Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH2:19][O:20][C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:38])[CH2:29][C:30]([CH2:36][CH3:37])([CH2:34][CH3:35])[C:31]([OH:33])=[O:32])[CH:24]=[CH:25][CH:26]=3)=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(N(CC)CC)C>[Pd].O1CCCC1>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH2:19][O:20][C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:38])[CH2:29][C:30]([CH2:36][CH3:37])([CH2:34][CH3:35])[C:31]([OH:33])=[O:32])[CH:24]=[CH:25][CH:26]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: CCC(CC)(CC(=O)Nc1cccc(OCc2ccc3ccc(OCc4ccccc4)cc3n2)c1)C(=O)O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(CC)(CC(=O)Nc1cccc(OCc2ccc3ccc(O)cc3n2)c1)C(=O)O
Reaction time: 3 h

Procedure:
A mixture consisting of 0.37 g of 4-[3-(7-benzyloxy-2-quinolinylmethoxy)phenylamino]-2,2-diethyl-4-oxobutanoic acid (Example 18), 2 ml of triethylamine, 0.0185 g of palladium/activated carbon catalayst and 10 ml of tetrahydrofuran is hydrogenated for 3 hours under normal pressure. The reaction mixture is then filtered and concentrated by evaporation. The residue is chromatographed on silica gel using methylene chloride/methanol 95:5 and 9:1. The title compound is obtained in the form of a slightly yellowish amorphous solid; 1H-NMR, 400 MHz, DMSO, delta (ppm)=10.3 (s, 1H), 8.20 (d, 1H), 7.28 (m, 2H), 7.25 (d, 1H), 7.1-7.18 (m, 3H), 6.65 (dd, 1H), 5.22 (s, 2H), 2.47 (s, 2H), 1.49 (m, 4H), 0.78 (t, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([S:10][CH3:11])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:19](Cl)([Cl:21])=[O:20]>O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([S:10][CH3:11])[N:7]([C:19]([Cl:21])=[O:20])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cl
Reactant: CSc1cc(C(C)(C)C)n[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1cc(C(C)(C)C)nn1C(=O)Cl
Reaction time: 2 h
Yield: 64 %

Procedure:
A solution of 3-t-butyl-5-(methylthio)pyrazole (10 g), and triethylamine (6.0 g) were added dropwise at -20° to a stirred solution of phosgene (7.5 ml) in tetrahydrofuran (75 ml). The solution was allowed to come to room temperature, and was then stirred for 2 hours. Excess phosgene was removed by drawing dry air through the mixture for 1/2 hour. The reaction mixture was filtered, and evaporated to give a yellow oil which quickly crystallised. Recrystallisation from petrol gave 3-tert-butyl-1-chlorocarbonyl-5-(methylthio)pyrazole, 5.0 g (64% yield), melting point 64°-6°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](Cl)=[CH:4][N:3]=1.[F:9][C:10]([F:22])([F:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>[Pd]>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:9])([F:21])[F:22])=[CH:17][CH:16]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Clc1cnc(Cl)nc1
Agent: [Pd]
Product: FC(F)(F)Oc1ccc(-c2cnc(Cl)nc2)cc1

Procedure:
The compound was prepared by palladium-catalyzed arylation of 2,5-dichloropyrimidine with 4-trifluoromethoxyphenyl boronic acid.
Reaction SMILES: [F:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].O.S(Cl)([Cl:17])(=O)=O>>[F:1][CH:2]([Cl:17])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4]
Reactant: O=C(CF)c1ccc(F)cc1F
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Product: O=C(c1ccc(F)cc1F)C(F)Cl

Procedure:
A solution of 2,2',4'-trifluoroacetophenone (1.60 g; 9.2 mM) in sulphuryl chloride (4 ml) was heated at 75° for 18 hours. The mixture was then cooled and iced-water (40 ml) was added. The product was extracted into ether (80 ml), which was washed with water and aqueous sodium bicarbonate solution, and then dried over magnesium sulphate. Evaporation yielded the desired product as a colourless, intensely lachrymatory liquid (2.0 g; 100%).
Reaction SMILES: CS(O[CH:6]([CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=O)=O.[C-:27]#[N:28].[Na+].O>CN(C=O)C>[CH2:7]([CH:6]([CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:27]#[N:28])[CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: [C-]#N
Reactant: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)OS(C)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC/C=C\CCCC(C#N)CCC/C=C\CCCCC
Yield: 106 %

Procedure:
A solution of (6Z,15Z)-henicosa-6,15-dien-11-yl methanesulfonate 5 (7.6 g, 19.6 mmol) and sodium cyanide (4.8 g, 98.1 mmol) in anhydrous DMF (60 mL) was heated to 60° C. overnight. Upon completion, the reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (3×100 mL). The combine ethyl acetate extracts were washed with brine (3×100 mL), dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The product was purified by column chromatography (100% Hexanes to 1% ethyl acetate in hexanes) to afford (Z)-2-((Z)-dec-4-enyl)dodec-6-enenitrile 6 as a colorless oil (6.6 g, 97%). Rf 0.75 (10% EtOAc-Hexanes).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[CH:11]1([CH2:16][C:17](Cl)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:5]([NH:6][C:17](=[O:18])[CH2:16][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([Cl:10])[CH:3]=1
Reactant: Nc1c(Cl)cc(Br)cc1Cl
Reactant: O=C(Cl)CC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CC1CCCC1)Nc1c(Cl)cc(Br)cc1Cl
Temperature: 25 °C
Yield: 79.4 %

Procedure:
4-Bromo-2,6-dichloroaniline (12.1 g) and cyclopentylacetyl chloride (8.1 g) were dissolved in tetrahydrofuran (100 mL) and sodiumcarbonate (6.4 g) is added, followed by heating to reflux for 6 hours. The reaction mixture was cooled to ambient temperature and filtered and diluted with water (250 ml). After extraction, the combined organic phase was concentrated in vacuo to furnish 14.0 g (80% yield) of the title compound as a white solid. LC-MS (m/z) 352 (MH+); tR=3.47, (UV, ELSD) 96%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.12 (m, 2H), 1.50 (m, 4H), 1.80 (m, 2H), 2.15 (m, 1H), 2.50 (d, 2H), 5.70 (broad s, 1H), 7.45 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[CH:4][CH:3]=1.Cl.[NH2:11]O.C([O-])(=O)C.[Na+]>CO>[Cl:1][C:2]1[C:7]([C:8]#[N:11])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1cnccc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N#Cc1cnccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
The compound (19) (27.0 g, 0.19 mol), hydroxylamine hydrochloride (13.01 g, 0.19 mol) and sodium acetate (15.6 g, 0.19 mol) were suspended in methanol (100 ml) and the mixture was stirred at room temperature for 2 hrs. The solvent was evaporated and the residue was dissolved in chloroform (100 ml). Phosphorus oxychloride (125 g) was added and the mixture was heated under ref lux for 3 hrs. The solvent was evaporated and the residue was added to water (200 ml), which was adjusted to pH=7 with sodium carbonate. The mixture was extracted with ethyl acetate (200 ml×2) and the organic layer was dried (MgSO4). The solvent was evaporated under reduced pressure to give the title compound (18 g, 68%).
Reaction SMILES: [N:1]1C=CC(N2CCC3(CCNCC3)C2)=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.[C:31]([C:33]1[CH:48]=[CH:47][C:36]([CH2:37][CH2:38][NH:39]C(=O)OC(C)(C)C)=[CH:35][CH:34]=1)#[N:32].C(N)CN>>[NH:1]1[CH2:2][CH2:3][N:32]=[C:31]1[C:33]1[CH:34]=[CH:35][C:36]([CH2:37][CH2:38][NH2:39])=[CH:47][CH:48]=1
Reactant: c1cc(N2CCC3(CCNCC3)C2)ccn1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C#N)cc1
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: NCCN
Product: NCCc1ccc(C2=NCCN2)cc1
Temperature: 120 °C

Procedure:
Boc2O (818 mg, 3.75 mmol, 1.5 eq.) was added to a stirred solution of 2-(4-bromophenyl)ethanamine (500 mg, 2.5 mmol, 1.0 eq.) and TEA (1.5 ml, 7.5 mmol, 3.0 eq.) in DCM (25 ml) at 0° C. and resulting reaction mixture is stirred at 25° C. for 6 h. The reaction mixture was diluted with DCM (75 ml), washed with water (2×50 ml) and brine (50 ml) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue triturated with hexanes to yield the desired product as an off white solid. Yield: 100% (750 mg, 2.5 mmol) 2. A mixture of tert-butyl 4-bromophenethylcarbamate (750 mg, 2.5 mmol, 1.0 eq.) and Zn(CN)2 (439 mg, 3.75 mmol, 1.5 eq.) in dry DMF (15 ml) was degassed with argon for 15 min. Xanthphos (290 mg, 0.5 mmol, 0.2 eq.) and Pd2(dba)3 (229 mg, 0.25 mmol, 0.1 eq.) were added to the reaction mixture and it was heated to 100° C. for 18 h. The reaction mixture was diluted with water (40 ml) and extracted with ethyl acetate (2×50 ml). The organic layer was washed with brine (50 ml) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (neutral alumina, 10% ethyl acetate in hexanes) to yield the desired product as a reddish solid. Yield: 73% (450 mg, 1.83 mmol) 3. P2S5 (48 mg) was added to a mixture of tert-butyl 4-cyanophenethylcarbamate (450 mg, 1.83 mmol, 1.0 eq.) and freshly distilled ethylenediamine (2.4 ml, 33.85 mmol, 18.5 eq.) and the resulting reaction mixture was heated to 120° C. for 4 h. The reaction mixture was cooled to 25° C. and poured into ice-cold water (20 ml). It was then extracted with DCM (40 ml). The organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure to yield the desired product. Yield: 94% (500 mg, 1.73 mmol) 4. TFA (1 ml) was added to a solution of tert-butyl 4-(4,5-dihydro-1H-imidazol-2-yl)phenethylcarbamate (214 mg, 0.74 mmol, 1.0 eq.) in DCM (3 ml) at 0° C. and the resulting reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product which was directly used in the next step.
Reaction SMILES: [NH2:1][C@H:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].N1C=CC=CC=1.[CH2:30]([O:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)[C:31]#[C:32][CH3:33]>C(Cl)(Cl)Cl.CCOCC>[C:20]([O:19][C:17]([NH:16][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([C@@H:2]([NH:1][S:41]([C:38]2[CH:37]=[CH:36][C:35]([O:34][CH2:30][C:31]#[C:32][CH3:33])=[CH:40][CH:39]=2)(=[O:43])=[O:42])[C:3]([O:5][CH3:6])=[O:4])=[CH:12][CH:11]=1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@H](N)c1ccc(OCCNC(=O)OC(C)(C)C)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)OC)c2ccc(OCCNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.8 %

Procedure:
To a solution of 0.682 g (2.10 mmol) of methyl (2R)-amino(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl)ethanoate dissolved in 10 mL of chloroform and 2.2 mL of pyridine was added 0.566 g (2.315 mmol) of 4-but-2-ynyloxy-benzenesulfonyl chloride. The reaction was stirred at room temperature for 15 h and then diluted with ether. The organics were washed with water, 5% HCl solution and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 0.691 g of methyl (2R)-(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl)({[4-(2-butynyloxy)phenyl]sulfonyl}amino)ethanoate as a white foam Electrospray Mass Spec 533.1 (M+H)+
Reaction SMILES: [CH3:1][C:2]([NH:4][C@H:5]1[C@H:10]([C@H:11]([OH:16])[C@H:12]([OH:15])[CH2:13][OH:14])[O:9][C@:8]([O:20]P(OC[C@H]2O[C@@H](N3C(=O)N=C(N)C=C3)[C@H](O)[C@@H]2O)(O)=O)([C:17]([OH:19])=[O:18])[CH2:7][C@@H:6]1[OH:41])=[O:3].OC(C1(O[C@@H]([C@@H]([C@@H](CO)O)O)[C@H](NC(C)=O)[C@@H](O)C1)O)=O.CC(NC1C(C(O)C(O)CO)OC(OP(OC[C@H]2O[C@@H](N3C(=O)N=C(N)C=C3)[C@H](O)[C@@H]2O)([O-])=O)(C(O)=O)CC1O)=O.[Na+].[O:105]=[CH:106][C@@H:107]([C@H:109]([C@H:111]([C@@H:113]([CH2:115][OH:116])[OH:114])[OH:112])O)[OH:108]>>[OH:19][C:17]([C@@:8]1([O:9][C@@H:10]([C@@H:11]([C@@H:12]([CH2:13][OH:14])[OH:15])[OH:16])[C@H:5]([NH:4][C:2]([CH3:1])=[O:3])[C@@H:6]([OH:41])[CH2:7]1)[O:20][C@H:109]1[C@@H:111]([OH:112])[C@@H:113]([CH2:115][OH:116])[O:114][C@@H:106]([OH:105])[C@@H:107]1[OH:108])=[O:18]
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)O[C@](OP(=O)(O)OC[C@H]2O[C@@H](n3ccc(N)nc3=O)[C@H](O)[C@@H]2O)(C(=O)O)C[C@@H]1O
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: CC(=O)NC1C(O)CC(OP(=O)([O-])OC[C@H]2O[C@@H](n3ccc(N)nc3=O)[C@H](O)[C@@H]2O)(C(=O)O)OC1C(O)C(O)CO
Agent: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)O)C[C@@H]1O
Agent: [Na+]
Product: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)O[C@@](O[C@@H]2[C@@H](O)[C@H](O)O[C@H](CO)[C@@H]2O)(C(=O)O)C[C@@H]1O

Procedure:
The resulting CMP-sialic acid analogue (which in FIG. 3 is illustrated as the CKP derivative of Neu5Ac, i.e., CMP-Neu5Ac) is then combined with the derivatized βGal(1→3)βGlcNAc--OR compound in the presence of the βGal(1→3/4)βGlcNAc α(2→3)sialyltransferase under conditions wherein sialic acid is transferred to the 3 position of the galactose to form a αNeu5Ac(2→3)βGal linkage. Suitable conditions, known in the art, include the addition of the sialyltransferase to a mixture of the derivatized βGal(1→4)βGlcNAc--OR compound and of the CMP-sialic acid in a appropriate buffer such as 0.1M sodium cacodylate in appropriate conditions of pH and temperature such as at a pH of 6.5 to 7.5 and a temperature between 25° and 45° C., preferably 35°-40° C., while incubating for 12 hours to 4 days. The resulting sialylated product can be isolated and purified using conventional methodology comprising HPLC, ion exchange-, gel-, reverse-phase- or adsorption chromatography.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[CH:6]=1.[F:25][C:26]([F:42])([F:41])[C:27]1[CH:28]=[C:29]([S:37](Cl)(=[O:39])=[O:38])[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:37]([C:29]3[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=[C:27]([C:26]([F:25])([F:41])[F:42])[CH:28]=3)(=[O:39])=[O:38])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[CH:6]=1
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(N)cc2)c1C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(NS(=O)(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.1 %

Procedure:
To a solution of [4-(4-amino-phenyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (55 mg, 0.17 mmol) and 3,5-bis(trifluoromethyl)benzenesulfonyl chloride (54 mg, 0.17 mmol) in THF (3 mL) was added diisopropylethylamine (62 mg, 0.48 mmol) at 0° C. under nitrogen. After addition, the reaction mixture was warmed to room temperature and stirred for 3 hours. The solvent was removed under vacuum and the residue was diluted with water (10 mL). The mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (20 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum gave the crude residue which was purified using an ISCO (12 g) column, eluting with 2-25% ethyl acetate in hexanes, to afford {4-[4-(3,5-bis-trifluoromethyl-benzenesulfonylamino)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (21.5 mg, 21%) as a light brown solid. 1H NMR (300 MHz, CDCl3) δ ppm 8.23 (s, 2 H), 8.09 (s, 1 H), 7.78 (dd, J=8.8, 5.7 Hz, 1 H), 7.73 (s, 1 H), 7.11-7.24 (m, 5 H), 7.04 (s, 1 H), 6.73 (d, J=10.9 Hz, 1 H), 3.87 (s, 2 H), 3.75 (s, 3 H), 2.07 (s, 3 H). HRMS calcd. for C28H19F7NO4S [(M−H)−] 598.0928, obsd. 598.0925.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=S)[NH:8][NH2:9].Cl.[Cl:13][CH:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[ClH:13].[CH2:18]([O:17][C:15]([C:14]1[C:7]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:11])[CH3:1])=[N:8][NH:9][C:20]=1[CH3:22])=[O:16])[CH3:19]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CN(C)CCCNC(=S)NN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(NCCCN(C)C)n[nH]c1C
Yield: 71.4 %

Procedure:
A stirred solution of 7.05 g (0.04 mole) of 4-(3-dimethylaminopropyl)-3-thiosemicarbazide in 50 mL of absolute ethanol under nitrogen atmosphere was treated with 40 mL of 2N ethanolic hydrogen chloride and then with 6.6 g (0.04 mole) of ethyl 2-chloroacetoacetate, stirred at ambient temperature for 2 hr and heated at reflux for 5 hr. The reaction mixture was filtered hot to remove some crystalline sulfur and the filtrate solidified on cooling to give 8.3 g of crude product. After 5 recrystallizations from methyl ethyl ketone/methanol with charcoal treatment of the final recrystallization, a crystalline product was obtained, 3.4 g, mp 195°-196° C. After drying at 82° C. under reduced pressure, it was submitted for elemental analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH:10]=1.[Br:11]Br>C(Cl)(Cl)Cl.[OH-].[NH4+].C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[N:7][C:6]=2[C:10]=1[Br:11]
Reactant: BrBr
Reactant: Nc1ccc2scnc2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Nc1ccc2scnc2c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
To a cooled (5° C.) solution of 2.04 g of 5-aminobenzothiazole in 60 mL of chloroform are added dropwise 2.15 g of bromine while maintaining the temperature below 10° C. After completion of the addition, the reaction mixture is stirred for 30 minutes at room temperature, then diluted with 14 mL of concentrated ammonium hydroxide and 16 mL of methylene chloride. The aqueous layer is washed with methylene chloride (2×16 mL) and the combined organic layers are rotary evaporated. The residue is purified by an aspirator vacuum-filtration through silica gel, eluting with 15% to 30 ethyl acetate in hexanes to provide 2.44 g of 5-amino-4-bromobenzothiazole as a reddish solid.
Reaction SMILES: [C:1]1([C:7](=[N:14]C2C=CC(C3CCCC(CC(OCC)=O)C3)=CC=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:34]1[CH:39]=[CH:38][C:37]([C@@H:40]2[CH2:44][CH2:43][C:42](=[CH:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:41]2)=[CH:36][CH:35]=1>>[C:1]1([C:7](=[N:14][C:34]2[CH:39]=[CH:38][C:37]([C@@H:40]3[CH2:44][CH2:43][C:42](=[CH:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:41]3)=[CH:36][CH:35]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC1CCCC(c2ccc(N=C(c3ccccc3)c3ccccc3)cc2)C1
Reactant: CCOC(=O)C=C1CC[C@@H](c2ccc(Br)cc2)C1
Product: CCOC(=O)C=C1CC[C@@H](c2ccc(N=C(c3ccccc3)c3ccccc3)cc2)C1

Procedure:
Following the procedure described for ethyl (3-{4-[(diphenylmethylene)amino]phenyl}cyclohexyl)acetate (Intermediate 89(iii)), replacing ethyl [3-(4-{[(trifluoromethyl)sulphonyl]oxy}phenyl)cyclohexyl]acetate with ethyl [(3R)-3-(4-bromophenyl)cyclopentylidene]acetate, the title compound was obtained; MS m/e MH+ 410.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]([N:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1)([CH3:22])[CH3:21].[F:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]2[N:47]=[CH:46][C:45]3[C:40](=[CH:41][C:42](O)=[CH:43][CH:44]=3)[N:39]=2)=[CH:33][C:32]=1[CH3:49]>C1COCC1>[F:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]2[N:47]=[CH:46][C:45]3[C:40](=[CH:41][C:42]([O:29][CH:26]4[CH2:27][CH2:28][N:23]([CH:20]([CH3:22])[CH3:21])[CH2:24][CH2:25]4)=[CH:43][CH:44]=3)[N:39]=2)=[CH:33][C:32]=1[CH3:49]
Reactant: Cc1cc(Nc2ncc3ccc(O)cc3n2)ccc1F
Reactant: CC(C)N1CCC(O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(Nc2ncc3ccc(OC4CCN(C(C)C)CC4)cc3n2)ccc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of triphenylphosphine (2 eq) in THF was added di-terbutylazodicarboxylate (2 eq). The mixture was stirred 15 minutes at ambient temperature under nitrogen atmosphere. To that was added 1-isopropylpiperidine-4-ol (5 eq). The mixture was stirred 15 minutes at ambient temperature followed by addition of 2-(4-fluoro-3-methylphenylamino) quinazolin-7-ol (1 eq). The mixture was stirred overnight at ambient temperature. The LC-MS of reaction mixture shows the presence of two product (2:1) with identical mass. The reaction mixture was concentrated and purified by semi-preparative HPLC to provide (N-(4-fluoro-3-methylphenyl)-7-(1-isopropyl-piperidin-4-yloxy)-quinazolin-2-amine as a major product ES/MS m/z 395.2 (MH+).
Reaction SMILES: C([C:3]1[CH:16]=[CH:15][C:6]([NH:7][C:8]([O:10]C(C)(C)C)=O)=[CH:5][CH:4]=1)#N.S.[C:18]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[S:34])[NH2:33])=[CH:28][CH:27]=1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>N1C=CC=CC=1.CO>[C:21]([O:20][C:18](=[O:19])[NH:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[S:34][CH:16]=[C:3]([C:4]3[C:8](=[O:10])[NH:7][C:6]4[C:5]([CH:5]=3)=[CH:4][CH:3]=[CH:16][CH:15]=4)[N:33]=2)=[CH:30][CH:31]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#N)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(N)=S)cc1
Agent: S
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2nc(-c3cc4ccccc4[nH]c3=O)cs2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-cyano-tert-butyloxycarbonylaniline (2.20 g, 10.0 mmol) in 20 mL of pyridine and 5 mL of TEA was purged with H2S gas for 7.0 h. Solvents were removed under vacuum. The resulting crude 4-Boc-aminobenzene-thiocarboxamide (yellow residue, 70% purity) was used directly in the next step. A solution of 4-Bocamino-benzenethiocarboxamide (205 mg, 70% pure, 0.57 mmol) and 3-(2-bromoacetyl)hydroquinolin-2-one (Example 27b, 78 mg, 0.29 mmol) in 50 mL of MeOH was heated at reflux for 4 h. After cooling to RT, the precipitates were collected by filtration to provide the title compound as an off-white solid. MS m/z: 420.2 (M+1). HRMS m/z: 420.1358 (M+H+, C23H21N3O3S Calc'd 420.1376).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:28]([N:35]1[C:43]2[CH:42]=[CH:41][NH:40][C:39](=O)[C:38]=2[CH:37]=[CH:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCOCC1>[CH2:28]([N:35]1[C:43]2[CH:42]=[CH:41][N:40]=[C:39]([Br:1])[C:38]=2[CH:37]=[CH:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=c1[nH]ccc2c1ccn2Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Brc1nccc2c1ccn2Cc1ccccc1
Reaction time: 1 h

Procedure:
35 g of N-bromosuccinimide are added to a solution of 52 g of triphenylphosphine in 1.5 1 of dioxane. After stirring the mixture for 1 hour, 9 g of 1-benzyl-1,5-dihydro-pyrrolo[3,2-c]pyridin-4-one in 200 ml of dioxane are added and the mixture is heated at reflux for 15 hours. After removal of the dioxane under reduced pressure, 100 ml of triethylamine are added to the residue and the whole is then concentrated in vacuo. Chromatography on silica gel (cyclohexane/ethyl acetate: 50/50) enables the expected product to be isolated.