Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:17][C:16](=[O:18])[O:15][O:14][C@H:13](/[CH:19]=[CH:20]/[CH2:21][CH2:22][SH:23])[CH2:12][C:11](=[O:24])[NH:10][C@H:9]([CH:25]([CH3:27])[CH3:26])[C:8](=[O:28])[NH:7][C@H:6]([CH3:29])[C:5](=[O:30])[NH:4][C@@H:3]1[CH:31]([CH3:33])[CH3:32].C(N(C(C)C)CC)(C)C.[C:43](Cl)(=[O:45])[CH3:44].Cl>C(Cl)Cl.CCOC(C)=O>[OH:1][C@H:2]1[CH2:17][C:16](=[O:18])[O:15][O:14][C@H:13](/[CH:19]=[CH:20]/[CH2:21][CH2:22][S:23][C:43](=[O:45])[CH3:44])[CH2:12][C:11](=[O:24])[NH:10][C@H:9]([CH:25]([CH3:27])[CH3:26])[C:8](=[O:28])[NH:7][C@H:6]([CH3:29])[C:5](=[O:30])[NH:4][C@@H:3]1[CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)[C@H]1NC(=O)[C@@H](C)NC(=O)[C@@H](C(C)C)NC(=O)C[C@@H](/C=C/CCS)OOC(=O)C[C@@H]1O
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)SCC/C=C/[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N[C@H](C)C(=O)N[C@H](C(C)C)[C@@H](O)CC(=O)OO1
Yield: 41 %

Procedure:
To a solution of 9 (24.7 mg, 0.035 mmol) in CH2Cl2 (1.4 mL) was added triethylsilane (28 μL, 0.175 mmol) followed by the dropwise addition of TFA (0.35 mL, 25% v/v). After stirring for 1 h the reaction mixture was concentrated in vacuo and put under high vacuum for 2 h to give the crude thiol 10. At 0° C. to a solution of thiol 10 in CH2Cl2 (0.45 mL) was added diisopropylethylamine (30 μL, 0.172 mmol) followed by acetyl chloride (2.43 μL, 0.034 mmol) in CH2Cl2 (0.1 mL). After stirring for 2 h 10 min 1M HCl (1 mL) was added followed by EtOAc (10 mL) the layers were separated and the organic layer was washed with sat. brine (10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography (eluent 1:0-98:2-96:4-94:6-92.8 CH2Cl2/MeOH) gave the product 11 (7.3 mg, 0.014 mmol, 41%) as a white solid: Rf 0.47 MeOH/CH2Cl2 (1:9).
Reaction SMILES: O[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1O>CCCCCC.C(OCC)(=O)C>[CH:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:2]2[C:17]3[C:16]([CH3:15])=[CH:21][CH:20]=[C:19]([CH3:22])[C:18]=3[O:5][C:3]2=[O:4])=[CH:7][CH:8]=1)([CH3:14])[CH3:13]
Reactant: CC(C)c1ccc(C(O)C(=O)O)cc1
Reactant: Cc1ccc(C)c(O)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(C)c2c1OC(=O)C2c1ccc(C(C)C)cc1
Yield: 20 %

Procedure:
Using hydroxy(4-isopropylphenyl)acetic acid and 2,5-dimethylphenol synthesized in Reference Example 1, the title compound was synthesized in the same manner as in Reference Example 2. Yield 20%. Melting point: 107-109° C. (hexane-ethyl acetate).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C@:17]3([C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[C@H:20]([C:30](O)=[O:31])[NH:19][C@H:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][S:64]([CH2:67][CH2:68][CH2:69][O:70][C:71]1[CH:76]=[CH:75][C:74]([NH2:77])=[C:73]([O:78][CH3:79])[CH:72]=1)(=[O:66])=[O:65]>>[CH3:63][S:64]([CH2:67][CH2:68][CH2:69][O:70][C:71]1[CH:76]=[CH:75][C:74]([NH:77][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C@:17]3([C:12]4[C:11](=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:73]([O:78][CH3:79])[CH:72]=1)(=[O:65])=[O:66]
Reactant: COc1cc(OCCCS(C)(=O)=O)ccc1N
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OCCCS(C)(=O)=O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Yield: 52.6 %

Procedure:
In a manner similar to the method described in Example 5, chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 136 (0.2 g, 0.35 mmol), was reacted with diisopropylethylamine (0.22 g, 1.7 mmol), diphenylphosphinic chloride (0.16 g, 0.7 mmol), then reacted with 4-(3-methanesulfonyl-propoxy)-2-methoxy-phenylamine prepared in Example 180 (0.13 g, 0.5 mmol) to give chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [4-(3-methanesulfonyl-propoxy)-2-methoxy-phenyl]amide as a yellow solid (Yield 0.13 g, 51%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])#[N:2].S(Cl)([Cl:14])=O.CN(C)C=O>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:14])=[O:7])#[N:2]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: N#Cc1cccc(C(=O)Cl)c1
Temperature: 80 °C

Procedure:
In 1 liter of toluene, 200 g of 3-cyanobenzoic acid were suspended, followed by the addition of 128 ml of thionyl chloride and 1 ml of N,N-dimethylformamide. The resulting mixture was stirred under heating at 80° C. for 5 hours. After cooling of the reaction mixture, the solvent was distilled off under reduced pressure. To the residue, n-hexane was added. By distilling off the solvent under reduced pressure, 3-cyanobenzoyl chloride was obtained. The resulting 3-cyanobenzoyl chloride was dissolved in 3 liters of dried 1,2-dichloroethane, followed by the addition of 200 g of 2-amino-4-methoxycarbonyl-1,3-thiazole. The resulting mixture was heated under reflux for 5 hours. The reaction mixture was cooled. Crystals so precipitated were collected by filtration and then washed with water, whereby 289 g of 2-[N-(3-cyanobenzoyl)amino]-4-methoxycarbonyl-1,3-thiazole.hydrochloride were obtained. Yield: 80%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]=[N:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[CH3:21].C[Si]([C:26]#[N:27])(C)C>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15](=[O:17])(=[O:18])[NH2:16])=[CH:13][CH:14]=2)[C:26]#[N:27])=[CH:5][C:4]=1[CH3:21]
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1C
Product: COc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1C

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(4-methoxy-3-methylbenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a white powder (yield 63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.C(O)(=O)C.[CH2:18]([NH2:21])[CH2:19][CH3:20].[BH3-]C#N.[Na+]>ClC(Cl)C.CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:21][CH2:18][CH2:19][CH3:20])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCCN
Reactant: COc1ccc2c(c1)CC(=O)CC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CC(Cl)Cl
Product: CCCNC1CCc2ccc(OC)cc2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7-Methoxy-2-tetralone (6.21 g, 35.2 mmol) and acetic acid (5.3 ml, 105.6 mmol) were dissolved in dichloroethane (100 ml) and cooled to 0° C. Propyl amine (5.7 ml, 70.4 mmol) was added and the mixture was stirred under a N2 atmosphere for 30 min. NaCNBH3 (5.5 g, 80.8 mmol) in anhydrous MeOH (15 ml) was then added to the mixture and allowed to stir overnight at ambient temperature. The volatiles were then evaporated and the mixture was partioned between ethyl acetate and 1 M NaOH. The organic layer was separated, dried (Na2SO2), filtered, and concentrated. The crude residue was then taken up in EtOAc, at which time ethereal HCl was added, and the material evaporated to dryness. The crude salt was dissolved in a minimum volume of MeOH, and precipitated by the gradual addition of diethyl ether. The salt was collected via filtration and dried to yield 5.09 g (64%, free base) and used in the subsequent transformations. 1H NMR (free base) (400 MHz, CDCl3) 0.91-0.95 (t, 3H, J=7.6 Hz), 1.38 (bs, 1H), 1.48-1.60 (m, 3H), 2.04-2.09 (m, 1H), 2.54-2.62 (m, 2H), 2.67-2.71 (t, 3H, J=7.6 Hz), 2.88-2.92 (m, 2H), 2.97-3.04 (m, 1H), 3.81 (s, 3H), 6.60-6.61 (dd, 1H, J=1.6 Hz), 6.65-6.78 (m, 1H), 6.95-6.98 (d, 1H, J=8.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=O)[CH:5]=[CH:4][N:3]=1.Cl[C:20]1[N:25]=[C:24](/[CH:26]=[C:27](\[C:29]2C=C(C=CC=2)C#N)/O)C=C[N:21]=1.C1C(=O)N(Br)C(=O)C1.NC1C=CC=CN=1>C(Cl)Cl.CCOC(C)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[N:25]3[CH:24]=[CH:26][CH:27]=[CH:29][C:20]3=[N:21][C:9]=2[C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1cccc(C(=O)Cc2ccnc(Cl)n2)c1
Reactant: N#Cc1cccc(/C(O)=C\c2ccnc(Cl)n2)c1
Agent: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Temperature: 0 °C
Yield: 75 %

Procedure:
A mixture of tautomers, 3-[(2-chloro-4-pyrimidinyl)acetyl]benzonitrile and 3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]benzonitrile, (1.56 g, 6.05 mmol) was dissolved in 100 mL of DCM with stirring and cooled to 0° C. NBS (1.08 g, 6.07 mmol) was added and the reaction was allowed to warm to rt. The reaction was stirred for one hour and concentrated in vacuo. The residue was dissolved in dioxane with stirring. 2-Aminopyridine (1.71 g, 18.2 mmol) was added, and the reaction was heated to 60° C. The reaction was stirred overnight and cooled to rt. The reaction was poured into H2O and EtOAc. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with DCM (2×) and EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography, and fractions containing product were concentrated in vacuo. The residue was triturated with diethyl ether and hexanes (˜1:1), filtered, and the solid was washed with diethyl ether and hexanes (˜1:1). The solid was collected to provide 1.50 g (75%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.35 (d, J=7.0 Hz, 1H), 8.60 (d, J=5.3 Hz, 1H), 8.14 (s, 1H), 7.98 (d, J=7.9 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.67 (t, J=7.9 Hz, 1H), 7.59 (dd, J=6.8, 1.1 Hz, 1H), 7.31-7.17 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:47]=[CH:46][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:17]3[C:18](=[O:31])[C@@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH:14]=[C:13]2[O:32]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+](C1C=CC(COC(C2N3C(=O)[C@@H](NC(=O)COC4C=CC=CC=4)[C@H]3SCC=2OC(C2C=CC=CC=2)C2C=CC=CC=2)=O)=CC=1)([O-])=O>FC(F)(F)C(O)=O.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C:12]2[N:17]3[C:18](=[O:31])[C@@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH2:14][C:13]=2[OH:32])=[O:11])=[CH:46][CH:47]=1)([O-:3])=[O:2]
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(OC(c3ccccc3)c3ccccc3)=CS[C@H]12
Agent: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OC(c3ccccc3)c3ccccc3)CS[C@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of 340 mg of the resulting isomer mixture, consisting of 7β-phenoxyacetamido-3-diphenylmethoxy-ceph-2-em-4α-carboxylic acid p-nitrobenzyl ester and 7β-phenoxyacetamido-3-diphenylmethoxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester, in a mixture of 0.5 ml of trifluoroacetic acid and 9.5 ml of methylene chloride is stirred for 40 minutes at room temperature. The mixture is concentrated by evaporation in vacuo, toluene is added to the residue, and the mixture is again concentrated by evaporation. The resulting residue (which still contains trifluoroacetic acid) is chromatographed on 15 g of acid-washed silica gel, using toluene/ethyl acetate (3:1), whereby 7β-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester is obtained; IR spectrum (methylene chloride): characteristic bands at 2.95, 3,3, 5.6, 5.75 sh, 5.9, 5.95 sh, 6.55, 7.45, 8.15 and 8.3μ; NMR spectrum (deuterochloroform): characteristic bands at 3.4 (2H, AB q, l=17 Hz), 4.57 (2H, s), 5.06 (1H, d,l=5 Hz), 5.35 (2H, AB q, l=14 Hz), 5.7 (1H, dd, l=5, 10 Hz), 6.8-8.4 (10 H, c), 11.4 (1H, br. s.) ppm.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:21])=[C:9]([NH:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][N:15]=[C:14](Cl)[N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH:24]1[CH2:29][CH2:28][CH:27]([CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:21])=[C:9]([NH:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][N:15]=[C:14]([N:34]3[CH2:35][CH2:36][CH:31]([CH2:30][C:27]4[CH:26]=[CH:25][N:24]=[CH:29][CH:28]=4)[CH2:32][CH2:33]3)[N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cnc(Cl)nc1Nc1cc(C(C)(C)C)ccc1C
Reactant: c1cc(CC2CCNCC2)ccn1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(N2CCC(Cc3ccncc3)CC2)nc1Nc1cc(C(C)(C)C)ccc1C
Yield: 68.2 %

Procedure:
A solution of the product of Step 1 (166 mg, 0.543 mmol), 4-piperidin-4-ylmethylpyridine dihydrochloride (162 mg, 0.651 mmol) and diisopropylethylamine (1.5 mL) was irradiated in 2-propanol (1.5 mL), in a microwave oven, at 180° C. for 2.5 hrs. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (Biotage system, MeOH/dichloromethane, 0%-15%) to give the product (165 mg, 68.2%) as a solid. 1H-NMR (600 MHz, CDCl3) δ=1.21 (2H, m), 1.28 (9H, s), 1.60 (2H, d, J=13.19), 1.74 (1H, m), 2.23 (3H, s), 2.49 (2H, d, J=7.35), 2.72 (2H, td, J=12.76, 1.51), 3.80 (3H, s), 4.64 (2H, d, J=13.35), 6.96 (1H, s), 6.99 (1H, dd, J=7.88, 1.9), 7.03 (2H, d, J=5.43), 7.08 (1H, d, J=8.15), 7.60 (1H, s), 8.27 (1H, d, J=1.9), 8.44 (2H, d, J=5.7), LC-ESMS observed [M+H]+ 446.2 (calcd 446.6).
Reaction SMILES: [C:1]([OH:20])(=O)[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][CH2:17][CH3:18].[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26]>>[C:1]([NH:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[CH3:21])(=[O:20])[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][CH2:17][CH3:18]
Reactant: CN(C)CCCN
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCN(C)C
Temperature: 180 °C

Procedure:
A 300 g (1.05 mol) portion of octadecanoic acid was put into a flask and melted by stirring at 180° C. in an atmosphere of nitrogen. To this was added dropwise 113.1 g (1.11 mol) of N,N-dimethyl-1,3-diaminopropane spending 3 hours, thereby effecting the reaction while evaporating the generated water. After completion of the dropwise addition, this was further stirred at 180° C. for 4 hours in an atmosphere of nitrogen. Thereafter, the unreacted material amine remained in the reaction mixture was evaporated under a reduced pressure to obtain the title compound as a light brown waxy solid (melting point 64-67° C.).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C@H:8]2[N:11]([CH2:19][CH3:20])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO.CS(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:14]([O:13][C:12]([N:11]([CH2:19][CH3:20])[C@H:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:12]([O:13][CH3:14])=[O:18])[CH:10]=2)[CH2:6][CH2:7]1)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H]1CCc2ccc(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CS(C)=O
Product: CCN(C(=O)OC(C)(C)C)[C@@H]1CCc2ccc(C(=O)OC)cc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
(R)-tert-Butyl 6-bromo-2,3-dihydro-1H-inden-1-yl(ethyl)carbamate (15 g, 44.12 mmol, 1 eq) was dissolved in MeOH (180 ml) and DMSO (30 ml). The mixture was degassed for 30 minutes with argon, and then Pd(OAc)2 (0.513 g, 2.21 mmol, 0.05 eq), 1,3-bis(diphenyl-phosphino)propane (0.911 g, 2.21 mmol, 0.05 eq) and TEA (18.4 ml, 132.35 mmol, 3 eq) were added. The reaction mixture was stirred for 16 hours at 80° C. in an autoclave under CO pressure (80 psi) and then concentrated under reduced pressure. The residue was taken up in water (200 ml) and extracted with ethyl acetate (2×400 ml). The combined org. phases were washed with sat. NaCl solution (500 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 8% ethyl acetate in hexane). Yield: 77% (10.84 g, 33.97 mmol)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][C:3]=1[O:19][CH3:20].C(#N)C.C1C(=O)N([Br:31])C(=O)C1>O>[ClH:1].[Br:31][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([O:19][CH3:20])=[CH:4][C:5]=1[NH:8][CH:9]1[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12][C:13]([CH3:15])([CH3:16])[CH2:14]1
Reactant: COc1cc(NC2CC(C)(C)NC(C)(C)C2)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: COc1cc(NC2CC(C)(C)NC(C)(C)C2)c(Br)cc1Cl
Product: Cl
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of (4-chloro-3-methoxyphenyl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine 0.40 g, 1.3 mmol), acetonitrile (10 ml) and NBS (0.23 g, 1.3 mmol) was stirred for 1 h at 100° C. Water (25 ml) was added and the mixture was extracted with diethyl ether (2×50 ml). Hydrochloric acid in ether was added and the hydrochloric acid salt was precipitated and stirred, followed by filtration. Yield 0.40 g, (75%). Mp >270° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH2:14][O:15][CH3:16])=[N:4][N:3]=1.[NH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:20][CH2:19]1>C(O)(C)C>[ClH:1].[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]([CH2:14][O:15][CH3:16])=[N:4][N:3]=[C:2]2[NH:17][CH:18]2[CH2:19][CH2:20][N:21]([CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)[CH2:22][CH2:23]2)=[CH:7][CH:8]=1.[ClH:1]
Reactant: COCc1nnc(Cl)c2cc(OC)ccc12
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Solvent: CC(C)O
Product: COCc1nnc(NC2CCN(Cc3ccc4ccccc4c3)CC2)c2cc(OC)ccc12
Product: Cl

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-7-methoxy-4-methoxymethylphthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine. The hydrochloride is obtained after treatment with a solution of hydrogen chloride in isopropanol.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11])[CH2:6][CH2:7][CH3:8].[O-:17][C:18]#[N:19].[K+]>C1C=CC=CC=1>[CH2:13]([N:12]1[C:18](=[O:17])[NH:19][C:1](=[O:2])[N:9]([CH2:5][CH2:6][CH2:7][CH3:8])[C:10]1=[O:11])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCNC(=O)NCCCC
Reactant: N#C[O-]
Reactant: O=C(Cl)Cl
Agent: [K+]
Solvent: c1ccccc1
Product: CCCCn1c(=O)[nH]c(=O)n(CCCC)c1=O
Yield: 38 %

Procedure:
A benzene solution (50 ml) of 5,3-dibutyl allophanoyl chloride (0.1 mole) was prepared by reaction of phosgene with 1,3-dibutyl urea by the method of Example 2. This material was reacted with 16.0 g (0.2 mole) of potassium cyanate as described above. After work-up, 9.3 g (38% yield) of dibutyl isocyanuric acid was obtained; m.p. 86°-88° C. IR and nmr analysis was consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[CH:13](OCC)(OCC)OCC>C1(C)C=CC=CC=1>[O:8]1[C:7]2[CH:6]=[CH:5][C:4]([CH2:9][C:10]([OH:12])=[O:11])=[CH:3][C:2]=2[N:1]=[CH:13]1
Reactant: CCOC(OCC)OCC
Reactant: Nc1cc(CC(=O)O)ccc1O
Solvent: Cc1ccccc1
Product: O=C(O)Cc1ccc2ocnc2c1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
The mixture of (3-amino-4-hydroxy-phenyl)-acetic acid (250 mg, 1.5 mmol) and triethyl orthoformate (30 mg, 2.0 mmol) in toluene was refluxed for 3 h, cooled to room temperature and concentrated. The resulting solid was collected, washed with 1:3 ethyl acetate:hexane and dried to give the title compound (220 mg, 83%). 1H NMR (400 MHz, DMSO) δ 12.4 (b s, 1H), 8.70 (s, 1H), 7.68 (d, J=6.7 Hz, 1H), 7.66 (s, 1H), 7.31 (d, J=6.8 Hz, 1H), 3.33 (s, 2H). Mass spectrum (LCMS, ESI pos.): Calcd for C9H7NO3: 177.2. Found: 178.2 (M+H).
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([Si:7](Cl)([CH2:9]Cl)[CH3:8])=[CH:3][CH:2]=1.[Na].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.[CH3:24][OH:25]>CN(C)C=O.O>[C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([SiH:7]([CH2:9][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH2:8][O:25][CH3:24])=[CH:3][CH:2]=1
Reactant: C[Si](Cl)(CCl)c1ccc(-c2ccccc2)cc1
Reactant: CO
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: COC[SiH](Cn1cncn1)c1ccc(-c2ccccc2)cc1
Reaction time: 1 h

Procedure:
A mixture of (1,1'-biphenyl-4-yl)chlorochloromethylmethylsilane and two equivalents of 1,2,4-triazole sodium salt in dimethylformamide is warmed to 80°-90° C. for 2 hours. Ten equivalents of methanol is then added, and the mixture is held at 70° C. for 1 hour, cooled, diluted with water, and quickly extracted with ether. Washing the ether solution with water and brine, drying over magnesium sulfate, and evaporation leaves the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2sccc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2sccc2c1
Temperature: 76 °C
Yield: 94.5 %

Procedure:
In a flask was placed 5-methyl-benzo[b]thiophene (3.64 g, 24.56 mmol) and carbon tetrachloride (75 mL). To the reaction mixture was then added N-bromosuccinimide (5.68 g, 31.92 mmol) and benzoyl peroxide (892 mg, 3.68 mmol) and it was the final solution was then heated at 76° C. for 6 h. After this time the reaction mixture was cooled to 0° C. in an ice bath and the solids were filtered off and the filterate was concentrated in vacuo and purified on an AnaLogix Intelliflash system (120 g column, 3% ethyl acetate/hexanes) to afford 5-bromomethyl-benzo[b]thiophene (5.27 g, 94%) as a yellow solid.
Reaction SMILES: C([N:8]([CH2:14][C:15]1[C:19]2[N:20]=[CH:21][N:22]=[C:23]([OH:24])[C:18]=2[NH:17][CH:16]=1)[CH2:9][C@@H:10]([OH:13])[CH2:11][OH:12])C1C=CC=CC=1.[H][H]>O.[Pd]>[OH:24][C:23]1[C:18]2[NH:17][CH:16]=[C:15]([CH2:14][NH:8][CH2:9][C@@H:10]([OH:13])[CH2:11][OH:12])[C:19]=2[N:20]=[CH:21][N:22]=1
Reactant: [H][H]
Reactant: OC[C@H](O)CN(Cc1ccccc1)Cc1c[nH]c2c(O)ncnc12
Agent: [Pd]
Solvent: O
Product: OC[C@H](O)CNCc1c[nH]c2c(O)ncnc12
Temperature: 25 °C
Yield: 99.1 %

Procedure:
(R)-3-(Benzyl((4-hydroxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)amino)propane-1,2-diol (0.1 g, 0.305 mmol) was dissolved in hot water (20 ml), cooled to rt and 10% Pd—C (50 mg) added. Hydrogen was added from a balloon and the mixture stirred at rt. After 4 h tlc (CH2Cl2-MeOH-cNH3, 5:4.5:0.5) showed reaction over. The hydrogen was replaced with Ar and the mixture heated to 80° C. to ensure product was in solution then the mixture filtered through Celite and the solvent evaporated to give (R)-3-((4-hydroxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)propane-1,2-diol as a colourless solid (0.072 g, 99%). The product was converted to its hydrochloride salt with 5% HCl. 1H NMR (D2O+DCl, 300 MHz), δ ppm, 9.07 (s, 1H), 7.91 (s, 1H), 4.53 (s, 2H), 4.06 (m, 1H), 3.69-3.57 (m, 2H), 3.33 (dd, 1H, J 12.9, 2.9 Hz), 3.17 (dd, 1H, J 12.9, 9.8 Hz). 13C NMR (D2O+DCl, 75.5 MHz), δ ppm, 153.8 (C), 146.1 (CH), 134.1 (C), 133.1 (CH), 119.6 (C), 104.1 (C), 68.5 (CH), 64.5 (CH2), 50.2 (CH2), 41.8 (CH2). [α]D18 +12.6 (c, 0.565, H2O). +ESMS Found 261.0952 (M+Na)+ C10H14N4O3Na requires 261.0964.