Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:18][C@H:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[CH3:20]>>[CH3:28][O:27][C:25]([C:24]1[CH:29]=[CH:30][C:21]([C@@H:19]([NH:18][C:14]([CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[CH3:20])=[CH:22][CH:23]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)C2CCCCN2C(=O)OC(C)(C)C)cc1
Yield: 97.9 %

Procedure:
The title compound (D4) (1.95 g) was prepared according to the general procedure for amides preparation starting from 1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (1.17 g, available from Sigma Aldrich #495875), and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (1.1 g, for preparation see published International Patent application WO 2005/105733). Reaction time: 18 hrs.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:22][CH2:21][CH2:20][C@H:19]2[CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:17])=[C:12]([F:29])[CH:11]=1>>[F:29][C:12]1[CH:11]=[C:10]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][C:13]=1[C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:17]
Reactant: OB(O)c1cccs1
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: O=C(c1ccc(-c2cccs2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure Q starting from 2-thiophene boronic acid and (4-Bromo-2-fluoro-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone to give 29 mg (58%). MS (ES+) 359.1
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:7]=1[O:15][CH3:16])=[O:4].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C1COCC1>[CH3:16][O:15][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: C1COCCN1
Reactant: COc1cccc([N+](=O)[O-])c1NC(=O)CBr
Solvent: C1CCOC1
Product: COc1cccc([N+](=O)[O-])c1NC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 75.6 %

Procedure:
To a solution of 2-bromo-N-(2-methoxy-6-nitrophenyl)acetamide (Step 1, 8.8 g, 30 mmol) in THF (240 mL) was added morpholin (11 mL, 122 mmol) at 0° C. and warmed to rt. After 2.5 h, the reaction mixture was quenched by addition of water (200 mL) and extracted with ethyl acetate (200 mL×2). The combined organic layers were washed with water (200 mL), brine (100 mL) dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2/1) to afford 6.7 g (75%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([O:17]CC)=[O:16].[OH-].[Na+].C(OCC)(=O)C>CO>[O:1]=[C:2]1[CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)CN1CCCC(c2ccccc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)CN1CCCC(c2ccccc2)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of the product from Example 91C (2.7 g, 10.33 mmol) in methanol (10 mL) was added sodium hydroxide (2.0 M) (10.33 ml, 20.66 mmol). After stirring for 30 minutes, thin layer chromatography (100% ethyl acetate) showed complete consumption of the starting material. The reaction was diluted with ethyl acetate (50 mL), washed with 1 N HCl (50 mL) and brine (50 mL), dried over magnesium sulfate, and concentrated to supply the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.41-7.15 (m, 5H), 4.35 (d, J=16.9, 1H), 4.01 (d, J=16.9, 1H), 3.80-3.69 (m, 1H), 3.68-3.51 (m, 1H), 3.44 (dt, J=5.6, 11.3, 2H), 2.31-2.12 (m, 1H), 2.09-1.77 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[C:3]=1[C:4]#[N:5].CS(O)(=O)=[O:16].ClCCl.Cl>O>[NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[C:3]=1[C:4]([NH2:5])=[O:16]
Reactant: CS(=O)(=O)O
Reactant: COc1cc(N)c(C#N)c(OC)c1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COc1cc(N)c(C(N)=O)c(OC)c1
Temperature: 107.5 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
2-amino-4,6-dimethoxybenzonitrile (50.0 g, 0.2805 mol, 1 eq.) was charged to a 3-L glass vessel under N2 atmosphere and agitation was started. Methanesulfonic acid (537 mL, 8.29 mol, 29.5 eq.) was charged to the vessel and the reaction was heated at 100-115° C. for 1-2 hours. Upon verification of reaction completion by HPLC, the batch was cooled to 20-30° C. Upon cooling, dichloromethane (334 mL) and cool water (807 mL) (5-10° C.) was added to keep the temperature in the range of 10-30° C. 50% caustic (423 mL) was charged to the vessel using an addition funnel while maintaining 0-30° C. Fine pH adjustment to 6.5 to 7.5 was completed using either 32% HCl or 50% caustic, or diluted solutions thereof. Upon equilibration, the first organic phase cut was performed. The aqueous layer was extracted two additional times with DCM (371 mL and 286 mL respectively). Dichloromethane (271 mL) was added to the combined organic layers and the organic layer was washed with water (714 mL) to remove methanesulfonate salts. Dichloromethane (79 mL) was added to the combined organic layers and the organic layer was washed once more with water (714 mL) to remove methanesulfonate salts. The batch was distilled using (5-10 inches Hg) vacuum to a pot volume of 6 volumes DCM (300 mL). Solvent exchange with isopropyl acetate (2 exchanges of 402 mL and 484 mL respectively) was completed when less than 1-2% DCM remained and the pot volume was between 400-450 mL. The contents of the vessel were stirred for 1 hour at 85-90° C. The vessel was cooled to 50° C. over at least 2 hours with slow agitation. The vessel was slowly charged with MtBE (250 mL) and the batch was agitated for 30 min at 50° C. The batch was slowly cooled to 30° C. over at least 1 hour. The batch was cooled to −5° C. and 5° C. over at least 2 hours. The batch was held between −5° C. and 5° C. over at least 1 hour. Precipitation was verified through collection of at least two samples from the liquor to determine the amount of 2-amino-4,6-dimethoxybenzamide remaining in solution. The batch was isolated by filtration and the wet cake washed with cold (0° C.) MtBE (100 mL). The 2-amino-4,6-dimethoxybenzamide wet cake was dried in a vacuum oven (40-45 C, 25 inches Hg) to give 2-amino-4,6-dimethoxybenzamide (42.79 g, 0.218 mol, 77.7% yield; 54.5% yield over 5 steps from 3,5-dimethoxyaniline). Variations of the volumes of solvent used during extraction and the precipitation portions in this example may give improved or reduced yield and/or purity. One skilled in the art may modify these conditions for the desired result.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:13][CH2:14][C@@H:15]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]1>C(O)C>[CH3:12][C:2]1[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[F:13][CH2:14][C@@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CF)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: FC[C@@H]1CCNC1

Procedure:
Prepare using the method of Intermediate 49 with p-toluenesulfonic acid monohydrate (0.304 g, 1.87 mmol), tert-butyl (3R)-3-(fluoromethyl)pyrrolidine-1-carboxylate (See Intermediate 56) (0.325 g, 1.87 mmol) and ethanol (2 mL) to give the title compound as a white solid (0.421 g): MS (m/e): 104 (M+1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Cl[C:13]1[N:18]2[CH:19]=[CH:20][N:21]=[C:17]2[N:16]=[C:15]([CH3:22])[CH:14]=1>C(O)C>[CH3:22][C:15]1[CH:14]=[C:13]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=2)[N:18]2[CH:19]=[CH:20][N:21]=[C:17]2[N:16]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(Cl)n2ccnc2n1
Solvent: CCO
Product: Cc1cc(Nc2ccc(C(F)(F)F)cc2)n2ccnc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
4-(trifluoromethyl)aniline (602 mg, 3.74 mmol) was added to the stirred solution of 5-chloro-7-methylimidazo[1,2-a]pyrimidine (522 mg, 3.12 mmol) in excess of absolute ethanol. The reaction mixture was heated intermittently to maintain homogeneity (clear) of the reaction mixture. After stirring overnight at room temperature, the excess ethanol was removed in vacuo and the resultant crude was purified using column chromatography. Yield 0.593 mg (65% yield).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[S:25][C:26]2[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:27]=2[N:28]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH:15]([CH2:14][N:13]([C:24]3[S:25][C:26]4[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:27]=4[N:28]=3)[CH2:12]2)[CH2:16]1)=[O:8]
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Reactant: COc1ccc2nc(Cl)sc2c1
Product: COc1ccc2nc(N3CC4CN(C(=O)c5ccccc5-c5ccccc5)CC4C3)sc2c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-6-methoxy-benzothiazole. MS (ESI): mass calculated for C27H25N3O2S, 455.57; m/z found 456.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[NH2:17].[Br-].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Zn+]>C1COCC1.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>[N+:14]([C:4]1[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=[C:2]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[C:3]=1[NH2:17])([O-:16])=[O:15]
Reactant: [Zn+]c1ccccn1
Reactant: Nc1c(Br)cc(-c2cccnc2)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Nc1c(-c2ccccn2)cc(-c2cccnc2)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A mixture of 2-bromo-6-nitro-4-pyridin-3-yl-phenylamine (100 mg, 1 eq), 2-pyridylzinc bromide (6 eq) and tetrakis(triphenylphosphine)palladium (0.1 eq) in THF (10 mL) was heated at 100° C. for 18 hours. The reaction was quenched with water (2 mL). The product was extracted with EtOAc (20×3). The combined organic layer was then concentrated in vacuo and the residue was purified by chromatography (Silica Gel, EtOAC) to afford the title compound (75 mg) as a yellow solid. (M+1) 293.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[C:12]([O:16][C:17](=O)[O:18]C(C)(C)C)([CH3:15])([CH3:14])[CH3:13]>>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:17](=[O:18])[O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: CNc1ccc(CCN)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Product: CNc1ccc(CCNC(=O)OC(C)(C)C)cc1
Yield: 94.6 %

Procedure:
2.03 g of 2-(4-methylaminophenyl)ethylamine and 3.20 g of di-t-butylcarbonate were subjected to an acylation reaction to obtain 3.20 g of t-butyl 2-(4-methylaminophenyl)ethyl-carbamate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][C:7]=1[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:22][C:23]1[S:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:22][C:23]2[S:27][C:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=3)=[N:25][C:24]=2[CH2:38][O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:8][C:7]=1[CH3:13]
Reactant: FC(F)(F)c1ccc(-c2nc(COc3ccccc3)c(CCl)s2)cc1
Reactant: COC(=O)CCc1ccc(S)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)CCc1ccc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COc2ccccc2)cc1C
Temperature: 25 °C
Yield: 34.5 %

Procedure:
3-(4-Mercapto-2-methyl-phenyl)-propionic acid-methyl ester (126 mg, 0.600 mmol) is dissolved into anhydrous acetonitrile (ACN) (2 mL). Cesium carbonate (326 mg, 1.00 mmol) is added to the reaction, followed by the addition of 5-Chloromethyl-4-phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazole (200 mg, 0.5211 mmol). The reaction is allowed to stir under nitrogen at room temperature and monitored by TLC and HPLC. Upon complete consumption of the chloride, the reaction is diluted with diethyl ether and quenched with 0.1N NaOH. The two phases are separated, then the organic layer washed with water and brine. The organic phase is dried over anhydrous sodium sulfate and concentrated under vacuum. The residue is further purified using either EtOAc/Hexanes (1:9) or Acetone/Hexanes (1:9) gradients on silica gel chromatography to yield 3-{2-Methyl-4-[4-phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenyl}-propionic acid methyl ester (100 mg, 0.1796 mmol) or 30%.
Reaction SMILES: CC(C)([O-])C.[K+].C1(C)C=CC(S([CH2:16][N+:17]#[C-:18])(=O)=O)=CC=1.[C:20]([O:25][CH3:26])(=[O:24])/[CH:21]=[CH:22]/[CH3:23].O>O1CCCC1>[CH3:23][C:22]1[C:21]([C:20]([O:25][CH3:26])=[O:24])=[CH:16][NH:17][CH:18]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: C/C=C/C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c[nH]cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.9 %

Procedure:
To a suspension of potassium tert-butoxide (76.7 g) in tetrahydrofuran (900 mL) was added dropwise a solution of p-toluenesulfonylmethyl isocyanide (94.6 g) and methyl crotonate (48.5 g) in tetrahydrofuran (900 mL) over 30 min. The reaction mixture was stirred at room temperature for 3 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1) to give the title compound as a white solid (yield 16.8 g, 25%).
Reaction SMILES: [C:1]1([CH:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:8][CH2:9][N:10]([CH:30]([CH3:32])[CH3:31])[C:11]([NH:13][C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=3)[N:18]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:39]N1C(=O)CCC1=O>CN(C=O)C>[Cl:39][C:16]1[S:15][C:14]([NH:13][C:11](=[O:12])[N:10]([CH2:9][CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:30]([CH3:31])[CH3:32])=[N:18][C:17]=1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:21][CH:20]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)N(CCC(c1ccccc1)c1ccccc1)C(=O)Nc1nc(-c2ccc(NS(C)(=O)=O)cc2)cs1
Solvent: CN(C)C=O
Product: CC(C)N(CCC(c1ccccc1)c1ccccc1)C(=O)Nc1nc(-c2ccc(NS(C)(=O)=O)cc2)c(Cl)s1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1-(3,3-diphenylpropyl)-1-isopropyl-3-(4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)urea (0.101 g, 0.18 mmol) in DMF (1 mL) at room temperature was added 1-chloropyrrolidine-2,5-dione (0.035 g, 0.26 mmol). The reaction mixture was stirred at room temperature for 2 d. Direct purification by flash column chromatography on silica gel (eluted with 20% to 60% EtOAc in hexanes) gave N-(4-(5-chloro-2-(((3,3-diphenylpropyl)(1-methylethyl)carbamoyl)amino)-1,3-thiazol-4-yl)phenyl)methanesulfonamide 69. Mass spectrum, calculated for C29H31ClN4O3S2 582.2; found 583.1 (M++1).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3].[CH2:18]([O:20][C:21]([CH:23]([S:25][CH2:26][C:27](=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:24])=[O:22])[CH3:19].C([BH3-])#N.[Na+]>C(O)C>[CH2:18]([O:20][C:21]([CH:23]([S:25][CH2:26][CH:27]([NH:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:24])=[O:22])[CH3:19]
Reactant: C[C@H](N)C(=O)N1C2CCCCC2C[C@H]1C(=O)O
Reactant: CCOC(=O)C(=O)CSC(C)C(=O)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CSC(C)C(=O)OCC)N[C@@H](C)C(=O)N1C2CCCCC2C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1 g (4.17 m mols) of (2S)-1-[(S)-alanyl]-2-carboxyperhydroindole, prepared as described in Example 3, Step F, and 4.72 g (19 m mols) of ethyl [(1RS)-1-ethoxycarbonylethylthio]-pyruvate are dissolved in 50 ml of anhydrous ethanol in the presence of 15 g of molecular sieve 4 Å. After 45 minutes' stirring at room temperature, 0.25 g of sodium cyanoborohydride in solution in 2.25 ml of anhydrous ethanol are added within 6 hours.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)=[O:3].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:7]2[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(O)cc1
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(Oc2ccc(C(C)=O)cc2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
138 mg (1 mmol) of 4-fluoroacetophenone were taken and 124 mg (1 mmol) of 4-methoxyphenol were dissolved in DMSO and added thereto, then 200 mg (1.45 mmol) of K2CO3 were added and the mixture was stirred for 8 h at 80° C., then for 6 h at 100° C., then for 3 h at 120° C. and for 3 h at 140° C. The reaction mixture was filtered through basic Alox, washed with DMF/methanol=9/1 and concentrated by rotary evaporation. The substance was purified by reversed-phase chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([NH:11][O:12][CH3:13])=[O:10])=[CH:4][C:3]=1[NH:14][C:15]1[C:20]2=[C:21]([CH:27]([CH3:29])[CH3:28])[C:22]([C:24]([OH:26])=O)=[CH:23][N:19]2[N:18]=[CH:17][N:16]=1.C(N(CC)CC)C.C1(P([N:51]=[N+:52]=[N-:53])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9](=[O:10])[NH:11][O:12][CH3:13])=[CH:4][C:3]=1[NH:14][C:15]1[C:20]2=[C:21]([CH:27]([CH3:28])[CH3:29])[C:22]([C:24]([N:51]=[N+:52]=[N-:53])=[O:26])=[CH:23][N:19]2[N:18]=[CH:17][N:16]=1
Reactant: CONC(=O)c1cc(Nc2ncnn3cc(C(=O)O)c(C(C)C)c23)c(F)cc1F
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CONC(=O)c1cc(Nc2ncnn3cc(C(=O)N=[N+]=[N-])c(C(C)C)c23)c(F)cc1F
Temperature: 40 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a solution of Example 22 (1.11 g, 2.74 mmol) in dioxane (25 mL) was added triethylamine (0.57 mL, 4.1 mmol) followed by diphenylphosphoryl azide (0.77 mL, 3.57 mmol) and the resulting mixture was stirred at 40° C. After 1 h, the mixture was concentrated and the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexanes to afford acyl azide, 4-(2,4-difluoro-5-methoxycarbamoyl-phenylamino)-5-isopropyl-pyrrolo[2, 1-f][1,2,4]triazine-6-carbonyl azide (0.95 g, 81%) as pale yellow foam.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.C([Li])CCC.[CH2:12]([SiH:16]([CH2:23]F)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][CH:14]=[CH2:15]>C1COCC1>[CH2:12]([SiH:16]([CH2:23][CH:2]1[S:3][CH2:4][CH2:5][CH2:6][S:1]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][CH:14]=[CH2:15]
Reactant: C=CCC[SiH](CF)c1ccccc1
Reactant: C1CSCSC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCC[SiH](CC1SCCCS1)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 1,3-dithiane (11.1 g, 91.9 mmol) in THF (150 mL) at −78° C. was added dropwise over 10 min n-butyllithium (1.6 M in hexane, 76.6 mmol), and the solution was stirred for 2 h under argon. A solution of 42 (11.9 g, 61.3 mmol) in THF (120 mL) was added dropwise over 30 min, and the mixture was stirred for 3 h at −78° C. and overnight at rt. The reaction mixture was quenched with water (100 mL) and extracted thrice with 100-mL portions of EtOAc. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated. Flash chromatography over silica gel (1/9 EtOAc:hexane) gave 43 contaminated with 1,3-dithiane. The latter was removed by sublimation (54° C., 8.0 mm Hg) to provide pure 43 as a yellow oil (9.0 g, 50% for three steps from dichlorosilane): Rf=0.55 (1/9 EtOAc:hexane); 1H NMR (300 MHz, CDCl3) δ 7.63–7.61 (m, 2H), 7.42–7.38 (m, 3H), 5.97–5.84 (m, 1H), 5.06–4.90 (m,2H), 3.95 (s, 1H) 2.93–2.83 (m, 2H), 2.72–2.67 (m, 2H), 2.21–1.97 (m, 4H), 1.18–1.09 (m, 2H), 0.49 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 141.0, 134.5, 134.1, 129.9, 127.9, 113.2, 32.9, 31.1, 31.0, 27.2, 25.8, 10.8, −7.0; MS (FAB) m/e (rel. intentsity) 293 (MH+, 23), 239 (21), 175 (20), 159 (9), 149 (58), 121 (100), 119 (37), 115 (23), 105 (34), 97 (28), 92 (22); HRMS (FAB) calcd for C15H23S2Si: 293.0854, found: 293.0861. Anal. Calcd for C15H22S2Si: C, 61.16; H, 7.53. Found C, 61.31; H, 7.74.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[OH:10].[CH2:11](N(CC)CC)[CH3:12].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)(=O)C>C1(C)C(C)=CC=CC=1>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]2[N:1]=[C:11]([CH3:12])[O:10][C:3]=2[CH:4]=1
Reactant: CCN(CC)CC
Reactant: Cc1cc(Br)cc(O)c1N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Solvent: CC(=O)Cl
Product: Cc1nc2c(C)cc(Br)cc2o1

Procedure:
To 1.5 g (7.42 mmol) 2-amino-5-bromo-3-methyl-phenol in 30 mL xylene is added 1.15 mL (8.19 mmol) triethylamine, 0.68 g (2.70 mmol pyridinium p-toluenesulfonate and 0.55 mL (7.74 mmol) acetyl chloride. The mixture is refluxed for 3 d. Subsequently the solvent is removed in vacuo, and the residue is treated with 50 mL ethylacetate. The mixture is extracted twice with water. The combined aq. layers are extracted with ethylacetate. The combines organic layers are dried and concentrated to yield the desired product.
Reaction SMILES: [NH2:1][CH:2]([C:7]([F:10])([F:9])[F:8])[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])O.[Na+].[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31](ON3C(=O)CCC3=O)=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.Cl>O.O1CCCC1>[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([NH:1][CH:2]([C:7]([F:10])([F:9])[F:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: NC(CC(=O)O)C(F)(F)F
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 47.5 %

Procedure:
3-Amino-4,4,4-trifluorobutyric acid (10 g, 63.7 mmol) was added to a solution of sodium hydrogen carbonate (6.95 g, 82.8 mmol) in water (100 mL). A solution of 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy-2,5-pyrrolidinedione (Fmoc-OSu; 25.78 g, 76.4 mmol) in tetrahydrofuran (200 mL) was added. The solution was stirred at room temperature for 19 h and then acidified to pH 1 with 3 M HCl (250 mL). The mixture was extracted with ethyl acetate (250 mL then 100 mL) and the combined organic layers were washed with saturated brine (3×100 mL), dried (Na2SO4), filtered and concentrated to approximately 200 mL. Crystallization occurred on concentration. The mixture was allowed to stand for 10 min, then the solid was filtered off, washed with ethyl acetate and dried in a vacuum oven at 50° C. to give 3-[N-[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4,4,4-trifluorobutyric acid (11.47 g) as a white solid, mp 187-189° C. The mother liquor was concentrated to 80 mL. Crystallization occurred on concentration. The solid was filtered off, washed with ethyl acetate and dried in a vacuum oven at 50° C. to give a second batch of product (4.69 g). The overall yield was16.16 g (67%).