Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:13][C:14](=[O:17])[CH:15]=[CH2:16])([CH3:12])[CH3:11])=[CH:6][CH:5]=1)#[N:2].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:13][C:14](=[O:17])[CH2:15][CH2:16][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)([CH3:12])[CH3:11])=[CH:6][CH:5]=1)#[N:2]
Reactant: c1c[nH]cn1
Reactant: C=CC(=O)NC(C)(C)c1ccc(CC#N)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(NC(=O)CCn1ccnc1)c1ccc(CC#N)cc1

Procedure:
A mixture of N-{1-[4-(cyanomethyl)phenyl]-1-methylethyl}acrylamide (20.5 g), imidazole (6.11 g), benzyltrimethylammonium hydroxide (74 mg) and 1,4-dioxane (300 ml) gave N-{1-[4-(cyanomethyl)phenyl]1-methylethyl}-3-(imidazol-1-yl)propionamide as an oil.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[N:32][CH:31]=[N:30]1)[C:23](O)=[O:24]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:12]=[CH:13][C:14]([CH2:17][CH3:18])=[CH:15][N:16]=3)[CH2:7][CH2:6]2)[C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([N:29]3[CH:33]=[N:32][CH:31]=[N:30]3)=[C:20]([F:19])[CH:21]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(-n2cncn2)c(F)c1
Reactant: CCc1cnc(N2CCC(NC3CC3)CC2)nc1
Product: CCc1cnc(N2CCC(N(C(=O)c3ccc(-n4cncn4)c(F)c3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-amine and 3-fluoro-4-[1,2,4]triazol-1-yl-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=4.25 min; Mass spectrum (ESI+): m/z=436 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[NH:14][C@@H:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:12][S:11]2)=[C:5]([CH2:19][CH3:20])[CH:4]=1)#[N:2].[CH2:21](Br)[CH:22]([CH3:24])[CH3:23]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[N:14]([CH2:21][CH:22]([CH3:24])[CH3:23])[C@@H:13]([CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:12][S:11]2)=[C:5]([CH2:19][CH3:20])[CH:4]=1)#[N:2]
Reactant: CCc1cc(C#N)ccc1N=C1N[C@@H](CC(C)C)CS1
Reactant: CC(C)CBr
Product: CCc1cc(C#N)ccc1N=C1SC[C@H](CC(C)C)N1CC(C)C

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was reacted with SOCl2 followed by 4-cyano-2-ethylphenyl isothiocyanate according to Method C2a to give (4S)-2-(4-cyano-2-ethylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-cyano-2-ethylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:18][C:19]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:22]3[CH2:23][CH2:24][C:19]([OH:18])([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:20][CH2:21]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Reactant: OC1(c2ccccc2)CCNCC1
Product: CC(C)(C)OC(=O)N1Cc2ccc(N3CCC(O)(c4ccccc4)CC3)cc2C1

Procedure:
Prepared in analogy to Example A3(d) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 4-hydroxy-4-phenylpiperidine. Yellow solid. MS (m/e): 395.1 ([M+H]+, 100%).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:23])[CH:7]2[CH:12]([C:13](=[O:15])[CH:14]=1)[C:11]1([Cl:19])[C:16]([Cl:18])([Cl:17])[C:8]2([Cl:22])[C:9]([Cl:21])=[C:10]1[Cl:20])([CH3:4])([CH3:3])[CH3:2]>N1C=CC=CC=1.CO>[C:1]([C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:11]3([Cl:19])[C:16]([Cl:17])([Cl:18])[C:8]([Cl:22])([C:9]([Cl:21])=[C:10]3[Cl:20])[C:7]=2[C:6]=1[OH:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1=CC(=O)C2C(C1=O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)(C)c1cc(O)c2c(c1O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl

Procedure:
10 g. of 6-tert-butyl-1,2,3,4,9,9-hexachloro-1,4,4a,8a-tetrahydro-1,4-methanonaphthalene-5,8-dione, prepared according to Example 8, were dissolved in 50 ml. of methanol. A few drops of pyridine were added and the solution was refluxed strongly for three hours. Evaporation of the methanol yielded an oily material which upon recrystallization twice from Skelly B gave white needle crystals melting at 96° C.-98° C.
Reaction SMILES: [H-].[Na+].CS([C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:10]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:8]=1)(=O)=O.[CH3:25][O:26][CH2:27][CH2:28][OH:29].[Cl-].[Na+]>CN(C=O)C>[CH3:25][O:26][CH2:27][CH2:28][O:29][C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:10]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:8]=1
Reactant: CS(=O)(=O)c1cc(-c2ccccn2)nc(-c2ccccn2)c1
Reactant: COCCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Sodium hydride (60% content, oil dispersion, 1.20 g, 0.030 mol) was added to a mixture of 4'-methanesulfonyl-2,2':6',2"-terpyridine (3.11 g, 0.010 mol), 2-methoxyethanol (1.14 g, 0.015 mol) and DMF (0.1 liter) over a period of 10 minutes and then stirred for another 30 minutes. Thereafter, the reaction mixture was refluxed for 3 hours and then cooled to room temperature. The reaction mixture was then poured into an aqueous 4M sodium chloride solution and the crystal that precipitated was taken out by filtration under suction and then washed with water and hexane The crystal thus taken out was purified by passing the same into an alumina column using chloroform as an eluent, whereby 2.92 g of the above-entitled product (T-7) was obtained. Yield: 95%. m.p. 105.0 to 105.5° C.
Reaction SMILES: [CH:1]([NH:4][NH:5][C:6]([CH:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1)=[O:7])([CH3:3])[CH3:2].[Br:14][C:15]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:16]=1[O:17][CH2:18][C:19](O)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>CN(C=O)C>[Br:14][C:15]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:16]=1[O:17][CH2:18][C:19]([N:4]([CH:1]([CH3:3])[CH3:2])[NH:5][C:6]([CH:8]1[CH2:9][CH2:10][S:11][CH2:12][CH2:13]1)=[O:7])=[O:20]
Reactant: O=C(O)COc1ccc(F)cc1Br
Reactant: CC(C)NNC(=O)C1CCSCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)N(NC(=O)C1CCSCC1)C(=O)COc1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.1 %

Procedure:
A solution of tetrahydro-thiopyran-4-carboxylic acid N′-isopropyl-hydrazide (300 mg, 1.48 mmol) and (2-bromo-4-fluoro-phenoxy)-acetic acid (369 mg, 1.48 mmol) in DMF (6 ml) was treated at rt with HOBT (240 mg, 1.78 mmol), EDCI (341 mg, 1.78 mmol), and triethylamine (0.620 ml, 4.45 mmol). The reaction mixture was stirred at room temperature for 18 hours and then partitioned between 1N HCl solution and ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated under vacuum. The crude was purified by RP HPLC to afford the product as a solid (116 mg, 18.1%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[C@@H:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.O>[CH:14]1([CH2:13][CH:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][N:6]=2)=[O:27])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COC(=O)c1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: O=C(Nc1ccc(CO)cn1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A solution of 6-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid methyl ester (prepared as in Example 45, 398 mg, 0.95 mmol) in diethyl ether (30 mL) was cooled to 0° C. and then treated with lithium aluminum hydride (54 mg, 1.4 mmol) in one portion. There was immediate gas evolution. The reaction mixture was allowed to slowly warm to 25° C. and was stirred at 25° C. 16 h. After such time, the reaction mixture was diluted with water (10 mL) and then extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-hydroxymethyl-pyridin-2-yl) propionamide (131 mg, 35%) as a white foam: FAB-HRMS m/e calcd for C20H22Cl2N2O2 (M+H)+ 392.1058, found 392.1062.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:10][C:9]([I:17])=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:18].C(N(CC)CC)C.[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>ClCCl>[Cl:2][C:3]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:16][C:29](=[O:30])[NH:28][CH2:26][CH3:27])=[CH:10][C:9]([I:17])=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:18]
Reactant: NCCCOc1cc(I)c2c(c1Cl)CNC2=O
Reactant: CCN=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)NCCCOc1cc(I)c2c(c1Cl)CNC2=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 92.1 %

Procedure:
4-Chloro-5-(3-aminopropoxy)-7-iodoisoindolinone hydrochloride (100 mg, 0.248 mmol) was suspended in dichloromethane (3.0 mL), and the suspension was added with triethylamine (0.104 mL, 0.744 mmol) and ethyl isocyanate (0.029 mL, 0.372 mmol), followed by stirring at room temperature for 13 hours. The solvent was evaported under reduced pressure and the residue was purified by slurry using water and acetonitrile to obtain 4-chloro-5-[3-(ethylcarbamoylamino)propoxy]-7-iodoisoindolinone (100 mg, yield 93%).
Reaction SMILES: O[C:2]1[C:7](C)=[CH:6][C:5]([O:9][CH3:10])=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH2:15](Cl)[Cl:16]>>[Cl:16][CH2:15][C:2]1[CH:7]=[CH:6][C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: ClCCl
Reactant: COc1cnc(O)c(C)c1
Solvent: O=S(Cl)Cl
Product: COc1ccc(CCl)nc1

Procedure:
To a solution of 2-hydroxy-methyl-5-methoxy-pyridine (0.68 g, 4.9 mmol) in dry DCM was added dropwise excess thionyl chloride (2.0 mL), and the mixture was refluxed for 2 hours. The solvent was removed in vacuo, and the residue was taken up in EtOAc and washed with NaHCO3 (aq), dried (MgSO4, and concentrated in vacuo. The extremely volatile 2-chloromethyl-5-methoxy-pyridine was obtained as a solution in ethyl acetate to give (984.0 mg, 83.5%) yield.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[OH:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].C(N(CC)CC)C.[C:27](Cl)(=[O:30])[CH2:28][CH3:29]>O1CCCC1>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[O:13][C:27](=[O:30])[CH2:28][CH3:29])=[CH:5][C:4]=1[C:16]([F:19])([F:17])[F:18])#[N:2]
Reactant: CCC(=O)Cl
Reactant: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=O)On1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(C#N)cc21
Yield: 95 %

Procedure:
A solution of 0.4 g (1.48 mmol) 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline -2,3(1H,4H)-dione in 50 ml dry tetrahydrofuran was added 0.25 ml (1.82 mmol) dry triethylamine and 0.15 ml (1.72 mmol) propionyl chloride. The mixture was refluxed for 30 min., and then evaporated in vacuo. The residue was stirred with water to give 0.46 g (95%) 7-cyano-1-propionyloxy-6-trifluoromethyl-quinoxaline-2,3(1H,4H)-dione. M.p. 227° C. 1H-NMR (DMSO-d6): 8.37 (1H, s), 7.73 (1H, s), 4.5 (2H, q), 1.35 (3H, t).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)=[C:4]([CH2:16][Br:17])[CH:3]=1.[N+:18]([O-])([O-:20])=[O:19].[K+]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:11]([N+:18]([O-:20])=[O:19])=[C:10]2[C:5]([N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)=[C:4]([CH2:16][Br:17])[CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: COc1nc2cc(Br)cc(CBr)c2nc1OC
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1nc2c(CBr)cc(Br)c([N+](=O)[O-])c2nc1OC
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
20 ml of sulfuric acid are cooled to 0° C. and then 5 g (13.8 mmol) of 7-bromo-5-bromomethyl-2,3-dimethoxy-quinoxaline are added. After a further 15 minutes, 1.46 g (1.05 equiv.) of potassium nitrate are added and the mixture is stirred for 15 hours at 20° C. The mixture is poured onto ice, and the solid is filtered off and washed with water. The title compound is obtained in the form of a beige solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([OH:21])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:22][CH:23]([CH3:29])[CH2:24][CH2:25][C:26](Cl)=[O:27].C(N(CC)CC)C>C(Cl)Cl>[CH3:22][CH:23]([CH3:29])[CH2:24][CH2:25][C:26]([NH:1][CH2:2][CH2:3][C@H:4]([OH:21])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:27]
Reactant: CC(C)CCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCC(=O)NCC[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
To (3S,4S)-1-amino-3-hydroxy-4-t-butyloxycarbonylamino-5-cyclohexylpentane (30.8 mg, 0.102 mmol) in dry methylene chloride (3 mL) at 0° C. was added 4-methylpentanoyl chloride (17.0 microliters, 0.123 mmol) and triethylamine (20.0 microliters, 0.143 mmol). The mixture was stirred at 0° C. for 1 hour, evaporated, taken up in methanol (3 mL) and treated with 1M NaOH (1 mL). After stirring for 1 hour, the mixture was diluted with ether, washed sequentially with 0.5M H3PO4, saturated NaHCO3 solution, and brine, and then dried over Na2SO4 and evaporated to afford 41.0 mg (100%) of the desired product as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:32])[C@@H:9]([CH3:31])[C:10]([NH:12][C@@H:13]([CH:28]([CH3:30])[CH3:29])[C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C@H:17]1[C:25]([OH:27])=O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[F:66][C:67]1[CH:73]=[CH:72][CH:71]=[CH:70][C:68]=1[NH2:69]>CN(C=O)C>[F:66][C:67]1[CH:73]=[CH:72][CH:71]=[CH:70][C:68]=1[NH:69][C:25]([C@H:17]1[N:16]([C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([N:8]([CH3:32])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH3:31])[CH:28]([CH3:29])[CH3:30])[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18]1)=[O:27]
Reactant: Nc1ccccc1F
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
In a 50 mL round-bottomed flask, (S)-1-((S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-3-methylbutanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Intermediate 8) (50 mg, 111 μmol, Eq: 1.00) and HATU (50.9 mg, 134 μmol, Eq: 1.2) were combined in DMF to give a colorless solution. Diisopropylethylamine (23.4 μL, 134 μmol, Eq: 1.2) and 2-fluoroaniline (14.9 mg, 134 μmol, Eq: 1.2) were added. The reaction was stirred at rt for 1 h and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 10% to 40% EtOAc in hexanes) to give tert-butyl (S)-1-((S)-1-((S)-2-(2-fluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate as a colorless oil (39 mg), m/z=542 (M+H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].CO[CH:12]([N:15]([CH3:17])[CH3:16])OC>>[CH2:8]([O:7][C:1](=[O:6])[C:2](=[CH:12][N:15]([CH3:17])[CH3:16])[C:3](=[O:4])[CH3:5])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: COC(OC)N(C)C
Product: CCOC(=O)C(=CN(C)C)C(C)=O
Yield: 99.3 %

Procedure:
Add ethyl acetoacetate (15 mL, 0.118 mol) to dimethoxymethyl-dimethyl-amine (19 mL, 0.142 mol) and reflux the mixture for 1 hr. Evaporate the mixture to give 2-dimethylaminomethylene-3-oxo-butyric acid ethyl ester (21.7 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3B3OC(C)(C)C(C)(C)O3)[S:8][C:7]=2[CH:6]=1)=[O:4].Cl[C:29]1[O:30][C:31]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:32][C:33](=[O:35])[CH:34]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:10]3[C:9](=[CH:14][CH:13]=[CH:12][C:11]=3[C:29]3[O:30][C:31]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[CH:32][C:33](=[O:35])[CH:34]=3)[S:8][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=c1cc(Cl)oc(N2CCOCC2)c1
Reactant: COC(=O)c1ccc2c(c1)Sc1cccc(B3OC(C)(C)C(C)(C)O3)c1S2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)Sc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Temperature: 90 °C

Procedure:
6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-thianthrene-2-carboxylic acid methyl ester (1.1 g, 2.83 mmol), 2-chloro-6-morpholin-4-yl-pyran-4-one (0.73 g, 3.4 mmol) and K2CO3 (0.8 g, 5.66 mmol) were dissolved in dry 1,4-dioxane (7 ml). The mixture was degassed for 15 mins and Pd(PPh3)4 (0.16 g, 5 mol %) was then added The dark brown mixture was heated to 90° C. under an atmosphere of N2 for 24 hour. The reaction mixture was concentrated in vacuo and water (100 ml) was added. The brown solid was filtered and washed with water (1.23 g, 96%). m/z (LC-MS, ESP), RT=4.49 min, (M++1)=454.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.CCCCCC>C(OCC)(=O)C>[CH2:1]([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)[CH:16]=2)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1ccc2c(c1)C1(CCCCC1)C(=NOCc1ccccc1)N2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Fc1ccc(-c2ccc3c(c2)C2(CCCCC2)C(=NOCc2ccccc2)N3)cc1
Yield: 65.4 %

Procedure:
Prepared from 5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′(1′H)-one 2′(O-benzyloxime) (1.0 g, 2.6 mmol), and 4-fluorophenyl boronic acid (0.72 g, 5.2 mmol) according to Example 45 procedure A. The product was purified by flash silica gel chromatography; (eluant: 10:0.5 hexane: ethyl acetate) to give the desired product (0.70 g, 1.7 mmol, 67%) as a viscous oil. 1H NMR (500 MHz, DMSO-d6) δ1.42-1.77 (8H, m) 1.95-1.99 (2H, q) 5.00 (2H, s) 6.84 (1H, d, J=8.1 Hz) 7.21-7.63 (1H, m) 9.58 (1H, s); MS (ESI(−ve)) m/z 399 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([CH3:12])([CH3:11])[CH2:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:5]=2[N:6]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>N1C=CC=CC=1>[CH3:13][C:8]1([CH3:14])[CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][CH3:20])[S:3][C:4]=2[C:10]([CH3:12])([CH3:11])[CH2:9]1
Reactant: CCOC(=O)Cl
Reactant: CC1(C)Cc2nc(N)sc2C(C)(C)C1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc2c(s1)C(C)(C)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Amino-5,5,7,7-tetramethyl-4,5,6,7-tetrahydrobenzothiazole (16 grams; 0.075 mol) dissolved in pyridine (100 ml) was charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. Ethyl chloroformate (11 grams; 0.1 mol) was then added dropwise with stirring and cooling of the reaction mixture. After the addition was completed the reaction mixture was allowed to warm to room temperature and stirring was continued for a period of about 1 hour. After this time the reaction mixture was poured into ice water resulting in a white precipitate. The precipitate was recovered by filtration, was dried and recrystallized from methanol to yield the desired product ethyl N-(5,5,7,7-tetramethyl-4,5,6,7-tetrahydrobenzothiazol-2-yl) carbamate having a melt point of 124° to 125° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][CH2:43][N:44]1[CH2:48][CH2:47][CH2:46][C:45]1=O>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14](=[O:15])[NH:41][CH2:42][CH2:43][N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: NCCN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCCN1CCCC1
Yield: 8.9 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (100 mg, 0.18 mmol) and N-(2-aminoethyl)-pyrrolidinone (33 mg, 0.29 mmol) according to Method C with HPLC purification to give the title compound (10 mg). 1H-NMR (400 MHz, CD3OD) δ 1.36 (s, 9H) 2.05 (s, 4H) 2.68-3.20 (m, 8H) 3.39 (m, 4H) 4.28 (m, 1H) 4.39 (m, 1H) 4.69 (s, 2H) 7.05-7.40 (m, 7H) 7.52 (s, 1H); HRMS m/z 626.2929 (calc. of monoisotopic mass for C32H42N4O9 gives 626.2952).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:8])[CH:7]=1.[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH2:27][CH2:28][O:29][S:30]([CH3:33])(=[O:32])=[O:31])=[C:22]([CH:25]=1)[CH:23]=O.[Na]>ClC(Cl)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH:8][CH2:23][C:22]2[CH:25]=[C:18]([O:17][CH3:16])[CH:19]=[CH:20][C:21]=2[O:26][CH2:27][CH2:28][O:29][S:30]([CH3:33])(=[O:31])=[O:32])[CH:7]=1
Reactant: COc1ccc(OCCOS(C)(=O)=O)c(C=O)c1
Reactant: Nc1cc(F)ccc1Oc1ccccc1
Agent: [Na]
Solvent: O
Solvent: CC(Cl)Cl
Product: COc1ccc(OCCOS(C)(=O)=O)c(CNc2cc(F)ccc2Oc2ccccc2)c1
Yield: 62 %

Procedure:
To stirred solution of 9.1 g (45 mmol) 1b, 12.3 g (45 mmol) 4a and one drop of glacial acid in 60 ml dichloroethane (pH=5) were added 14.8 g (70 mmol) sodium tris-acetoxy hydro borane. The reaction mixture was stirred over night and diluted with 5 ml water. The pH value was adjusted with aqueous sodium hydroxyd solution to pH=8-9. The mixture was extracted three times with dichloromethane. The combined organic phases were washed with water and brine and were dried with magnesium sulfate. The desired crude product 4b was obtained in 62% yield (12.9 g, 27.9 mmol) as yellow oil. The crude product 4b was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([C:11]([OH:13])=[O:12])[CH2:6][CH2:5]2.Cl.[CH3:15]O>O1CCOCC1>[CH3:15][O:12][C:11]([CH:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)=[O:13]
Reactant: O=C(O)C1CCc2cc(Br)ccc21
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C1CCc2cc(Br)ccc21
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of (rac)-5-bromo-indan-1-carboxylic acid (1.326 g, 5.5 mmol) in MeOH (55 ml) was treated with 4N HCl in dioxane (15 ml) and the mixture was stirred at reflux for 7 h. The yellow solution was allowed to cool to room temperature and all volatiles were removed. The remaining brown oil was purified by chromatography (silica gel; heptane/EtOAc 95:5) to obtain the title compound as light yellow oil (1.31 g, 93%).