Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:38][S:39](O)(=[O:41])=[O:40]>C(OCC)(=O)C>[CH3:38][S:39]([O:21][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=3)[C:12]=2[O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:25][CH:24]=2)[CH:17]=1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Reactant: CS(=O)(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Reaction time: 1 h

Procedure:
Heat approximately 1.0 g of the compound of Example 3 in a solvent mixture consisting of 3 mL of 3A-ethanol and 5 mL ethyl acetate to provide a thin slurry. Add methanesulfonic acid (185 mg) in 1 mL of 3A-ethanol to the hot slurry. Cool and stir for approximately 1 hour upon reaching room temperature. Filter the slurry and rinse with ethyl acetate. Vacuum dry the filter cake at 45° C. over 2-3 days to recover approximately 1.11 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[C:17](=O)[C:16](=[O:19])[N:6]2[C:7]=1[C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9].Cl.[CH3:21][O:22][NH2:23].N1C=CC=CC=1.C(Cl)Cl>CN(C)C=O>[CH3:21][O:22][N:23]=[C:17]1[C:16](=[O:19])[N:6]2[C:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])=[C:2]([CH3:1])[CH2:3][S:4][C@H:5]12
Reactant: CON
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(=O)[C@H]2SC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON=C1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(C)CS[C@H]12

Procedure:
In dimethylformamide (20 ml) are dissolved 2,2,2-trichloroethyl 3-methyl-7-oxo-3-cephem-4-carboxylate (3.63 g) and methoxyamine hydrochloride (2.63 g), followed by addition of pyridine (0.83 g) and methylene chloride (70 ml). The mixture is refluxed in a Dean-Stark trap packed with Molecular Sieve 3A for 2 hours. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in ethyl acetate. This solution is washed with water, 1 N-HCl and aqueous sodium chloride in the order mentioned, dried over magnesium sulfate and concentrated under reduced pressure. The residual oil is subjected to silica gel (35 g) column chromatography and elution is carried out with methylene chloride. By the above procedure is obtained 2,2,2-trichloroethyl 7-methoxyimino-3-methyl-3-cephem-4-carboxylate as as oil (3.66 g).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][N:10]1[C:14]([CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:13][NH:12][CH2:11]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:49][C@H:50]([CH2:68][C:69]1[CH:74]=[CH:73][C:72]([O:75][CH3:76])=[CH:71][CH:70]=1)[C:51]([N:53]1[CH2:56][C:55]([CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:54]1)=[O:52].[OH-].[Na+]>CN(C=O)C.CCCCCCC>[CH3:76][O:75][C:72]1[CH:71]=[CH:70][C:69]([CH2:68][C@@H:50]([NH:49][C:17](=[O:19])[CH2:16][CH2:15][C:14]2[N:10]([CH3:9])[CH:11]=[N:12][CH:13]=2)[C:51](=[O:52])[N:53]2[CH2:56][C:55]([CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[CH2:54]2)=[CH:74][CH:73]=1
Reactant: CCCCCC1(c2ccccc2)CN(C(=O)[C@H](N)Cc2ccc(OC)cc2)C1
Reactant: CN1CNC=C1CCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCCCCCC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCC1(c2ccccc2)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)CCc2cncn2C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.7 %

Procedure:
0.17 ml (1.23 mmol) of triethylamine is carefully added to a solution containing 87 mg (0.45 mmol) of 3-(3-methyl-1H-imidazol-4-yl)propionic acid hydrochloride and 160 mg (0.49 mmol) of TBTU in 1 ml of DMF. After stirring for 60 minutes at ambient temperature, 200 mg (0.32 mmol) of (R)-2-amino-3-(4-methoxyphenyl)-1-(3-pentyl-3-phenylazetidin-1-yl)propan-1-one trifluoroacetate (cf. procedure 9-3) are added and the reaction medium is left to stir for three days. The reaction medium is treated with a 2 heptane/8 EtOAc mixture and a 1N aqueous solution of sodium hydroxide. The organic phase is dried over MgSO4, filtered and evaporated. The residue obtained is purified by silica chromatography (eluent 9 DCM/1 MeOH). 21 mg of N—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(3-methyl-3H-imidazol-4-yl)propionamide are obtained with a yield of 9%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1.C(N(CC)CC)C.[CH3:22][Si:23](Cl)([CH3:25])[CH3:24]>O1CCCC1>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2([CH3:14])[O:10][CH2:11][CH2:12][O:13]2)=[C:2]([O:1][Si:23]([CH3:25])([CH3:24])[CH3:22])[CH:7]=1
Reactant: CC1(c2ccc(Br)cc2O)OCCO1
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(c2ccc(Br)cc2O[Si](C)(C)C)OCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.6 %

Procedure:
Under ice-cooling, to a solution of 3.11 g (12 mmol) of 2-(2-hydroxy-4-bromophenyl)-2-methyl-1,3-dioxolane in 24 ml of tetrahydrofuran were added dropwise successively, 1.84 ml (13.2 mmol) of triethylamine and 1.68 ml (13.2 mmol) of trimethylsilyl chloride with stirring. The mixture was stirred at room temperature for 3 hours and filtered. The filtrate was concentrated under reduced pressure to give 4.0 g of the crude product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([Cl:21])=[CH:16][N:15]=1.CCN(C(C)C)C(C)C>CS(C)=O.C(Cl)Cl>[Cl:13][C:14]1[N:19]=[C:18]([NH:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][O:2][CH3:1])[C:17]([Cl:21])=[CH:16][N:15]=1
Reactant: COCCOc1ccccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COCCOc1ccccc1Nc1nc(Cl)ncc1Cl
Yield: 66.5 %

Procedure:
A solution of 2-(2-methoxy-ethoxy)-phenylamine (800 mg) in DMSO (15 mL) was treated with 2,4,5-trichloropyrimidine (1.1 g) and DIEA (1.8 mL) for 16 hours. The mixture was diluted with DCM (50 mL) and washed with brine three times. The organic layer was dried over sodium sulfate and concentrated. Silica gel chromatography provided 1.0 g of (2,5-dichloro-pyrimidin-4-yl)-[2-(2-methoxy-ethoxy)-phenyl]-amine: 1H NMR (300 MHz, CDCl3) δ8.48 (d, 1H), 8.28 (bs, 1H), 8.19 (s, 1H), 7.06 (m, 2H), 6.95 (d, 1H), 4.20 (t, 2H), 3.75 (t, 2H), 3.42 (s, 3H); MS (m/e) 314 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:3]=1.CCCCCC.[Li]CCCC.[C:39]1([N:45]=[C:46]=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(OCC)C>[C:39]1([NH:45][C:46]([C:2]2[CH:7]=[C:6]([N:8]([CH3:16])[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[C:4]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[N:3]=2)=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C=Nc1ccccc1
Reactant: CN(Cc1ccccc1)c1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CN(Cc1ccccc1)c1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)Nc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
1.00 g (0.0023 mol) of 2-bromo-4-{methyl(phenylmethyl) amino}-6-{3-(trifluoromethyl)phenoxy} pyridine was dissolved in about 20 ml of diethyl ether. While cooling the solution in a dry ice-acetone bath in an argon atmosphere, 2.2 ml of a 1.6M-hexane solution of BuLi (0.0023×1.5 mol) was added to the solution, followed by stirring the obtained mixture for about 10 minutes. After 0.62 g (0.0023×2.3 mol) of phenyl isocyanate dissolved in about 5 ml of diethyl ether was added to the reaction solution, the obtained solution was removed from the bath and stirred at room temperature for about one hour. The reaction solution was mixed with about 5 ml of a 1.2N-aqueous hydrochloric acid solution, and then distributed in ethyl acetate-water, followed by washing with saturated sodium bicarbonate water and saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (eluting solution: ethyl acetate/hexane) to separate a main fraction therefrom. The fraction was concentrated and then subjected to precipitation using hexane, thereby obtaining an aimed product.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14]([N:16]1[CH2:20][CH2:19][C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25](I)[CH:24]=2)([O:21][CH3:22])[CH2:17]1)=[O:15])[CH3:12]>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([S:1][C:27]2[CH:28]=[C:23]([C:18]3([O:21][CH3:22])[CH2:19][CH2:20][N:16]([C:14]([O:13][CH2:11][CH3:12])=[O:15])[CH2:17]3)[CH:24]=[CH:25][CH:26]=2)=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CCOC(=O)N1CCC(OC)(c2cccc(I)c2)C1
Reactant: CC(=O)c1ccc(S)cc1
Product: CCOC(=O)N1CCC(OC)(c2cccc(Sc3ccc(C(C)=O)cc3)c2)C1
Yield: 24 %

Procedure:
Using an analogous procedure to that described in Example 10, 4'-mercaptoacetophenone was reacted with 1-ethoxycarbonyl-3-(3-iodophenyl)-3-methoxypyrrolidine to give 3-[3-(4-acetylphenylthio)phenyl]-1-ethoxycarbonyl-3-methoxypyrrolidine as a gum in 24% yield.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([NH2:19])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([CH:30]=1)[C:27](O)=[O:28]>>[CH:1]1([C:7]2[CH:8]=[C:9]([NH:19][C:27](=[O:28])[C:26]3[CH:30]=[C:22]([O:21][CH3:20])[CH:23]=[N:24][CH:25]=3)[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:16])([F:17])[F:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cncc(C(=O)O)c1
Reactant: Nc1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Product: COc1cncc(C(=O)Nc2cnc(OCC(F)(F)F)c(C3CCCCC3)c2)c1
Yield: 56.3 %

Procedure:
This compound was prepared following the same procedure as described for Example 3 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (Example 8b) (100 mg, 0.36 mmol) and 5-methoxy-nicotinic acid (50.5 mg, 0.33 mmol) as starting materials. The title compound (76 mg, 51.0%) was isolated as off white solid; MS (ESI): 410 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:7])=[CH:4][CH:3]=1.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1>>[CH2:9]([NH:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:29][C:28]2[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:33])[F:34])=[CH:32][CH:31]=2)=[CH:22][CH:21]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(N)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Product: CCCCCCCCCCCCNC(=O)c1ccc(NCc2ccc(C(F)(F)F)cc2)cc1
Yield: 74 %

Procedure:
The same procedure as employed in the preparation of Example 228 (step a) using 4-amino-N-dodecylbenzamide (Example 150, step b) and 4-(trifluoromethyl)benzaldehyde gave the title compound as colorless oil (74%). 1H NMR(DMSO-d6, 300 MHz) δ 7.68 (d, 2H, J=8.3 Hz), 7.47-7.60 (m, 4H), 6.53 (d, 2H, J=8.6 Hz), 4.41 (s, 2H), 3.31 (s, 2H), 3.14 (t, 2H, J=6.8 Hz), 1.35-1.51 (m, 2H), 1.11-1.32 (m, 18H), 0.83 (t, 3H, J=6.7 Hz). HPLC (Condition A), Rt: 7.00 min (HPLC purity: 91.2%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].Cl[C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16](=O)[C:17](=O)N2>>[C:15]1([CH:16]([C:17]2[CH:4]=[CH:3][CH:2]=[CH:10][CH:6]=2)[N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[C:7](=[O:12])[C:8]2=[O:11])[CH:19]=[CH:20][CH:21]=[CH:22][CH:14]=1
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Reactant: O=C1Nc2c(F)cccc2C1=O
Product: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2c(F)cccc21

Procedure:
Following the procedure as described in PREPARATION 4A, and making non-critical variations using 7-fluoro-1H-indole-2,3-dione (Kalia, N., et al., J. Med. Chem. 2007; 50:21-39) to replace 4-chloro-1H-indole-2,3-dione, 1-(diphenylmethyl)-7-fluoro-1H-indole-2,3-dione was obtained (56%) as an orange solid: 1H NMR (300 MHz, CDCl3) δ 7.52-7.47 (m, 1H), 7.42-7.30 (m, 10H), 7.29-7.21 (m, 1H), 7.13-7.05 (m, 1H), 6.99 (br s, 1H); MS (ES+) m/z 353.9 (M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[CH:6]=[N:5]2.[H-].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>CN(C=O)C>[CH2:21]([O:20][C:18]([CH2:17][N:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[C:11]([Cl:12])[CH:10]=2)[N:5]=[CH:6][C:7]1=[O:13])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=c1cnc2cc(Cl)c(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cn1c(=O)cnc2cc(Cl)c(Cl)cc21)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
Under a nitrogen atmosphere 6,7-dichloroquinoxalin-2(1H)-one (10.0 g, 46.5 mmol) (Liebigs Ann. Chem, (1982), 754) was suspended in 135 ml of dry DMF and sodium hydride (2.23 g, 55.8 mmol (60% mineral oil dispersion)) was added. After stirring for 2 h, benzyl bromoacetate (9.18 ml, 58.6 mmol) was added and the mixture was stirred for 3.5 h. The reaction mixture was poured onto 300 g of crushed ice and the precipitate was filtered off, washed with water and dried. The product was triturated with ether (500 ml), the precipitate filtered off, washed with ether and dried to afford 13.3 g of 1-benzyloxycarbonylmethyl-6,7-dichloroquinoxaline-2(1H)-one. 1H-NMR (DMSO-d6):δ5.18(s, 2H), 5.23(s, 1H), 8.18(s, 1H), 8.38(s, 1H).
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[C:55]([C:58]1[CH:59]=[C:60]([C:69]([CH3:72])([CH3:71])[CH3:70])[C:61]2[O:66][CH2:65][C:64](=[O:67])[NH:63][C:62]=2[CH:68]=1)(=[O:57])[CH3:56].C(Cl)Cl.CO>C(Cl)(Cl)Cl>[Br:1][CH2:56][C:55]([C:58]1[CH:59]=[C:60]([C:69]([CH3:72])([CH3:71])[CH3:70])[C:61]2[O:66][CH2:65][C:64](=[O:67])[NH:63][C:62]=2[CH:68]=1)=[O:57]
Reactant: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCC(=O)N2
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)CBr)cc2c1OCC(=O)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
Tetra-n-butylammonium tribromide (64 mg, 0.13 mmol) was added to a solution of the 6-acetyl-8-(tert-butyl)-3,4-dihydro-2H-1,4-benzoxazin-3-one (30 mg, 0.12 mmol) in a methylene chloride (0.4 ml)-methanol (0.1 ml) mixed solvent under a nitrogen atmosphere, and the mixture was stirred at room temperature for 3 hours. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel chromatography (Wakogel-C200,1 g) to yield the title compound (36 mg, 91% yield) as light yellow needle-like crystals from the chloroform fraction.
Reaction SMILES: Cl[C:2]1[N:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[N:9]([N:10]=[C:11]([CH3:13])[CH:12]=3)[C:4]=2[CH:3]=1.C(O)(=[O:19])C>[Cl-].[Zn+2].[Cl-]>[OH:19][C:2]1[N:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[N:9]([N:10]=[C:11]([CH3:13])[CH:12]=3)[C:4]=2[CH:3]=1
Reactant: CC(=O)O
Reactant: Cc1cc2[nH]c(=O)c3cnc(Cl)cc3n2n1
Agent: [Cl-]
Agent: [Zn+2]
Product: Cc1cc2[nH]c(=O)c3cnc(O)cc3n2n1
Temperature: 25 °C

Procedure:
2.3 g. of 8-chloro-2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-5(4H)-one of Example 1b are refluxed with 1 g. of zinc chloride in 20 ml. of acetic acid for 100 hours. The mixture is cooled to room temperature, diluted with 10 ml. of water and the precipitated 8-hydroxy-2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidin5(4H)-one is filtered off, yield: 1.7 g. (81%); m.p. > 300° (DMF).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[O:27]=[C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:38][CH2:39][C:40]([NH:42][NH2:43])=[O:41])[CH:34]=2)[NH:29]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:43][NH:42][C:40](=[O:41])[CH2:39][O:38][C:33]2[CH:34]=[C:35]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28](=[O:27])[CH:37]=[CH:36]3)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: NNC(=O)COc1ccc2[nH]c(=O)ccc2c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(COc1ccc2[nH]c(=O)ccc2c1)NNC(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
To a stirred solution of 2-(3,4-dichlorophenyl)acetic acid (0.440 g, 2.144 mmol) in DMF (15 mL), EDC (0.616 g, 3.22 mmol) and HOBT (0.328 g, 2.144 mmol) were added. The reaction mixture was stirred at room temperature for 10 min. To this suspension was added 2-((2-oxo-1,2-dihydroquinolin-6-yl)oxy)acetohydrazide (0.5 g, 2.144 mmol) and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated and ice cold water was added and stirred for 10 min. The solid which separated was filtered, washed with water, and dried to afford crude 2-(3,4-dichlorophenyl)-N′-(2-((2-oxo-1,2-dihydroquinolin-6-yl)oxy)acetyl)acetohydrazide as a brown solid (0.7 g, 78%). LCMS: RT 1.581 min. LCMS (ES-API), m/z 420.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].C(C1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C2[O:28][C:27]3C(=CC(C(C)(C)C)=CC=3P(C3C=CC=CC=3)C3C=CC=CC=3)C(C)(C)C=2C=1)(C)(C)C>>[OH:28][CH2:27][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:13]
Reactant: CC(C)(C)c1cc(P(c2ccccc2)c2ccccc2)c2c(c1)C(C)(C)c1cc(C(C)(C)C)cc(P(c3ccccc3)c3ccccc3)c1O2
Reactant: C=CCCCCCCCC(=O)OC
Product: COC(=O)CCCCCCCCCCO
Temperature: 85 °C
Reaction time: 16 h

Procedure:
A hydroformylation reaction was carried out in a Parr reactor (300 mL capacity) equipped with a mechanical stirrer, gas inlet tube, heating jacket, pressure transducer and thermocouple. The reactor was charged with methyl-9-decenoate (100 g, 0.54 mol), acetylacetonate(dicarbonyl)-rhodium (II) [Rh(CO)2acac] (32 mg, 0.12 mmol), and 2,7-di-tert-butyl-9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (342 mg, 0.49 mmol) under nitrogen, and then the reactor was sealed. The reactor was connected to a feed line for delivering synthesis gas (CO/H2, 1:1). The system was flushed with synthesis gas twice and then pressurized to 450 psi (3,103 kPa). The reactor was heated to 85° C. for 16 h while maintaining 450 psi (3,103 kPa) of syn gas pressure. After 16 h, the temperature was raised to 100° C. and heated for an additional 4 h. The reactor was cooled to ambient temperature and the unreacted gas was vented. After flushing the reactor with nitrogen to remove the last traces of syn gas, dioxane (50 ml) and 1 g of 5% Pt/SiO2 were introduced to the reactor. The system was flushed with hydrogen twice and pressurized to 500 psi (3,448 kPa) with hydrogen. The mixture was then heated to 150° C. for 20 h maintaining 500 psi (3,448 kPa) of hydrogen pressure. After cooling, the contents were filtered to remove the solid catalyst, and the solvent was removed by rotary evaporation. The resulting liquid was subjected to distillation under reduced pressure. The fraction boiling at 140-150° C. (1.5 mm pressure) was collected and dissolved in 1200 mL of hexanes. The solution was then allowed to crystallize in a freezer for 18 h. White crystals were collected by cold filtration and washed once with cold hexanes. Drying under reduced pressure yielded methyl 11-hydroxyundecanoate as white solid (77 g; 65% overall yield). Conversion of methyl 11-hydroxyundecanoate via transesterification with a polyol, such as glycerol, to the corresponding polyester polyol, such as the triglyceride of 11-hydroxyundecanoic acid, can be effected by transesterification methods known in the art.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([N:9]2[CH2:30][CH2:29][C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH:17][C:18]4[CH:26]=[C:25]5[C:21]([C:22]([CH3:28])([CH3:27])[CH2:23][NH:24]5)=[CH:20][CH:19]=4)[C:11]=3[CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:31]N(C=O)C.C([O-])([O-])=O.[K+].[K+].CI>CCOC(C)=O>[Cl:2][C:3]1[C:4]([N:9]2[CH2:30][CH2:29][C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH:17][C:18]4[CH:26]=[C:25]5[C:21]([C:22]([CH3:27])([CH3:28])[CH2:23][N:24]5[CH3:31])=[CH:20][CH:19]=4)[C:11]=3[CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC1(C)CNc2cc(Nc3ncnc4c3CN(c3ncccc3Cl)CC4)ccc21
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1CC(C)(C)c2ccc(Nc3ncnc4c3CN(c3ncccc3Cl)CC4)cc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred mixture of [6-(3-chloro-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-amine HCl salt (10 mg), DMF (5 mL), and K2CO3 (50 mg) was added MeI (50 μL). The reaction-mixture was stirred at rt for 5 h, and then diluted with EtOAc (50 mL). The organic phase was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by column to give an off-white solid (7 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:11]2[N:12]([S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[CH:13]=[C:14]([CH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][CH3:19])[N:15]=2)[OH:10])=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[CH:31][C:32]([Sn](C)(C)C)=[N:33][CH:34]=1>COCCOC.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:20][C:17]([CH3:21])([CH2:18][CH3:19])[CH2:16][C:14]1[N:15]=[C:11]([CH:9]([OH:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:34][N:33]=3)=[CH:3][CH:4]=2)[N:12]([S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[CH:13]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(O)Cc2ccc(Br)cc2)n1
Reactant: C[Sn](C)(C)c1ccc(F)cn1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(O)Cc2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
Palladium tetrakis(triphenylphosphine) (16 mg, 0.01 mmol) was added to a degassed, ambient temperature solution of 2-[2-(4-bromophenyl)-1-hydroxyethyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (65 mg, 0.14 mmol) and 5-fluoro-2-(trimethylstannyl)pyridine (solution from the previous step containing 1.7 mmol) in 1,2-dimethoxyethane (10 mL). After stirring at 95° C. for 8 h, the reaction mixture was diluted with ethyl acetate and washed with water, dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-80% ethyl acetate/hexane afforded 4-(2,2-dimethylbutyl)-2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-hydroxyethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>>[CH2:24]([NH:26][C:27]([NH:21][C:20]1[CH:22]=[CH:23][C:17]([C:5]2[C:6]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]4[NH:14][CH:15]=[CH:16][C:9]=34)=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=2)=[CH:18][CH:19]=1)=[O:28])[CH3:25]
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Reactant: CCN=C=O
Product: CCNC(=O)Nc1ccc(-c2nn(CC)cc2-c2ccnc3[nH]ccc23)cc1

Procedure:
Following the procedure described in Example 1 with 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and ethyl isocyanate provided the title compound. ESMS [M+H]+: 375.2