Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:29]1.CCN(C(C)C)C(C)C>CCCCO>[Br:1][C:2]1[C:3]([N:28]2[CH2:33][CH2:32][CH2:31][C@@H:30]([NH:34][C:35]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:41])[CH2:29]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CN(C(=O)OC(C)(C)C)CCO4)c23)C1
Temperature: 120 °C
Reaction time: 36 h

Procedure:
A mixture of tert-butyl 2-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbamoyl)morpholine-4-carboxylate (660 mg, 1.49 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (1.49 g, 7.44 mmol), and DIEA (1.30 mL, 7.44 mmol) in n-BuOH (6 mL) was stirred at 120° C. for 36 hours. The reaction was then cooled to room temperature and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (0-50% CH3CN/water) to give the separated diastereomers of tert-butyl 2-(5-bromo-4-((R)-3-(tert-butoxycarbonylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylcarbamoyl)morpholine-4-carboxylate in the following yields: diastereomer #1 (70 mg, 7.5%) diastereomer #2 (80 mg, 8.6%).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[CH:16][N:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27](Cl)[C:22]=4[C:21](=[O:29])[N:20]4[CH2:30][CH2:31][C@H:19]4[C:18]=23)[N:10]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].ClCC1ON=C(C2N=CN3C4C=CC([F:53])=CC=4C(=O)N4CCC4C=23)N=1.C(NCCC)CC>CN(C)C=O>[CH2:1]([N:4]([CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[CH:16][N:17]3[C:23]4[CH:24]=[CH:25][C:26]([F:53])=[CH:27][C:22]=4[C:21](=[O:29])[N:20]4[CH2:30][CH2:31][C@H:19]4[C:18]=23)[N:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: O=C1c2cc(F)ccc2-n2cnc(-c3noc(CCl)n3)c2C2CCN12
Reactant: C=CCN(CC=C)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)no1
Solvent: CCCNCCC
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2cc(F)ccc2-3)no1
Yield: 85 %

Procedure:
1.8 g (5 mmol) of (S) 1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature overnight with mmol) of dipropylamine and 20 ml of N,N-dimethylformamide. By evaporation of the solvent and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 1.8 g (85%) of (S)-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride (amorphous).
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N+:14]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>CO.C(OCC)(=O)C.[Pd]>[C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH2:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1Oc1ccncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccccc1Oc1ccncc1N
Reaction time: 2 h
Yield: 97.9 %

Procedure:
137a (1.332 g, 4.891 mmol) was dissolved in a 1:1 mixture of methanol and ethyl acetate (30 mL). Palladium on charcoal (10%, 200 mg, 0.188 mmol) was added, and the mixture was stirred 2 h under hydrogen atmosphere (40 psi). The reaction mixture was filtered over Celite® and concentrated to afford 1.16 g (98% yield, 100% pure) of 4-(2-tert-butylphenoxy)pyridin-3-amine (137b) as a white solid. [M+H]+=243.17. 1H NMR (500 MHz, deuterochloroform) δ ppm 8.07 (s, 1H), 7.75 (d, 1H, J=5.0 Hz), 7.32 (d, 1H, J=10.0 Hz), 7.03 (m, 2H), 6.77 (d, 1H, J=5.0 Hz), 6.41 (d, 1H, J=5.0 Hz), 4.26 (br, 2H),1.27 (s, 9H); 13C (125 MHz, deuterochloroform) δ (ppm), 152.89, 150.65, 140.96, 139.93, 137.42, 134.21, 127.13, 126.93, 124.22, 120.56, 110.45, 34.19, 29.86.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].Br[CH2:11][CH2:12][CH2:13][Cl:14].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:14][CH2:13][CH2:12][CH2:11][N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: ClCCCBr
Reactant: CC1(C)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)N(CCCCl)C1=O

Procedure:
A mixture of 5,5-dimethylhydantoin (5.25 g), 1-bromo-3-chloropropane (8.5 mL), and Cs2CO3 (20.78 g) in 40 mL DMF was allowed to react overnight. The reaction was poured into 125 mL H2O, extracted with ether, and the combined extracts dried over MgSO4. The crude extract was filtered, then reduced in vacuo to yield a clear oil. The residue was chromatographed (50% EtOAc in hexanes) to yield 3-(3-chloropropyl)-5,5-dimethylimidazolidinedione as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[Cl:15][C:12]([F:13])([F:14])[C:6]1[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH:29][C:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Reactant: CC(C)(C)N
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1NC(C)(C)C
Yield: 19.9 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 3.9 ml (0.036 mol) of t-butylamine in 30 ml of DMF were reacted affording a residue which was kugelrohr distilled at 133 Pa, pot temperature 126° C., giving 4.49 g. Purification by HPLC using 5% ethyl acetate/cyclohexane as eluting solvent afforded 1.12 g (19.9%) of product as a white solid; mp 51.5°-53° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.Br[C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][N:19]=[CH:20]2>>[NH:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:15]2[C:16]3[CH:17]=[CH:18][N:19]=[CH:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)[CH2:3]1
Reactant: Brc1cccc2cnccc12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Product: c1cc(N[C@H]2CCNC2)c2ccncc2c1

Procedure:
Reaction of (5)-tert-butyl 3-aminopyrrolidine-1-carboxylate and 5-bromoisoquinoline using the method of Example 16 followed by deprotection using the method of Example 4 afforded the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH2:8][CH2:9][C:10](O)=[S:11])=[N:5][N:4]=[N:3]1.[CH2:13]([N:15](CC)[CH2:16][CH3:17])[CH3:14].ClC(OCC(C)C)=O.C(NCC)C>O1CCCC1>[CH2:13]([N:15]([CH2:16][CH3:17])[C:10](=[S:11])[CH2:9][CH2:8][CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1)[CH3:14]
Reactant: CCN(CC)CC
Reactant: Cn1nnnc1CCCC(O)=S
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCNCC
Product: CCN(CC)C(=S)CCCc1nnnn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
3-(1-Methyl-1,2,3,4-tetrazol-5-yl)methylthiopropionic acid (2 g) is dissolved in tetrahydrofuran (50 ml), and thereto is added triethylamine (1.1 g). To the mixture is added dropwise with stirring isobutyl chloroformate (1.5 g) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise with stirring diethylamine (0.9 g) at the same temperature, and the mixture is further stirred for 3 hours. After distilling off the solvent, the resulting residue is subjected to column chromatography (Kieselgel 60, made by Merck & Co., eluting solvent, chloroform:methanol=50:1, V/V) to isolate N,N-diethyl-3-(1-methyl-1,2,3,4-tetrazol-5-yl)methylthio-propionamide (1.5 g), colorless liquid, nD25 =1.5200.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])C)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.[CH3:29]O.[BH4-].[Li+].Cl>O1CCCC1.O>[CH2:20]([NH:19][N:16]1[C:17](=[O:18])[C:12]([C:4]2[NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[S:2](=[O:1])(=[O:28])[N:3]=2)=[C:13]([OH:27])[C:14]2[S:26][CH:25]=[CH:24][C:15]1=2)[CH2:21][CH2:23][CH3:29]
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: CO
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCNn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.075 g, 0.18 mmol) in tetrahydrofuran (4 mL) and methanol (0.029 mL, 0.5 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 2% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (t, J=7.17 Hz, 3 H) 1.39 (dd, J=15.08, 7.35 Hz, 2 H) 1.50 (m, 2 H) 3.02 (t, J=6.43 Hz, 2 H) 6.65 (s, 1 H) 7.43 (d, J=5.15 Hz, 1 H) 7.55 (t, J=7.72 Hz, 1 H) 7.64 (d, J=8.09 Hz, 1 H) 7.77 (t, J=7.72 Hz, 1 H) 7.92 (d, J=8.09 Hz, 1 H) 8.34 (d, J=5.15 Hz, 1 H) 14.21 (s, 1 H) 14.83 (s, 1 H). MS (ESI−)m/z 417 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: Brc1cnc(I)nc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Yield: 110.3 %

Procedure:
A mixture consisting of 5-bromo-2-iodopyrimidine (Bridge Organics, 10.0 g, 35.1 mmol), benzene boronic acid (Alfa Aesar, 4.25 g, 35.1 mmol), tetrakis(triphenylphosphine)palladium (Strem, 0.405 g, 0.351 mmol), toluene (150 mL), and a 2 M aqueous sodium carbonate solution (35 mL) was stirred at 115° C. (degrees Celsius) under a nitrogen atmosphere for 16 hours. After cooling to room temperature, the mixture was partitioned between chloroform (250 mL) and brine (200 mL). The phases were separated and the organic phase was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give an orange oil (9.1 g). The crude product was purified by flash silica column chromatography. Elution through a 500-g Analogix® flash silica cartridge with 100% hexanes afforded the title intermediate as a white solid (3.15 g, 38% yield). Rf 0.69 with 9:1 v/v hexanes-ethyl acetate; 1H-NMR (400 MHz; CDCl3) δ 8.83 (s, 2H), 8.44-8.38 (m, 2H), 7.52-7.46 (m, 3H); MS (APCI+) m/z 236.9 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[O:6][CH2:7][C:8](=[O:12])[NH:9][C:10]=2[N:11]=1.[O:19]1[CH2:23][CH:20]1[CH2:21][OH:22]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[OH:19][CH:20]([CH2:21][OH:22])[CH2:23][N:9]1[C:8](=[O:12])[CH2:7][O:6][C:5]2[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:3][C:2]([CH3:1])=[N:11][C:10]1=2
Reactant: Cc1nc2c(c(N3CCOCC3)n1)OCC(=O)N2
Reactant: OCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: c1ccccc1
Product: Cc1nc(N2CCOCC2)c2c(n1)N(CC(O)CO)C(=O)CO2
Reaction time: 7 h
Yield: 80.2 %

Procedure:
A mixture containing 1 g of 2-methyl-4-(4-morpholinyl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one, 0.59 g of 2,3-epoxypropanol, 0.128 g of tetra(n-butyl)ammonium bromide and 60 ml of abs. benzene is refluxed under stirring for 7 hours. After filtering, the precipitate is washed with benzene and ether and dried to give 1.04 g (77%) of the product, m.p.: 153°-155° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]2[C:15]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:16][C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:18][CH:19]=2)[CH:5]=[C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]=1[O:8][CH3:9].[CH3:30][S:31]([NH:34][C:35]1[CH:45]=[CH:44][C:38](/[CH:39]=[CH:40]/B(O)O)=[CH:37][CH:36]=1)(=[O:33])=[O:32]>>[C:10]([C:6]1[C:7]([O:8][CH3:9])=[C:2]([CH:3]=[C:4]([C:14]2[C:15]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[N:16][C:17]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[N:18][CH:19]=2)[CH:5]=1)/[CH:40]=[CH:39]/[C:38]1[CH:37]=[CH:36][C:35]([NH:34][S:31]([CH3:30])(=[O:32])=[O:33])=[CH:45][CH:44]=1)([CH3:12])([CH3:13])[CH3:11]
Reactant: COc1c(Br)cc(-c2cnc(OC(C)(C)C)nc2OC(C)(C)C)cc1C(C)(C)C
Reactant: CS(=O)(=O)Nc1ccc(/C=C/B(O)O)cc1
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2)cc(-c2cnc(OC(C)(C)C)nc2OC(C)(C)C)cc1C(C)(C)C

Procedure:
The product from Example 2 Part A (55.9 mg, 0.12 mmol) and (E)-4-(methylsulfonamido) styrylboronic acid (28.9 mg, 0.120 mmol) were reacted in the same manner as Example 2 Step B. The crude product was purified by silica gel flash chromatography eluting with ethyl acetate/hexane (5% to 25%) to give the title compound.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[CH:14]=[O:15].[Cl:16][C:17]1[CH:18]=[C:19]([SH:24])[CH:20]=[C:21]([Cl:23])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:16][C:17]1[CH:18]=[C:19]([S:24][C:2]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:5]=[C:4]([CH3:13])[C:3]=2[CH:14]=[O:15])[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: Cc1nn(-c2ccccc2)c(Cl)c1C=O
Reactant: Sc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1C=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
A solution containing 175 mg of 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde, 142 mg of 3,5-dichlorothiophenol and 132 mg of potassium carbonate in 5 ml of anhydrous N,N-dimethylformamide was stirred under nitrogen at 60° C. for 2 h. The mixture was diluted with 10 ml of water and extracted three times with 8 ml of dichloromethane. The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane for the elution to give 164 mg of 5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde as a yellow oil.
Reaction SMILES: C(O)=O.[C:4]([O:7][C:8](=O)[CH3:9])(=[O:6])C.[C:11]([O:15][C:16](=[O:36])[NH:17][C@@H:18]([CH2:26][NH:27]OCC1C=CC=CC=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:14])([CH3:13])[CH3:12].C([O-])(O)=O.[Na+]>ClCCl>[C:11]([O:15][C:16](=[O:36])[NH:17][C@@H:18]([CH2:26][NH:27][C:4]([O:7][CH2:8][C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:26]=1)=[O:6])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNOCc1ccccc1)Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=CO
Product: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 176.5 %

Procedure:
To a cold mixture of formic acid (2.3 g, 73.0 mmol) and acetic anhydride (0.56 mL, 6.0 mmol) was added dropwise [(R)-1-(Benzyloxyaminomethyl)-2-phenyl-ethyl)-carbamic acid tert-butyl ester (0.20 g, 0.56 mmol) in dichloromethane (2.8 mL) at 0° C. The reaction mixture was stirred at 0° C. for 3 hours, and then treated with saturated aq. NaHCO3 (5 mL). The aqueous layer was extracted with dichloromethane (10 mL×2). The organic extracts were washed with water and brine, and dried over MgSO4. After removal of the solvent under reduced pressure, purification by flash column chromatography using an eluting system of hexane/EtOAc (2:1) yielded 0.19 g (86%) of the title compound 1H NMR (400 MHz, CDCl3): δ 8.14 (br s, 1H), 7.32-7.07 (m, 10H), 4.90-4.67 (m, 2H), 4.15 (m, 1H), 3.74 (m, 1H), 3.36 (m, 1H), 2.78 (m, 1H), 2.68 (m, 2H), 1.32 (m, 9H). MH+385.
Reaction SMILES: O.C1(C)C=CC(C([C@](C(O)=O)(O)[C@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=[O:9])=CC=1.[CH2:30]([N:33]1[C:37]([CH2:38][S:39][C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[CH:36][N:35]=[CH:34]1)[CH2:31][CH3:32].Cl>C(OCC)(=O)C>[CH2:30]([N:33]1[C:37]([CH2:38][S:39]([C:40]2[CH:41]=[CH:42][C:43]([NH2:46])=[CH:44][CH:45]=2)=[O:9])=[CH:36][N:35]=[CH:34]1)[CH2:31][CH3:32]
Reactant: Cc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Reactant: CCCn1cncc1CSc1ccc(N)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CCCn1cncc1CS(=O)c1ccc(N)cc1

Procedure:
To (−)-4-{[(1-propyl-1H-imidazol-5-yl)methyl]sulfenyl}phenylamine di-p-toluoyl-D-tartarate monohydrate (5 g) were added 1N hydrochloric acid (25 ml) and ethyl acetate (15 ml) to effect reverse extraction. To the aqueous layer was added aqueous 25% potassium carbonate solution (25 ml) (pH 9) and the mixture was extracted with 25 ml of ethyl acetate-IPA (4:1) three times. The organic layer was washed with saturated brine (25 ml) and dried with magnesium sulfate. The solvent was distilled off to give (−)-4-{[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl}-phenylamine.
Reaction SMILES: [CH3:1][CH2:2][CH:3](P(OCC)(OCC)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:17]([O-])([O-])=O.[K+].[K+].C=O.O>CCOCC>[CH2:17]=[C:3]([CH2:2][CH3:1])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: C=C(CC)C(=O)OCC
Temperature: 80 °C
Yield: 86.2 %

Procedure:
A mixture of 5.0 g (0.019 mol) of triethyl 2-phosphonobutyrate, 5.5 g (0.039 mol) of K2CO3, 6.2 g (0.076 mol) of 37% aqueous formaldehyde solution, and 15 mL of water was heated to about 80° C. for about 45 min. After cooling to RT, 75 mL of ether was added and the organic layer was separated, washed with brine (1×20 mL), dried (MgSO4), and filtered. The ether was carefully removed by distillation, leaving behind 2.1 g (87%) of the title compound as a clear oil which was used directly without further purification. 1H NMR (CDCl3): δ 1.01 (3 H, t, J=7), 1.24 (3 H, t, J=7), 2.26 (2 H, q, J=7), 4.14 (2 H, q, J=7), 5.45 (1 H, s), 6.06 (1 H, s).
Reaction SMILES: C(NC(=O)C(N[C:13]([C:15]1[N:16]([CH3:44])[C:17]2[C:22]([C:23]=1[Cl:24])=[CH:21][C:20]([NH:25][C:26]([C:28]1[C:29]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=3)=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:27])=[CH:19][CH:18]=2)=[O:14])C1C=CC=CC=1)C.CC(C[AlH]CC(C)C)C>C1COCC1.OS([O-])(=O)=O.[Na+].CCOC(C)=O>[Cl:24][C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([NH:25][C:26]([C:28]3[C:29]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([F:41])([F:43])[F:42])=[CH:36][CH:35]=4)=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:27])[CH:21]=2)[N:16]([CH3:44])[C:15]=1[CH:13]=[O:14]
Reactant: CCNC(=O)C(NC(=O)c1c(Cl)c2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2n1C)c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(C=O)c(Cl)c2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Temperature: -78 °C
Reaction time: 6 h
Yield: 51.2 %

Procedure:
To a solution of the product from step (a) (1.56 g, 3.02 mmol) in THF (25 ml) at −78° C. was added DIBAL in THF (1.0 M, 12 ml), and the reaction mixture was stirred at −78° C. for 6 h. The reaction mixture was diluted with NaHSO4 (0.25 M, 86 ml) and EtOAc (115 ml), and the aqueous layer was extracted with EtOAc (2×100 ml). The combined organic layers were dried (MgSO4) and concentrated in vacuo to about 30 ml in volume. The product was purified by flash chromatography using 1:1 EtOAc/hexane to afford 0.706 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:8]=[N:9][C:10]([N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:14])=[CH:11][CH:12]=1)[CH3:2].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]([NH:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:7]1[CH:8]=[N:9][C:10]([N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:14])=[CH:11][CH:12]=1)[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C=Cc1ccc(N(C)C(=O)OC(C)(C)C)nc1
Product: CCOC(=O)CC(NCc1ccccc1)c1ccc(N(C)C(=O)OC(C)(C)C)nc1
Temperature: 95 °C

Procedure:
A mixture of 11-4 (1.7 g, 5.6 mmol) and benzylamine (8 mL, 73.2 mmol) was heated in a sealed-tube at 95° C. for 24 hr. The crude reaction mixture was purified using silica gel flash chromatography (EtOAc/hexanes 1:3 to 1:1) to afford the desired product 11-5 as an oil.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[O:11][C:12]3[C:17]([C:18](=[O:20])[CH:19]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][C:4]=1[CH3:21].CC(O)=O.O>I>[OH:2][C:3]1[C:4]([CH3:21])=[CH:5][C:6]([C:10]2[O:11][C:12]3[C:17]([C:18](=[O:20])[CH:19]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][C:8]=1[CH3:9]
Reactant: COc1c(C)cc(-c2cc(=O)c3ccccc3o2)cc1C
Agent: I
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(-c2cc(=O)c3ccccc3o2)cc(C)c1O
Temperature: 110 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 2-hydroxyacetophenone (1.361 g, 10 mmol) in 20 mL anhydrous pyridine was added 3,5-dimethyl-4-methoxybenzoic acid (2.162 g, 12 mmol). The mixture was cooled to 0° C. and phosphorous oxychloride (1 mL) was added. A white precipitate was formed. The reaction mixture was stirred at rt for 2 h under nitrogen atmosphere. Then the reaction mixture was poured into 100 mL cold 2N HCl and extracted with EtOAc (2×200 mL). The combined organic layers were washed with water and brine and dried over anhydrous Na2SO4. The solvent was removed under vacuum to give a colorless liquid (2.89 g, 97%), which was used in the next step without further purification. The compound (2.88 g, 9.65 mmol) was dissolved in 10 mL anhydrous pyridine. Powdered potassium hydroxide (1.62 g, 28.95 mmol) was added and the reaction mixture was stirred at rt overnight under nitrogen. Water (100 mL) was added and the mixture was neutralized to pH 7 with conc. HCl. The yellow solid was filtered off, washed with water and dried under vacuum. Yield: 1.16 g, 40%. To a suspension of the yellow solid (1.14 g, 3.83 mmol) in 8 mL glacial AcOH was added 4 drops of conc. HCl and the reaction mixture was stirred at 110° C. for 2 h. The mixture was cooled to rt and water (50 mL) was added. The solid was isolated by filtration and washed with water and dried under vacuum to give 2-(4-methoxy-3,5-dimethyl phenyl)chromen-4-one (1.05 g, 98%) as a pale green solid. 2-(4-methoxy-3,5-dimethyl phenyl) chromen-4-one was suspended in 20 mL hydroiodic acid and 8 mL glacial AcOH was added. The reaction mixture was stirred at 110° C. for 2 h. The mixture was cooled to rt. Water (100 mL) was added and the solid was isolated by filtration, washed with water and dried under vacuum. The crude compound was washed with 1:1 dichloromethane and methanol (20 mL) to give 0.763 g of 2-(4-hydroxy-3,5-dimethylphenyl)-4H-chromen-4-one (85%) as a pale yellow solid. MS (ES) m/z: 267.06 (M+1); Mp. 255-256° C.