Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([C@H:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Cl:29])=[CH:21][N:22]=[C:23]([Cl:28])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)[CH3:9])=O)(C)(C)C.C(OC([NH:37][C@H]1CCN(S(C2C3C(Cl)=CN=C(Cl)C=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[NH2:37][C:23]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:18]([S:15]([N:12]3[CH2:13][CH2:14][C@H:10]([NH:8][CH3:9])[CH2:11]3)(=[O:17])=[O:16])[C:19]=2[C:20]([Cl:29])=[CH:21][N:22]=1.[ClH:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Product: CN[C@H]1CCN(S(=O)(=O)c2cccc3c(N)ncc(Cl)c23)C1
Product: Cl

Procedure:
Intermediate 25a was used in the method of Example 39-1 instead of Intermediate 26a to obtain the title compound as hydrochloride.
Reaction SMILES: [C:1]1([OH:21])[C:2]([C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:12]=2)=[CH:3][CH:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.[CH2:22]=[CH:23][CH3:24]>O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.P.[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].C1(C)C(C)=CC=CC=1>[CH:23]([C:3]1[CH:4]=[C:5]2[C:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)=[C:1]([OH:21])[C:2]=1[C:11]1[CH:20]=[CH:19][C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:24])[CH3:22]
Reactant: C=CC
Reactant: Oc1c(-c2ccc3c(c2)CCCC3)ccc2c1CCCC2
Agent: [W]
Agent: P
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(C)c1cc2c(c(O)c1-c1ccc3c(c1)CCCC3)CCCC2
Temperature: 140 °C
Yield: 42 %

Procedure:
A mixture of 5,5′,6,6′,7,7′,8,8′-octahydro-2,2′-binaphthol (30.0 g), xylene (5 ml) and phosphotungstic acid (1.5 g) was heated to 140° C. To the mixture was added propylene (8.9 g) slowly via a dry-ice condenser. GC analysis of the reaction mixture indicated that 98% conversion of the 5,5′,6,6′,7,7′,8,8′-octahydro-2,2′-binaphthol. Small amounts of isopropylated xylene were observed as well. The mixture was purified by flash column to give 14.5 g of 3-isopropyl-5,5′,6,6′,7,7′,8,8′-octahydro-2,2′-binaphthol, mp 110° C.; 3.7 g of 3,3′-diisopropyl-5,5′,6,6′,7,7′8,8′-octahydro-2,2′-binaphthol, mp 152–3° C.; and a mixture (15 g) containing 38% of 3-isopropyl-5,5′,6,6′,7,7′,8,8′-octahydro-2,2′-binaphthol and 33% of 3,3′-diisopropyl-5,5′,6,6′,7,7′8,8′-octahydro-2,2′-binaphthol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22]C)=[O:21])=[CH:16][CH:15]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]1[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(/C=C/c2ccc(C(=O)OC)cc2Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(/C=C/c2ccc(C(=O)O)cc2Cl)cc1

Procedure:
A suspension of 3.0 g of dimethyl (E)-2-chloro-stilbene-4,4'-dicarboxylate in 30 ml of methanol was treated with 36 ml of 1M sodium hydroxide solution and heated under reflux for 5 hours. After cooling, 37 ml of 1M hydrochloric acid were added dropwise. The resulting slurry was suction filtered; the residue was washed with water and dried at 70° C. in a vacuum to give (E)-2-chloro-stilbene-4,4'-dicarboxylic acid, MS: m/z 302 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:14][CH2:13][NH:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:15](O)(=O)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)C1CCNC1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(C(=O)c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
To a solution (4-bromo-phenyl)-pyrrolidin-3-yl-methanone (2.24 g, 8.81 mmol) in methanol (44 mL), add acetic acid (1.01 mL, 17.6 mmol) and formaldehyde (2.15 g, 26.4 mmol, 37% aqueous solution). After 15 min, add sodium triacetoxyborohydride (5.60 g, 26.4 mmol) and allow the mixture to stir at RT for one hour. Concentrate the reaction mixture. Add water and adjust the solution to pH=10 with 2 N NaOH. Extract the aqueous with ethylacetate. Dry the combined organic layers over Na2SO4, filter, and concentrate. Purify the crude material by flash chromatography, eluting with 5-10% MeOH (2N NH3)/CH2Cl2 to give 1.61 g (68%) of the title compound. LC-MS/ES m/z (79Br) 268.0 [M+H]+.
Reaction SMILES: I[C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12].C(N(CC)C(C)C)(C)C.CN1C(=O)CCC1>[Cu]I.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.O>[CH3:10][Si:11]([C:14]#[C:15][C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1)([CH3:13])[CH3:12]
Reactant: Nc1ccc(I)c(N)n1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: C[Si](C)(C)C#Cc1ccc(N)nc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-iodo-pyridin-2,6-diamine (20 g) described in Manufacturing Example 4-1, trimethylsilyl acetylene (24 mL), copper(I) iodide (3.3 g), N,N-diisopropylethylamine (19 g), and NMP (290 mL) was added tetrakis(triphenylphosphine)palladium(0) (9.8 g), which was stirred for 30 minutes at room temperature under an argon atmosphere. Water was added to the reaction solution, which was then extracted with ethyl acetate. The ethyl acetate layer thus obtained was washed with water 4 times and dried over sodium sulfate. The sodium sulfate was filtered off, the solvent was evaporated under a reduced pressure, and the residue was purified by NH silica gel chromatography (heptane:ethyl acetate=4:1, then 1:1). The eluate was concentrated under a reduced pressure, and the resulting solids were washed with heptane containing a small amount of ethyl acetate to obtain the titled compound (11 g).
Reaction SMILES: CO[C:3]1[CH2:4][CH:5]([CH3:11])[CH2:6][CH2:7][CH:8]([CH3:10])[N:9]=1.[Cl-:12].[NH4+:13]>CCO>[ClH:12].[CH3:11][CH:5]1[CH2:6][CH2:7][CH:8]([CH3:10])[NH:9][C:3](=[NH:13])[CH2:4]1
Reactant: [NH4+]
Reactant: COC1=NC(C)CCC(C)C1
Reactant: [Cl-]
Solvent: CCO
Product: CC1CCC(C)NC(=N)C1
Product: Cl
Yield: 77.8 %

Procedure:
The product of EXAMPLE 130 (250 mg, 1.6 mmol) in 2.5 mL of EtOH was reacted with ammonium chloride (86.0 mg, 1.6 mmol) by the method of EXAMPLE 27 to yield 220 mg (75%) of the white solid title material.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11](=[O:21])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH3:22][N:14]1[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11](=[O:21])[CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:15]1=[O:16]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NC1CC(=O)c2ccccc2NC1=O
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)C(NC(=O)OC(C)(C)C)CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.3 %

Procedure:
A solution of 3-tertbutyloxycarbonylamino-2,3,4,5-tetrahydro-2,5-dioxobenzo[b]azepine (5 g, 17.2 mmole) in DMF (50 mL) was treated with potassium carbonate (4.76 g, 34.4 mmole) and methyl iodide (4.88 g, 34.4 mmole). The reaction was stirred at ambient temperature for 4 hours. The mixture was diluted with ethyl acetate (300 ml) and saturated aqueous sodium hydrogen carbonate (500 ml). The organic layer was separated and the aqueous layer was extracted again with ethyl acetate (2×300 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was swished with warm ethyl ether (200 mL) and collected by filtration to give 4.1 g of the product. mp 205°-206° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[NH:48]1[CH2:53][CH2:52][CH2:51][CH:50]([C:54]([OH:57])([CH3:56])[CH3:55])[CH2:49]1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:48]2[CH2:53][CH2:52][CH2:51][CH:50]([C:54]([OH:57])([CH3:56])[CH3:55])[CH2:49]2)=[O:15])=[CH:6][CH:7]=1
Reactant: CC(C)(O)C1CCCNC1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2oncc2C(=O)N2CCCC(C(C)(C)O)C2)cc1
Reaction time: 2 h
Yield: 54.8 %

Procedure:
A solution of 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10 mg, 0.05 mmol), TBTU (19 mg, 0.06 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (17 μL, 0.10 mmol, 2 equ) in DMF (0.3 mL) was added to 2-piperidin-3-ylpropan-2-ol hydrochloride (9 mg, 0.05 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (9 mg). MS (ESI, pos. ion) m/z calcd for C19H24N2O3: 328.1787, found 328.1787.
Reaction SMILES: C([Li])CCC.CN1[CH2:12][CH2:11][CH2:10][N:9](C)C1=O.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C1COCC1>[CH:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]#[C:11][CH2:10][NH2:9])=[CH:17][CH:18]=1
Reactant: CN1CCCN(C)C1=O
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: NCC#CCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 36.6 %

Procedure:
The compound resulting from Example 60A (4.35 g of -75% pure material, -16.5 mmol) was dissolved in THF (87 mL), cooled to 0° C., then n-butyllithium (16.5 mL of 1.6M hexanes solution) was added dropwise, followed by 1,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone (3.20 mL, 3.39 g, 26.5 mmol) and benzyl bromide (3.50 mL, 5.03 g, 29.4 mmol). The reaction was stirred at 0° C. for 3 hours, then 1N HCl was added. After washing with 3×Et2O, the pH was adjusted to 10 with 4N NaOH, then extracted with 4×Et2O. The second set of Et2O layers were combined, dried over Na2SO4, filtered and concentrated to give a residue which was purified by silica gel chromatography eluting with a gradient of 99:1, 98.75:1.25, and 98:2 CHCl3 -MeOH to afford 1.41 g (59%) of the title compound as a light brown oil. 1H NMR (CDCl3) δ 7.35,7.24 (both m, total 5H), 3.60 (t, 2H), 3.47 (t, 2H), 1.38 (br s, 2H). MS (DCl/NH3) m/e 146 (M+H)+, 163 (M+H+NH3)+.
Reaction SMILES: [OH:1][C@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2.N1CCCCC1>C(O)C>[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])/[C:28]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@H:2]([OH:1])[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Temperature: 25 °C
Yield: 100.6 %

Procedure:
(R)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 1f (200 g, 0.623 mmol), 5-fluoro-1,3-dihydro-indol-2-one (84.67 mg, 0.56 mmol) and piperidine (30.8 μL, 0.31 mmol) were dissolved in 1.09 mL of ethanol under stirring at room temperature. The reaction system was stirred at 80° C. in an oil bath in dark for 2 hours.The reaction was completed until TLC showed the disappearance of starting materials, and the oil bath was removed. The reaction system was allowed to cool down to room temperature to precipitate solids. The resulting solids were filtered to give the title compound (R,Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 1 (256 mg, 90%) as a yellow solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][C:17]([F:20])([F:19])[F:18])[S:15][C:9]=2[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:24][CH:23]=2)[C:7]1=[O:36].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[O:36]=[C:7]1[N:8]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:26][CH:27]=2)[C:9]2[S:15][C:14]([CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=2[C:11](=[O:12])[NH:6]1
Reactant: COc1ccc(Cn2c(=O)c3cc(CC(F)(F)F)sc3n(Cc3ccc(-c4ccccc4C#N)cc3)c2=O)c(OC)c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1-c1ccc(Cn2c(=O)[nH]c(=O)c3cc(CC(F)(F)F)sc32)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 143.6 %

Procedure:
A mixture of 4′-{[3-(2,4-dimethoxybenzyl)-2,4-dioxo-6-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (1.68 g) and trifluoroacetic acid (30 mL) was stirred at 50° C. for 2 hr. To the reaction mixture was added toluene (30 mL), under reduced pressure, and concentrated. The precipitated solid was collected by filtration to give the title compound as a colorless solid (1.8 g, 100%).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[NH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>CCCCO>[Cl:9][C:6]1[N:5]=[C:4]([NH2:10])[N:3]=[C:2]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:7]=1[NH2:8]
Reactant: COc1ccc(CN)cc1
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Solvent: CCCCO
Product: COc1ccc(CNc2nc(N)nc(Cl)c2N)cc1

Procedure:
A mixture of 4,6-dichloro-pyrimidine-2,5-diamine and 1-aminomethyl-4-methoxybenzene was refluxed in n-BuOH for 15 h, following the general procedure 1. HPLC RT was 4.675 min. 1HNMR (CDCl3) δ 7.29–7.27 (d, 2H), 6.91–6.89 (d, 2H), 5.62 (br. t, 1H) 4.67 (s, 2H), 4.56–4.54 (d, 2H), 3.84 (s, 3H), 2.74 (s, 2H).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][C@@H:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:20][C:21]1[CH:26]=[C:25]([C:2]2[C:11]3[O:10][C@@H:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=3[S:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C[C@H]1CN(C(=O)OC(C)(C)C)Cc2scc(-c3cccc(F)c3)c2O1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
A mixed solution of tert-butyl (2S)-8-bromo-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (434 mg), (3-fluorophenyl)boronic acid (227 mg), dichlorobis(triphenylphosphine)palladium (44 mg) and potassium carbonate (518 mg) in DME-water (1:1, 12 mL) was stirred at 85° C. for 2 hr under a nitrogen stream. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 5→15% ethyl acetate/hexane) to give the title compound (430 mg, 95%) as a colorless oil.
Reaction SMILES: NC1SC=[C:5]([C@@H:7]([NH:20]C(C2C=CC3N(C4CCCCC4)C(C4C=COC=4)=NC=3C=2)=O)[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[N:17][NH:18][N:19]=3)=[CH:11][CH:10]=2)N=1.CCN(C(C)C)C(C)C.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)Cl)C=CC=CC=1.[OH-:72].[Na+].Cl.C1C[O:78]CC1>>[NH:16]1[C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:8][C@@H:7]([C:5]([OH:78])=[O:72])[NH2:20])=[CH:10][CH:11]=2)=[N:19][N:18]=[N:17]1
Reactant: C1CCOC1
Reactant: Nc1nc([C@H](Cc2ccc(-c3nn[nH]n3)cc2)NC(=O)c2ccc3c(c2)nc(-c2ccoc2)n3C2CCCCC2)cs1
Reactant: [OH-]
Agent: Cl
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: N[C@@H](Cc1ccc(-c2nnn[nH]2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The tetrazole compound from above (0.752 g, 2.16 mmol) was dissolved in THF (20 mL) and DIEA (0.75 mL, 4.3 mmol) and triphenylchloromethane (trityl chloride, 0.604 g, 2.16 mmol) were added. The reaction was stirred for 1 h at room temperature and then quenched with 1 N NaOH (13 mL, 13 mmol). After stirring overnight at room temperature, the reaction mixture was cooled in ice and acidified to pH 3-4 with 1 N HCl. The product was extracted into EtOAc (50 mL), washed with brine and the solution dried (Na2SO4). Evaporation of the solvent gave a yellow residue that was purified by passing through a pad of silica gel using EtOAc as eluent. The product was then dissolved in TBME (5 mL) and hexane (10 mL) was added. The precipitated material was collected by filtration and dried to give the desired 4-tetrazolyl-L-phenylalanine free acid as a white solid (0.784 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C@H:8]([C:17]1[CH:22]=[CH:21][C:20]([O:23][Si](C(C)(C)C)(C)C)=[CH:19][CH:18]=1)[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOCC>[C:1]([O:5][C:6](=[O:31])[NH:7][C@H:8]([C:17]1[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=1)[CH2:9][N:10]1[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCN(C[C@H](NC(=O)OC(C)(C)C)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1CCN(C[C@H](NC(=O)OC(C)(C)C)c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [(R)-1-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-(4-methyl-piperazin-1-yl)-ethyl]-carbamic acid tert-butyl ester (370 mg, 0.82 mmol) in THF (3 ml) was added TBAF (1M in THF, 1 ml, 1 mmol). The resulting mixture was stirred at rt for 3 h. The reaction mixture was diluted with ether and quenched with aq. NH4Cl. The organic layer was washed with water and brine, and then dried over MgSO4. Removal of the solvent provided the titled compound.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH:4]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25]C(OC(C)(C)C)=O)[CH:20]=1)[CH2:5][P:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:8])=[O:7].[OH-].[Na+]>CO.C1COCC1.O>[NH2:25][C:21]1[CH:20]=[C:19]([CH:4]([CH2:5][P:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([OH:8])=[O:7])[C:3]([OH:33])=[O:2])[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)C(CP(=O)(O)CCCCc1ccccc1)c1cccc(NC(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccc(C(CP(=O)(O)CCCCc2ccccc2)C(=O)O)c1
Reaction time: 0.75 h

Procedure:
2-(3-(t-Butoxycarbonylamino)phenyl)-3-((4-phenylbutyl)(hydroxy)-phosphinoyl)propanoic acid methyl ester (845 mg, 1.8 mmol) was stirred in 1 M NaOH (5.3 mL, 5.3 mmol) in methanol/THF/H2O for 1.5 hours. The product was concentrated in vacuo. The residue was dissolved in 10 mL methylene chloride and TFA (10 mL) was added. After 45 minutes, the reaction mixture was concentrated to provide 2-(3-aminophenyl)-3-((4-phenylbutyl)(hydroxy)phosphinoyl)propanoic acid, NMR (DMSO-d6) 1.30-1.45 (m, 8), 1.80 (m, 1), 2.35 (m, 1), 3.62 (m, 1), 6.58-6.65 (m, 3), 7.05 (m, 1), 7.15 (m, 3), 7.23 (m, 2) ppm; as a crude product. Pure product was obtained by preparative reversed-phase HPLC.
Reaction SMILES: CO[C:3]([CH:5]1[C:14](=O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:7][CH2:6]1)=[O:4].[C:16]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1)#[N:17].C(O)(=O)C(C)(C)C>>[O:4]=[C:3]1[N:24]([C:21]2[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[CH:19][CH:20]=2)[NH:25][C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[S:7][CH2:6][C:5]1=2
Reactant: COC(=O)C1CSc2ccccc2C1=O
Reactant: N#Cc1ccc(NN)cc1
Agent: CC(C)(C)C(=O)O
Product: N#Cc1ccc(-n2[nH]c3c(c2=O)CSc2ccccc2-3)cc1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
4-Oxo-thiochroman-3-carboxylic acid methyl ester (0.200 g, 0.90 mmol), 4-cyanophenylhydrazine (0.132 g, 0.99 mmol) together with a small amount of pivalic acid was heated at 118° C. in an oil bath under N2. After 1 h the mixture was cooled to room temperature and then triturated with ether. The precipitate was filtered and dried to yield 4-(3-oxo-1,4-dihydro-3H-thiochromeno[4,3-c]pyrazol-2-yl)-benzonitrile (0.233 g): 1H NMR (400 MHz, DMSO-d6) δ 8.06 (2H, d), 7.92 (2H, d), 7.80-7.83 (1H, m), 7.30-7.33 (1H, m), 7.18-7.25 (2H, m), 3.91 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:21](=[O:43])[N:22]2[CH2:27][CH2:26][N:25]([C:28]3[C:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][N:31]=[C:30]4[NH:40][CH:41]=[CH:42][C:29]=34)[CH2:24][CH2:23]2)[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[C:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][N:31]=[C:30]4[NH:40][CH:41]=[CH:42][C:29]=34)[CH2:26][CH2:27]2)=[O:43])=[CH:4][CH:3]=1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC[C@@H](C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 39.8 %

Procedure:
(S)-tert-Butyl 2-(4-chlorophenyl)-3-oxo-3-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)propyl(isopropyl)carbamate (0.003 g, 0.0050 mmol) was placed in DCM (2 mL) at room temperature. TFA (0.4 mL) was then added, and the reaction was stirred for 1 hour. The reaction was concentrated to dryness. The crude residue was dissolved in minimal DCM and added dropwise to a stirring solution of 1M HCl in ether (10 mL). The solid product was then filtered, washed with ether, and dried to give (S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propan-1-one (0.001 g, 40% yield) as the dihydrochloride salt. MS ESI (+) m/z 503 detected.
Reaction SMILES: [C:1]([N:4]1[CH2:11][CH2:10][CH2:9][C@H:5]1[C:6]([OH:8])=O)(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33](=[O:38])[C:32]([C:39]([OH:41])=[O:40])=[CH:31]2.C(N(CC)CC)C.Cl[Si](C)(C)C.N1CCC[C@H]1C(O)=O>ClCCl>[C:1]([N:4]1[CH2:11][CH2:10][CH2:9][CH:5]1[C:6]([NH:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33](=[O:38])[C:32]([C:39]([OH:41])=[O:40])=[CH:31]2)=[O:8])(=[O:3])[CH3:2]
Reactant: Nc1ccc2[nH]c(=O)c(C(=O)O)cc2c1
Reactant: CC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Product: CC(=O)N1CCCC1C(=O)Nc1ccc2[nH]c(=O)c(C(=O)O)cc2c1
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
A solution of 4.71 g (30 mmol) of N-acetyl-L-proline and 60 ml of dichloromethane is cooled to -18° and 3.3 ml (30 mmol) of N-methyl morpholine and 3.9 ml (30 mmol) of isobutyl chloroformate is added, and the reaction mixture is stirred for 30 minutes at -10° to -20°. A mixture of 4.08 g (20 mmol) of 6-amino-1,2-dihydro-2-oxo-3-quinolinecarboxylic acid, 150 ml of dichloromethane, 8.4 ml (60 mmol) of triethylamine, and 7.6 ml (60 mmol) of chlorotrimethylsilane is stirred at room temperature for 35 minutes. The silylation mixture is cooled to -20° and the mixed anhydride of proline is added and stirred with cooling overnight. The reaction mixture is evaporated to dryness, and the residue is treated with ethanol to yield 4.42 g of 6-[[(1-acetyl-2-pyrrolidinyl)carbonyl]-amino]-1,2-dihydro-2-oxo-3-quinolinecarboxylic acid, mp 303° dec.