Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:19]2[C:14](=[C:15]([OH:20])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)(=[O:10])=[O:9].[C:21](#[N:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].ICC#N>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:19]2[C:14](=[C:15]([O:20][CH2:22][C:21]#[N:23])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)(=[O:9])=[O:10]
Reactant: O=S(=O)(c1ccccc1F)n1ccc2c(O)cccc21
Reactant: CC#N
Agent: N#CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: N#CCOc1cccc2c1ccn2S(=O)(=O)c1ccccc1F
Temperature: 0 °C
Yield: 77 %

Procedure:
A 50 mL round-bottomed flask equipped with a magnetic stirrer was charged with 1-(2-fluorobenzenesulfonyl)-4-hydroxy-1H-indole (0.600 g, 0.002 mol), 25 mL of anhydrous acetonitrile and potassium carbonate (1.104 g, 0.008 mol). The reaction mixture was cooled to 0° C. and iodoacetonitrile (0.500 g, 0.003 mol) was added dropwise over five minutes. The reaction mixture was allowed to warm to ambient temperature and stirred for eighteen hours. The mixture was taken in ether (200 mL), washed with water (2×30 mL) and brine (1×30 mL), dried over MgSO4 and concentrated in vacuo. The resulting oily brown residue was purified by flash chromatography (8:2 ethyl acetate/hexanes) to give [1-(2-fluoro-benzenesulfonyl)-1H-indol-4-yloxy]acetonitrile as a crystalline solid (0.507 g, 77%). 1H NMR (300 MHz, CDCl3) δ: 4.87 (s, 2 H), 6.76 (d, 1 H, J=13.18), 6.77 (d, 1 H, J=1.51), 7.11 (dt, 1 H, J=8.29, J=1.13), 7.23 (t, 1 H, J=8.29), 7.29 (dt, 1 H, J=7.73, J=1.13), 758 (m, 4 H), 8.03 (m, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([C:24]1[N:25]=[CH:26][N:27](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:28]=1)([OH:23])[CH:20]([CH3:22])[CH3:21])[CH:13]=[CH:12]2)[C:2]1C=CC=CC=1.C1C[O:51]CC1>CO.[C].[Pd]>[C:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)([OH:23])[CH:20]([CH3:22])[CH3:21])[CH:13]=[CH:12]2)(=[O:51])[CH3:2]
Reactant: CC(C)C(O)(c1ccc2cc(OCc3ccccc3)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: C1CCOC1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Oc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Reaction time: 5 h

Procedure:
1-(6-Benzyloxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (2.4 g) was dissolved in a mixed solution of THF and methanol (1:1, 160 ml). To the solution was added 10% palladium carbon (0.8 g). The mixture was stirred for 5 h under hydrogen atmosphere. The catalyst was filtered off, and filtrate was concentrated. The residue was crystallized from THF-ethyl acetate to give the titled compound (1.20 g) as a colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([F:17])[CH:13]([NH2:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.Br[CH2:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30].CCN(CC)CC>CCOC(C)=O>[F:17][CH:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH:13]1[N:18]1[CH2:25][CH2:26][CH2:27][CH2:28][C:29]1=[O:30]
Reactant: O=C(Cl)CCCCBr
Reactant: NC1CN(C(=O)OCc2ccccc2)CCC1F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(F)C(N2CCCCC2=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-amino-4-fluoro-piperidine-1-carboxylic acid benzylester 37.1 (1.0 eq) in THF (40 eq) cooled in an ice water bath was added 5-bromo-pentanoyl chloride (1 eq) and Et3N (2 eq) dropwise. The reaction mixture was warmed to RT and stirred for 2 h, diluted with EtOAc and washed with aq 5% citric acid (500 mL), dried over Na2SO4, concentrated in vacuo to afford an oil. The oil was purified by flash chromatography (10% EtOAc/Hexane to 100% EtOAc) to provide the amide intermediate which was dissolved in THF (30 mL) and treated with sodium hydride (60% in mineral oil, 5 eq) at 65° C. for 16 h. The reaction mixture cooled in an ice water bath and methanol added dropwise, diluted with EtOAc and washed with aq. 5% citric acid, dried over Na2SO4 and concentrated to afford an oil. The oil was purified by flash chromatography (EtOAc to 5% CH3OH/EtOAc) to provide compound 37.2 as a colorless oil (62% yield). EIMS (m/z): calcd. for C18H23FN2O3 (M++1) 335.39. Found 335.00.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH2:7][C:6]=2[CH:16]=1.CCN(CC)CC.[CH2:24]([S:27](Cl)(=[O:29])=[O:28])[CH2:25][CH3:26]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH:10]3[CH2:11][CH2:12][N:13]([S:27]([CH2:24][CH2:25][CH3:26])(=[O:29])=[O:28])[CH2:14][CH2:15]3)[CH2:7][C:6]=2[CH:16]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: Brc1ccc2c(c1)CC(C1CCNCC1)O2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of 4-(5-bromo-2,3-dihydrobenzofuran-2-yl)piperidine (Compound 9A, 185 mg, 0.656 mmol) and Et3N (0.18 mL, 1.311 mmol) in CH2Cl2 (6 mL) at 0° C. was added propane-1-sulfonyl chloride (140 mg, 0.983 mmol). Upon completion of addition, the reaction mixture was warmed to room temperature, where it stirred for 2 hours. After this time, the reaction mixture was diluted with CH2Cl2 (5 mL) and washed with aqueous NaHCO3 (saturated, 5 mL). The organic layer was separated, dried (Na2SO4), filtered, and concentrated to yield a residue. The residue was purified by column chromatography (silica gel, hexanes/EtOAc gradient 0 to 50% EtOAc) to afford Compound 10A as a white solid (213 mg, 0.549 mmol, 84% yield). 1H NMR (500 MHz, CDCl3) δ ppm 7.27-7.25 (m, 1 H), 7.21 (dd, J=8.4, 2.1 Hz, 1 H), 6.63 (d, J=8.3 Hz, 1 H), 4.63-4.53 (m, 1 H), 3.93-3.84 (m, 2 H), 3.22 (dd, J=15.7, 9.1 Hz, 1 H), 2.96 (dd, J=15.8, 8.1 Hz, 1 H), 2.91-2.86 (m, 2 H), 2.80-2.71 (m, 2 H), 2.05-1.99 (m, 1 H), 1.90-1.81 (m, 2 H), 1.80-1.71 (m, 2 H), 1.53-1.41 (m, 2 H), 1.07 (t, J=7.4 Hz, 3 H). LC/MS (m/z)=389 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)[CH2:3]O.C([O-])([O-])=O.[K+].[K+].[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>ClCCCl>[S:21]([N@@:1]1[CH2:3][CH:2]1[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]
Reactant: N[C@@H](CO)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)[N@@]2CC2c2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a solution of the crude product from Step B (1.11 g, 5.45 mmol) in 1,2-dichloroethane (25 mL) at 0° C. are added K2CO3 (2.26 g, 16.4 mmol) and TsCl (2.60 g, 13.6 mmol). The reaction mixture is stirred at room temperature overnight. If reaction is not done at this point, additional K2CO3 (0.75 g, 5.45 mmol) and TsCl (1.04 g, 5.45 mmol) are added and the reaction mixture is stirred for another 24 h. After removal of the solvent, the residue is taken in cold saturated NaHCO3 aqueous solution (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layer is washed with brine, dried over MgSO4, concentrated, and purified by silica gel chromatography (0˜35% EtOAc/Hexanes) to provide (R)-1-tosyl-2-(3-(trifluoromethyl)phenyl)aziridine (1.74 g, 94% yield); 1H NMR (CDCl3, 400 MHz) δ 7.88 (d, 2H), 7.54 (m, 1H), 7.43 (m, 3H), 7.36 (d, 2H), 3.81 (dd, 1H), 3.01 (d, 1H), 2.45 (s, 3H), 2.39 (d, 1H); HPLC-MS calculated for C16H14F3NO2S (M+H+) 342.1, found 342.1.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:20]=3[CH:30]=2)[C@@H:11]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][O:38][CH2:39][C@H:40]([O:42][CH2:43][CH3:44])[CH3:41])=[CH:33][CH:32]=2)[C@H:10]([CH:45]=O)[CH2:9]1)=O)(C)(C)C.[Cl-].[O:48]=[C:49]([N:70]1[CH2:74][CH2:73][CH2:72][CH2:71]1)[CH2:50][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O(C)[Na]>CO>[CH2:43]([O:42][C@H:40]([CH3:41])[CH2:39][O:38][CH2:37][C:34]1[CH:33]=[CH:32][C:31]([C@@H:11]2[C@@H:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:20]=4[CH:30]=3)[CH2:13][NH:8][CH2:9][C@H:10]2[CH2:45][CH2:50][C:49]([N:70]2[CH2:74][CH2:73][CH2:72][CH2:71]2)=[O:48])=[CH:36][CH:35]=1)[CH3:44]
Reactant: CCO[C@H](C)COCc1ccc([C@H]2[C@H](C=O)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reactant: O=C(C[P+](c1ccccc1)(c1ccccc1)c1ccccc1)N1CCCC1
Agent: CO[Na]
Agent: [Cl-]
Solvent: CO
Product: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CCC(=O)N3CCCC3)CNC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1 mmol of (3S,4R,5R)-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-3-formyl-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester (example 12b) and 1.1 mmol of (2-oxo-2-pyrrolidin-1-yl-ethyl)-triphenyl-phosphonium chloride in 5 ml MeOH is added 1.05 mmol of NaOCH3 The reaction mixture is stirred at RT overnight. The reaction mixture is quenched by addition of 0.1 N HCl and H2O. The phases are separated and the organic phase is washed with saturated aqueous NaHCO3 solution and brine. The combined aqueous phases are extracted with TBME. The combined organic layers are dried over Na2SO4 and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) and is identified based on the Rf value.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[NH:13][CH2:14][C:15]([OH:17])=O.[Cl:18][C:19]1[CH:20]=[C:21]([NH2:33])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30]>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:33][C:15](=[O:17])[CH2:14][NH:13][C:3]2[CH:4]=[CH:5][C:6]([O:8][C:9]([F:10])([F:11])[F:12])=[CH:7][C:2]=2[Cl:1])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30]
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Reactant: O=C(O)CNc1ccc(OC(F)(F)F)cc1Cl
Product: CCN(CC)CCOc1ccc(NC(=O)CNc2ccc(OC(F)(F)F)cc2Cl)cc1Cl

Procedure:
The product was prepared according to general working method I from (2-chloro-4-trifluoromethoxy-phenyl-amino)-acetic acid (Example 165b) and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z1b).
Reaction SMILES: Cl[P:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[O:3]1.[CH2:16]([OH:18])[CH3:17].N>C1(C)C=CC=CC=1>[CH2:16]([O:18][P:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[O:3]1)[CH3:17]
Reactant: CCO
Reactant: ClP1Oc2ccccc2-c2ccccc21
Agent: N
Solvent: Cc1ccccc1
Product: CCOP1Oc2ccccc2-c2ccccc21
Yield: 96 %

Procedure:
300 g (1.28 mol) of 6-chloro-(6H)-dibenzo[c,e][1,2]-oxaphosphorine, dissolved in 346 ml of toluene, are added dropwise with stirring to a mixture of 76.5 g (1.663 mol) of absolute ethanol and 807 ml of toluene at -15° to -20° C. in the course of 1.5 hours. 23 g (1.35 mol) of ammonia are then introduced rapidly at this temperature. The mixture is further stirred and filtered off with suction and washed with toluene. The filtrate is concentrated by distillation at 12 mbar to an internal temperature of 75° C., finally at 1 mbar. 300 g of 6-ethoxy-(6H)-dibenzo[c,e][1,2]oxaphosphorine as solidified melt are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([C:23]4[C:24]([O:30]C)=[N:25][CH:26]=[CH:27][C:28]=4I)[NH:20]3)=[C:16]([CH3:32])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[ClH:33].C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([C:23]4[C:24](=[O:30])[NH:25][CH:26]=[CH:27][C:28]=4[Cl:33])[NH:20]3)=[C:16]([CH3:32])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cl
Reactant: COc1nccc(I)c1-c1nc2c(C)nc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2[nH]1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Temperature: 75 °C
Reaction time: 6 h

Procedure:
To a solution of 4-[8-(4-iodo-2-methoxy-pyridin-3-yl)-6-methyl-9H-purin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (1.4 g, 2.54 mmol) in glacial acetic acid (30 mL) was added 11.6 M HCl (30 mL). The reaction mixture was stirred at 75° C. for 6 hours in a sealed tube and concentrated. The residue was dissolved in CH2Cl2 (250 mL) followed by the addition of triethylamine (2.78 mL, 20 mmol). The solution was cooled to 0° C. and di t-butyl dicarbonate (573 mg, 2.63 mmol) was added. The reaction mixture was stirred at 23° C. for 2 hours, poured on saturated NaHCO3 solution and extracted with CH2Cl2 (3×200 mL). The combined organic layers, were dried over MgSO4 and concentrated to give the title compound as a yellow solid. (0.691 g, 62%). HPLC 93%; LCMS (+ESI, M+H+) m/z 446; IR (KBr, cm−1) 3431, 2974, 1700, 1506, 1229; 1H NMR (400 MHz, DMSO+D2O) δ 7.64 (d, J=7.0 Hz, 0.7H), 7.32 (d, J=7.0 Hz, 0.3H), 6.89 (d, J=7.0 Hz, 0.3H), 6.59 (d, J=7.0 Hz, 0.7H), 3.75 (br s, 4H), 3.45 (br s, 4H), 2.60 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].S(O)(O)(=O)=O.CS[C:15](=[NH:17])[NH2:16]>O>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:5])[N:17]=[C:15]([NH:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][NH2:7])[N:16]=1
Reactant: CSC(=N)N
Reactant: NCCCCCN
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(C)nc(NCCCCCN)n1
Reaction time: 1 h

Procedure:
To 1,5-pentanediamine (1 g) dissolved in 10 ml water was added S-methylthiopseudourea sulfate (1.36 g) in 10 ml. of water. The amine solution was held at 45°-48° during the addition which took 1 hour. Stirring was continued for 8 hours. The volume was evaporated to about 10 ml under a stream of N2 on the steam bath. Ethanol (10 ml) and 10% NaHCO3 (10 ml) plus 10 ml of 2,4-pentanedione were added and the solution refluxed overnight. After brief cooling the solution was acidified to pH 1-2 and heated at 90° for 10 min. The cooled acidified mixture was then extracted thoroughly with ether, basified with 2N NaOH, and extracted with CHCl3. The combined CHCl3 extracts were evaporated to yield the crude product which was used without purification, wt 996 mg.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[C:13]=1[CH2:14][N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C@@H:16]1[C:21](O)=[O:22].Cl.[NH2:33][CH:34]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:35]([OH:42])[C:36]([NH:38][CH:39]1[CH2:41][CH2:40]1)=[O:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH:39]1([NH:38][C:36](=[O:37])[CH:35]([OH:42])[CH:34]([NH:33][C:21]([C@H:16]2[CH2:17][CH2:18][C:19](=[O:20])[N:15]2[CH2:14][C:13]2[C:24]([C:28]([F:31])([F:29])[F:30])=[CH:25][CH:26]=[CH:27][C:12]=2[O:11][CH3:10])=[O:22])[CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40][CH2:41]1
Reactant: COc1cccc(C(F)(F)F)c1CN1C(=O)CC[C@@H]1C(=O)O
Reactant: NC(Cc1ccccc1)C(O)C(=O)NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C(F)(F)F)c1CN1C(=O)CC[C@@H]1C(=O)NC(Cc1ccccc1)C(O)C(=O)NC1CC1
Reaction time: 8 h
Yield: 126.1 %

Procedure:
DIPEA (0.8 ml, 4.58 mmol) was added to a mixture of (R)-1-(2-methoxy-6-(trifluoromethyl)benzyl)-5-oxopyrrolidine-2-carboxylic acid (234 mg, 0.74 mmol) and 3-amino-N-cyclopropyl-2-hydroxy-4-phenylbutanamide hydrochloride (200 mg, 0.74 mmol) in DCM (50 mL). After stirring for 10 min HATU (337 mg, 0.89 mmol) was added and the stirring was continued overnight. The reaction mixture was diluted with DCM and water was added. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with saturated aqueous NaHCO3 solution, saturated aqueous NaCl solution and dried over MgSO4. Removal of the solvent in vacuo provided the title compound (498 mg, 95%, ca. 75% purity).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[C:6]([O:10][C:11](=[O:26])[NH:12][CH2:13][CH:14]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[CH3:25])[CH2:15][CH2:16][OH:17])([CH3:9])([CH3:8])[CH3:7].[NH4+].[Cl-]>C(Cl)Cl>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([CH:14]([CH2:13][NH:12][C:11]([O:10][C:6]([CH3:8])([CH3:9])[CH3:7])=[O:26])[CH2:15][CH2:16][O:17][S:1]([CH3:4])(=[O:3])=[O:2])=[C:19]([CH3:25])[CH:20]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(Br)ccc1C(CCO)CNC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1cc(Br)ccc1C(CCOS(C)(=O)=O)CNC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Mesyl chloride (7.53 mL, 0.09726 mol) was added, at −78° C., to a solution of [2-(4-bromo-2-methyl-phenyl)-4-hydroxy-butyl]-carbamic acid tert-butyl ester (30.3 g, 0.08457 mol) in DCM (600 mL) followed by TEA (27 mL, 0.1945 mol). The reaction mixture was stirred at −78° C. for 1 hour, then allowed to reach room temperature with stirring for an additional hour. A saturated aqueous solution of NH4Cl was added, and the resulting mixture was extracted with DCM. The combined organic extracts were dried over MgSO4, filtered, and evaporated under reduced pressure to give methanesulfonic acid 3-(4-bromo-2-methyl-phenyl)-4-tert-butoxycarbonylamino-butyl ester, which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:32])[N:25]([CH3:31])[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=2)=[C:19]([CH3:33])[CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7].[OH-].[Na+]>C(O)C>[Cl:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:15])[C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:34])=[O:2])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:32])[N:25]([CH3:31])[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=2)=[C:19]([CH3:33])[CH:18]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)c(C)c1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)ccc1-c1cn(C)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
To a suspension of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester (0.1 mmol, 59 mg) in ethanol (1 mL) was added aqueous 1.0 N sodium hydroxide (0.2 mL) at room temperature. The mixture was stirred for 2 h at room temperature. The ethanol was removed under reduced pressure and the residue was diluted with water (10 mL). The aqueous solution was washed with diethyl ether (20 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N HCl and the product was extracted into ethyl acetate (2×15 mL). The combined organic extracts were washed with brine solution (50 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the filtrate afforded 20 mg (41% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine as an amorphous white solid. ES-HRMS m/e calcd for C23H21C2N3O5 (M+Na) 512.0752, found 512.0754.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=O)([O-:3])=[O:2].C(P(CCCC)(CCCC)[CH2:22][CH:23]1[O:27][CH2:26][CH2:25][O:24]1)CCC.CC([O-])(C)C.[K+].O>CS(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[CH:22][CH:23]1[O:27][CH2:26][CH2:25][O:24]1)([O-:3])=[O:2]
Reactant: CCCC[PH](CCCC)(CCCC)CC1OCCO1
Reactant: O=Cc1cccn1-c1ccccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1-n1cccc1C=CC1OCCO1
Yield: 66 %

Procedure:
2.98 g (13.8 mmol) 2a, 1.2 eqv. of tributyl-[1,3]dioxolan-2-ylmethyl-λ5-phosphane and 1.5 eqv. KOtBu in DMSO was stirred at 60° C. for 24 hours. The reaction was monitored by TLC (EtOAc:petroleum ether 1:2). After cooling, the reaction mixture was poured into water and extracted with ether and the solvent was evaporated. The semi-solid residue was diluted with ether and filtrated to remove residual Bu3PO and the product was purified by column chromatography (EtOAc: petroleum ether 1:2) to yield 2.6 g (66%) of 3a.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:4][C@H:3]1[C:5](OCC1C=CC=CC=1)=[O:6].[F:15][C:16]1[CH:17]=[C:18]([C:24]2[CH:28]=[C:27]([NH2:29])[S:26][N:25]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].C[Al](C)C>ClCCl.CCOC(C)=O.Cl.O>[F:15][C:16]1[CH:17]=[C:18]([C:24]2[CH:28]=[C:27]([NH:29][C:5]([C@@H:3]3[CH2:4][C@H:2]3[CH3:1])=[O:6])[S:26][N:25]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(-c2cc(N)sn2)cc1F
Reactant: C[C@@H]1C[C@H]1C(=O)OCc1ccccc1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc(NC(=O)[C@@H]3C[C@H]3C)sn2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
Add benzyl (R,R)-2-methylcyclopropanecarboxylate (0.55 g, 2.89 mmol) to a 0° C. solution of 3-(3-fluoro-4-methoxyphenyl)isothiazol-5-ylamine (0.59 g, 2.63 mmol) and trimethylaluminum (2.0 M in toluene, 5.26 mmol) in dichloromethane (5 mL) and allow reaction to naturally warm to room temperature. Warm the reaction mixture to 40° C. and allow to stir overnight. Dilute the reaction mixture with EtOAc (100 mL) and 1 N HCl (40 mL) and water (100 mL), collect the organic phase, and evaporate. Chromatography over silica gel eluting with 25-50% EtOAc in hexane affords (R,R)—N-[3-(3-fluoro-4-methoxyphenyl)isothiazol-5-yl]-2-methylcyclopropane-carboxamide. Yield: 55.9%. ES-MS: m/e 307.0 (m+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25](Br)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:4][CH2:3]1.[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([C:34]3[CH:35]=[N:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:4][CH2:3]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(Br)cccc2[nH]1
Product: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCN(CCN5CCC(O)CC5)CC4)cc23)cn1

Procedure:
This compound is synthesized from compound 196 (see example 172) and (6-methoxy-pyridin-3-yl)-boronic acid analogously to the method described in Example 156.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[CH2:15]=O>C(Cl)Cl>[CH3:1][C@@H:2]1[N:7]([CH3:15])[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: C=O
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C

Procedure:
Commercially available 1,1-dimethylethyl (3S)-3-methyl-1-piperazinecarboxylate (3.05 g, 15.23 mmol), formaldehyde (37% in water) (2.13 mL), sodium triacetoxy borohoydride (5.52 g, 26.04 mmol) and DCM (250 mL) were stirred overnight. The solvent was removed, and 1N NaOH was added to the residue. The mixture was extracted with dichloromethane, and the organics were dried (Na2SO4) and concentrated in vacuo to provide 1,1-dimethylethyl (3S)-3,4-dimethyl-1-piperazinecarboxylate as a clear oil (3.15 g. 97%). LCMS: (M+H)+=215.3.