Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([O:24]C)=O)[CH:20]=3)[NH:15][C:14]=2[OH:26])=[N:11][CH:12]=1)[CH2:4][CH3:5])[CH3:2].[ClH:27].[NH2:28][CH2:29][CH2:30][S:31]([CH3:34])(=[O:33])=[O:32]>C(#N)C>[ClH:27].[CH3:34][S:31]([CH2:30][CH2:29][NH:28][C:22]([C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([OH:26])=[C:13]2[C:10]1[CH:9]=[CH:8][C:7]([CH2:6][N:3]([CH2:1][CH3:2])[CH2:4][CH3:5])=[CH:12][N:11]=1)=[O:24])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)CCN
Reactant: CCN(CC)Cc1ccc(-c2c(O)[nH]c3ccc(C(=O)OC)cc23)nc1
Agent: Cl
Solvent: CC#N
Product: CCN(CC)Cc1ccc(-c2c(O)[nH]c3ccc(C(=O)NCCS(C)(=O)=O)cc23)nc1

Procedure:
The title compound was prepared as described for Example 67 using methyl 3-{5-[(diethylamino)methyl]pyridin-2-yl}-2-hydroxy-1H-indole-5-carboxylate (0.071 g, 0.2 mmol) and (2-aminoethyl)methylsulfone hydrochloride (0.080 g, 0.5 mmol) as starting materials. The base was obtained after preparative HPLC purification (XTerra®PrepMS C8 columns 10 μm, 19×300 mm; 0.1 M NH4OAc buffer/acetonitrile, from 90:10 to 40:60, as eluent gradient) as an orange yellow solid (0.030 g, 34% yield), which was transformed to the yellow hydrochloride salt (0.023 g, 72% yield): 1H NMR (CD3OD, 400 MHz) δ 8.21 (s, 1H), 8.11 (s, 1H), 7.95 (s, 2H), 7.60 (dd, J=8.0, 1.2 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 4.35 (s, 2H), 3.93 (t, J=6.4 Hz, 2H), 3.51 (t, J=6.4 Hz, 2H), 3.29 (m, 4H), 3.09 (s, 3H), 1.43 (t, J=7.2 Hz, 6H); MS (EI) m/z 445 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][C:11]=2[CH2:19][O:20][CH2:21][C:22]([OH:24])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:28])=O>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][C:11]=2[CH2:19][O:20][CH2:21][C:22]([Cl:28])=[O:24])=[CH:4][CH:3]=1
Reactant: O=C(O)COCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)COCc1nc2ccccn2c1C#Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.5 g (4.63 mmol) of 2-((3-((4-fluorophenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methoxy)acetic acid were suspended in 40 ml of dichloromethane with magnetic stirring, the mixture was placed in a bath at 0° C. and then 1.215 ml (13.88 mmol) of oxalyl chloride were added dropwise, finally, a few drops of dimethylformamide were added. The cold bath was withdrawn and then the mixture was stirred at r.t. for 1 h. The reaction medium was concentrated in vacuo and immediately used in the next step.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:7][NH:6][CH2:5][CH:4]1[C:8]1[NH:13][C:12](=[O:14])[C:11]2=[CH:15][N:16]=[C:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:10]2[N:9]=1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.[BH3-]C#N.[Na+]>ClCCCl.C(O)(=O)C>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:6]2[CH2:7][CH:3]([CH3:2])[CH:4]([C:8]3[NH:13][C:12](=[O:14])[C:11]4=[CH:15][N:16]=[C:17]([CH:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)[N:10]4[N:9]=3)[CH2:5]2)=[CH:27][CH:26]=1
Reactant: CC1CNCC1c1nn2c(C3CCOCC3)ncc2c(=O)[nH]1
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC1CN(Cc2ccc(F)cc2)CC1c1nn2c(C3CCOCC3)ncc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.5 %

Procedure:
To a solution of compound 9 (80 mg, 0.263 mmol) and 4-fluorobenzaldehyde (326 mg, 2.63 mmol) in 1,2-dichloroethane (15 mL) was added 2 drops of acetic acid. The resulting solution was stirred at room temperature for one hour. Then NaBH3CN (178 mg, 2.63 mmol) was added to the reaction in portions. The resulting mixture was stirred at room temperature for 16 hours. LC-MS showed that the starting material was almost consumed. The reaction mixture was quenched with water (40 mL), and extracted with CH2Cl2 (30 mL×3). The combined organic phases were washed with brine (30 mL), and dried over Na2SO4. After filtered, the filtrate was concentrated in vacuum. The residue was purified by preparative TLC to afford the desired product (20 mg, 21% yield) as a white solid. LC-MS: m/z 412.2 [M+1]+. 1H NMR (400 MHz, CD3OD-d4): δ 8.27 (s, 1H), 7.61 (s, 1H), 7.35˜7.31 (m, 2H), 7.02˜6.98 (m, 2H), 3.96˜3.93 (m, 2H), 3.79˜3.70 (m, 2H), 3.51˜3.39 (m, 3H), 3.15˜3.11 (m, 1H), 3.05˜2.95 (m, 2H), 2.84˜2.79 (m, 1H), 2.61˜2.57 (m, 1H), 2.33˜2.29 (m, 1H), 1.93˜1.87 (m, 2H), 1.80˜1.77 (m, 2H), 1.09 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5]Br)[CH3:2].[C:8]1([CH2:14][O:15][C:16]([NH:18][CH:19]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=3[NH:21][C:20]2=[O:36])=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][N:21]1[C:22]2[CH:35]=[CH:34][CH:33]=[CH:32][C:23]=2[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:25][CH:19]([NH:18][C:16]([O:15][CH2:14][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:17])[C:20]1=[O:36])[CH3:2]
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2)c2ccccc21

Procedure:
The procedure of Example 4 was employed using equimolar amounts of ethylbromoacetate and 1,3-dihydro-3(R,S)-(phenylmethyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one. The chromatographed product (ethyl acetate-hexane) was dried in vacuo at room temperature over P2O5 : m.p. 65°-66° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:7](=[O:8])[C:6]([CH3:10])([CH3:9])[C:5](=[O:11])[CH2:4][C:3]1=[O:12].[F:14][CH:15]([F:29])[C:16]1[C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]([C:26](O)=[O:27])=[CH:18][CH:17]=1.C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C[Si](C#N)(C)C>[F:29][CH:15]([F:14])[C:16]1[CH:17]=[CH:18][C:19]([C:26]([CH:4]2[C:3](=[O:12])[C:2]([CH3:13])([CH3:1])[C:7](=[O:8])[C:6]([CH3:9])([CH3:10])[C:5]2=[O:11])=[O:27])=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2
Reactant: O=C(O)c1ccc(C(F)F)c2ncccc12
Reactant: CC1(C)C(=O)CC(=O)C(C)(C)C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)C(C(=O)c2ccc(C(F)F)c3ncccc23)C(=O)C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
0.26 g (1.4 mmol) of 2,2,4,4-tetramethylcyclohexane-1,3,5-trione was dissolved in 10 ml of acetonitrile, 0.34 g (1.4 mmol) of 8-difluoromethyl-5-quinolinecarboxylic acid and 0.38 g (1.9 mmol) of dicyclohexylcarbodiimide were added and the mixture was stirred at 25° C. for 17 hours. 0.57 g (5.6 mmol) of triethylamine and 5 drops of trimethylsilyl cyanide were then added to the suspension, and stirring was continued at 25° C. for a further 25 hours. 50 ml of 5% strength potassium carbonate solution were subsequently added, the mixture was filtered, the filtrate was washed with methyl tert-butyl ether, the aqueous phase was adjusted to pH 2 using concentrated hydrochloric acid and the precipitate was filtered off, washed with water and dried. Yield: 0.25 g (colorless crystals);
Reaction SMILES: [CH3:1][C:2]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH:11]=[O:12])[CH2:6]1)([CH3:4])[CH3:3].[CH3:13][C:14]([CH3:17])([O-])[CH3:15].[K+].C(Cl)C(=C)C>CN(C=O)C>[CH3:15][C:14](=[CH2:13])[CH2:17][C:7]1([CH:11]=[O:12])[CH2:8][CH2:9][CH2:10][CH:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:6]1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)C1CCCC(C=O)C1
Agent: C=C(C)CCl
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)CC1(C=O)CCCC(C(C)(C)C)C1
Temperature: 155 °C
Yield: 39.1 %

Procedure:
Similar to Example 6, 17.0 g of 3-(1,1-dimethylethyl)cyclohexane carboxaldehyde (prepared by the method of E. Heilweil and J. Virgilio, Organic Preparations and Procedures, 14 (1-2), 9 (1982) at a purity of 87% (0.088 mole) in 20 ml of DMF, 11.9 g of potassium t-butoxide (0.10 mole) in 60 ml of DMF, and 12.0 g of methallyl chloride (0.13 mole) in 10 ml of DMF were reacted in the usual manner. The resulting mixture of O- and C-alkylates, 21.6 g, was heated at 155° C. for 1 hour. The crude aldehyde so obtained, 19 g, was distilled to afford 8.7 g of purified product (45% yield). BP 57° C./0.1 mmHg; 1H-NMR (300 MHz), δ 0.85 (9H, s), 0.97-1.45 (3H, m), 1.66 (3H, s), 1.68-1.74 (3H, m), 2.03-2.40 (5H, m), 4.66 (1H, s), 4.84 (1H, s), 9.50 (1H, s); 13C-NMR (75 MHz), δ 23.26, 24.63, 26.60, 27.34, 31.40, 32.46, 33.79, 44.31, 47.74, 50.56, 115.33, 140.77, 207.33; IR (Neat), 2970, 2690, 1720, 1635, 1450, 1360, 895 cm-1 ; MS (m/e), 222 (M+), 207, 166 (Base), 137, 123, 109, 95, 81, 57, 41.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][CH3:28])[CH2:25]O)[C:5]1=[O:29])[CH:2]=[CH2:3].C1(S)C=CC=CC=1.[CH3:38][Si:39]([CH2:42][SH:43])([CH3:41])[CH3:40]>>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][S:43][CH2:42][Si:39]([CH3:41])([CH3:40])[CH3:38])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CC)CO)C1=O
Reactant: C[Si](C)(C)CS
Agent: Sc1ccccc1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CSC[Si](C)(C)C)C1=O

Procedure:
The title compound was prepared from (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B) by a procedure similar to the one described in Example 300, Step A, replacing benzenethiol with the appropriate amount of (trimethylsilyl)methanethiol.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:10]2[C:15]([C:16]=1[NH2:17])=[CH:14][C:13]([C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[N:9]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:10]2[C:15]([C:16]=1[N:17]=[C:33]=[O:35])=[CH:14][C:13]([C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)c2cc(C(F)(F)F)ccc2n1C(=O)OCc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1c(N=C=O)c2cc(C(F)(F)F)ccc2n1C(=O)OCc1ccccc1

Procedure:
To a solution of 3-amino-1-benzyloxycarbonyl-5-trifluoromethylindole-2-carboxylic acid tert-butyl ester 5D (1.78 g, 4.10 mmol) in anhydrous toluene (40 mL) was added triphosgene (0.42 g, 1.41 mmol) and triethylamine (0.83 g, 8.22 mmol). The reaction mixture was heated under reflux for 2 hours. Toluene (50 mL) was added and the organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure to provide 1-benzyloxycarbonyl-3-isocyanato-5-trifluoromethylindole-2-carboxylic acid tert-butyl ester 5E which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([C:11]#[C:12][CH3:13])[C:5]=1[NH2:14].[CH:16]#CCC.COC(=O)C1C=C(Cl)C=C(I)C=1N>C(N(CC)CC)C.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([C:11]#[C:12][CH2:13][CH3:16])[C:5]=1[NH2:14]
Reactant: CC#Cc1cc(Cl)cc(C(=O)OC)c1N
Reactant: C#CCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: COC(=O)c1cc(Cl)cc(I)c1N
Solvent: CCN(CC)CC
Product: CCC#Cc1cc(Cl)cc(C(=O)OC)c1N
Yield: 37 %

Procedure:
The title compound was synthesized in analogy to 2-amino-5-chloro-3-prop-1-ynylbenzoic acid methyl ester (described in example S85) using 1-butyne (excess ca 3 ml), 2-amino-5-chloro-3-iodo-benzoic acid methyl ester (prepared as described in example S85) (430 mg, 1.38 mmol), copper (I) iodide (19 mg, 0.10 mmol) and bis(triphenyl-phosphine) palladium (II) chloride (71 mg, 0.10 mmol) in triethylamine (10 ml). The final compound was purified by flash column chromatography (9:1 cyclohexane:EtOAc) to give 2-amino-3-but-1-ynyl-5-chlorobenzoic acid methyl ester (120 mg, 37%) as a yellow oil. 1H NMR (CDCl3, 300 MHz): δ 7.76 (d, J=2.5 Hz, 1H), 7.35 (d, J=2.5 Hz, 1H), 6.37 (br s, 2H), 3.87 (s, 3H), 2.49 (q, J=7.5 Hz, 2H), 1.27 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C@@H:9]1[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCC[CH2:38]1.C1(C)C=CC=CC=1>C[C-]1C=CC=C1.[C-]1(C)C=CC=C1.[Ti+2].C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([O:14][C:15]([C:16]2[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:21]=2)=[CH2:38])[C@@H:9]1[C:30]1[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: Fc1ccc([C@H]2[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)OCCN2Cc2ccccc2)cc1
Agent: [Ti+2]
Agent: C[c-]1cccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=C(O[C@H]1OCCN(Cc2ccccc2)[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 69 %

Procedure:
A solution of 4-benzyl-2-(R)-[3,5-bis(trifluoromethyl)benzyloxy]-3-(S)-(4-fluorophenyl)morpholine (2.50 g, 4.9 mmol) and dimethyl titanocene (2.50 g, 12.0 mmol) in 35 ml of a 1:1 v/v tetrahydrofuran:toluene mixture is stirred in an oil bath at 80° C. for sixteen hours. The reaction mixture is cooled and centrated in vacuo. Flash chromatography on 150 grams of silica gel using 3:1 v/v hexanes:methylene chloride as the eluant affords 1.71 grams (69%) of the title compound as a solid. If desired, an anlytical sample may be obtained by recrystallization from isopropanol.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28]I>C1COCC1.CCOC(C)=O>[Si:1]([O:8][C@@H:9]1[CH2:14][C@@H:13]([O:15][CH3:28])[CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CO[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a solution of (3R,5R)-benzyl 3-(tert-butyldimethylsilyloxy)-5-hydroxypiperidine-1-carboxylate (1 eq) in 30 mL of THF was added sodium hydride (1.5 eq) and followed by methyl iodide (5 eq) at 0° C. The reaction mixture was allowed to stir at room temperature for 3 hours. The crude mixture was diluted with 120 mL of EtOAc, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:5) to yield (3R,5R)-benzyl 3-(tert-butyldimethylsilyloxy)-5-methoxypiperidine-1-carboxylate (93%). LC/MS (m/z): 380.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]([CH3:18])[CH2:16][O:15][C:14]1=[O:19])[C:5]([O:7]CC)=[O:6].[OH-].[Li+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]([CH3:18])[CH2:16][O:15][C:14]1=[O:19])[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)c1ccc(N2C(=O)OCC2C)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC1COC(=O)N1c1ccc(C(=O)O)cc1Cl

Procedure:
0.90 g (3.17 mmol) ethyl 3-chloro-4-(4-methyl-2-oxo-oxazolidin-3-yl)-benzoate are stirred for 1 hour in 50 ml of methanol with 10 ml 1-molar aqueous lithium hydroxide solution at ambient temperature. The mixture is then evaporated down to 20 ml i. vac., acidified with conc. hydrochloric acid and extracted with ethyl acetate. The combined organic phases are washed with sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac. The residue is crystallised from a little diethyl ether and suction filtered.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.C1CCCCC1.[CH2:15]([O:22][C:23](=[O:39])[CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.IC>C1COCC1.CCOCC>[CH2:15]([O:22][C:23](=[O:39])[CH:24]([CH3:2])[CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:28][CH2:27]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)OCc2ccccc2)CC1
Agent: [Li+]
Solvent: CI
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CC(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a cooled (−78° C.) solution of 1.5M LDA/cyclohexane (6.48 mL, 9.73 mmol) in 50 mL of THF was added dropwise under a nitrogen atmosphere a solution of tert-butyl 4-[3-(benzyloxy)-3-oxopropyl]piperidine-1-carboxylate (2.60 g, 7.48 mmol) in 20 mL of THF. The resulting mixture was stirred at −78° C. for 45 min then was treated dropwise with neat iodomethane (1.40 mL, 22.4 mmol). After stirring at −78° C. for an additional 30 min, the reaction mixture was permitted to warm to rt and stir overnight. The reaction mixture was diluted with ether and washed in sequence with 1N HCl solution, saturated NaHCO3 solution, and brine. The ethereal layer was dried over anhydrous MgSO4, filtered, and concentrated. Purification by MPLC (silica, 25% ethyl acetate/hexanes) afforded tert-butyl 4-[3-(benzyloxy)-2-methyl-3-oxopropyl]piperidine-1-carboxylate.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:35])([F:34])[F:33])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:36](=O)[CH3:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH2:36]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:33])([F:35])[F:34])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3]1)[CH3:37]
Reactant: CC=O
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCNCC3)cc2)ncc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCN1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
To a suspension of 2-(2-(2-(2-((4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (1) (0.020 g, 0.041 mmol) in anhydrous methanol (1.5 mL) were added acetaldehyde (0.0090 mL, 0.17 mmol) and sodium triacetoxyborohydride (0.044 g, 0.21 mmol) under an atmosphere of nitrogen The reaction was stirred at room temperature for 18 hours, the volatiles were removed in vacuo and the residue was diluted with EtOAc (15 mL) and sat. aq. NaHCO3 (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (10 mL), the combined organic layers were washed with water (10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to give a solid which was taken up in DCM (˜10 mL) and methanol (˜1 mL) and concentrated in vacuo. The process was repeated with only DCM twice after which the sample was further dried on high-vacuum to give the title compound (10) (0.016 g, 76% yield) as an white solid; 1H NMR (400 MHz, d6-DMSO) δ 9.97 (s, 1H), 8.60 (s, 1H), 7.57 (d, J=8.9 Hz, 2H), 7.43 (s, 1H), 7.26-7.13 (m, 4H), 6.97-6.87 (m, 3H), 3.50 (s, 2H), 3.13-2.94 (m, 8H), 2.36 (q, J=7.2 Hz, 2H), 1.03 (t, J=7.2 Hz, 3H). 4 Aliphatic protons obscured by the residual DMSO. LCMS Method C: rt 4.82 min; m/z 513.3 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]([NH:15][C@@H:16]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:17][C@H:18]([OH:37])[C@@H:19]([NH:27][C:28]([O:30][CH2:31][C:32]1[S:36][CH:35]=[N:34][CH:33]=1)=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.[ClH:45]>O1CCOCC1>[ClH:45].[NH2:8][C@H:9]([C:13]([NH:15][C@@H:16]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:17][C@H:18]([OH:37])[C@@H:19]([NH:27][C:28]([O:30][CH2:31][C:32]1[S:36][CH:35]=[N:34][CH:33]=1)=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 135 mg (0.27 mmol) of (2S,3S,5S)-5-(N-(N-(t-butyloxycarbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane was added 8 ml of 4M HCl in dioxane. The resulting mixture was stirred at ambient temperature for 1 h and concentrated in vacuo to provide the crude desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1C=[C:5]([CH:39]=[C:40](OC)[C:41]=1OC)[C:6]([N:8]1[CH2:12][CH2:11][C:10](CCN2CCC(NC3NC4C=CC=CC=4N=3)CC2)(C2C=CC(Cl)=C(Cl)C=2)[CH2:9]1)=O.CN(C)C=[O:49].[H-].[Na+].C(OCCCl)C>ClCCl.CO.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:40]([CH2:41][C:3]([O:2][CH3:1])=[O:49])[CH3:39].[CH2:6]([N:8]([CH2:12][CH3:11])[CH2:9][CH3:10])[CH3:5]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: CN(C)C=O
Agent: CCOCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCC(=O)OC
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (0.54 g, 0.82 mmol) and dimethylformamide (15 mL). Add sodium hydride (0.07 g, 60% in oil, 1.8 mmol). After 1 hour, add 2-chloroethyl ethyl ether (1 mL). Heat to 100° C. After 18 hours, cool to ambient temperature and dilute the reaction mixture with dichloromethane. Extract three times with water, dry the organic layer over Na2SO4, filter and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 25/75/1 methanol/ethyl acetate/triethylamine. Collect the product containing fractions, evaporate in vacuo to give a residue, and chromatograph on silica gel eluting with 20/80/0.5 methanol ethyl acetate/triethylamine to give the title compound: Rf=0.23 (silica gel, 30% methanol/ethyl acetate).
Reaction SMILES: C([NH:11][C:12](=[N:46]C(OCC1C=CC=CC=1)=O)[NH:13][CH2:14][CH2:15][CH2:16][C@@H:17]([C:34]([NH:36][C@H:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:38][OH:39])=[O:35])[NH:18][C:19](=[O:33])[CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(OCC1C=CC=CC=1)=O.CC(O)=O.[ClH:61]>[Pd].CO>[ClH:61].[C:21]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:19]([NH:18][C@H:17]([C:34]([NH:36][C@H:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:38][OH:39])=[O:35])[CH2:16][CH2:15][CH2:14][NH:13][C:12](=[NH:11])[NH2:46])=[O:33])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(N=C(NCCC[C@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: N=C(N)NCCC[C@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1

Procedure:
Prepared according to the method described in Example 1(g) above from (R)-Nω,Nω '-bis(Cbz)-N2 -(diphenylacetyl)-(S)-N-(2-hydroxy-1-phenylethyl)-arginine amide (0.250 g; from step (e) above), 10% Pd/C (200 mg) and, instead of HOAc, 50 mL of MeOH with 1 mL of concentrated HCl, yielding 78 mg of the title compound.