Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[S:10]([CH2:15][C:16](O)=[O:17])[CH2:11][C:12]([OH:14])=[O:13].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C1COCC1.O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:16](=[O:17])[CH2:15][S:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(O)CSCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1ccc(NC(=O)CSCC(=O)O)cc1
Yield: 15.3 %

Procedure:
A solution of 4-aminobenzonitrile (500 mg, 4.23 mmol), 2,2′-thiodiacetic acid (3.18 g, 21.2 mmol), WSC (4.87 g, 25.4 mmol), DMAP (258 mg, 0.21 mmol) and DIEA (5.47 g, 42.3 mmol) in THF (200 mL) was stirred at room temperature for 60 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give 2-((2-((4-cyanophenyl)amino)-2-oxoethyl)thio)acetic acid (162 mg, 15.3%) as a pale-yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)=[CH:4][C:3]=1[NH:23][C:24]([C:26]1[CH:27]=[C:28]([CH2:38][C:39](O)=[O:40])[CH:29]=[C:30]([S:32]([F:37])([F:36])([F:35])([F:34])[F:33])[CH:31]=1)=[O:25].C[N:43](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.N.CCCCC.C(OC(C)C)(C)C>CN(C=O)C.C1COCC1>[NH2:43][C:39](=[O:40])[CH2:38][C:28]1[CH:27]=[C:26]([CH:31]=[C:30]([S:32]([F:36])([F:37])([F:34])([F:33])[F:35])[CH:29]=1)[C:24]([NH:23][C:3]1[CH:4]=[C:5]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[O:25]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1cc(C)c(-n2ccn3nc(-c4cccnc4)cc23)cc1NC(=O)c1cc(CC(=O)O)cc(S(F)(F)(F)(F)F)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)OC(C)C
Product: Cc1cc(C)c(-n2ccn3nc(-c4cccnc4)cc23)cc1NC(=O)c1cc(CC(N)=O)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
85 mg (0.128 mmol) of the compound of Example 151 and 58 mg (0.154 mmol) of HATU were initially charged in 2 ml of DMF, and 67 μl (0.384 mmol) of N,N-diisopropylethylamine and 1.3 ml (0.640 mmol) of a 0.5 M solution of ammonia in THF were then added. After the reaction mixture had been stirred at RT for about 16 h, the entire mixture was separated into its components by preparative HPLC (Method 36). The product fractions were combined and concentrated to dryness on a rotary evaporator. For further purification, the product was triturated for 10 min at RT with a few ml of pentane/diisopropyl ether 4:1. The solid was separated off and dried under high vacuum. This gave 9 mg (11% of theory, 95% pure) of the title compound.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]([NH:19][NH2:20])=[O:18]>C(O)C>[CH3:15][O:16][C:17]([NH:19][N:20]=[C:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:18]
Reactant: COC(=O)NN
Reactant: O=C1CCCCC1Cc1ccccc1
Solvent: CCO
Product: COC(=O)NN=C1CCCCC1Cc1ccccc1
Reaction time: 2 h
Yield: 69.9 %

Procedure:
18.83 g (0.1 mole) of 2-benzylcyclohexan-1-one and 9.0 g (0.1 mole) of N-methoxycarbonyl hydrazine are dissolved in 100 cm3 of anhydrous ethanol, and the solution is boiled for 2 hours. Then it is cooled, and the separated crystals are filtered off. 18.2 g (96.9%) of the named compound are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:15]3[CH2:23][NH:22][CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:26]=[C:27]([C:33]([F:36])([F:35])[F:34])[C:28]([O:31][CH3:32])=[N:29][CH:30]=1.CC(C)([O-])C.[Na+].C(O)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1N(C)C)(C)(C)C.CCOC(C)=O.CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:15]3[CH2:23][N:22]([C:25]4[CH:30]=[N:29][C:28]([O:31][CH3:32])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ncc(Br)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ncnc3c2CNCC3)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: COc1ncc(N2CCc3ncnc(N[C@H]4CCN(C(=O)OC(C)(C)C)C4)c3C2)cc1C(F)(F)F
Temperature: 100 °C
Reaction time: 5 h
Yield: 73.8 %

Procedure:
To a glass vial was added (S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 23) (3.5 g, 10.96 mmol), 5-bromo-2-methoxy-3-(trifluoromethyl)pyridine (intermediate 1) (3.09 g, 12.05 mmol), sodium tert-butoxide (1.58 g, 16.44 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.502 g, 0.548 mmol), 2-di-t-butylphosphino-2′-(N,N-dimethylamino)biphenyl (0.225 g, 0.657 mmol) and anhydrous tert-butanol (6 mL). The vial was flushed with a stream of argon for 15 sec and capped. The mixture was heated with stirring for 5 h at 100° C. Allowed to cool and partitioned between EtOAc (100 mL) and water (20 mL) and filtered the biphasic mixture through a celite pad. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. Purified by flash column chromatography through Biotage® amino silica gel eluting with heptane/EtOAc, 100/0 to 0/100 then EtOAc/MeOH (90/10) to give (S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow foam (4.00 g, 74% yield). LCMS: [M+H]+=495.2, Rt(3)=1.59 min.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:8]1=[O:27]>C(OC)(C)(C)C>[O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@:9]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:8]1=[O:27]
Reactant: O=C1N(C[C@@H]2CCCO2)c2ccccc2C12COc1cc3c(cc12)CCO3
Solvent: COC(C)(C)C
Product: O=C1N(C[C@@H]2CCCO2)c2ccccc2[C@]12COc1cc3c(cc12)CCO3
Yield: 64 %

Procedure:
1′-[(2S)-Tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was resolved on chiral semi-prep HPLC IA column with tert-butylmethyl ether (100%) to afford (3S)-1′-[(2S)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (64%): 1H NMR (300 MHz, CDCl3) δ 7.32-6.97 (m, 4H), 6.48 (s, 1H), 6.38 (s, 1H), 4.77 (ABq, 2H), 4.51 (t, J=8.3 Hz, 2H), 4.32-4.21 (m, 1H), 3.91-3.68 (m, 4H), 2.97 (t, J=8.5 Hz, 2H), 2.10-1.63 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 178.3, 161.7, 161.2, 142.8, 132.7, 128.6, 123.6, 123.2, 120.4, 119.8, 118.9, 109.5, 93.1, 80.6, 76.8, 72.3, 68.1, 57.6, 44.5, 29.0, 25.6; MS (ES+) m/z 363.8 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([OH:12])[C:9]([O:13][CH3:14])=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2].C1(C)C=CC(S(O[CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(#N)C.O>[N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:28][CH2:27]2)[C:9]([O:13][CH3:14])=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1cc(C#N)c([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C#N)c([N+](=O)[O-])cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 80.5 %

Procedure:
2-nitro-4-hydroxy-5-methoxybenzonitrile (388 mg, 2 mmol) in DMF (5 ml) and acetonitrile (5 ml) was reacted with 4-(4-tolylsulphonyloxymethyl)-1-tert-butyloxycarbonyl-piperidine (738 mg, 2 mmol) and K2CO3 (414 mg, 3 mmol) at 110° C. for 3.5 hours. The mixture was diluted with water, extracted with ethylacetate, washed HCl (2N), dried over MgSO4, evaporated to give title compound (630 mg, 80%).
Reaction SMILES: C(OCC([NH:12][C:13]([C:15]1[C:20]([I:21])=[C:19](N2C(=O)CCC2CI)[C:18]([I:30])=[C:17]([C:31]([NH:33]C(COC(=O)C)COC(=O)C)=[O:32])[C:16]=1[I:45])=[O:14])COC(=O)C)(=O)C.C([O-])(=O)C.C([N+](CC)(CC)CC)C>C(#N)C>[I:45][C:16]1[C:17]([C:31]([NH2:33])=[O:32])=[C:18]([I:30])[CH:19]=[C:20]([I:21])[C:15]=1[C:13]([NH2:12])=[O:14]
Reactant: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c(I)c(N2C(=O)CCC2CI)c1I
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Solvent: CC#N
Product: NC(=O)c1c(I)cc(I)c(C(N)=O)c1I
Reaction time: 18 h
Yield: 15.8 %

Procedure:
To a solution of N,N'-bis[2-(acetyloxy)-1-[(acetyloxy)methyl]ethyl]-5-[2-(iodomethyl)-5-oxo-1-pyrrolidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide (12.00 g, 110 mmol) in acetonitrile (150 ml) was added tetraethylammonium acetate (5.74 g, 22 mmol) and the mixture stirred at 50° for 18 hours. Acetonitrile was removed in vacuo at 60°, the residue dissolved in ethyl acetate (200 ml), and the resulting solution washed with brine (2×100 ml) and with water (100 ml). The ethyl acetate layer was dried and removal of the solvent afforded the crude product as a colorless glassy solid. This material was purified by column chromatography over silica gel, using 20% hexane in ethyl acetate as eluent, to obtain N,N-bis-[2-(acetyloxy)-1-[(acetyloxy)methyl]ethyl]-5-[2-[acetyloxy)methyl)-5-oxo-1-pyrrolidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide as a colorless solid (9.4 g, 83.6% yield).
Reaction SMILES: [CH:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)=O.[Br-].[O:16]([CH2:23][CH2:24][CH2:25][CH2:26][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[O:16]([CH2:23][CH2:24][CH2:25][CH:26]=[CH:1][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)COc1ccc(C=O)cc1
Reactant: c1ccc(OCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: COC(=O)COc1ccc(C=CCCCOc2ccccc2)cc1

Procedure:
Preparation takes place in analogy to Example XLIII from methyl (4-formylphenoxy)acetate and (4-phenoxybutyl)(triphenyl)phosphonium bromide. The product is obtained as an E/Z mixture.
Reaction SMILES: [O:1]=[C:2]([CH3:14])[CH2:3][CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[O:1]=[C:2]([CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CCCC#CCCC(C)=O
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: COC(=O)/C=C\CCCCCC(C)=O
Reaction time: 0.58 h
Yield: 75.7 %

Procedure:
The methyl 9-oxo-5-decynoate (31.5 g, 0.16 mol) was dissolved in 250 ml MeOH containing 0.6 g quinoline. Five percent of Pd/BaSO4 (0.6 g) was added. One equivalent of H2 was absorbed at room temperature and 1 atm in 35 minutes. The catalyst was filtered, the solvent evaporated, and the residue taken up in 500 ml of ethyl acetate. It was washed twice with 125 ml 1N HCl, H2O, and brine. After drying over anhydrous MgSO4, the solvent was removed and distillation gave 24 g (80%) of methyl 9-oxo-cis-decenoate as a colorless oil, bp 93-94° C./0.4 mm. The NMR spectrum was identical to an authentic sample prepared by the Sih process. NMR (CDCl3): 1.3-2.6(m, 10H), 2.13(s, 3H), 3.65(s, 3H), 5.2-5.5ppm(m, 2H).
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1O.[NH2:9][C:10]([NH2:12])=[S:11]>C(O)CCCCC>[N:9]1[C:10](=[S:11])[N:12]=[C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=12
Reactant: OC1CCCCC1O
Reactant: NC(N)=S
Solvent: CCCCCCO
Product: S=C1N=C2CCCCC2=N1
Temperature: 25 °C
Yield: 19.5 %

Procedure:
Part A. A solution of 2-hydroxycyclohexanol (2.28 g, 0.02 mol), thiourea (1.52 g, 0.02 mol) and hexanol (30 ml), equipped with a column of 4Å sieves and a condenser, was heated to 160° for five hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to ambient temperature and was concentrated in vacuo to give a solid. The solid was triturated with ethyl ether (3×50 ml) to give 4,5,6,7-tetrahydrobenzimidazol-2-thione (0.6 g, 0.0039 mol) which was not purified but was taken on to the next step as a crude solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[N+:23]([O-])=O)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH2:23][C:22]1[CH:21]=[CH:20][C:4]([O:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:11][CH2:12]2)=[CH:3][C:2]=1[CH3:1]
Reactant: [H][H]
Reactant: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reaction time: 16 h
Yield: 65.8 %

Procedure:
tert-Butyl 4-((3-methyl-4-nitrophenoxy)methyl)piperidine-1-carboxylate (5.68 g, 16.22 mmoles) was dissolved in ethyl acetate (60 ml) and methanol (40 ml). The solution was treated with 600 mg of 10% palladium on carbon (50% water w/w). The slurry was then shaken on a Parr hydrogenator and treated with a 40 psi of hydrogen gas, at room temperature. After 16 hours, the slurry was filtered through a plug of Celite, which was subsequently washed with ethyl acetate (50 ml) and methanol (50 ml). The resulting filtrate was then evaporated at reduced pressure to give 3.42 g of tert-butyl 4-((4-amino-3-methylphenoxy)methyl)piperidine-1-carboxylate as a pink solid (100% yield). The material was used in the next step without any further purification. 1H-NMR (400 MHz, DMSO-d6) d 6.34 (d, 1H), 6.32 (s, 1H), 6.23 (d, 1H), 5.84 (br s, 2H), 3.90 (s, 2H), 3.34 (m, 4H), 2.00 (m, 1H), 1.46 (m, 4H), 1.42 (s, 9H). MS (EI): 321 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.Cl[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:8][C:7]1[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=1[N+:9]([O-:11])=[O:10])[CH3:18]
Reactant: O=[N+]([O-])c1cccc(Cl)c1O
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c(Cl)cccc1[N+](=O)[O-]

Procedure:
A solution of 6-chloro-2-nitrophenol (1.7 g.) and ethyl chloroacetate (2.1 ml.) in dimethylformamide (12 ml.) with potassium carbonate (1.5 g.) was stirred at 75°-80° C. for 3 hours. The mixture as poured into water (120 ml.) and extracted with ethyl acetate (4× 50 ml.). The organic layer on evaporation yielded 6-chloro-2-nitrophenoxyacetic acid ethyl ester as a yellow oil.
Reaction SMILES: [CH:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]([CH3:17])([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.[CH3:20][C:21]1[N:22]=[CH:23][O:24][C:25]=1[CH2:26][NH2:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:16][C:8]([O:7][C:6]1[CH:18]=[CH:19][C:3]([CH2:1][NH:27][CH2:26][C:25]2[O:24][CH:23]=[N:22][C:21]=2[CH3:20])=[CH:4][CH:5]=1)([CH3:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(C=O)cc1
Reactant: Cc1ncoc1CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ncoc1CNCc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.25 g (4.73 mmol) of tert-butyl 2-(4-formylphenoxy)-2-methylpropanoate (Example I-4) and 0.64 g (5.67 mmol) of (4-methyl-1,3-oxazol-5-yl)methylamine (Example III-28) are together initially charged in 1,2-dichloroethane. At room temperature, 1.50 g (7.09 mmol) of sodium triacetoxyborohydride are added. The reaction mixture is stirred at room temperature for 4 hours and then admixed with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and freed from the solvent under reduced pressure. The residue is purified chromatographically on silica gel (dichloromethane/methanol 30:1) and then dried under reduced pressure. This gives 1.104 g (65% of theory) of the title compound.
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].B.C1C[O:31]CC1.[OH-].[Na+].OO.Cl>C1COCC1.O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@@:4]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)([CH2:1][CH2:2][CH2:3][OH:31])[O:9][C:8]2=[O:10])[CH3:12])=[CH:14][CH:15]=1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: C1CCOC1
Agent: B
Agent: Cl
Agent: OO
Solvent: O
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (1 g, 2.4 mmol) in dry THF (15 mL) was added dropwise BH3.THF (5 mL, 1 M) at 0° C. After stirring for 2 h at rt, the reaction mixture was cooled to 0° C. and water (1 mL), aqueous NaOH (0.5 mL, 3 M) and H2O2 (0.5 mL, 30%) were successively added. The mixture was stirred for 2-3 h at rt and diluted with water (8 mL). The pH was adjusted to 6-7 with 0.5 N HCl. The layers were separated, and the aqueous phase was extracted with EtOAc (3×10 mL). The combined organic layers were washed with a satd aq NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by preparative TLC to afford (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (400 mg, 38%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:24]C(=O)OC(C)(C)C)[CH2:10][NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[CH:5]=[C:6]([I:8])[CH:7]=1.[C:32]([O-])([O-])=O.[K+].[K+].IC.Cl>CN(C=O)C.O.CCOC(C)=O.C(Cl)Cl.O1CCOCC1>[NH2:24][C@@H:9]([C:4]1[CH:5]=[C:6]([I:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:10][N:11]([CH3:32])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(F)cc(I)c1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(C[C@@H](N)c1cc(F)cc(I)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-tert-butyl (1-(3-fluoro-5-iodophenyl)-2-(2-nitrophenylsulfonamido)ethyl)carbamate (290 mg, 0.513 mmol) was dissolved in DMF (5.1 mL) and K2CO3 (142 mg, 1.026 mmol) followed by iodomethane (48.1 μl, 0.769 mmol) were added. The mixture was agitated at room temperature for 1 h upon which complete reaction observed. RM diluted with water and EtOAc. The organic layer was washed with water twice and dried (magnesium sulfate), filtered and concentrated in vacuo to give relatively pure product which was dissolved in DCM (5 mL) and treated with 4N HCl in dioxane (2 mL) and the mixture agitated at room temperature overnight and the mixture concentrated in vacuo to afford the desired product (S)—N-(2-amino-2-(3-fluoro-5-iodophenyl)ethyl)-N-methyl-2-nitrobenzenesulfonamide as the hydrochloride salt. LCMS (m/z): 480.4 (MH+), 0.72 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1)[CH3:2].[CH:14](O)=[O:15]>C(OC(C)C)(C)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][CH:14]=[O:15])[CH:7]=1)[CH3:2]
Reactant: O=CO
Reactant: CCOC(=O)Cc1cccc(N)c1
Solvent: CC(C)OC(C)C
Product: CCOC(=O)Cc1cccc(NC=O)c1
Yield: 88 %

Procedure:
A solution of 3-aminophenylacetic acid ethyl ester (3.0 g; 0.017 mol; from Example T(i) above), and formic acid (1.5 g; 0.034 mol) in diisopropylether (150 mL) was refluxed with a Dean-Stark trap overnight. The solution was concentrated to dryness, dissolved in ether and washed with diluted HCl to remove remaining starting material. Drying (Na2SO4) and concentration yielded the sub-title compound (3.1 g; 89%).
Reaction SMILES: O=[C:2]1[C:7]2=[CH:8][CH:9]=[C:10]3[C:14]([CH3:15])=[C:13]([CH3:16])[O:12][C:11]3=[C:6]2[O:5][C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:3]1.S1C=CC=C1.[H][H]>CO.[Pd]>[CH3:16][C:13]1[O:12][C:11]2=[C:6]3[O:5][CH:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:3][CH2:2][C:7]3=[CH:8][CH:9]=[C:10]2[C:14]=1[CH3:15]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(=O)c2ccc3c(C)c(C)oc3c2o1
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Product: CCOC(=O)C1CCc2ccc3c(C)c(C)oc3c2O1
Yield: 72.9 %

Procedure:
A solution of ethyl 6-oxo-2,3-dimethyl-6H-furo[3,2-h][1]benzopyran-8-carboxylate (0.1 mol) in methanol (250 ml) was hydrogenated for 10 hours at 170° C. (pressurized) with palladium on activated carbon, palladium content 5% (2 g) as a catalyst in the presence of a 4% thiophene solution (10 ml). After uptake of hydrogen (3 equiv), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by flash column chromatography over silica gel (eluent: CH2Cl2). The desired fractions were collected and the solvent was evaporated, yielding 20 g (72.9%) of (±)-ethyl 7,8-dihydro-2,3-dimethyl-6H-furo[3,2-h][1]benzopyran-8-carboxylate (interm. 16-a).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[N:3]=1.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:21][CH2:17][CH2:18][CH2:19][CH3:20])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[N:3]=1
Reactant: CCCCN
Reactant: Nc1nc(Cl)nc(-c2ccc(Cl)c(Cl)c2)n1
Solvent: C1COCCO1
Product: CCCCNc1nc(N)nc(-c2ccc(Cl)c(Cl)c2)n1
Yield: 80.6 %

Procedure:
2-Amino-4-chloro-6-(3,4-dichlorophenyl)-s-triazine (melting point 249° to 250° C.) (2.75 grams) and 2.0 grams of n-butylamine were heated to reflux with stirring for four hours in 25 milliliters of dioxane. The reaction solution was evaporated to dryness in vacuo, the residue was washed with water and then with methanol, and 2.51 grams of 2-amino-4-butylamino-6-(3,4-dichlorophenyl)-s-triazine was obtained. Melting point 176° to 179° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:22][C:23](=[O:36])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N+:33]([C:29]1[CH:28]=[C:27]([C:25]2[CH2:24][C:23](=[O:36])[NH:22][C:9]3[CH:10]=[C:11]([C:14]#[C:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:32]=[CH:31][CH:30]=1)([O-:35])=[O:34]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1NC(=O)CC(=O)c1cccc([N+](=O)[O-])c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc([N+](=O)[O-])c2)=Nc2ccc(C#Cc3ccccc3)cc2N1
Yield: 85.3 %

Procedure:
Prepared from {2-[3-(3-nitro-phenyl)-3-oxo-propionylamino]-4-phenylethynyl-phenyl}-carbamic acid tert.-butyl ester (Example K31) (970 mg, 1.94 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (631 mg).