Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:41]=[CH:40][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([NH:32]C(OC(C)(C)C)=O)[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[NH2:32][CH:27]([CH2:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][N:13]2[C:12]3[CH:40]=[CH:41][C:9]([C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][C:11]=3[S:15][C:14]2=[O:16])=[CH:25][CH:24]=1)[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(N)Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4 g of the compound obtained in Step C of Example 10 are dissolved in 200 ml of dichloromethane and the temperature is lowered to 0° C. 12.47 ml of trifluoroacetic acid are then added and the reaction mixture is stirred at ambient temperature for 4 hours.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([CH2:14][CH2:15][CH2:16][C:17]2[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[NH:19][C:18]=2[CH:26]=[O:27])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30].ClCCl.CO>CN(C)C=O>[CH2:32]([O:31][C:29]([N:11]1[CH2:12][CH2:13][N:8]([CH2:14][CH2:15][CH2:16][C:17]2[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[NH:19][C:18]=2[CH:26]=[O:27])[CH2:9][CH2:10]1)=[O:30])[CH3:33]
Reactant: O=Cc1[nH]c2c(c1CCCN1CCNCC1)CCCC2
Reactant: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)N1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1
Temperature: 0 °C
Yield: 53.5 %

Procedure:
Triethylamine (146 μl, 1.0 mmol) was added to 3-(3-piperazin-1-yl-propyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (192 mg, 0.7 mmol) in 5 ml of dimethylformamide at 0° C. Ethyl chloroformate (87 μl, 0.91 mmol) was dropped in the mixture. The reaction mixture was stirred at 0° C. which was raised slowly to room temperature over night. Thin layer chromatography (dichloromethane: methanol 10:1) showed on major spot. The solvent was evaporated then the residue was purified by flash chromatography and eluting with (dichloromethane/methanol =50/1, 40/1, 30/1) to give 130 mg of 4-[3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-piperazine-1-carboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:12]#[C:13]Br.[OH-].[Na+]>C(O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][NH:11][C:13]1=[NH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCNCc1ccccc1
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=C1NCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of N-benzylethane-1,2-diamine (1.00 g, 6.65 mmol) in absolute ethanol (25 mL) was added cyanogen bromide (0.92 g, 8.65 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, then cooled in an ice water bath. The pH of the solution was adjusted to ˜10 by the addition of 1 M sodium hydroxide solution dropwise. The solvent was concentrated in vacuo. The residue was diluted with ethyl acetate (100 mL), washed with water (200 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the concentrated in vacuo. The residue was recrystallized in ethyl acetate and hexane to yield the title compound as a colorless solid in 96% yield (1.12 g): mp 165-167° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.39-7.24 (m, 6H), 4.47 (s, 2H), 3.49-3.33 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 159.4, 136.0, 129.1, 128.2, 128.1, 48.1, 47.4, 41.3; MS (ES+) m/z 176.3 (M+1).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]([C:14]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]([O:30]CC)=[O:29])[CH:23]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])[CH:7]=[C:8]([CH3:10])[CH:9]=1>CO.C(OCC)(=O)C>[C:28]([C:24]1[CH:23]=[C:22]([CH2:21][S:20][C:15]2[C:14]([C:12]([NH:11][C:6]3[CH:7]=[C:8]([CH3:10])[CH:9]=[C:4]([CH3:3])[CH:5]=3)=[O:13])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:27]=[CH:26][N:25]=1)([OH:30])=[O:29]
Reactant: CCOC(=O)c1cc(CSc2ncccc2C(=O)Nc2cc(C)cc(C)c2)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(C(=O)O)c2)c1
Yield: 84 %

Procedure:
A 1N aqueous sodium hydroxide solution (0.5 mL) was added to a solution of N-(3,5-dimethylphenyl)-2-(2-ethoxycarbonylpyridin-4-ylmethylthio)pyridine-3-carboxamide (95 mg, 0.22 mmol, Compound No. 1-241) in methanol (2 mL), then the mixture was stirred at room temperature for 1.5 hours. 1N hydrochlroric acid (1 mL) was added to the reaction mixture, and this mixture was diluted with ethyl acetate (35 mL). The mixture was washed with brine (20 mL), and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, then the resulting residue was filtered off. The solid was washed with diethyl ether, and then dried at 50° C. under reduced pressure to give 74 mg of the target compound as an orange solid. (Yield 84%)
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][C:13]([CH2:16][CH3:17])([CH3:15])[NH:12][C:11]([CH2:19][CH3:20])([CH3:18])[CH:10]1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:24](=O)(O)[O-].[Na+]>C(O)=O>[CH2:1]([O:8][CH:9]1[CH2:14][C:13]([CH2:16][CH3:17])([CH3:15])[N:12]([CH3:24])[C:11]([CH2:19][CH3:20])([CH3:18])[CH:10]1[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: CCC1(C)CC(OCc2ccccc2)C(C)C(C)(CC)N1
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Product: CCC1(C)CC(OCc2ccccc2)C(C)C(C)(CC)N1C
Temperature: 25 °C

Procedure:
To 1.0 g of 4-benzyloxy-2,6-diethyl-2,3,6-trimethylpiperidine (Compound 95 - prepared as described in Preparation 5) were added 0.52 g of formic acid and 1.22 g of 37 % formalin at 0° - 5° C. The mixture was stirred at room temperature and then refluxed by heating for 3 hours. When the reaction was complete, the reaction mixture was adjusted to a pH value of 8.0 by addition of a 5 % aqueous solution of sodium bicarbonate; the mixture was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulphate and the solvent was removed by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel using benzene as eluent; the resulting product was then distilled under reduced pressure, giving 0.6 g of Compound 100 as a pale yellow liquid (bp 132° - 135° C/0.2 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)=[O:6].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:8]2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(O)c2cccc(Cl)c2)C1
Yield: 90.1 %

Procedure:
To a solution of (R)-tert-butyl 3-(3-chlorobenzoyl)piperidine-1-carboxylate (10 g, 0.031 mol) in ethanol was added NaBH4 (4.71 g, 0.124 mol) portionwise. When the reaction was complete, the ethanol was distilled off, and water (100 mL) and EtOAc (100 mL) were added to the mixture. The organic phase was separated and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic phases ware washed with water, dried over Na2SO4 and concentrated to give (3R)-tert-butyl 3-((3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (9.1 g, 90%), which used without purification. 1H NMR (400 MHz, CDCl3): 1.24-1.45 (m, 4H), 1.46 (m, 9H), 1.61-1.68 (m, 1H), 1.73-1.84 (m, 1H), 3.05-3.26 (m, 2H), 3.55-3.66 (m, 1H), 3.82-3.96 (m, 1H), 4.42 (m, 1H), 7.20 (m, 1H), 7.27-7.30 (m, 2H), 7.32 (s, 1H). MS (E/Z): 326 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([CH:24]=[CH2:25])[CH:23]=1.O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:25][CH2:24][C:22]3[CH:21]=[N:20][CH:19]=[C:18]([C:17]([F:27])([F:16])[F:26])[CH:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1cncc(C(F)(F)F)c1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2cncc(C(F)(F)F)c2)C1
Temperature: 25 °C

Procedure:
8-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.165 g, 0.75 mmol), 3-(trifluoromethyl)-5-vinylpyridine (0.13 g, 0.75 mmol) and tetra butyl ammonium chloride (2 mg, 0.0375 mmol) in 5 ml, 50% aqueous NaOH was heated at 100° C. for 8 hrs. The reaction mixture was cooled at RT, added 5 ml water and extracted with ethyl acetate. Dried on anhydrous sodium sulphate and concentrated and submitted for Prep HPLC to get 8-chloro-2-methyl-5-(2-(5-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]([O:8][C:9]([CH:11]2[C:13]([CH3:15])([CH3:14])[CH:12]2[CH:16]=[C:17]([CH3:19])[CH3:18])=[O:10])[CH2:6][C:4](=[O:5])[C:3]=1[CH2:20][C:21]#[CH:22].[NH2:23][C@H:24]([C:32]([NH:34][C@H:35]([C:54]([OH:56])=[O:55])[CH2:36][C:37]1[N:41]=[CH:40][N:39](C2C=CC([N+]([O-])=O)=CC=2[N+]([O-])=O)[CH:38]=1)=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH:57]1([CH2:63][C@H:64]([NH-:75])[CH:65]([OH:74])[CH2:66][C:67]2[O:68][CH2:69][C:70]([CH3:73])([CH3:72])[N:71]=2)[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1.C1(S)C=CC=CC=1>>[CH3:1][C:2]1[CH:7]([O:8][C:9]([CH:11]2[C:13]([CH3:14])([CH3:15])[CH:12]2[CH:16]=[C:17]([CH3:19])[CH3:18])=[O:10])[CH2:6][C:4](=[O:5])[C:3]=1[CH2:20][C:21]#[CH:22].[NH2:23][C@H:24]([C:32]([NH:34][C@H:35]([C:54]([OH:56])=[O:55])[CH2:36][C:37]1[N:41]=[CH:40][NH:39][CH:38]=1)=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH:57]1([CH2:63][C@H:64]([NH-:75])[CH:65]([OH:74])[CH2:66][C:67]2[O:68][CH2:69][C:70]([CH3:73])([CH3:72])[N:71]=2)[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1cn(-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cn1)C(=O)O
Agent: C#CCC1=C(C)C(OC(=O)C2C(C=C(C)C)C2(C)C)CC1=O
Agent: CC1(C)COC(CC(O)[C@@H]([NH-])CC2CCCCC2)=N1
Agent: Sc1ccccc1
Product: N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
300 mg of Etoc-Phe-His(DNP)-1(S)-cyclohexylmethyl-2(R,S)-hydroxy-3-(4,4-dimethyloxazolin-2yl)propylamide are reacted with thiophenol to give the title compound in analogy to reference example 1(a).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[C:26]([CH3:27])=[CH:25][C:16]([O:17][CH2:18][C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21])=[CH:15][C:14]=2[CH3:28])(=[O:12])=[O:11])=[C:5]([N+:29]([O-:31])=[O:30])[CH:4]=1.[C:32]1([CH3:44])[CH:37]=[CH:36][C:35]([S:38]([CH:41](O)[CH3:42])(=[O:40])=[O:39])=[CH:34][CH:33]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[C:14]([CH3:28])=[CH:15][C:16]([O:17][CH2:18][C:19]([CH3:24])([CH3:23])[C:20]([O:22][CH2:42][CH2:41][S:38]([C:35]3[CH:36]=[CH:37][C:32]([CH3:44])=[CH:33][CH:34]=3)(=[O:40])=[O:39])=[O:21])=[CH:25][C:26]=2[CH3:27])(=[O:12])=[O:11])=[C:5]([N+:29]([O-:31])=[O:30])[CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)C(C)O)cc1
Reactant: COc1ccc(NS(=O)(=O)c2c(C)cc(OCC(C)(C)C(=O)O)cc2C)c([N+](=O)[O-])c1
Solvent: ClCCl
Product: COc1ccc(NS(=O)(=O)c2c(C)cc(OCC(C)(C)C(=O)OCCS(=O)(=O)c3ccc(C)cc3)cc2C)c([N+](=O)[O-])c1
Temperature: 36 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-{4-[4-methoxy-2-nitrophenylaminosulfonyl}-3,5-dimethylphenoxy]-2,2-dimethylpropionic acid (Intermediate A10, 24.2 g, 0.054 mol) and carbonyldiiuidazole (9.5 g, 0.059 mol) was diluted with 45 mL dichloromethane and warmed in a 36° C. bath for 15 min. Then, 4-tolylsulfonylethanol was added, the bath temperature was raised to 55° C., and the solvent was blown off in a nitrogen stream. After 1.5 hr, the stream was stopped, and after 2.5 hr, the cooled reaction mixture was partitioned between ethyl acetate and 1.2 M hydrochloric acid. The aqueous layer was extracted with additional ethyl acetate, and the combined organic layers were washed with water and saturated sodium chloride, concentrated at aspirator pressure and high vacuum. The product, title compound, (34 g, 99%) was carried on without further purification.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]=2[CH2:19][NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)O1.Br[C:29]1[N:34]=[C:33]([C:35]([NH:38][C:39]2[C:44]([CH2:45][CH3:46])=[CH:43][CH:42]=[CH:41][C:40]=2[CH2:47][CH3:48])([CH3:37])[CH3:36])[CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].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.C1(C)C=CC=CC=1.CO>[NH:20]([CH2:19][C:10]1[CH:11]=[CH:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]=1[C:29]1[N:34]=[C:33]([C:35]([NH:38][C:39]2[C:44]([CH2:45][CH3:46])=[CH:43][CH:42]=[CH:41][C:40]=2[CH2:47][CH3:48])([CH3:37])[CH3:36])[CH:32]=[CH:31][CH:30]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCc1cccc(CC)c1NC(C)(C)c1cccc(Br)n1
Reactant: CC1(C)OB(c2c(CNc3ccccc3)ccc3ccccc23)OC1(C)C
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: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CCc1cccc(CC)c1NC(C)(C)c1cccc(-c2c(CNc3ccccc3)ccc3ccccc23)n1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 2.17 g (6.00 mmol) of N-{[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]methyl}-aniline, 4.33 g (6.00 mmol) of N-[1-(6-bromopyridin-2-yl)-1-methylethyl]-2,6-diethylaniline and 1.60 g (15.10 mmol) of Na2CO3×10H2O, 65 ml of water, 18 ml of methanol and 80 ml of toluene was purged with argon for 30 min. To this solution 0.35 g (0.30 mmol) of Pd(PPh3)4 was added. This mixture was stirred for 12 h at 80° C., then cooled to room temperature. The organic layer was separated, the aqueous layer was extracted with 3×200 ml of ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel 60 (40-63 um, eluent: dichloromethane-ethyl acetate=20:1, vol.). Yield 2.35 g (76%) of yellow oil. Anal. calc. for C35H37N3: C, 84.13; H, 7.46; N, 8.41. Found: C, 84.34; H, 7.55; N, 8.35. 1H NMR (CDCl3): δ 7.87-7.90 (m, 2H, 4, 8-H in naphtalene), 7.81 (t, J=7.8 Hz, 1H, 4-H in pyridine), 7.70 (dd, J=7.8 Hz, J=0.6 Hz, 1H, 5-H in pyridine), 7.67 (d, J=8.6 Hz, 1H, 3-H in naphtalene), 7.45-7.49 (m, 2H, 5, 7-H in naphtalene), 7.38-7.42 (m, 1H, 6-H in naphtalene), 7.31 (dd, J=7.8 Hz, J=0.6 Hz, 1H, 3-H in pyridine), 7.10 (m, 2H, 3, 5-H in Ph), 6.93-7.00 (m, 3H, 3, 4, 5-H in 2, 6-Et2C6H3), 6.66 (m, 1H, 4-H in Ph), 6.58 (m, 2H, 2, 6-H in Ph), 4.12-4.28 (m, 4H, CH2NH and NHCMe2), 2.44 (q, J=7.6 Hz, 4H, CH2Me), 2.43 (q, J=7.6 Hz, 4H, CH2Me), 1.54 (s, 3H, CMeMe′), 1.44 (s, 3H, CMeMe′), 1.02 (t, J=7.6 Hz, 6H, CH2Me).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]2[C:12](=[C:13]3[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]3)[CH:11]=[CH:10][CH:9]=[CH:8]2)=[N+]=[N-]>[Pd].CO>[CH:11]1[C:12]2[C:7](=[N:6][C:5]([CH2:4][NH2:1])=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[CH:17]3)[CH:8]=[CH:9][CH:10]=1
Reactant: [N-]=[N+]=NCc1nc2ccccc2c2ccccc12
Agent: [Pd]
Solvent: CO
Product: NCc1nc2ccccc2c2ccccc12
Reaction time: 3.5 h

Procedure:
Activated palladium on carbon (10% w/w, 26 mg) was added to a solution of the azide 7 (258 mg, 1.10 mmol) in MeOH (40 mL). The reaction flask was purged thrice with H2 (g), pressurized to 4 bar with H2 (g), and mechanically shaken in a Parr hydrogenator for 3.5 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to yield amine 8 as a yellow oil that was used immediately in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.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>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:12]([O:11][CH3:10])=[O:13])=[CH:15][CH:16]=2)[CH:3]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(N)cc1Br
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: [Cs+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(N)ccc2C)cc1
Temperature: 90 °C
Yield: 51.8 %

Procedure:
3-Bromo-4-methylaniline (744 mg, 4.0 mmol), (4-methoxycarbonylphenyl)boronic acid (864 mg, 4.8 mmol), tetrakis(triphenylphosphine)palladium (100 mg, 0.087 mmol) and caesium carbonate (2.4 g, 7.37 mmol) were mixed in DME (30 ml) and heated at 90° C. for 20 h. The reaction was absorbed onto silica applied to a silica SPE (10 g) and eluted with ethyl acetate/cyclohexane (0-100% ethyl acetate). The solvent was evaporated from the product fractions under vacuum to give methyl 5′-amino-2′-methyl-1,1′-biphenyl-4-carboxylate (500 mg, 43%). NMR; δH CDCl3 8.07,(2H, d), 7.38,(2H, d), 7.07,(1H, d), 6.67,(1H, dd), 6.60,(1H, d), 3.94,(3H, s), 2.14,(3H, s).
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]([CH3:15])=[C:11]([CH:13]=O)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[NH:17][NH2:18]>>[CH2:21]([O:20][C:16](=[O:19])[NH:17][N:18]=[CH:13][C:11]1[N:12]=[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:9][C:10]=1[CH3:15])[CH3:22]
Reactant: Cc1[nH]c(Cc2ccccc2)nc1C=O
Reactant: CCOC(=O)NN
Product: CCOC(=O)NN=Cc1nc(Cc2ccccc2)[nH]c1C

Procedure:
A 4.08 gm. portion of 2-benzyl-5-methyl-4-imidazolecarboxaldehyde and 2.29 gm. of ethyl carbazate are reacted as described in Example 32 giving the desired product, m.p. 190°-191.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:23])=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:25]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:23])=[C:18]([NH:19][S:30]([C:26]3[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=3)(=[O:32])=[O:31])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccnc3)c2F)c(-c2ccnc(Cl)n2)s1
Yield: 75.3 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-isopropylthiazol-4-yl)-2-fluoroaniline (3 g, 8.6 mmol) and pyridine-3-sulfonyl chloride (1.68 g, 9.5 mmol) the title compound of Step A was obtained (2.1 g, 75.3% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.97-9.01 (br, 1H), 8.76-8.79 (m, 1H), 8.35 (d, J=5.3 Hz, 1H), 8.08-8.12 (m, 1H), 7.68-7.74 (m, 1H), 7.40-7.44 (m, 1H), 7.22-7.34 (m, 3H), 6.69 (d, J=5.3 Hz, 1H), 3.29-3.38 (m, 1H), 1.44 (d, J=6.8 Hz, 6H). MS (ES+): 490 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])=[CH:17][CH:16]=2)[CH2:10]1)(C)(C)C.O1CCOCC1>Cl>[ClH:29].[Cl:29][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:30])[C:23]=1[CH2:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH:11]2[O:12][CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:6]([OH:31])=[O:5])[CH2:10]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(OCc3c(Cl)cccc3Cl)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCN1CCOC(c2ccc(OCc3c(Cl)cccc3Cl)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 176.3 %

Procedure:
3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acid tert-butyl ester (0.59 g; 1.27 mmol) was dissolved in a 4M solution of HCl in 1,4-dioxane (6.33 mL, 25.30 mmol) and stirred overnight at RT. Subsequently, the solvent was removed in vacuo and the residue treated with iPr2O, the precipitate was collected by filtration and dried overnight under reduced pressure to afford 3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-propionic acid hydrochloride (0.50 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.88-2.97 (2 H, m) 3.11 (1 H, t, J=11.7 Hz) 3.15-3.23 (1 H, m) 3.30-3.43 (2 H, m) 3.49 (1 H, d, J=12.0 Hz) 3.55-3.64 (1 H, m) 4.01-4.20 (2 H, m) 4.88 (1 H, d, J=12.0 Hz) 5.24 (2 H, s) 7.04-7.12 (2 H, m) 7.35 (2 H, d, J=8.7 Hz) 7.40-7.49 (1 H, m) 7.49-7.56 (2 H, m).
Reaction SMILES: [C:1]1([S-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[CH3:9][O:10][C:11](=[O:18])[CH2:12][CH2:13][C:14](=[O:17])[CH2:15]Br>>[CH3:9][O:10][C:11](=[O:18])[CH2:12][CH2:13][C:14](=[O:17])[CH2:15][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCC(=O)CBr
Reactant: [S-]c1ccccc1
Agent: [Na+]
Product: COC(=O)CCC(=O)CSc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 100 ml of a 1M methanolic sodium thiophenolate solution there was added 22 g (0.1 mole) 5-bromo-4-oxo-valeric acid methylester during 40 minutes and the reaction mixture was stirred for two hours at room temperature. The methanol was distilled off in vacuo, to the residue there was added 200 ml ethyl acetate, and the mixture was washed successively with 30 water, 30 ml sodium bicarbonate solution, 30 ml saturated saline solution, then dried over magnesium sulfate, filtered, and the solvent was distilled off. The residue was chromatographed on a column using a 4:1 mixture of hexane and ethyl acetate as an eluent.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]([CH3:16])C)=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.CN[C@H](C(O)=O)C[C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28]C=1>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][C:16]2[NH:28][C:29]3[C:34]([CH:26]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CN[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: COC(=O)[C@@H](NC(=O)Cc1cc(F)cc(F)c1)C(C)C
Agent: Cl
Product: COC(=O)[C@H](Cc1cc2ccccc2[nH]1)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
A method similar to that used for the preparation of (107a) was used except that methyl-L-triptophane hydrochloride (214 mg) was used instead of methyl-L-valinate hydrochloride to afford the desired product (365 mg). 1H NMR (300 MHz, CDCl3) δ 3.17 (m, 2H), 3.43 (s, 2H), 4.90 (m, 1H), 5.94 (d, 1H, J=7 Hz), 6.62 (m, 2H), 6.71 (m, 1H), 7.12 (m, 1H), 7.17 (m, 1H), 7.36 (d, 1H, J=8 Hz), 7.39 (d, 1H, J=8 Hz), 8.09 (s, 1H). MS APCI, m/z=373(M+1). LC/MS: 2.28 min.