added 10% aqueous sodium hydroxide solution (3 mL). After 2 h, The mixture was concentrated, and the residue was treated with 10% aqueous HCl solution. The resulting mixture was extracted with ethyl acetate, and the organic extracts were washed with water and brine, dried over sodium sulfate, and concentrated to afford 1.06 g of [2-(N,N'-di-tert-butyloxycarbonylguanidino)ethyl]thioacetic acid as a white solid. 1H NMR (CDCl3) δ1.50 (s, 18), 2.89 (t, 2, J=8), 3.34 (s, 2), 3.72 (m, 2), 8.82 (br s, 2).
Reaction SMILES: C([C:3]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:7](O)=O)[C:4]([OH:6])=[O:5])C.N1CCC[CH2:20][CH2:19]1.C=O>>[CH2:7]=[C:3]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:4]([O:6][CH2:19][CH3:20])=[O:5]
Reactant: C1CCNCC1
Reactant: CCC(CCc1ccccc1)(C(=O)O)C(=O)O
Agent: C=O
Product: C=C(CCc1ccccc1)C(=O)OCC
Temperature: 57.5 °C
Yield: 89 %

Procedure:
Monoethyl 2-[2-(phenyl)ethyl]malonic acid (47.2 g, 200 mole) was added to 40 mL round bottom flask fitted with a Teflon coated stirring bar. Piperidine (3 mL) and paraformaldehyde (8.4 g, 280 mmole) were added to the flask and the flask was heated to 55-60° C., until gas evolution ceased. TLC indicated that no starting material remained. The solution was worked up by removing the solvent under reduced pressure. Water (50 mL) and enough 12N HCl was added to the flask to acidify the mixture (pH>3). The mixture was extracted with ether (3×50 mL) and back extracted with brine. The solution was dried over MgSO4 and filtered. The reaction mixture was shown to be clean by NMR and TLC and used without further purification. Recovered 36.3 g material (89% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1NCCC(C)C)=[O:5])[CH3:2].CS(NC1C=CC2NC(CC(O)=O)=NS(=O)(=O)C=2C=1)(=O)=O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCCC1NCCC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of cis-(2-(3-methylbutylamino)-cyclohexanecarboxylic acid ethyl ester (58.7 mg, 0.243 mmol) in N,N-dimethylformamide (5.0 mL) was added (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 162.0 mg, 0.486 mmol) and a 1.0 M solution of N,N′-dicyclohexylcarbodiimide in dichloromethane (0.49 mL, 0.49 mmol). After stirring at 25° C. for 12 h, the mixture was diluted with dichloromethane and the precipitated N,N′-dicyclohexylurea byproduct was removed by filtration. The filtrate was concentrated and dried in vacuo to afford the crude product, cis-2-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(3-methylbutyl)amino]-cyclohexanecarboxylic acid ethyl ester, as a yellowish oil. The crude product was used in the next step without further purification. LC-MS (ESI) calcd for C24H36N4O7S2 556.20, found 557.3 [M+H+].
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[C:5]([C:14]([OH:16])=[O:15])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2>C(O)(=O)C>[Br:1][C:7]1[CH:6]=[C:5]([C:14]([OH:16])=[O:15])[C:4]([OH:3])=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2
Reactant: BrBr
Reactant: O=C(O)c1ccc2cccnc2c1O
Solvent: CC(=O)O
Product: O=C(O)c1cc(Br)c2cccnc2c1O
Temperature: 50 °C
Yield: 87.9 %

Procedure:
Bromine (819.8 mg, 5.13 mmol) was added dropwise to a suspension of 8-hydroxyquinolin-7-carboxylic acid (970 mg, 5.13 mmol) in glacial acetic acid (24 mL). The reaction mixture was refluxed for 1 h, allowed to cool to 50° C. and poured onto ice water. The yellow solid formed was filtered on a Buckner funnel, washed with H2O and dried under vacuum, affording the title compound (1.20 g, 4.51 mmol) as a light brown solid that was used in the next step without any further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:28][C:29](=[O:30])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Product: COc1cccc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4ncccc34)cc2)c1

Procedure:
55.5 mg of solid beige-coloured 3-{4-[3-(3-methoxyphenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 3-methoxyphenyl isocyanate.
Reaction SMILES: B(F)(F)F.[CH2:5]([O:12][C@@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:14]=[CH2:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[BH4-].[Na+].[OH-:23].[Na+].OO>O1CCCC1.O>[CH2:5]([O:12][C@@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][CH2:15][OH:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=C[C@H](CCCCC)OCc1ccccc1
Reactant: [OH-]
Agent: FB(F)F
Agent: OO
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC[C@@H](CCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of borontrifluoride. etherate (2.1ml.; 16.7 millimole) in dry tetrahydrofuran (5 ml.) is added dropwise to a stirred mixture of 3(S)-benzyloxy-1-octene (2.19 g., 10 millimole) and sodium borohydride (0.47 g., 12.5 millimole) in dry tetrahydrofuran (25 ml.) maintained at 0° to 5° C. under a nitrogen atmosphere. The resulting reaction mixture is warmed to and maintained at room temperature for 15 hours. After cooling to 0° to 5° C., the reaction mixture is treated cautiously via successive dropwise additions with water (2 ml.), 5N sodium hydroxide (4 ml.) and 30% hydrogen peroxide (8 ml.). After stirring at room temperature for 1/2 hour, the resulting mixture is diluted with ice water and extracted with chloroform three times. The combined organic extract is washed with saturated aqueous brine, dried over magnesium sulfate, and filtered. Evaporation of the filtrate in vacuo provides the title compound as a viscous oil (2.37 g., 100%).