Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1(O[C:11]2[C:12]3[N:13]=[CH:14][N:15]([C:24]=3[N:25]=[CH:26][N:27]=2)[C@@H:16]2[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[CH2:17]2)C2C=CC=CC=2N=N1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC>[C@@H:16]1([N:15]2[CH:14]=[N:13][C:12]3[C:24]2=[N:25][CH:26]=[N:27][C:11]=3[N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[CH2:17]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: OC[C@H]1O[C@@H](n2cnc3c(N4CCOCC4)ncnc32)C[C@@H]1O
Yield: 51.7 %

Procedure:
As described for the synthesis of 6-(morpholin-1-yl)-9-[2-deoxy-3,5-bis-O-(tert-butyldimethylsilyl)-β-D-erythro-pentofuranosyl]purine, this morpholino derivative was prepared by a reaction between O6-(benzotriazol-1-yl)-2′-deoxyinosine (28) (36.9 mg, 0.100 mmol), and morpholine (17.5 μL, 0.200 mmol) in the presence of Cs2CO3 (65.2 mg, 0.200 mmol) in dry DME (1.0 mL) at room temperature over 1 h. Chromatographic purification (SiO2, elution with 5% MeOH in CH2Cl2) afforded 16.6 mg (52% yield) of the title compound as a clear gum. Rf (10% MeOH in CH2Cl2)=0.34. 1H NMR (500 MHz, CDCl3): δ 8.26 (s, 1H, Ar—H), 7.77 (s, 1H, Ar—H), 6.88 (br, 1H, OH, CD3OD exchangeable), 6.30 (dd, 1H, H-1′, J=9.8, 5.4), 4.77 (d, 1H, H-3′, J=4.8), 4.30 (br, 4H, 2CH2), 4.21 (br s, 1H, H-4′), 3.96 (dd, 1H, H-5′, J=12.7, 1.2), 3.81 (t, 4H, 2CH2, J=4.9), 3.77 (br d, 1H, H-5′, J=13.2), 3.10 (ddd, 1H, H-2′, J=13.7, 9.3, 4.9), 2.65 (br, 1H, OH, CD3OD exchangeable), 2.26 (dd, 1H, H-2′, J=13.7, 5.6). 13C NMR (126 MHz, CDCl3): δ 154.1, 151.6, 149.4, 138.3, 121.7, 89.7, 87.8, 73.6, 67.0, 63.5, 45.6, 40.5.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[OH:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:29][O:28][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:11]=1[O:10][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)[N:18]=[CH:17][N:16]=[C:15]2[O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: ClCCN1CCCC1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCN1CCCC1
Temperature: 110 °C
Yield: 14.8 %

Procedure:
1-(2-Chloroethyl)pyrrolidine hydrochloride (1.27 g, 7.5 mmol) was added to 7-hydroxy-6-methoxy-4-phenoxyquinazoline (1.0 g, 3.7 mmol), and potassium carbonate (3.9 g, 28.3 mmol) in DMF (30 ml). The mixture was heated at 110° C. for 4 hours and allowed to cool. The mixture was filtered, and the volatiles were removed from the filtrate by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol/ammonia, (100/8/1) to give an oil which was triturated with ethyl acetate to give 6-methoxy-4-phenoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline (200 mg, 15%) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][N:6]([C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH:27]([CH2:29][CH3:30])[CH3:28])[CH:21]=2)=[C:14]([Cl:31])[CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])C.[OH-].[Na+]>CO.O>[CH:27]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[OH:26])[O:19][C:15]1[C:14]([Cl:31])=[CH:13][C:12]([N:6]([CH2:5][C:4]([OH:32])=[O:3])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:17][C:16]=1[Cl:18])([CH2:29][CH3:30])[CH3:28]
Reactant: CCOC(=O)CN(C(=O)OCC)c1cc(Cl)c(Oc2ccc(O)c(C(C)CC)c2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC(=O)N(CC(=O)O)c1cc(Cl)c(Oc2ccc(O)c(C(C)CC)c2)c(Cl)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
The ester (0.77 g, 1.5 mmol) was dissolved in MeOH (18 mL) and to it a solution of NaOH (0.19 g, 4.75 mmol) in H2O (5.6 mL) was added and it was stirred at 60° C. for 1 hr. Methanol was evaporated from the reaction mixture and H2O was added, washed with diethyl ether. Aqueous layer was acidified to pH 4 using 10% HCl solution and extracted with ethyl acetate. The organic layer was washed with H2O, brine & dried over sodium sulphate, filtered and concentrated to give 0.75 g of crude product. The crude product was purified by column chromatography (Silica gel, Chloroform Methanol) gradient elution from 95:5 to 90:10 to give pure {[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonyl-amino}-acetic acid. (0.125 g, 18% yield)
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>C(OCC)C>[F:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: Nc1ncccc1OCc1c(F)cccc1Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1cccc(Cl)c1COc1cccnc1NC(=S)Nc1ccc(Cl)cc1

Procedure:
A mixture of 2-amino-3-(2-fluoro-6-chlorobenzyloxy)pyridine (3.46 g, 0.014 mol), 4chlorophenyl isothiocyanate (2.55 g, 0.015 mol) and toluene (10 ml) was refluxed for 2 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 4.64 g (73%), m.p. 162°-164 ° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[C:25]([C:29]1[CH:34]=[CH:33][C:32](/[C:35](/[C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([O:46][CH3:47])[N:40]=2)=[CH:36]\CO)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26].O>O1CCCC1>[Br:24][CH2:20]/[CH:36]=[C:35](/[C:39]1[N:40]=[C:41]([O:46][CH3:47])[C:42]([Cl:45])=[CH:43][CH:44]=1)\[C:32]1[CH:31]=[CH:30][C:29]([C:25]([CH3:28])([CH3:26])[CH3:27])=[CH:34][CH:33]=1
Reactant: COc1nc(/C(=C/CO)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(/C(=C/CBr)c2ccc(C(C)(C)C)cc2)ccc1Cl
Yield: 118 %

Procedure:
Triphenylphosphine (1.10 g) and carbon tetrabromide (1.81 g) were sequentially added to a solution of (2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-en-1-ol (912 mg) in tetrahydrofuran (30 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 1.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the title compound as a black powder (1.28 g).
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]2([CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:31][CH2:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][C@@H:34]6[CH2:38][CH2:37][CH2:36][O:35]6)[CH:28]=5)[C:23]4=[O:39])=[CH:18][C:17]=3F)[CH2:12]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)[C:43](O)=[O:44]>>[CH2:9]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][C@@H:34]6[CH2:38][CH2:37][CH2:36][O:35]6)[CH:28]=5)[C:23]4=[O:39])=[CH:18][C:17]=3[O:44][CH3:43])[CH2:12]2)[CH2:11][NH:8]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC2(CCN(c3ccc(N4CCc5cc(OC[C@@H]6CCCO6)ccc5C4=O)cc3F)C2)C1
Product: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1N1CCC2(CNC2)C1

Procedure:
Reaction of 6-(2-Fluoro-4-{1-oxo-6-[(S)-1-(tetrahydro-furan-2-yl)methoxy]-3,4-dihydro-1H-isoquinolin-2-yl}-phenyl)-2,6-diaza-spiro[3.4]octane-2-carboxylic acid tert-butyl ester with trifluoroacetic acid by method H2 resulted in the desired product with the molecular weight 451, 55 (C26H30FN3O3); MS (ESI): 452 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:14])[C:7](=[O:13])[NH:8]2>[Pd].CCOC(C)=O>[CH2:3]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:14])[C:7](=[O:13])[NH:8]2)[CH:2]([CH3:15])[CH3:1]
Reactant: CC(C)=Cc1cccc2c1C(=O)C(=O)N2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)Cc1cccc2c1C(=O)C(=O)N2
Reaction time: 1 h
Yield: 13.3 %

Procedure:
A mixture of 0.20 g (1.0 mmol) of 4-(2-methyl-propenyl)-1H-indole-2,3-dione and 0.05 g of 10% palladium on charcoal in 25 mL of EtOAc was subjected to hydrogenation on a Parr apparatus at 46 psi for 1 h. The mixture was filtered through celite, and the filtrate was concentrated to dryness. The solid was purified by chromatography on silica gel, eluting with hexane:EtOAc (4:1), to furnish 0.027 g (13%) of 4-isobutyl-1H-indole-2,3-dione: 1H NMR (DMSO-d6): δ0.89 (d, J=6.7 Hz, 6H), 1.86 (nonet, J=6.7 Hz, 1H), 2.72 (d, J=6.7 Hz, 1H), 6.74 (d, J=7.8 Hz, 1H), 6.86 (d, J=7.8 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 11.03 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([BH3-])#N>C(O)(=O)C.ClC(Cl)C>[CH2:11]([NH:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1sc(N)c(C#N)c1C
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1sc(NCc2ccccc2)c(C#N)c1C
Reaction time: 0.08 h

Procedure:
To a solution of 2-amino-4,5-dimethylthiophene-3-carbonitrile (151 mg, 1.0 mmol) and benzaldehyde (106 mg, 1 mmol) in 15 mL of 4% acetic acid in dichloroethane was added silica supported cyanoborohydride (2.0 g. 2.0 mmol). The reaction was placed in a microwave reactor for 5 minutes at 135° C. Silica supported cyanoborohydride was removed by filtration, and the product was purified by prep HPLC using acetonitrile/water as solvent. MS 243 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4]([CH:8]([NH:11]C(=O)OC(C)(C)C)[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.Cl>ClCCl.O1CCOCC1>[ClH:1].[NH2:11][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:19])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC(CO)c1cccc(Cl)c1F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(CO)c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Of the compound from Example 160A, 1.74 g (6.01 mmol) were introduced in 20 ml of dichloromethane. A quantity of 22 ml (88.00 mmol) of 4M hydrogen chloride in dioxane was added. After stirring at RT for 1 h, the reaction mixture was evaporated to dryness on a rotary evaporator and dried in an HV. This gave 1.38 g (88% of theory) of the title compound in approximately 87% purity.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[C:7]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[C:32]([NH2:34])[C:31]([C:35]#[N:36])=[CH:30][C:29]=2[O:37][CH2:38][CH2:39][O:40][CH3:41])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:42][N:43]([CH:45](OC)OC)[CH3:44]>CCOCC>[C:4]([C:3]1[CH:6]=[C:7]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[C:32](/[N:34]=[CH:42]/[N:43]([CH3:45])[CH3:44])[C:31]([C:35]#[N:36])=[CH:30][C:29]=2[O:37][CH2:38][CH2:39][O:40][CH3:41])[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:9][C:2]=1/[N:1]=[CH:42]/[N:43]([CH3:45])[CH3:44])#[N:5]
Reactant: COC(OC)N(C)C
Reactant: COCCOc1cc(C#N)c(N)cc1OCCOCCOCCOCCOc1cc(C#N)c(N)cc1OCCOC
Solvent: CCOCC
Product: COCCOc1cc(/N=C/N(C)C)c(C#N)cc1OCCOCCOCCOCCOc1cc(/N=C/N(C)C)c(C#N)cc1OCCOC

Procedure:
2-Amino-5-(2-(2-(2-(2-(5-amino-4-cyano-2-(2-methoxyethoxy)phenoxy)ethoxy)ethoxy)ethoxy)ethoxy)-4-(2-methoxyethoxy)benzonitrile (0.18 g) was added to DMF-DMA (3 mL), the resulting mixture was heated to reflux overnight under N2 atmospheres. After reaction finished, the mixture was diluted with Et2O (30 mL) and solid was collected. The solid was washed with Et2O and air-dried to give (E)-N′-(2-cyano-4-(2-(2-(2-(2-(4-cyano-5-((E)-((dimethylamino)methylene)amino)-2-(2-methoxyethoxy)phenoxy)ethoxy)ethoxy)ethoxy)ethoxy)-5-(2-methoxyethoxy)phenyl)-N,N-dimethylformimidamide (0.2 g) as a yellow solid, which was used in next step directly without any purification.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([F:11])[C:3]=1[NH2:4].[N:12]([O-])=O.[Na+].Cl.C(O)(=O)C>S(=O)(=O)(O)O>[F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([F:11])[C:3]=1[NH:4][NH2:12]
Reactant: Nc1c(F)cc(F)c(F)c1F
Reactant: O=N[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: NNc1c(F)cc(F)c(F)c1F
Yield: 61 %

Procedure:
2,3,4,6-Tetrafluoroaniline (27.5 g) was diazotised with sodium nitrite (12.5 g) in a mixture of concentrated hydrochloric acid (580 ml) and glacial acetic acid (110 ml). The filtered diazonium salt solution was reduced by the addition of a solution of stannous chloride dihydrate (108 g) in concentrated sulphuric acid (108 ml) at 0°-10° C. The resulting hydrazine hydrochloride solution was evaporated to dryness and the residue was dissolved in water and basified by the addition of aqueous ammonia solution (S.G. 0.880). The precipitated solid was filtered off and the filter pad was well washed with diethyl ether. The ethereal washings were combined with ether extracts of the filtrate, dried over sodium sulphate, filtered and evaporated to dryness. Trituration of the residue with hexane gave 2,3,4,6-tetrafluorophenylhydrazine (18.3 g), m.p. 74°-76° C., in the form of off-white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].[Cl:14][C:15]1[CH:16]=[N:17][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([C@H:27]3[CH2:29][C@H:28]3[CH2:30][CH2:31]O)[CH2:23][CH2:22]2)=[N:19][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Cl:14][C:15]1[CH:16]=[N:17][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([C@H:27]3[CH2:29][C@H:28]3[CH2:30][CH2:31][O:8][C:6]3[CH:5]=[CH:4][C:3]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:2]([F:1])[CH:7]=3)[CH2:23][CH2:22]2)=[N:19][CH:20]=1
Reactant: COC(=O)Cc1ccc(O)cc1F
Reactant: OCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl (2-fluoro-4-hydroxyphenyl)acetate (1.3 g, 4.61 mmol) in 15 ml anhydrous dichloromethane at RT was added a solution of 2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (1.02 g, 1.70 mmol) in 5 ml of anhydrous dichloromethane, followed by triphenylphosphine (polymer-bound, 3.63 g, 10.5 mmol) and di-tert-butyl azodicarboxylate (2.13 g, 9.23 mmol). The mixture was stirred at RT for 3 hours, filtered through Celite and concentrated. The residue was purified by column chromatography on silica gel (Biotage 100 g) using a gradient eluent of 0-50% ethyl acetate in hexanes (1500 ml) to afford the title compound. LC/MS (m/z) 448.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].C(=O)(O)[O-].[Na+].[CH2:30]([O:32][C:33](Cl)=[O:34])[CH3:31]>C(Cl)(Cl)Cl>[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([C:5]2([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9][N:8]([C:33]([O:32][CH2:30][CH3:31])=[O:34])[CH2:7][CH2:6]2)(=[O:13])=[O:12])=[CH:19][CH:18]=1)[C:22]#[C:23][CH3:24]
Reactant: CCOC(=O)Cl
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)OCC)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.4 %

Procedure:
To a solution of 4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (400 mg, 1.03 mmol) in chloroform (10 ml) was added sodium bicarbonate (865 mg, 10.3 mmol), ethylchloroformate (0.147 ml, 1.54 mmol). The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 425 mg (98%) of the product as a solid. MS-ES: m/z 424.4 (M+H)+.
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:13].[CH2:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](Cl)=[O:36])=[CH:30][CH:29]=1)[CH3:26]>[Zn].CCOC(C)=O>[CH2:17]([N:14]([CH2:15][CH3:16])[C:12]([C:11]1[CH:19]=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:9]([NH:8][C:35](=[O:36])[CH2:34][C:31]2[CH:32]=[CH:33][C:28]([O:27][CH2:25][CH3:26])=[CH:29][CH:30]=2)[CH:10]=1)=[O:13])[CH3:18]
Reactant: CCN(CC)C(=O)c1ccc([N+](=O)[O-])c(N)c1
Reactant: CCOc1ccc(CC(=O)Cl)cc1
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOc1ccc(CC(=O)Nc2cc(C(=O)N(CC)CC)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a stirring toluene solution (100 mL) of 3-amino-N,N-diethyl-4-nitro-benzamide (1.00 g, 4.21 mmol) were added 4-ethoxyphenylacetyl chloride (1.25 g, 1.5 eq) and zinc dust (415 mg, 1.5 eq). The solution was stirred at rt overnight. Another 0.5 eq of acid chloride and zinc dust were then added and the solution stirred at rt for another 24 h. The solution was then filtered through celite and rinsed with EtOAc. The organic phase was washed with saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography using 1:1/hex:EtOAc on silica gel to furnish the desired product (1.52 g, 90% yield). 1H NMR (400 MHz, CDCl3) d 8.81 (s, 1H), 8.20 (d, J=8.8 Hz, 1H), 7.26 (m, 3H), 7.15 (d, J=8.8 Hz, 1H), 6.94 (d, J=8.4 Hz, 2H), 4.06 (q, J=7.2 Hz, 2H), 3.75 (s, 2H), 3.54 (q, J=6.8 Hz, 2H), 3.24 (q, J=6.8 Hz, 2H), 1.59 (br s, 1H), 1.42 (t, J=6.8 Hz, 3H), 1.25 (t, J=6.8 Hz, 3H), 1.16 (t, J=6.8 Hz, 3H).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].Br[CH2:35][CH2:36][CH2:37][CH:38]=[CH2:39]>>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][N:25]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:39][CH2:38][CH2:37][CH:36]=[CH2:35])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NNS(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Reactant: C=CCCCBr
Product: C=CCCCN(NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NO)S(C)(=O)=O

Procedure:
The starting material was prepared in an analogous manner to that described in Example 15, part (iii), starting from (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methylvalerohydrazide and 5-bromo-1-pentene.
Reaction SMILES: CC([N:5]([C@H:9]([CH3:29])[C:10]([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[CH:21]=2)=[CH:17][CH:18]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:28][CH:26]([C:22]1[CH:21]=[C:20]([O:19][C:16]2[N:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH3:29])[NH2:5])=[CH:18][CH:17]=2)[CH:25]=[CH:24][CH:23]=1)[CH3:27]
Reactant: CC(C)c1cccc(Oc2ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
1,1-dimethylethyl{(1R)-1-methyl-2-[(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)amino]-2-oxoethyl}carbamate (Intermediate 25, 56 mg) was dissolved in 3 mL of dry dichloromethane. To this solution at 0° C. were added dropwise 30 equivalents of TFA (0.324 mL). The reaction was stirred at 0° C. for 3 hours. The reaction mixture was evaporated. The crude obtained was purified by SCX on a 5 g cartridge. 3 CV of methanol were used first, then the residue was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with 2 CV of methanolic ammonia (1N). Evaporation of the volatiles, afforded the title compound (38 mg).
Reaction SMILES: [C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH3:22][O:23][CH:24]([O:32][CH3:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH:24]([O:23][CH3:22])[O:32][CH3:33])[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: COC(CCCCCC=O)OC
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(CCCCCCN1CC[C@@H](C(C(N)=O)(c2ccccc2)c2ccccc2)C1)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To a three-necked 500 mL flask equipped with a mechanical stirrer, a nitrogen inlet, cooling bath, and a thermometer was added (S)-3-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (25 g, 0.089 mol) and dichloromethane (200 m]L). This mixture was cooled to about 0° C. and 7,7-dimethoxyheptanal (18.6 g, 0.107 mol) was added slowly. During the addition, the reaction temperature was maintained at 5° C. or less. The resulting mixture was stirred at 0 to 5° C. for 1 hour and then sodium triacetoxyborohydride (24.6 g, 0.116 mol) was then added over a 30 minute period. During this addition, the reaction temperature was also maintained at 5° C. or less. The resulting mixture was then stirred at 0 to 5° C. for 6 hours. The reaction was then quenched by adding 5% aqueous potassium carbonate solution (200 mL) while keeping the reaction temperature less than about 20° C. and the resulting mixture was stirred for 1 hour at room temperature. The organic layer was separated and washed with brine (100 mL) and then dried with sodium sulfate (20 g). The organic layer was then concentrated under vacuum to a volume of about 100 mL and this mixture was purified by silica gel chromatography eluting with a gradient of 1 to 10% v/v methanol in dichloromethane. The fractions containing the desired product were combined and concentration under vacuum to afford 28 g of the title intermediate as an oil (72% yield).
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[NH2:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([O:13]C)=O>O.C(O)(=O)C>[NH:5]1[C:6]2[CH:10]=[CH:9][S:8][C:7]=2[C:11](=[O:13])[NH:3][C:2]1=[O:1]
Reactant: N#C[O-]
Reactant: COC(=O)c1sccc1N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2sccc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
To a solution in which sodium cyanate (5.0 g, 77.0 mmol) was dissolved in water (15.0 mL), methyl 3-aminothiophen-2-carboxylate (6.05 g, 38.4 mmol) dissolved in a mixture solution (90 mL) of 50% glacial acetic acid and water was slowly added dropwise. After stirring for 5 hours at room temperature, thus prepared white precipitate was filtered. The white solid was dissolved in 2.0 N sodium hydroxide solution (90.0 mL). The mixture solution was cooled to 0° C. and acidified using acetic acid. Filtration of thus prepared white solid followed by drying yielded the target compound thieno[3,2-d]pyrimidin-2,4(1H,3H)-dione (5.2 g, 81% yield).