Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=[CH:9]2)[N:3]=1.[C:14]1([CH:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][NH2:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[C:12]([C:11]1[C:2]([NH:22][CH2:21][CH:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:3][C:4]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)#[N:13]
Reactant: N#Cc1c2cccccc-2nc1Cl
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c2cccccc-2nc1NCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.6 %

Procedure:
To a solution of 0.38 g (0.002 mol) of 2-chloro-3-cyano-1-azaazulene in 7 ml of dimethylformamide were added 0.43 g (0.0022 mol) of 2,2-diphenylethylamine. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into water with ice to allow precipitate to separate out. The precipitate was filtered and dried to give 0.55 g of title compoind (yield: 78.6%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:19][CH:20]([CH:28]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:20]([CH:28]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:19][N:18]([CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:11]([O:10][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:12])[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NCCCCC(NC(=O)OC(C)(C)C)C(CCCCCCO)CN(CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCC(NC(=O)OC(C)(C)C)C(CCCCCCOS(C)(=O)=O)CN(CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulphonyl chloride (1.25 ml, 16.21 mmol) was added to a stirred solution of B6 (9.67 g, 13.5 mmol) in dry dichloromethane (100 ml) containing triethylamine (2.82 ml, 20.26 mmol) at 0° C. The flask was stirred at 0° C. for 1 hr, then overnight at room temperature. The solvent was removed and the residue chromatographed (silica—50% ethyl acetate in hexane) to yield the title compound (8.5 g, 79%. C38H74N4O11S requires 794. Found DCl: M++1, 795.6. δH (CDCl3) 3.45 (2H, t, CH2O), 2.9-3.3 (12H, m, CH2N), 2.99 (3H, s, MeS), 1.95 (1H, brm, CH2CH(CH2)2), 1.2-1.8 (50H, m, CH2).
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][NH2:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:23](OC)(=[O:28])[CH2:24][C:25]([CH3:27])=O>>[CH2:1]([NH:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][N:19]1[C:23](=[O:28])[CH2:24][C:25]([CH3:27])=[N:22][CH2:21][CH2:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COC(=O)CC(C)=O
Reactant: CCCCCCCCCCCCNCCNCCNCCN
Product: CCCCCCCCCCCCNCCNCCN1CCN=C(C)CC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 314.5 g (1 mole) of N-dodecyltriethylenetetramine and 116.1 g (1 mole) of methyl acetoacetate. At 140° to 150° C., 18 g of water and 32 g of methanol were distilled off to obtain 4-dodecylaminoethylaminoethyl-7-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.O[CH2:23][C:24]1[N:25]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2>C(Cl)Cl>[Br:20][CH2:23][C:24]1[N:25]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2
Reactant: Cc1ccc(S(=O)(=O)n2c(CO)cc3ccccc32)cc1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c(CBr)cc3ccccc32)cc1
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of triphenylphosphine (20.2 g, 77 mmol) in dry CH2Cl2 (80 mL) was added dropwise a solution of bromine (11.9 g, 77 mmol) in dry CH2Cl2 (40 mL). The stirring was continued for one hour and then a solution of compound of step 2 (23.2 g, 77 mmol) in dry CH2Cl2 (40 mL) was added dropwise. The resulting mixture left stirring for 12 hours. After removing the solvent the residue was taken up in ethyl acetate and washed with water. The organic extract was dried over MgSO4 and the solvent evaporated in vacuo The residue was chromatographed over silica gel using toluene as eluant to give a yellow oil (21.0 g, 75 %); IR (film) 1600 cm31 1, MS ((70 eV): m/z 363 (M+,12.6), 129 (100).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH:4]([P:30]([O:34]C)([O:32]C)=[O:31])[CH2:5][C:6]([CH3:29])=[CH:7][CH2:8][C:9]1[C:10]([O:22]CC[Si](C)(C)C)=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].C[Si](Br)(C)C.N1C(C)=CC=CC=1C>C(#N)C>[CH3:1][O:2][C:3](=[O:36])[CH:4]([P:30]([OH:34])([OH:32])=[O:31])[CH2:5][C:6]([CH3:29])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21]
Reactant: COC(=O)C(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)P(=O)(OC)OC
Agent: C[Si](C)(C)Br
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: COC(=O)C(CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)P(=O)(O)O
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a solution of 2-(dimethoxy-phosphoryl)-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid methyl ester (30 mg, 0.055 mmol) in acetonitrile (2 mL) was added trimethylsilyl bromide (0.18 mL). After 10 minutes, 2,6-lutidine (0.16 mL) was added to the reaction at ambient temperature. The reaction was allowed to proceed for 16 hours before it was concentrated to dryness. The residue was resuspended in a solution of DMF:H2O (8:2, 1 mL) and purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 18 mg of the product as a white powder. 1H NMR (300 MHz, CD3OD) δ 1.81 (s, 3H), 2.16 (s, 3H), 2.40-2.49 (m, 1H), 2.63 (dt, 1H, J=6, 17 Hz), 3.07 (ddd, 1H, J=4, 12, 23 Hz), 3.38 (3, 2H, J=7 Hz), 3.52 (s, 3H), 3.77 (s, 3H), 5.25 (s, 2H), 5.28 (t, 1H, J=7 Hz) ppm; 31P (121.4 MHz, CDCl3) δ 19.5 ppm; MS (m/z) 415.2 [M+H]+, 437.2 [M+Na]+.
Reaction SMILES: CC([C:5]1[CH:18]=[C:17]2[C:8]([N:9]=[C:10]3[C:15](=[C:16]2O)[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=1)(C)C>O=P(Cl)(Cl)Cl>[CH2:14]1[C:15]2[C:10](=[N:9][C:8]3[C:17]([CH:16]=2)=[CH:18][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)c1ccc2nc3c(c(O)c2c1)CCCC3
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2nc3c(cc2c1)CCCC3

Procedure:
7-(1,1-Dimethylethyl)-9-hydroxy-1,2,3,4-tetrahydroacridine (9.46 g) was refluxed for 30 minutes in 50 ml of POCl3. The volatiles were evaporated and the residue was distributed between aqueous NH3 and Et2O. Concentration of the organic phase gave 8.24 g of 9-chloro-7-1,1-dimethylethyl)-1,2,3,4-tetrahydroacridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9]C(OCC)=O.[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[OH:9]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)Oc1ccc(F)cc1F
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(O)c(F)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
50.5 g (250 mmol) of the resulting 2,4-difluoro-O-ethoxycarbonylphenol was dissolved in 115 ml of concentrated sulfuric acid, 15.9 ml of fuming nitric acid was added while maintaining the internal temperature at from 10° to 20° C. and the mixture was stirred at the same temperature for 1 hour. The reaction solution was poured into ice water and the mixture was extracted with 500 ml of ethyl acetate. The organic layer was washed twice with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was dissolved in 1.0 liter of methanol, 50 ml of water and 40 g of sodium bicarbonate were added and the mixture was stirred at room temperature for 16 hours. The reaction solution was filtered, methanol was distilled off under reduced pressure, and the mixture was adjusted to pH 5 by addition of 200 ml of water thereto and extracted twice with 200 ml of ethyl acetate. The organic layer was washed once with 400 ml of water and once with 400 ml of an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 41.6 g (95%) of 2,4-difluoro-5-nitrophenol.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Cl:23][C:24]1[N:29]=[C:28]([CH3:30])[C:27](B(O)O)=[CH:26][CH:25]=1>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:27]4[C:28]([CH3:30])=[N:29][C:24]([Cl:23])=[CH:25][CH:26]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1nc(Cl)ccc1B(O)O
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Product: Cc1nc(Cl)ccc1-c1ccc2c(c1)CC(C1CCN(C(=O)OC(C)C)CC1)O2

Procedure:
The title compound is prepared from 4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidine-1-carboxylic acid isopropyl ester and 6-chloro-2-methylpyridine-3-boronic acid following a procedure analogous to that described for Intermediate 15. LC (method 6): tR=1.41 min; Mass spectrum (ESI+): m/z=415 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:5]([OH:7])=[O:6].[CH3:19]OC(OC)OC.O>C(O)=O>[F:18][C:14]1[CH:13]=[C:12]([N:11]2[C:10]3[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=3[N:1]=[CH:19]2)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cc(C(=O)O)ccc1Nc1cccc(F)c1
Reactant: COC(OC)OC
Solvent: O
Solvent: O=CO
Product: O=C(O)c1ccc2c(c1)ncn2-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-amino-4-(3-fluorophenylamino)benzoic acid (4.96 g, 20.1 mmol) in formic acid (40 mL) was charged with trimethylorthoformate (2.4 mL, 22.0 mmol) and heated at reflux for 3 h after which time the mixture was allowed to cool to rt and stir for 12 h. The reaction mixture was then poured into 150 mL of H2O and stirred for 20 min yielding a precipitate which was isolated by filtration to give 1-(3-fluorophenyl)-1H-benzimidazole-5-carboxylic acid as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 8.73 (s, 1H), 8.32 (s, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.75-7.66 (m, 3H), 7.59 (d, J=8.0 Hz, 2H), 7.38 (t, J=8.8 Hz, 1H); MS (ES+): m/z 257 [MH+].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C@:8]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27][C:10]2([O:14][C@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C@@H:12]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:11]2)[CH2:9]1.F[C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[N+:41]([O-:43])=[O:42])[C:36]#[N:37]>C(#N)C>[CH3:7][C@:8]1([CH2:30][NH:31][C:39]2[CH:38]=[C:35]([CH:34]=[CH:33][C:40]=2[N+:41]([O-:43])=[O:42])[C:36]#[N:37])[CH2:29][CH2:28][CH2:27][C:10]2([O:11][C@H:12]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14]2)[CH2:9]1
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: C[C@]1(CN)CCCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@]1(CNc2cc(C#N)ccc2[N+](=O)[O-])CCCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2
Temperature: 40 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
A solution of acetonitrile (2049 mL) in a 3 L flask was heated to 40° C. Next, potassium carbonate (198 g, 1434 mmol), 1-[(2R,3R,7S)-7-methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-7-yl]methanamine (242 g, 717 mmol) and 3-fluoro-4-nitrobenzonitrile (119 g, 717 mmol) were added slowly. The mixture was allowed to stir at 40° C. for 2 h, and then cooled to RT. Stirring was continued at RT overnight. The next day, the slurry was filtered and the solids were washed with acetonitrile (500 mL). The filtrate was concentrated to afford the crude product (while keeping the temperature ˜60° C. during concentration). To the thick dark residue was added MeOH. The solution was heated to 60° C. on the rotovap and concentrated to a minimal volume. To the residue was added ˜500 mL of MeOH slowly with heating to avoid rapid crystallization, and the solution was heated to reflux. Once at reflux, an additional 250 mL MeOH was slowly added. The resulting slurry was allowed to stir at reflux for about 60 min, then heating was stopped and the slurry was allowed to cool to RT and stirring was continued for 3 days. The slurry was cooled to ˜10° C. with an ice/water bath. Stirring was continued for ˜2 h, and then the slurry was filtered and washed with cold MeOH (100 mL). The solids were dried under reduced pressure to give the desired product as a bright orange solid (245 g, 70.7% yield).
Reaction SMILES: [CH2:1]([C:3]1([CH3:17])[CH2:11][C:10]2[C:5](=[C:6]([CH3:16])[C:7]([CH:14]=O)=[C:8]([CH3:13])[C:9]=2[CH3:12])[CH2:4]1)[CH3:2].O.[OH-].[Na+].Cl.[CH3:22][C:23]([CH3:25])=[O:24]>>[CH2:1]([C:3]1([CH3:17])[CH2:11][C:10]2[C:5](=[C:6]([CH3:16])[C:7]([CH:14]=[CH:22][C:23](=[O:24])[CH3:25])=[C:8]([CH3:13])[C:9]=2[CH3:12])[CH2:4]1)[CH3:2]
Reactant: CC(C)=O
Reactant: CCC1(C)Cc2c(C)c(C)c(C=O)c(C)c2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC1(C)Cc2c(C)c(C)c(C=CC(C)=O)c(C)c2C1
Yield: 79 %

Procedure:
To a solution of 18.26 g of the 2-ethyl-2,4,5,7-tetramethylindan-6-carboxaldehyde in 58 ml of absolute acetone was added 28 ml of water and 32 g of 2% NaOH. After refluxing for 20 hours, the solution was acidified was 2N HCl and extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 19.38 g of the title compound as yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH:10]([CH3:12])[C:9]([OH:18])([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[CH2:8][CH:7]1[CH3:19])=[O:5])[CH3:2].[Br:20]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH:10]([CH3:12])[C:9]([C:13]2[S:14][C:15]([Br:20])=[CH:16][N:17]=2)([OH:18])[CH2:8][CH:7]1[CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC(C)C(O)(c2nccs2)CC1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC(C)C(O)(c2ncc(Br)s2)CC1C
Temperature: 55 °C
Reaction time: 3 h
Yield: 34.5 %

Procedure:
To a solution of the product of Step 1 (3.84 g, 8.54 mmol) in dimethylformamide (33.5 mL) was added N-bromosuccinimide (1.75 g, 9.82 mmol) and the solution stirred at 55° C. for 3 hours. A solution of sodium sulfite (0.538 g, 4.27 mmol) in water (60 mL) was added dropwise to the reaction. The mixture was diluted with ethyl acetate (100 mL) and washed the organic extract with water (2×100 mL). The combined aqueous layers were back extracted with ethyl acetate (3×100 mL) and the combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography provided a solid, which was triturated with hexanes, to give 4-(5-bromo-thiazol-2-yl)-4-hydroxy-2,5-dimethyl-cyclohexanecarboxylic acid ethyl ester (1.07 g, 2.95 mmol). MS ESI: [M]+ m/z 362.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[CH3:29][O:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[F:16][C:14]([F:17])([F:15])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=1)=[CH:3][C:2]([N:34]1[CH2:35][CH2:36][CH:31]([O:30][CH3:29])[CH2:32][CH2:33]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: COC1CCNCC1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Product: COC1CCN(c2ccc3nc(C)c(C(=O)C(F)(F)F)c(-c4ccc(S(C)(=O)=O)cc4)c3c2)CC1
Yield: 14 %

Procedure:
The title compound was prepared from 1-[6-bromo-4-(4-methanesulfonyl-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 23] and 4-methoxy-piperidine according to the procedure of example 25. Yield: 14%; MS: m/z=507 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[C:23]([C:24]([NH:26][CH3:27])=[O:25])=[C:22]3[C:17]([CH:18]=[C:19]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:20]([CH:28]4[CH2:30][CH2:29]4)=[CH:21]3)=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36](OC1N=CC(N)=CC=1)[C:37]1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].BrCC>C(#N)C>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[C:23]([C:24]([NH:26][CH3:27])=[O:25])=[C:22]3[C:17]([CH:18]=[C:19]([N:31]([CH2:36][CH3:37])[S:32]([CH3:35])(=[O:33])=[O:34])[C:20]([CH:28]4[CH2:29][CH2:30]4)=[CH:21]3)=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(OCc2ccccc2)nc1
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(OCc2ccccc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCBr
Product: CCN(c1cc2nn(-c3ccc(OCc4ccccc4)nc3)c(C(=O)NC)c2cc1C1CC1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
2-(6-benzyloxy-3-pyridyl)-5-cyclopropyl-6-(methanesulfonamido)-N-methyl-indazole-3-carboxamide (109) ESI-MS m/z calculated for [M+H]+: 492.1 was prepared according to procedure outlined in Method A using 6-benzyloxypyridin-3-amine instead of 4-bromoaniline. To a solution of compound (109) (120 mg, 0.24 mmol) in acetonitrile (10 mL) was added potassium carbonate (100 mg, 0.72 mmol) followed by bromoethane (0.09 mL, 1.2 mmol). The mixture was heated to 80° C. and stirred for 1.5 h. The mixture was cooled to RT and the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (10 mL), washed with water (2 mL), brine (2 mL), dried (MgSO4) and concentrated in vacuo to afford 2-(6-benzyloxy-3-pyridyl)-5-cyclopropyl-6-[ethyl(methylsulfonyl)amino]-N-methyl-indazole-3-carboxamide (i) (100 mg, 80%). This material was used without purification.
Reaction SMILES: [C:1](=[O:9])([O:6][CH2:7][CH3:8])[O:2][CH:3](Cl)[CH3:4].[C:10]([NH:13][C:14]1[C:15]([I:29])=[C:16]([C:25]([NH:27][CH3:28])=[O:26])[C:17]([I:24])=[C:18]([C:21]([O-:23])=[O:22])[C:19]=1[I:20])(=[O:12])[CH3:11].[K+].[I-].[Na+]>CN(C=O)C>[C:10]([NH:13][C:14]1[C:15]([I:29])=[C:16]([C:25]([NH:27][CH3:28])=[O:26])[C:17]([I:24])=[C:18]([C:21]([O:23][CH:3]([O:2][C:1]([O:6][CH2:7][CH3:8])=[O:9])[CH3:4])=[O:22])[C:19]=1[I:20])(=[O:12])[CH3:11]
Reactant: CCOC(=O)OC(C)Cl
Reactant: CNC(=O)c1c(I)c(NC(C)=O)c(I)c(C(=O)[O-])c1I
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)OC(C)OC(=O)c1c(I)c(NC(C)=O)c(I)c(C(=O)NC)c1I
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1-Chloroethyl ethyl carbonate (1.67 g, 11.0 mmol) was added dropwise at room temperature to a solution of potassium 5-(N-acetylamino) -3-(N-methylaminocarbonyl)-2,4,6-triiodobenzenecarboxylate (6.52 g, 10.0 retool) and sodium iodide (150 rag, 1.0 retool) in dry DMF (50 ml). After stirring at 50° C. for 24 hours the solvent was removed at reduced pressure. The residue was dissolved in chloroform and washed four times with a saturated sodium hydrogen carbonate solution and twice with water. After drying with magnesium sulfate and filtration, the solvent was removed at reduced pressure to give the title compound. Yield: (2.2 g, 38 %). Purity by HPLC: 98%. 1H-NMR (DMSO (DMSO-6 ): delta=1.24 (t, J=7 Hz, CH3); 1.63 (d, J=6 Hz, CH3); 2.03 (s, CH3CO); 2.75 (d, J=3 Hz, NCH3); 4.21 (q, J=7 Hz, CH2): 6.93 (q, J=6 Hz, CH); 8.4-8.7 (m, NHMe); 10.03 ppm (s, NHAc).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[Br:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][C:37]=1[N+:44]([O-:46])=[O:45]>>[Br:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][O:1][CH:2]2[CH:7]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:10][CH:9]=3)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]2)=[CH:38][C:37]=1[N+:44]([O-:46])=[O:45]
Reactant: O=[N+]([O-])c1cc(CBr)ccc1Br
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(Br)c([N+](=O)[O-])c2)cc1

Procedure:
Analogously to Method D, 12.60 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 1-bromo-4-bromomethyl-2-nitrobenzene are reacted. The title compound is obtained as a yellow oil. Rf=0.21 (1:2 EtOAc-heptane); Rt=27.96 (II).
Reaction SMILES: [C:1]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C@@H:19]([C:21]([OH:23])=[O:22])[NH2:20])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CC[O:26][CH2:27][CH3:28].Cl>[OH-].[Na+]>[C:1]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C@@H:19]([C:21]([OH:23])=[O:22])[NH:20][C:27](=[O:26])[CH2:28][CH2:17][CH2:18][CH2:19][C:21]([OH:23])=[O:22])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOCC
Reactant: CCCCCCCCCCCC(=O)NCCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCC(=O)NCCCC[C@H](NC(=O)CCCCC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
Nε-Lauroyl-L-lysine (30 g) was dissolved in 0.2M aqueous NaOH solution (1 L), and ether was added. Adipic acid monoethyl ester acid chloride (26.4 g) was added to the ether layer, and the mixture was stirred at room temperature for 24 hr. To the aqueous solution was added hydrochloric acid with stirring, and the mixture was adjusted to about pH 1. The precipitated crystals were filtered and recrystallized to give Nε-lauroyl-Nα-(5-carboxypentanoyl)-L-lysine (27.42 g, yield 66%). 4.566 g thereof was dissolved in methanol (50 ml), 1M aqueous NaOH solution (10 ml) was added, and the mixture was stirred at room temperature for 3 hr. The solution was filtered, the solvent was removed, and the obtained solid was recrystallized. yield 4.7 g, 99%.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[CH:2].Cl[C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13]>>[CH3:15][O:14][C:12](=[O:13])[C:11]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:1]#[CH:2])=[CH:4][CH:5]=1)=[O:16]
Reactant: COC(=O)C(=O)Cl
Reactant: C#Cc1ccc(N)cc1
Product: C#Cc1ccc(NC(=O)C(=O)OC)cc1

Procedure:
The method described in Referential Example 242 was performed by use of 4-ethynylaniline and methyl chlorooxoacetate, whereby the title compound was obtained.
Reaction SMILES: [OH-:1].[Na+].[CH3:3][C:4]([NH:6][CH:7]1[C:11](=[O:12])[S:10][CH2:9][CH2:8]1)=[O:5]>Cl>[C:4]([NH:6][C@H:7]([C:11]([OH:12])=[O:1])[CH2:8][CH2:9][SH:10])(=[O:5])[CH3:3]
Reactant: CC(=O)NC1CCSC1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CC(=O)N[C@@H](CCS)C(=O)O
Temperature: 50 °C
Yield: 90 %

Procedure:
NaOH (1 M deoxygenated aqueous solution, 100 mL) was dropwise added to DL-N-acetylhomocysteine thiolactone (4.00 g, 25.124 mmol). Addition time: 15 min. The reaction mixture was warmed up to 50° C. and allowed to react for 30 min. The reaction was cooled down to 0° C., acidified with HCl (10% aqueous solution, 30 mL) and the product was extracted with nBuOH (4×70 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was slurred with Et2O/hexanes (1:3, 150 mL) to furnish 4.00 g of DL-N-acetylhomocysteine (white solid, yield: 90%).