Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(I)I.[C:4](=O)([O-])[O-].[K+].[K+].[C:10]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:28]=[C:27]3[C:22]([C:23]([OH:35])=[C:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:25]([SH:29])=[N:26]3)=[CH:21][C:20]=2[Cl:36])[CH2:15][CH2:14]1)(=[O:12])[CH3:11]>CN(C)C=O>[C:10]([N:13]1[CH2:14][CH2:15][N:16]([C:19]2[CH:28]=[C:27]3[C:22]([C:23](=[O:35])[C:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:25]4[S:29][CH2:4][N:26]43)=[CH:21][C:20]=2[Cl:36])[CH2:17][CH2:18]1)(=[O:12])[CH3:11]
Reactant: CCOC(=O)c1c(S)nc2cc(N3CCN(C(C)=O)CC3)c(Cl)cc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ICI
Product: CCOC(=O)c1c2n(c3cc(N4CCN(C(C)=O)CC4)c(Cl)cc3c1=O)CS2
Yield: 80.6 %

Procedure:
Into 50 ml of N,N-dimethylformamide were placed 2.35 g of methylene iodide and 2.5 g of potassium carbonate and a solution of 3.0 g of ethyl 7-(4-acetyl-1-piperazinyl)-6-chloro-4-hydroxy-2-mercaptoquinoline-3-carboxylate in 30 ml of N,N-dimethylformamide was gradually dropped in with stirring. After that, the mixture was stirred at room temperature for 1 hour, concentrated in vacuo, water was added to the residue, and insoluble crystals were collected by filtration. They were washed with water, dried, and recrystallized from a mixed solvent of ethanol and chloroform to give 2.49 g of colorless powdery crystals, m.p. 266°-268° C. (decompn).
Reaction SMILES: [OH:1][C@H:2]([C@@H:31]([NH:39][C:40](=[O:63])[C@@H:41]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([C:58]([OH:61])([CH3:60])[CH3:59])[N:53]=2)[C:47]1=[O:62])[C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:3][C@H:4]([NH:18][C:19]([C@@H:21]([NH:26][C:27](=[O:30])[O:28][CH3:29])[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1.C(N(CC)[P:67]([O:76][CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[O:68][CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)C.N1C=NN=N1.ClC1C=CC=C(C(OO)=[O:99])C=1>O1CCCC1.C(OCC)(=O)C.ClCCl>[P:67]([O:1][C@H:2]([C@@H:31]([NH:39][C:40](=[O:63])[C@@H:41]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([C:58]([OH:61])([CH3:60])[CH3:59])[N:53]=2)[C:47]1=[O:62])[C:42]([CH3:43])([CH3:44])[CH3:45])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:3][C@H:4]([NH:18][C:19](=[O:20])[C@H:21]([C:22]([CH3:25])([CH3:24])[CH3:23])[NH:26][C:27]([O:28][CH3:29])=[O:30])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:10][CH:11]=1)([O:68][CH2:69][C:70]1[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=1)([O:76][CH2:77][C:78]1[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=1)=[O:99]
Reactant: CCN(CC)P(OCc1ccccc1)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C(C)(C)O)n2)C1=O)C(C)(C)C)C(C)(C)C
Agent: c1nnn[nH]1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](OP(=O)(OCc1ccccc1)OCc1ccccc1)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C(C)(C)O)n2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
A solution of the compound of Example 50 (0.100 g, 0.116 mmol), dibenzyl diethylphosphoramidite (0.080 mL, 267 mmol), and 1H-tetrazole (0.040 g, 0.571 mmol) in tetrahydrofuran (1.0 mL) was stirred at room temperature for 12 hours. Dichloromethane (1.0 mL) was added and the mixture was cooled to −45° C., followed by addition of m-chloroperbenzoic acid (0.072 g, 0.417 mmol). After stirring for 30 minutes at −45° C., the reaction was diluted with ethyl acetate and washed twice with 10% Na2CO3 and then with brine. The organic phase was dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient starting with dichloromethane and ending with ethyl acetate, to give the title compound (0.104 g, 80% yield).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>>[ClH:12].[C:1]([Cl:12])(=[O:9])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccncc1
Product: Cl
Product: O=C(Cl)c1ccncc1

Procedure:
A solution of isonicotinic acid (0.10 g, 0.8 mmol) and thionyl chloride (1 mL) were heated to reflux for 2 h and concentrated. The product obtained was used immediately in the following step.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]1)=[CH2:2].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:13][S:14]([O:12][CH2:11][CH:8]1[CH2:9][CH2:10][CH:5]([CH2:4][O:3][CH:1]=[CH2:2])[CH2:6][CH2:7]1)(=[O:16])=[O:15]
Reactant: C=COCC1CCC(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=COCC1CCC(COS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
4-[(Vinyloxy)methyl]cyclohexylmethanol (2.0 g, 0.010 mol) was dissolved in chloroform (20 mL), cooled to 0° C., and then methanesulfonyl chloride (0.85 mL, 0.011 mol) and triethylamine (1.5 mL, 0.011 mol) were added. The reaction was stirred at 0° C. for 2 hours. The reaction was extracted with ethyl acetate, and the extracts were washed with water, brine, and then dried over MgSO4 and concentrated. The product was purified via column chromatography on silica gel (40% ethyl acetate, 60% hexanes), to give 1.53 g of the desired product as a 3:1 mixture of the two diastereomers. 1H NMR (400 MHz, CDCl3): δ 6.36-6.41 (m, 1H), 4.04-4.10 (m, 2H), 3.94-3.96 (m, 2H), 3.39-3.43 (m, 2H), 2.92 (s, 3H), 0.90-1.80 (m, 10H) (major diastereomer).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][CH:11]=2)[C:7]([NH:18][C:19]([C:21]2[NH:22][C:23]([C:26]#[N:27])=[CH:24][N:25]=2)=[O:20])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH2:28][CH2:29][CH2:30]O>>[CH3:16][C:13]1([CH3:17])[CH2:14][CH2:15][C:10]([C:8]2[C:7]([NH:18][C:19]([C:21]3[NH:25][CH:24]=[C:23]([C:26]#[N:27])[N:22]=3)=[O:20])=[CH:6][CH:5]=[C:4]([C:1]3([CH3:2])[NH:28][CH2:29][CH2:30][O:3]3)[N:9]=2)=[CH:11][CH2:12]1
Reactant: CC(=O)c1ccc(NC(=O)c2ncc(C#N)[nH]2)c(C2=CCC(C)(C)CC2)n1
Reactant: NCCO
Product: CC1(C)CC=C(c2nc(C3(C)NCCO3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1

Procedure:
The title compound is prepared from 5-cyano-1H-imidazole-2-carboxylic acid [6-acetyl-2-(4,4-dimethyl-cyclohex-1-enyl)-pyridin-3-yl]-amide (as prepared in the previous step) and 2-aminoethanol according to the procedure in Example 1, step (h).
Reaction SMILES: [CH:1]([C:3]([CH3:5])=[O:4])=[CH2:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14][C:15](=[O:20])[C:16]([NH2:19])([CH3:18])[CH3:17]>O1CCCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14][C:15](=[O:20])[C:16]([NH:19][CH2:2][CH2:1][C:3](=[O:4])[CH3:5])([CH3:17])[CH3:18]
Reactant: CC(C)(N)C(=O)Nc1cc(Cl)ccc1Cl
Reactant: C=CC(C)=O
Solvent: C1CCOC1
Product: CC(=O)CCNC(C)(C)C(=O)Nc1cc(Cl)ccc1Cl
Yield: 97.4 %

Procedure:
Methyl vinyl ketone (1.02 g) was added to a solution of N-(2,5-dichlorophenyl)-2-aminoisobutyramide (2.4 g) in tetrahydrofuran (10 mL) and the mixture was heated at reflux for 30 hours. After distilling off the solvent under reduced pressure, 3 g of N-(2,5-dichlorophenyl)-2-(3-oxobutylamino)isobutyramide was obtained.
Reaction SMILES: CS([Cl:5])(=O)=O.O[CH2:7][C:8]1([CH:21]([OH:24])[CH2:22][OH:23])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.C(N(CC)CC)C.O>ClCCl>[ClH:5].[OH:24][CH:21]1[C:8]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:7][O:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(C(O)CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cl
Product: OC1COCC12CCNCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.2 %

Procedure:
Methanesulfonyl chloride (173 μL, 2.2 mmol) in dichloromethane (100 mL) was added dropwise to a solution of (RS)-1,1-dimethylethyl 4-hydroxymethyl-4-(1,2-dihydroxyethyl)-1-piperidinecarboxylate (Description 98, 615 mg, 2.2 mmol) and triethylamine (933 μL, 6.6 mmol) in dichloromethane (150 mL) and the mixture was stirred at room temperature for 16 hours. Water (100 mL) was added and the layers were separated. The aqueous fraction was extracted with dichloromethane (2×100 mL), the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (50:50) and the residue was suspended in diethyl ether (50 mL) and treated with methanolic hydrogen chloride (0.25M, 3 mL). The mixture was stirred at room temperature for 30 minutes, then the solvent was evaporated under reduced pressure to give the title compound as a solid (150 mg, 35%). m/z (ES+) 158 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[NH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][C:46](=[O:55])[N:47]([CH3:54])[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[CH:41][CH:40]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:64]>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:36][CH2:37][CH2:38][C:39]3[CH:40]=[CH:41][C:42]([O:45][C:46](=[O:55])[N:47]([CH3:54])[C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)=[CH:43][CH:44]=3)=[O:15])=[CH:16][CH:17]=2)[CH2:6][CH2:7]1.[ClH:64]
Reactant: CN(C(=O)Oc1ccc(CCN)cc1)c1ccccc1
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Reactant: ClCCl
Agent: CCN=C=NCCCN(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2ccc(C(=O)NCCc3ccc(OC(=O)N(C)c4ccccc4)cc3)cc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-(4-methylpiperazinyl)methyl benzoic acid (0.3 mmol), EDAC (0.36 mmol) and triethylamine (1.0 mmol) in CH2Cl2 (10 mL) was added N-hydroxybenzoetriazole and N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.3 mmol). The mixture was stirred 16 h at rt and purified by preparative HPLC (Gilson) to give the title compound in 25% yield as its crystalline hydrochloride after treatment with HCl in diethyl ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8](CO)[CH2:9][C:10]#[N:11].C1(C)C=CC=CC=1.[C:21]1([C:27](Cl)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH2:41]>CO.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:41][C:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:9][C:10]#[N:11]
Reactant: O
Reactant: N#CC[C@@H](CO)c1ccccc1F
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: Cc1ccccc1
Product: N#CC[C@@H](OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1F
Temperature: 21 °C
Reaction time: 0.17 h

Procedure:
A mixture of 64.5 g of 2-fluoro-β(R)-(hydroxymethyl)benzenepropionitrile, 450 mL of toluene, and 106.2 g of triphenylmethyl chloride is stirred at 20-22° C. for 10 minutes to afford a brown solution; 54 g of triethylanine is added rapidly over a period of 10 minutes while maintaining an internal temperature of <30° C. The reaction mixture is stirred at an internal temperature of 35° C., (external temperature: 41° C.) for 24 hours to obtain a light, brown suspension. The tritylation reaction is catalyzed by water. The reaction progress is monitored by HPLC to determine if water addition is required. If after 4 hours, more than about 30% of starting material is left, 1 g of water is added. If after 20 hours, the amount of starting material is still more than 15%, an additional 1 g of water is added. After 24 hours, an additional 17 g of triphenylmethyl chloride and 7 g of triethylamine are added, the resulting suspension is stirred for an additional 24 hours at 35° C. and cooled to room temperature; 58 mL of methanol is added dropwise over 10 minutes, while maintaining an internal temperature of 30-35° C. The reaction mixture is stirred for 40 minutes at an internal temperature of 20-25° C. The mixture is concentrated under reduced pressure (20-50 mbar; bath temperature 45-50° C.) to obtain crude 2-fluoro-β(R)-[(triphenylmethyl)oxy]benzenepropionitrile as a red semi-solid. The semi-solid is suspended in 800 mL of methanol. The slurry is stirred at an internal temperature of 50° C. for 40 minutes, then at 20-22° C. for 30 minutes, and filtered to obtain, after washing the product with methanol and drying it under vacuum (30 mbar) at 45-50° C. for 4 hours or to constant weight, 2-fluoro-β(R)-[(triphenylmethyl)oxy]benzenepropionitrile; chiral purity:>99% ee.
Reaction SMILES: [CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5](Cl)=[O:6])[CH2:2][CH3:3].[Si:11]([O:18][C@H:19]1[CH2:28][C@H:27]([OH:29])[C@H:26]2[C:21]([CH:22]=[CH:23][C@H:24]([CH3:47])[C@@H:25]2[CH2:30][CH2:31][C@H:32]2[O:37][C:36](=[O:38])[CH2:35][C@H:34]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:33]2)=[CH:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>N1C=CC=CC=1.C(OCC)(=O)C.N1(C2C=CN=CC=2)CCCC1>[Si:11]([O:18][C@H:19]1[CH2:28][C@H:27]([O:29][C:5](=[O:6])[CH:4]([CH2:8][CH2:9][CH3:10])[CH2:1][CH2:2][CH3:3])[C@H:26]2[C:21]([CH:22]=[CH:23][C@H:24]([CH3:47])[C@@H:25]2[CH2:30][CH2:31][C@H:32]2[O:37][C:36](=[O:38])[CH2:35][C@H:34]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])[CH2:33]2)=[CH:20]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:13])[CH3:12]
Reactant: CCCC(CCC)C(=O)Cl
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Agent: c1cc(N2CCCC2)ccn1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCC(CCC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Temperature: 70 °C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
15 mg (0.1 mmol) of 4-(1-pyrrolidinyl)pyridine and 592 mg (3.6 mmol) of 2-propylvaleryl chloride were added to a solution of 1.0 g (1.8 mmol) of (4R,6R)-6-{2[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}-tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] in 5 ml of dry pyridine, whilst ice-cooling, and the resulting mixture was stirred at 70° C. for 3 hours. At the end of this time, the reaction mixture was diluted with 100 ml of ethyl acetate, and the diluted mixture was then washed with 100 ml of water, 100 ml of a 10% w/v aqueous solution of hydrogen chloride, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, in that order. The organic layer was then dried over anhydrous magnesium sulfate, after which this layer was removed by filtration. The resulting filtrate was concentrated by evaporation under reduced pressure and the residue obtained was purified by flash column chromatography through silica gel, using a 5:1 by volume mixture hexane and ethyl acetate as the eluent, to give 1.15 g (93% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[CH:27][O:28][CH3:29])[C:24]([O-:26])=[O:25].O.[CH3:31]N(C)C=O>>[CH2:1]([O:8][N:9]=[C:10]([O:12][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[CH:27][O:28][CH3:29])[C:24]([O:26][CH3:31])=[O:25])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC=C(C(=O)[O-])c1ccccc1CBr
Reactant: CC(=O)NOCc1ccccc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC=C(C(=O)OC)c1ccccc1COC(C)=NOCc1ccccc1
Reaction time: 0.17 h
Yield: 9.2 %

Procedure:
A solution of N-benzyloxyacetamide (1.65 g, 10 mmol) in 10 ml of dimethylformamide was cooled down in an ice bath, 60% sodium hydride (0.4 g, 10 mmol) was added thereto, and stirred for 10 minutes. After adding dropwise 20 ml of dimethylformamide solution of 2-bromomethylphenyl-3-methoxypropenoate (2.85 g, 10 mmol), the solution was allowed to react for 15 hours at room temperature. After completion of the reaction, the reaction solution was poured into 200 ml of water, and extracted with ethylacetate. The organic layer was rinsed with water and dried. After removing the solvent by evaporation, the residue was purified with silica gel chromatography to obtain 0.34 g of methyl 2-[2-(1-benzyloxyiminoethyl) oxymethylphenyl]-3-methoxypropenoate (yield: 9.2%). The proton NMR spectrum is 1.79 s (3H); 3.67 s (3H); 3.77 s (3H); 5.01 s (2H); 5.04 s (2H); 7.10-7.50 m (9H); 7.57 s (1H) (solvent: CDCl3).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([P:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)([O:3][CH3:4])=[O:2].[C:28]1([CH3:39])[CH:33]=[CH:32][C:31]([S:34]([O:37]C)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[C:28]1([CH3:39])[CH:29]=[CH:30][C:31]([S:34]([O-:37])(=[O:35])=[O:36])=[CH:32][CH:33]=1.[CH3:28][P+:15]([C:7]1[CH:6]=[C:5]([C:1]([O:3][CH3:4])=[O:2])[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc(C(=O)OC)cc(P(c2ccccc2)c2ccccc2)c1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: COC(=O)c1cc(C(=O)OC)cc([P+](C)(c2ccccc2)c2ccccc2)c1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 130 °C

Procedure:
A mixture of 9.46 g (2.5×10-2 mol) of 3,5-dicarbomethoxyphenyldiphenylphosphine (from Preparation 4), and 4.66 g (2.5×10-2 mol) of methyl p-toluenesulfonate was heated in a 130° C. bath with nitrogen bubbling through the melt for two hours. The resultant product was cooled to an amorphous glass.
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:8]1[CH:12]=[C:11]([C:13]2[C:18]([O:19][CH3:20])=[CH:17][N:16]=[C:15]([NH:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([OH:27])=O)[N:14]=2)[CH:10]=[N:9]1)[CH:5]1[CH2:7][CH2:6]1)#[N:2].[O:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[C:1]([CH2:3][CH:4]([N:8]1[CH:12]=[C:11]([C:13]2[C:18]([O:19][CH3:20])=[CH:17][N:16]=[C:15]([NH:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([NH:37][CH:34]3[CH2:35][CH2:36][O:31][CH2:32][CH2:33]3)=[O:27])[N:14]=2)[CH:10]=[N:9]1)[CH:5]1[CH2:7][CH2:6]1)#[N:2]
Reactant: NC1CCOCC1
Reactant: COc1cnc(Nc2cccc(C(=O)O)c2)nc1-c1cnn(C(CC#N)C2CC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(Nc2cccc(C(=O)NC3CCOCC3)c2)nc1-c1cnn(C(CC#N)C2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-({4-[1-(2-cyano-1-cyclopropylethyl)-1H-pyrazol-4-yl]-5-methoxypyrimidin-2-yl}amino)benzoic acid (30 mg, 0.00007 mol), tetrahydro-2H-pyran-4-amine (7.5 mg, 0.000074 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (39 mg, 0.000089 mol) in N,N-dimethylformamide (0.5 mL, 0.006 mol) was added N,N-diisopropylethylamine (31 μL, 0.00018 mol). The reaction was stirred at room temperature for 1 h, quenched with water, purified on HPLC to give the desired product as a diastereomeric mixture (free base). LCMS (M+H) 488.2.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C[O-].[Na+].[C:27](OC(=O)C)(=[O:29])C.O>CO.C(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:29][CH3:27])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N1CCN(c2ccc(OCCCCCCBr)cc2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COCCCCCCOc1ccc(N2CCN(C(C)=O)CC2)cc1
Reaction time: 6 h

Procedure:
A solution of crude 1-acetyl-4-[4-(6-bromohexyloxy)phenyl]piperazine (10.52 g) in methanol (105 ml) was treated with 28% sodium methoxide in methanol (105 ml), and the solution was refluxed for 7 hours. After cooling, the precipitate was removed by filtration. The filtrate was added to a mixture of methylene chloride and water. The organic layer was taken, dried over magnesium sulfate, filtered and evaporated to give a crude oil. This oil in methylene chloride (20 ml) was treated with acetic anhydride (6.4 ml) under ice-cooling. After 6 hours, the solution was added to a mixture of methylene chloride and water. The organic layer was taken, dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with a mixed solvent of methylene chloride-methanol (from 0% to 3% gradient elution) to give 1-acetyl-4-[4-(6-methoxyhexyloxy)phenyl]piperazine (5.38 g) as a pale red solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([Br:9])[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[C:17]([CH3:24])([CH3:23])[C:18](OCC)=[O:19]>CC(C)=O>[Br:9][C:4]1[CH:5]=[CH:6][C:7]2[O:8][C:17]([CH3:24])([CH3:23])[C:18](=[O:19])[NH:1][C:2]=2[N:3]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1nc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)Oc2ccc(Br)nc2NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a suspension of 2-amino-6-bromopyridin-3-ol (250 mg, 1.32 mmol) and K2CO3 in acetone (5 mL) was added ethyl 2-bromoisobutyrate (0.29 ml, 1.98 mmol) and the reaction was stirred for 1 hour at room temperature and overnight at reflux. The acetone was removed, and to the residue was added dichloromethane and water. The layers were separated and the aqueous was extracted with dichloromethane (1x). The organic layer was dried (MgSO4), filtered, and concentrated to afford 6-bromo-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one 7.27 (300 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C9H10BrN2O2: 257.0; found: 257.1.
Reaction SMILES: [N:1]([C:3]1[C:4]([O:11][CH2:12][CH3:13])=[N:5][C:6]([NH2:10])=[N:7][C:8]=1[NH2:9])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:10][C:6]1[N:5]=[C:4]([O:11][CH2:12][CH3:13])[C:3]([NH2:1])=[C:8]([NH2:9])[N:7]=1
Reactant: CCOc1nc(N)nc(N)c1N=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOc1nc(N)nc(N)c1N
Temperature: 60 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
To a suspension of the compound of example 3 (7.12 g, 38.9 mmoles) in water (150 ml) at 60° C. was added sodium dithionite (46.7 mmol, 8.12 g). Additional sodium dithionite was added till the pink colour completely dis-appeared and a yellow solution was formed. The solution was stirred at 60° C. for another 4 hours. Water was evaporated and the resulting residue was precipitated from a small amount of water, providing the title compound as a yellow powder (4.02 g, yield 61%). Spectral data are identical with literature data (W. Pfleiderer et al. cited supra).
Reaction SMILES: [ClH:1].[NH:2]=[C:3]1[N:7]([CH2:8][CH:9](OC(=O)C)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][S:4]1.P(Cl)(Cl)(Cl)(Cl)[Cl:21]>C(Cl)(Cl)Cl>[ClH:21].[NH:2]=[C:3]1[N:7]([CH2:8][CH:9]([Cl:1])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][S:4]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)OC(CN1CCSC1=N)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: N=C1SCCN1CC(Cl)c1ccccc1

Procedure:
The 2-imino-3-(2'-acetoxy-2'-phenylethyl)thiazolidine hydrochloride (0.01 mole) was heated under reflux with phosphorus pentachloride for one hour in chloroform (5 ml). The solvent was evaporated to leave a colourless solid which was crystallised from ethanol, yield 1.9 g. This compound was used in the synthesis of the compound of Example 75 as described for the corresponding 2-imino derivative in Example 75 Method A.