Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:18]([N+:31]([O-:33])=[O:32])([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])[CH2:19][CH2:20][C:21]([O:23]C)=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[Li+].[OH-].Cl>COCCOC>[CH2:1]([C:18]([N+:31]([O-:33])=[O:32])([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCCC(CCC(=O)OC)(CCC(=O)OC)[N+](=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCCC(CCC(=O)O)(CCC(=O)O)[N+](=O)[O-]
Yield: 72.3 %

Procedure:
Dimethyl 3-heptadecyl-3-nitropentane-1,5-dicarboxylate (7a) (138 mg, 0.29 mmol) was dissolved in DME (2 mL) and sat. aq LiOH solution (2 mL) was added. The mixture was let stand for 22 h, then it was acidified with dilute HCl (10%, 10 mL) and extracted with EtOAc (2×10 mL). The extracts were concentrated under a stream of dry N2 and the residue was subjected to flash column chromatography on silica (EtOAc/petroleum spirit, 15/85) to afford 3-heptadecyl-3-nitropentane-1,5-dicarboxylic acid (8a) (93 mg, 90%) as a white solid; mp 102° C.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1F.[H-].[Na+]>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1
Reactant: N#Cc1ccc2sc(S)nc2c1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2sc(Sc3ccc([N+](=O)[O-])cc3Cl)nc2c1
Yield: 92 %

Procedure:
The title compound was prepared using the method of example 258, starting with 2-mercapto-benzothiazole-5-carbonitrile (243) (960 mg, 5.0 mmol), 2-chloro-1-fluoro-4-nitrobenzene (Aldrich, 878 mg, 5.0 mmol) and NaH (Aldrich, 60% suspension, 200 mg, 5.0 mmol) in DMF (25 mL). Compound 263 (1.60 g, 92%) was obtained as a yellow solid.
Reaction SMILES: COC1C=C(C=C[N:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])C=CN=1.[CH3:22][OH:23]>[Pd]>[CH3:22][O:23][C:12]1[CH:13]=[C:18]([CH2:17][CH2:16][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:21])[NH:11][CH:20]=2)[CH:19]=[CH:20][N:11]=1
Reactant: CO
Reactant: COc1cc(C=Cn2ccc3ccccc3c2=O)ccn1
Agent: [Pd]
Product: COc1cc(CCc2c[nH]c(=O)c3ccccc23)ccn1

Procedure:
1.1 g of the above (E/Z) mixture of 4-[2-(2-methoxy-pyridin-4-yl)-vinyl-2H-isoquinolin-1-one in 20 ml of methanol are hydrogenated in the presence of 0.6 g of Pd/C (10%). Filtration through Celite, washing with a lot of methanol, concentrating by evaporation and column chromatography (SiO2, methylene chloride/acetone 3:1→aceton) yield 4-[2-(2-methoxy-pyridin-4-yl)ethyl]-2H-isoquinolin-1-one; 1H NMR (DMSO-d6) δ 11.10 (sb, HN), 8.22 (d, 1H), 8.03 (d, 1H), 7.81 (d, 1H), 7.75 (t, 1H), 7.50 (t, 1H), 6.92 (m, 1H), 6.88 (d, 1H), 6.70 (s, 1H), 3.80 (s, H3C), 2.93 (m, 2H), 2.84 (m, 2H).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[NH:27]([CH2:31][C:32]1[N:33]2[CH:39]=[N:38][CH:37]=[C:34]2[S:35][CH:36]=1)[C:28]([NH2:30])=[O:29]>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:38]3[CH:37]=[C:34]4[S:35][CH:36]=[C:32]([CH2:31][NH:27][C:28]([NH2:30])=[O:29])[N+:33]4=[CH:39]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: NC(=O)NCc1csc2cncn12
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc(CNC(N)=O)[n+]4c3)[C@H](C)[C@H]12
Yield: 3.9 %

Procedure:
The same procedure as in Example 1 was repeated except that 135 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 87 mg of 3-ureidomethylimidazo[5,1-b]thiazole were used, thereby obtaining 6 mg of the title compound.
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1/[CH:12]=[CH:13]/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([O:18]C)=[O:17].C(OC(C)C)(C)C>CO>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1/[CH:12]=[CH:13]/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([OH:18])=[O:17]
Reactant: COC(=O)/C(=C/C=C/c1cc2ccccc2[nH]1)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)OC(C)C
Product: CO/C(=C\C=C\c1cc2ccccc2[nH]1)C(=O)O
Temperature: 50 °C
Yield: 52.7 %

Procedure:
To a solution of KOH (0.26 g, 4.7 mmol) in methanol (13 ml), methyl (2Z,4E)-5-(2-indolyl)-2-methoxy-2,4-pentadienoate (0.3 g, 1.17 mmol) was added and the solution was heated at 50° C. for 1 hour under nitrogen. The solvent was removed under vacuum and the residue was dissolved in water (20 ml) and washed with isopropyl ether. The aqueous phase was adjusted to pH 5 with 10% HCl and then extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4 and the solvent removed under reduced pressure obtaining, after trituration with isopropyl ether, 0.15 g (52.7%) of the title compound as a solid, m.p.=189-190° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:45])=[C:4]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10](COCC[Si](C)(C)C)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.N>>[Cl:1][C:2]1[C:3]([OH:45])=[C:4]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cccc(Cl)c3O)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cccc(Cl)c5O)c34)n(-c3ccccc3)c(=O)c12
Yield: 22.3 %

Procedure:
(S)-2-(1-((5-(3-Chloro-2-hydroxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (58 mg, 0.07 mmol) was treated with trifluoroacetic acid (1.20 ml, 15.58 mmol) and a solution of ammonia (7N in methanol, 1.20 ml, 8.40 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 5% dichloromethane-2-propanol) to obtain 8 mg (21% yield) of the title compound.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[OH-].[Na+].[C:14](Cl)(=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C(O)(=O)C>C(Cl)Cl.O>[C:14]([NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([O:10][CH3:11])=[O:9])(=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccccc1N
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccccc1NC(=O)c1ccc(OC)cc1
Temperature: 23 °C
Yield: 96 %

Procedure:
A solution of 529.8 g (3.505 mole) methyl anthranilate and 294.4 g 50 weight percent NaOH (3.68 mole) in 3.6 L CH2Cl2 and 1.8 L H2O was stirred in an ice-bath as 627.8 g (3.680 mole) p-anisoyl chloride was added at such rate that the temperature did not exceed 10° C. (time required was 1.25 hr). The mixture was allowed to warm to 23° C. Acetic acid (50 mL) was added to adjust the pH to 5. The layers were separated and the organic layer was washed with 10% aqueous NaHCO3 (1×0.8 L) and brine (1×0.8 L). The solvent was removed in vacuo. The residual white solid was recrystallized from 7.0 L boiling methanol. The product (III) was dried in vacuo at 70° C. for 24 hr to yield 959.7 g (96.0%) white crystalline solid, m.p. 122.5°-124.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([F:18])[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=2)=[C:4]([F:19])[CH:3]=1.[N:20]#[C:21][NH2:22].OS(C(F)(F)F)(=O)=O>C1COCC1>[C:21](=[NH:20])([O:15][CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[C:16]([F:18])=[CH:17][C:2]([Cl:1])=[CH:3][C:4]=2[F:19])=[CH:8][CH:9]=1)[NH2:22]
Reactant: N#CN
Reactant: OCCc1ccc(Oc2c(F)cc(Cl)cc2F)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Product: N=C(N)OCCc1ccc(Oc2c(F)cc(Cl)cc2F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
To a solution of 2-(4-(4-chloro-2,6-difluorophenoxy)phenyl)ethanol (1.6 g, 5.62 mmol) and cyanamide (0.600 g, 14.27 mmol) in dry THF (10 mL) under nitrogen was added triflic acid (1.3 mL, 14.64 mmol) at 0° C. The mixture was stirred at room temperature for 2 h. Purification via reverse phase flash chromatography afforded the title compound (1.74 g, 3.65 mmol, 64.9% yield). LCMS: rt=2.66 min, [M+H+]=327
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:18][O:17][C:16]3[CH:19]=[CH:20][C:21]4[O:25][CH:24]=[CH:23][C:22]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:26]1[CH2:31][CH:30]=[C:29]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH:33]=2)[CH2:28][CH2:27]1.C(OCC)(=O)C>CS(C)=O>[O:14]1[C:15]2[C:22]3[CH:23]=[CH:24][O:25][C:21]=3[CH:20]=[CH:19][C:16]=2[O:17][CH2:18][CH:13]1[CH2:12][N:26]1[CH2:27][CH:28]=[C:29]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH:33]=2)[CH2:30][CH2:31]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4occc4c3O2)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C1=C(c2c[nH]c3ccccc23)CCN(CC2COc3ccc4occc4c3O2)C1
Temperature: 25 °C

Procedure:
A solution of 0.40 g (1.1 mmole) of (2R)-2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-ylmethyl 4-methylbenzenesulfonate and 1.0 g (5.0 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 10 mL of DMSO was heated under nitrogen at 80° C. for 4 hours. After the reaction had cooled to room temperature, 400 mL of ethyl acetate was added and the solution was washed with 250 mL portions of saturated aqueous sodium bicarbonate, water and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 2% methanol in chloroform to give 0.27 g of the (S)-enantiomer of the title compound as a white solid, m.p. 208-209° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH2:12][N:13]([CH3:15])[CH3:14])=[CH:7][CH:8]=2)[C:3]=1[CH2:16][C:17]([NH2:19])=[O:18].C[O:21][C:22](=O)[C:23]([C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH3:34])[CH:26]=1)=O.CC([O-])(C)C.[K+].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH2:12][N:13]([CH3:14])[CH3:15])=[CH:7][CH:8]=2)[C:3]=1[C:16]1[C:17](=[O:18])[NH:19][C:22](=[O:21])[C:23]=1[C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH3:34])[CH:26]=1
Reactant: CN(C)Cc1ccc2ccc(Cl)c(CC(N)=O)c2c1
Reactant: COC(=O)C(=O)c1cn(C)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)Cc1ccc2ccc(Cl)c(C3=C(c4cn(C)c5ccccc45)C(=O)NC3=O)c2c1
Reaction time: 1 h

Procedure:
Activated 3 Å molecular sieve (2.0 g) is added to a solution of 2-(2-Chloro-7-dimethylaminomethyl-naphthalen-1-yl)-acetamide (1.0 g, 3.61 mmol) and (1-Methyl-1H-indol-3-yl)-oxo-acetic acid methyl ester (1.02 g, 4.69 mmol) in dry THF (50 ml) under an atmosphere of argon. A solution of 1.0 M KOtBu in THF (10.9 ml, 10.9 mmol) is then added in one portion at RT. After 1 h at RT, TLC analysis indicates complete conversion of starting materials. The reaction mixture is diluted with EtOAc and poured into a saturated aqueous NH4Cl solution. The organic layer is separated, washed with brine, dried over Na2SO4, and the organic solvent is evaporated. The residue is purified by FCC (EtOAc/AcOH/H2O 600:150:150) to afford the title compound, which is dissolved in glacial AcOH and lyophilized. The title compound is obtained as the water soluble bis-acetate salt. 1H NMR (d6-DMSO, 400 MHz): δ 1.80 (s, 6H), 3.20-3.42 (m, 2H), 6.10 (d, J=9.0 Hz, 1H), 6.44 (t, J=9.0 Hz, 1H), 6.94 (t, J=9.0 Hz, 1H), 7.31 (d, J=9.0 Hz, 1H), 7.34 (d, J=9.0 Hz, 1H), 7.42 (s, 1H), 7.63 (d, J=10.8 Hz, 1H), 7.89 (d, J=9.6 Hz, 1H), 8.03 (d, J=9.0 Hz, 1H), 8.10 (s, 1H), 11.0-11.3 (br, 1H). ES+−MS: 444, 446 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[CH:12]([Mg]Br)=[CH2:13].[NH4+].[Cl-]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]2[C:3]=1[NH:9][CH:13]=[CH:12]2
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1ccc(Br)c2[nH]ccc12
Yield: 43.9 %

Procedure:
To a solution of 1-bromo-4-chloro-2-nitrobenzene (932 mg, 3.95 mmol) in tetrahydrofuran (10 mL), vinylmagnesium bromide (0.7 M in tetrahydrofuran) (12 mmol) in tetrahydrofuran (15 mL) was added drop wise at −40° C. After 1 h the reaction mixture was poured into saturated NH4Cl. The resulting organic layer was concentrated. The resulting residue was purified using a Teledyne ISCO chromatography system with a gradient eluent system of 2% ethyl acetate in hexane to yield the title compound (400 mg, 44%): 1H NMR (300 MHz, CDCl3) δ 6.73 (t, J=2.8 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H), 7.19-7.39 (m, 2H), 8.43 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].CCN(C(C)C)C(C)C.Br[CH2:21][CH2:22][O:23][CH2:24][CH2:25]Br>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ncc(N)cc1Br
Reactant: BrCCOCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ncc(N2CCOCC2)cc1Br
Temperature: 120 °C
Yield: 53 %

Procedure:
To a solution of 5-bromo-6-methoxypyridin-3-amine (1.0 equiv.) in DMF was added DIEA (3.0 equiv.) and 1-bromo-2-(2-bromoethoxy)ethane (1.0 equiv.). The solution was heated to 120° C. for 24 hours. Upon cooling to room temperature, the reaction was partitioned between water and ethyl acetate, the aqueous phase was extracted three times with ethyl acetate, the organics were combined, dried with sodium sulfate, filtered and concentrated. The crude material was purified via silica gel column chromatography eluting with 0-50% ethyl acetate in heptanes. The pure fractions were concentrated to yield 4-(5-bromo-6-methoxypyridin-3-yl)morpholine in 53% yield as an orange oil. LCMS m/z (M+H)=273/275, Rt=0.61 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 2.93-3.18 (m, 4H) 3.80-4.05 (m, 7H) 7.50 (d, J=2.74 Hz, 1H) 7.74 (d, J=2.74 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]([C:9]2[C:14]([OH:15])=[CH:13][C:12]([OH:16])=[C:11]([OH:17])[C:10]=2[OH:18])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23].[Cl-].[NH4+].Cl>>[CH3:23][C:22]([CH3:24])=[CH:21][CH2:20][C:11]1([OH:17])[C:12]([OH:16])=[C:13]([CH2:3][CH:2]=[C:1]([CH3:7])[CH3:6])[C:14]([OH:15])=[C:9]([C:7](=[O:8])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:10]1=[O:18]
Reactant: O=C(c1ccccc1)c1c(O)cc(O)c(O)c1O
Reactant: CC(C)=CCCl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)=CCC1=C(O)C(O)(CC=C(C)C)C(=O)C(C(=O)c2ccccc2)=C1O
Yield: 102.3 %

Procedure:
Under a stream of argon, 440 mg (11.0 mmol, 3.01 equivalents) of an oily dispersion of 60% sodium hydride was washed with hexane to remove the oil component. The dispersion kept cooled with cold water and 18.0 ml of dry dimethyl sulfoxide added were stirred together. To the stirred suspension, 900 mg (3.66 mmol) of phenyl-(2,3,4,6-tetrahydroxyphenyl) ketone (10) was added and stirred for 30 minutes. Further, 0.830 ml (7.32 mmol, 2.00 equivalents) of 1-chloro-3-methyl-2-butene was added dropwise stirring for two hours. The produced mixture was combined with 15 ml of a saturated aqueous ammonium chloride solution and 2 ml of 2 M hydrochloric acid solution and extracted by ether. The organic layer was washed with saturated brine, dried over sodium sulfate, concentrated under a reduced pressure, and subjected to silica gel chromatography (g of Wako Gel C-200, eluted with hexane ethyl acetate 4:1) to obtain 716 mg (yield 51.3%) of the product (32) in the form of yellow powdery crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:18]3[C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4CCCC[O:25]4)[C:15](=[O:30])[N:14]([CH3:31])[C:13]=3[N:12]=[CH:11][C:10]=2[O:32][C:33]2[CH:34]=[N:35][CH:36]=[C:37]([Cl:39])[CH:38]=2)=[CH:4][CH:3]=1>C(O)=O.[Zn]>[CH:24]([O:23][CH2:22][CH2:21][CH2:20][N:16]1[C:17](=[O:19])[C:18]2[C:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:10]([O:32][C:33]3[CH:34]=[N:35][CH:36]=[C:37]([Cl:39])[CH:38]=3)[CH:11]=[N:12][C:13]=2[N:14]([CH3:31])[C:15]1=[O:30])=[O:25]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cncc(Cl)c3)cnc21
Agent: [Zn]
Solvent: O=CO
Product: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cncc(Cl)c3)cnc21
Temperature: 70 °C
Yield: 38 %

Procedure:
To a solution of 5-((4-chlorophenyl)(hydroxy)methyl)-6-((5-chloropyridin-3-yl)oxy)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (120 mg, 0.204 mmol) in HCOOH (5 mL) was added Zn dust (66.8 mg, 1.02 mmol). The reaction was heated at 70° C. for 1.5 h, cooled to RT and filtered. The filtrate was concentrated to give 3-(5-(4-chlorobenzyl)-6-((5-chloropyridin-3-yl)oxy)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (40 mg, 38.0% yield) as an oil. LCMS MH+ 515 and TR=1.696 min. Used without further purification.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH:9]1[CH2:21][F:22])C1C=CC=CC=1.C(O)C.[C:26]([OH:29])(=[O:28])[CH3:27]>[Pd].CCOCC>[C:26]([OH:29])(=[O:28])[CH3:27].[C:26]([OH:29])(=[O:28])[CH3:27].[F:22][CH2:21][CH:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1
Reactant: FCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Solvent: CC(=O)O
Product: FCC1CNCCN1
Reaction time: 72 h

Procedure:
A mixture of 1,4-dibenzyl-2-fluoromethyl-piperazine (0.47 g, 1.6 mmol), ethanol (20 mL), acetic acid (0.4 mL) and 10% palladium on carbon (0.2 g) was hydrogenated at 20° C. and 4 bar for 72 h. Solids were removed by filtration and the filtrate evaporated in vacuo to give a colourless solid. Trituration (twice) with ether gave the title compound (0.332 g) as a colourless solid. 1H NMR (DMSO-d6): 7.38-5.74 (4H, m), 4.40-4.27 (1H, m), 4.27-4.14 (1H, m), 2.94-2.69 (4H, m), 2.69-2.58 (1H, m), 2.58-2.52 (1H, m), 2.32 (1H, dd), 1.87 (6H, s).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[C:7]2[CH:8]=[C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=[CH:11][C:6]=2[NH:5]C(=O)[NH:3]1>Cl.O>[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:14])=[O:15])=[CH:8][C:7]=1[S:2]([NH2:3])(=[O:1])=[O:18]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)NC(=O)N2
Agent: Cl
Solvent: O
Product: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 105 °C
Reaction time: 16 h
Yield: 45.6 %

Procedure:
N-(1,1,3-Trioxo-1,2,3,4-tetrahydro-1λ6-benzo[1,2,4]thiadiazin-7-yl)-methanesulfonamide (Example 3c, 1 g, 3.4 mmol) was suspended in 12 M aqueous hydrochloric acid solution (60 mL). The mixture was stirred at 105° C. for 16 h. All solids were dissolved at this point. The mixture was diluted with water (250 mL). The solution was concentrated in vacuo to an orange solid. The solid was dissolved in water (20 mL) and concentrated in vacuo to an orange solid. The solid was dissolved in water (5 mL) and the product was extracted into ethyl acetate (6×20 mL). The combined organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to an orange solid. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm, 75% ethyl acetate in hexanes) afforded the desired product, 2-amino-5-methanesulfonylamino-benzenesulfonamide (0.41 g, 1.55 mmol, 45% yield), as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 2.86 (3H, s), 5.77 (2H, s), 6.76 (1H, d, J=8.6 Hz), 7.11 (1H, dd, J1=8.6 Hz, J2=2.4 Hz), 7.25 (2H, bs), 7.43 (1H, d, J=3.1 Hz), 9.16 (1H, s).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][C:6]=1[CH3:14].[NH3:15]>CC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([S:10]([NH2:15])(=[O:12])=[O:11])=[CH:7][C:6]=1[CH3:14]
Reactant: N
Reactant: COCCc1sc(S(=O)(=O)Cl)cc1C
Solvent: CC(C)=O
Product: COCCc1sc(S(N)(=O)=O)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.40 g (55 mM) 5-(2-methoxy-ethyl)-4-methyl-thiophene-2-sulfonyl chloride in 20 ml acetone was added 5 ml of an aqueous solution of ammonia (25%) and the mixture was stirred at room temperature for 1 h. The mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was dried over sodium sulfate and evaporated. The residue purified by chromatography on silica gel crystallized form cyclohexane/diethyl ether to yield 0.89 g of the title compound as light red solid. MS (ISN) M−H+=233.8
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)=[CH:4][CH:3]=1.BrCC[CH:18]([O:21][CH:22](OC)[CH2:23]CBr)[O:19][CH3:20]>>[CH3:20][O:19][CH2:18][O:21][CH2:22][CH2:23][O:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(CCBr)OC(CCBr)OC
Reactant: O=C1N[C@@H](Cc2ccc(O)cc2)CO1
Product: COCOCCOc1ccc(C[C@H]2COC(=O)N2)cc1
Yield: 77 %

Procedure:
Compound 5a is synthesized by general procedure H from (S)-(−)-4-(4-hydroxybenzyl)-2-oxazolidinone (Tetrahedron; EN; 57; 39; 2001; 8313-8322) and 2-bromo-ethyl-methoxy-methyl-ether (Aldrich) at 10-fold scale in 77% yield (15.4 mmol, 4.33 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[N-:9]=[N+:10]=[N-:11].[Na+]>CN(C=O)C>[N:9]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[N+:10]=[N-:11]
Reactant: OCCCCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCCO
Temperature: 50 °C
Reaction time: 72 h
Yield: 99 %

Procedure:
6-Bromo-1-hexanol (5.00 g, 27.6 mmol) was dissolved in 12 mL of DMF. To this solution, sodium azide (4.00 g, 61.5 mmol) was added and the mixture was stirred at 50° C. for 3 days. The mixture was concentrated by evaporation, and distilled water (10 mL) was added thereto. This aqueous solution was extracted six times with diethyl ether, and the combined organic extracts were dried over magnesium sulfate, followed by evaporation to give a product (6-azido-1-hexanol). The yield was 99% or more.
Reaction SMILES: [C:1]([O:4][C:5]1[C:24]([O:25][CH3:26])=[CH:23][C:8]([C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)=[O:10])=[CH:7][C:6]=1[O:27][CH3:28])(=[O:3])[CH3:2].CC(C1C=C(C=C(C(C)(C)C)C=1O)C(NCC1C=CC([N+]([O-])=O)=CC=1)=O)(C)C>>[C:1]([O:4][C:5]1[C:24]([O:25][CH3:26])=[CH:23][C:8]([C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)=[O:10])=[CH:7][C:6]=1[O:27][CH3:28])(=[O:3])[CH3:2]
Reactant: COc1cc(C(=O)NCCc2ccc([N+](=O)[O-])cc2)cc(OC)c1OC(C)=O
Agent: CC(C)(C)c1cc(C(=O)NCc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Product: COc1cc(C(=O)NCCc2ccc(N)cc2)cc(OC)c1OC(C)=O

Procedure:
The experimental protocol used is the same as that described for intermediate 2.2, with 4-acetoxy-3,5-dimethoxy-N-[2-(4-nitrophenyl)ethyl]-benzamide replacing the 3,5-bis-(1,1,-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide. A colourless oil is obtained with a quantitative yield. The product is used directly in the following stage without additional purification.