Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[O-].[Na+].Cl.[C:6]([NH2:10])(=[NH:9])[CH2:7][CH3:8].[CH2:11]([O:13][C:14](=[O:25])[C:15](=[CH:21]OCC)[C:16](OCC)=[O:17])[CH3:12].Cl>>[CH2:11]([O:13][C:14]([C:15]1[C:16](=[O:17])[NH:10][C:6]([CH2:7][CH3:8])=[N:9][CH:21]=1)=[O:25])[CH3:12]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)c1cnc(CC)[nH]c1=O
Temperature: 0 °C
Yield: 86.6 %

Procedure:
To a cold (0° C.) solution of NaOEt (0.2 mol) in absolute alcohol (150 mL) was added propionamidine hydrochloride (10.9 g, 0.1 mol) in one portion. A solution of 2-ethoxymethylene-malonic acid diethyl ester (21.6 g, 0.1 mol) in absolute alcohol (60 mL) was added dropwise to the above mixture during 20 minutes. After the addition was completed, the whole mixture was heated to reflux for 2.5 hours, then cooled and poured to ice water. The aqueous solution was acidified to pH 5 with HCl (6 M), extracted with ethyl acetate (4 100 mL). The organic layer was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was re-crystallized with acetonitrile to afford 2-ethyl-6-oxo-1,6-dihydro-pyrimidine-5-carboxylic acid ethyl ester as white crystals (17 g, 86%). 1H NMR(CDCl3) δ 8.71 (s, 1H), 4.37-4.32 (q, 2H), 2.84-2.78 (q, 2H), 1.38-1.34 (m, 6H). MS (ESI) m/e (M+1)+197.2.
Reaction SMILES: [C:1]([O:6][CH:7]([O:11][C:12]([CH3:14])=[S:13])[CH:8]([CH3:10])[CH3:9])(=[O:5])[CH2:2][CH2:3][CH3:4].P([O-])([O-])([O-])=O>C(OC(C)C)(C)C.CCOCC>[C:1]([O:6][C@H:7]([O:11][C:12]([CH3:14])=[S:13])[CH:8]([CH3:10])[CH3:9])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OC(OC(C)=S)C(C)C
Agent: O=P([O-])([O-])[O-]
Solvent: CCOCC
Solvent: CC(C)OC(C)C
Product: CCCC(=O)O[C@H](OC(C)=S)C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 32 %

Procedure:
To a solution of 2-methyl-1-methylthiocarbonyloxypropyl butanoate (2d) (0.5 g) in 2 mL of diisopropyl ether, 0.025 g of lipase from Candida rugosa was added, followed by 10 mL of phosphate buffer. The mixture was stirred at room temperature for ca. 24 hrs. The reaction mixture was diluted with ether and the organic solution filtered through a pad of CELITE® 545. The ether solution was washed with water (2 times) and brine, and dried over anhydrous sodium sulfate (Na2SO4). The solvent was evaporated under reduced pressure to provide 0.16 g (64% yield) of the title compound (7). 1H-NMR using a chiral solvating agent showed a single isomer and the absolute configuration was confirmed by derivatization to a compound having a known stereochemistry.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)=[O:4].[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=O>>[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=[C:10]1[CH2:9][CH2:8][C:7]2[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:14]=[CH:13][C:12]=2[C:11]1=[O:15]
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Reactant: O=Cc1ccco1
Product: COC(=O)c1ccc2c(c1)CCC(=Cc1ccco1)C2=O
Yield: 80 %

Procedure:
The title compound was prepared from 5-oxo-5,6,7,8-tetrahydronaphtalene-2-carboxylic acid methyl ester (396 mg, 1.9 mmol) and 2-furaldehyde (192 mg, 2.0 mmol) according to Method A3 in 80% yield. ES-MS m/z 283 (M+H).
Reaction SMILES: [OH:1]O.[N+:3]1([O-:17])[C:8]2[CH:9]=[C:10]3[CH2:15][CH2:14][O:13][C:11]3=[CH:12][C:7]=2[N:6]=[C:5]([NH2:16])[N:4]=1>CC(O)=O>[N+:3]1([O-:17])[C:8]2[CH:9]=[C:10]3[CH2:15][CH2:14][O:13][C:11]3=[CH:12][C:7]=2[N+:6]([O-:1])=[C:5]([NH2:16])[N:4]=1
Reactant: OO
Reactant: Nc1nc2cc3c(cc2[n+]([O-])n1)CCO3
Solvent: CC(=O)O
Product: Nc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])OCC3
Temperature: 50 °C
Reaction time: 24 h
Yield: 36.9 %

Procedure:
H2O2 (70%, 1.2 mL, ca. 24.5 mmol) was added dropwise to a stirred solution of 1-oxide 204 (500 mg, 2.45 mmol) in HOAc (10 mL) and the solution stirred at 50° C. for 24 h. The solution was cooled to 0° C. and the precipitate filtered. The solid was recrystallised from DMF to give 1,4-dioxide 205 (199 mg, 37%) as a red solid: mp>300° C. (235-240° C. dec.); 1H NMR [(CD3)2SO] δ 8.06 (t, J=1.6 Hz, 1H, H-9), 7.86 (br s, 2H, NH2), 7.23 (s, 1H, H-5), 4.77 (t, J=8.3 Hz, 2H, H-8), 3.30-3.60 (m, 2H, H-7); HRMS calcd for C9H8N4O3 (M+) m/z 220.0596, found 220.0601.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13](Cl)[N:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([N:4]([CH2:5][CH3:6])[CH2:1][CH3:2])[N:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CC)c1ccc([N+](=O)[O-])c(N2CCN(C(C)=O)CC2)n1
Reaction time: 1.25 h
Yield: 136.1 %

Procedure:
A solution of 51.22 g of N-acetylpiperazine in 200 ml of acetonitrile was added over 50 minutes at 0° C. to a mixture of 78 g of 2,6-dichloro-3-nitropyridine, 600 ml of acetonitrile and 66.3 g of potassium carbonate. The mixture was allowed to return to room temperature and was stirred for 75 minutes. The inorganic salts were filtered off and after 180 ml of N,N-diethylamine and 76 g of potassium carbonate were added to the filtrate, the mixture was refluxed for 75 minutes. The inorganic salts were filtered off after cooling and the filtrate was evaporated to dryness under reduced pressure. The 166.9 g of residue were crystallized from 200 ml of ethyl acetate to obtain 87.4 g of the expected product melting at 120° C.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[NH2:15][C:16]1[C:17](=O)[NH:18][C:19](=[O:26])[N:20]([CH2:23][CH2:24][CH3:25])[C:21]=1[NH2:22]>N1C=CC=CC=1>[NH2:15][C:16]1[C:17]([SH:2])=[N:18][C:19](=[O:26])[N:20]([CH2:23][CH2:24][CH3:25])[C:21]=1[NH2:22]
Reactant: CCCn1c(N)c(N)c(=O)[nH]c1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CCCn1c(N)c(N)c(S)nc1=O
Temperature: 100 °C
Yield: 69.4 %

Procedure:
Phosphorus pentasulfide (27.1 g, 122 mmol, 1.5 equivalents) was suspended in pyridine (150 mL) and the mixture was heated to 100° C. To the suspension was gradually added 5,6-diamino-1-propyluracil (15.0 g, 81.3 mmol), which was obtained by the method described in Journal of Medicinal Chemistry (J. Med. Chem.), 32 (6), p. 1231, 1989, with heating and stirring, and then the mixture was stirred for 7 hours. After the reaction solution was cooled on ice, the deposited solid was separated by filtration using a filtration aid and washed with pyridine. The filtrate was concentrated, to the residue was added water (90 mL), and the mixture was stirred under reflux with heating for about 40 minutes until intense foaming ceased. The reaction mixture was cooled on ice and then further stirred overnight at room temperature. The deposited yellowish green ocher solid was collected by filtration, sufficiently washed with water and dried under reduced pressure to obtain 5,6-diamino-1,2-dihydro-4-mercapto-2-oxo-1-propylpyrimidine (Compound B4, 11.3 g, 69%). Compound B4 (10.0 g, 50.0 mmol) was suspended in 1,4-dioxane (200 mL) and water (100 mL), to the suspension were added cyclohexanecarboxylic acid (8.06 mL, 65.0 mmol, 1.3 equivalents) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (16.3 g, 85.0 mmol, 1.7 equivalents) at room temperature, and then the mixture was stirred overnight. To the reaction mixture was added 2 mol/L aqueous sodium hydroxide (100 mL), and the mixture was stirred with heating for 2.5 hours. The reaction mixture was cooled on an ice bath, adjusted to pH 6 with 4 mol/L hydrochloric acid and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in 0.5 mol/L aqueous sodium hydroxide (150 mL), and to the solution was added methyl iodide (4.70 mL, 75.0 mmol, 1.5 equivalents) and the mixture was stirred overnight at room temperature. The reaction mixture was cooled on an ice bath, adjusted to pH 6.5 with 4 mol/L aqueous hydrochloric acid and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 96:4) to obtain the title compound (11.8 g, 78%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH3:3].Cl[C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.C(Cl)(Cl)Cl>C(Cl)(Cl)Cl.CO>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)[CH3:3]
Reactant: CN(C)Cc1cccc(OCCCN)c1
Reactant: Clc1nc2ccccc2s1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C)Cc1cccc(OCCCNc2nc3ccccc3s2)c1

Procedure:
3-[3-(Dimethylaminomethyl)phenoxy]propylamine (2.38 g) and 2-chlorobenzthiazole (1.94 g) were fused at 130° C. for 2 hours. The cooled residue was subjected to column chromatography on silica using chloroform followed by chloroform:methanol (25:1) as eluants to give the title compound as a yellow oil. This was converted to 2-[3-[3-(dimethylaminomethyl)phenoxy]propylamino]benzthiazole dihydrochloride (0.37 g), m.p. 154°-155° C. (recrystallised from ethanol/ether).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[O:7]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:28]3[C:27]([NH2:29])=[N:26][CH:25]=[N:24][C:23]=3[NH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C)C=O>N1C=CC=CC=1>[C:1]([N:22]1[C:23]2[N:24]=[CH:25][N:26]=[C:27]([NH2:29])[C:28]=2[C:20]([C:17]2[CH:16]=[CH:15][C:14]([O:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:19][CH:18]=2)=[CH:21]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: CC(C)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)C(=O)n1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Temperature: 20 °C

Procedure:
Isobutyryl chloride (1.8 g) was added dropwise to a mixture of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (4.32 g), dry dimethyl-formamide (200 ml) and dry pyridine (2 ml) with stirring under nitrogen at 20° C. The mixture was stirred at ambient temperature for 1 hour and evaporated under vacuum. The residue was partitioned between water and ethyl acetate. The ethyl acetate was separated, dried and evaporated and the residue obtained was recrystallised from toluene to give 7-isobutyryl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 160.5-161° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=3)[C:13](=[O:21])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[C:11]=2[C:33](=[O:36])[CH2:34][CH3:35])=[CH:6][CH:5]=1.[CH2:38]1COCC1>ClCCl>[C:3]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=3)[C:13](=[O:21])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[C:11]=2[C:33](=[O:36])[CH2:34][CH3:35])=[CH:8][CH:9]=1)(=[O:2])[CH3:38]
Reactant: CCC(=O)c1c(-c2ccc(C(=O)OC)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Reactant: C1CCOC1
Solvent: ClCCl
Product: CCC(=O)c1c(-c2ccc(C(C)=O)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
To a solution (2.0 ml) of 4-[6-chloro-2-(4-methanesulfonylbenzyl)-1-oxo-3-propionyl-1,2-dihydroisoquinolin-4-yl]benzoic acid methyl ester (100 mg) in THF was added dropwise gently a methyl lithium diethyl ether solution (1.1 mol/l, 0.25 ml) at −50° C. with stirring, and the mixture was allowed to warm to room temperature and stirred for 18 hrs. The reaction mixture was diluted with dichloromethane, washed with 1N hydrochloric acid, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (9 mg) in beige crystals. 1H NMR (CDCl3) δ: 0.54 (3H, t, J=7.2 Hz), 1.78 (2H, q, J=7.2 Hz), 2.67 (3H, s), 3.02 (3H, s), 5.35 (2H, s), 7.19 (1H, d, J=2.1 Hz), 7.37-7.47 (4H, m), 7.54 (1H, dd, J=2.1 Hz), 7.89 (2H, d, J=8.7 Hz), 8.06 (2H, d, J=8.7 Hz), 8.47 (1H, d, J=8.7 Hz). HPLC analysis: purity 97.7% (retention time: 4.29 min). MS (ESI+): 522.0 (M+H), 524.0.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH:6]=[C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.Cl.N1C=CC=CC=1>Cl>[CH:18]1[C:9]2[CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:7](=[CH:6][C:5]3[CH:4]=[C:3]([OH:2])[CH:24]=[CH:23][CH:22]=3)[C:8]=2[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Temperature: 100 °C
Yield: 88.7 %

Procedure:
Stir a molten mixture of 5-(3-methoxy-benzylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (1.11 g, 3.55 mmol) and pyridine hydrochloride (10 g, 87 mmol) at 215° C. for 40 min. Cool the reaction mixture to 100° C., dilute with 1N HCl, and extract with ethyl acetate. Dry organics (MgSO4), filter, and concentrate to a brown oil containing the title compound. Purification via silica gel chromatography (1:6 ethyl acetate:hexanes) affords 940 mg (89%) of a tan oil. 1H NMR (CDCl3) δ 2.76-3.63 (br m, 4H), 4.59 (s, 1H), 6.45 (s, 1H), 6.64 (m, 2H), 6.75 (s, 1H), 6.99-7.52 (m, 9H); MS (ES) 299 (M+H), 297 (M−H). HPLC shows 97% purity.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].CN(C)C=O.[OH:19][C@H:20]1[CH2:24][CH2:23][NH:22][C:21]1=[O:25]>O>[Si:6]([O:19][C@H:20]1[CH2:24][CH2:23][NH:22][C:21]1=[O:25])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1NCC[C@@H]1O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCNC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
In an ice bath, 570 mg of imidazole and 947 mg of t-butyldimethylsilyl chloride were added to a dimethylformamide (5 ml) solution of 503 mg of (3S)-3-hydroxypyrrolidin-2-one, and stirred at room temperature for 1 hour. Water was added to the reaction liquid, extracted with ethyl acetate, the organic layer was washed with water and saturated saline water, and dried. The solvent was evaporated away under reduced pressure to obtain 452 mg of the entitled compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([OH:16])[CH2:13][N:12]1[C:17](=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[CH3:29]COCC>CN(C)C=O.[Ag]=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][CH3:29])[CH2:13][N:12]1[C:17](=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: O=C(Cc1ccc(F)cc1)N1CC(O)CN1C(=O)OCc1ccccc1
Agent: O=[Ag]
Solvent: CI
Solvent: CN(C)C=O
Product: COC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1
Reaction time: 8 h
Yield: 97 %

Procedure:
2-[2-(4-Fluorophenyl)acetyl]-4-hydroxy-pyrazolidine-1-carboxylic acid benzyl ester, 28, (2.55 g, 7.91 mmol) is dissolved in dimethylformamide (40 mL). Methyl iodide (1.97 mL, 31.6 mmol) is added followed by silver oxide (3.67 g, 15.8 mmol). The flask is cover with foil and stirred overnight in the absence of light. The reaction mixture is poured into ether (150 mL). The mixture is stirred vigorously at room temperature and filtered through a pad of Celite. The filtrate is washed with water (2×150 mL) and brine (150 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 2.58 g (97% yield) of the desired product as a yellow, clear oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:30])[CH3:9])=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>>[O:30]=[C:11]1[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccccc2)OC1=O
Reactant: OB(O)c1ccccn1
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)methanesulfonamide and pyridine-2-boronic acid following procedures analogous to those described in Example 75 Step 1. LC-MS Method 2 tR=1.017 min, m/z=494.1; 1H NMR (CDCl3) 1.37-1.48 (m, 1H), 1.49 (d, 3H), 1.67 (m, 1H), 1.82-1.99 (m, 2H), 2.05-2.18 (m, 1H), 2.12-2.23 (m, 2H), 2.82 (m, 4H), 3.00 (m, 2H), 4.25 (m, 1H), 5.65 (m, 1H), 6.96 (d, 2H), 7.14-7.29 (m, 6H), 7.55 (d, 1H), 7.65 (m, 3H), 8.58 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([NH:22][C:23]2[N:24]=[C:25](OS(C(F)(F)F)(=O)=O)[C:26]3[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29][C:27]=3[N:28]=2)[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1.Cl>CN(C=O)C>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([NH:22][C:23]2[N:24]=[C:25]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:26]3[CH2:32][NH:31][CH2:30][CH2:29][C:27]=3[N:28]=2)[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1
Reactant: COc1cc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C(=O)OC(C)(C)C)CC3)ccc1-n1cnc(C)c1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc3c(c(Nc4ccccc4)n2)CNCC3)ccc1-n1cnc(C)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
Aniline (0.032 g, 0.34 mmol) was added to a solution of tert-butyl 2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.2 g, 0.34 mmol, Example 7a) in DMF (2 mL). The solution was stirred at 70° C. for 1 h. HCl 2M aq (2 ml) was added and the solution heated to 76° C. for 1 h. Solvent was concentrated under reduced pressure and purified on preparative HPLC to give N2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N4-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (0.060 g, 41.0%). MS (ESI+)/(ESI−) m/z 428/426
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[C:12](=[CH:17][N:18]([CH3:20])[CH3:19])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Reaction time: 6 h

Procedure:
A mixture of 1-tert-butoxycarbonylpiperidin-4-one and N,N-dimethylformamide dimethylacetal was heated under reflux with stirring for 6 hours to yield 1-tert-butoxycarbonyl-3-[(dimethylamino)methylene]piperidin-4-one. A mixture of 1-tert-butoxycarbonyl-3-[(dimethylamino)methylene]piperidin-4-one obtained, 2-hydrazinoethanol, and MeOH was heated under reflux with stirring for 2 hours to yield a mixture of 2-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)ethanol and 2-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)ethanol. A mixture of the compounds obtained, 4M HCl-EtOAc solution, and EtOH was stirred at ambient temperature for 2 hours to yield a mixture of 2-(4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)ethanol dihydrochloride and 2-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)ethanol dihydrochloride.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:14]1[O:16][CH:15]1[CH2:17][OH:18]>>[OH:16][CH:15]([CH2:17][OH:18])[CH2:14][NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN
Reactant: OCC1CO1
Product: CCCCCCCCCCCCNCC(O)CO
Reaction time: 8 h

Procedure:
Dodecylamine (25.02 g, 0.13 moles) was heated at 85° C., and glycidol (10 g, 0.13 moles) was added dropwise. The reaction was heated under nitrogen for 3 hours then allowed to stir overnight. A white solid was recovered (crude yield=33.27 g), and the solid was recrystallized in hot hexane to give pure neosphingosine (yield=10.86 g).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[OH:5].[H-].[Na+].[CH3:17]I>CN(C)C=O.C(OCC)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[O:5][CH3:17]
Reactant: OC(c1ccco1)c1ccccc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(c1ccco1)c1ccccc1Cl
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A soluton of (±) 2-(2-chloro-α-hydroxybenzyl)furan [prepared as described in (j) above] (31.3 g.) in dimethylformamide (100 ml.) was treated with sodium hydride (4.1 g.) with ice cooling. Methyl iodide (28.4 g.) was added to the stirred solution over 15 minutes at 15°-30° C. with ice cooling and the mixture was allowed to stand at ambient temperature for 1 hour. The mixture was then diluted with diethyl ether (300 ml.) and filtered. The filtrate was washed with water (3 × 500 ml.), dried over sodium sulphate and evaporated to give a light red oil, which was distilled to give (±) 2-(2-chloro-α-methoxybenzyl)furan (30 g.), b.p. 115° C./0.1 mm.Hg.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH2:13]Br)[CH2:3]1.[OH:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH2:13][O:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:3]1
Reactant: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]12
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)COc3cccnc3)CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
To a solution of 3α-hydroxy-21-bromo-5β-pregnan-20-one-(300 mg, 0.76 mmol) in DMF (5 mL) was added 3-hydroxypyridine (215 mg, 2.27 mmol) and K2CO3 (313 mg, 2.27 mmol) and the mixture obtained was stirred at 25° C. for 0.5 h. The reaction mixture was then poured into a separatory funnel containing water (30 mL) and the mixture was extracted with EtOAc (3×35 mL). The combined extracts were washed with water (2×25 mL) and then dried over Na2SO4. Removal of the solvent in vacuo resulted in the crude product which was purified by flash chromatography over silica gel to yield the pure 3α-hydroxy-21-(pyrid-3-yl)oxy-5β-pregnan-20-one (50 mg); mp 63-66° C.; TLC Rf (MeOH:CH2Cl2 5:95)=0.5.