Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:17][C@@H:16]3[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][CH:10]=2)[N:6]=[CH:5]1.[I:23]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>ClCCl.FC(F)(F)C(O)=O>[F:1][CH2:2][CH2:3][N:4]1[C:8]([I:23])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:17][C@@H:16]3[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][CH:10]=2)[N:6]=[CH:5]1
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(-c2cn(CCF)cn2)cc1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(-c2ncn(CCF)c2I)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.3 %

Procedure:
To a solution of ethyl (1S,2S)-2-{4-[1-(2-fluoroethyl)-1H-imidazol-4-yl]phenyl}cyclopropanecarboxylate (450 mg, 1.488 mmol) in dichloromethane (5 mL) was added N-iodosuccinimide (352 mg, 1.563 mmol) and three drops trifluoroacetic acid. The reaction was stirred at rt for 3 h. The mixture was neutralized with aqueous sodium bicarbonate and the organics were extracted with dichloromethane. The organics were then washed with aqueous sodium thiosulfate, followed by three washes with water. The organics were dried (MgSO4), concentrated, and purified on 20 g of silica gel eluting a gradient of 35-100% ethyl acetate in hexanes to give rise to the title compound as a brown oil (110 mg, 0.257 mmol). LCMS: [M+1]+=429.
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][C@@H:7]([NH:32][CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C)[C:8]([N:10]2[CH:15]3[CH2:16][CH2:17][CH:11]2[CH2:12][CH:13]([N:18]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])[CH2:14]3)=[O:9])=[CH:4][CH:3]=1>Cl.C(OCC)C>[ClH:1].[NH2:35][CH2:34][CH2:33][NH:32][C@@H:7]([C:8]([N:10]1[CH:15]2[CH2:16][CH2:17][CH:11]1[CH2:12][CH:13]([N:18]([CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[C:19]([N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])=[O:20])[CH2:14]2)=[O:9])[CH2:6][C:5]1[CH:43]=[CH:44][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@@H](Cc1ccc(Cl)cc1)NCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@@H](Cc1ccc(Cl)cc1)NCCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
0.14 g of tert-butyl (2-{[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino)carbonyl]amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]amino}ethyl)-carbamate is placed in 1.1 ml of 2N hydrochloric acid in diethyl ether. The reaction medium is stirred at ambient temperature for 1 h. Trituration, rinsing with diethyl ether and filter-drying of the precipitate obtained are carried out. The salt thus obtained is chromatographed on silica gel, elution being carried out with a 98/2/0.2 and then 95/5/0.5 mixture of dichloromethane, methanol and aqueous ammonia. 0.05 g of N-{8-[N-(2-aminoethyl)-4-chloro-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N′,N′-diethylurea hydrochloride is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][C:6](Cl)=[C:7]([CH2:13][N:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([O-:22])=[O:21])=[CH:18][CH:17]=3)[CH3:15])[N:8]=2)[N:3]=1.[NH3:26]>>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][C:6]([NH2:26])=[C:7]([CH2:13][N:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[CH3:15])[N:8]=2)[N:3]=1
Reactant: CN(Cc1nc2c(N)nc(N)nc2nc1Cl)c1ccc(C(=O)[O-])cc1
Reactant: N
Product: CN(Cc1nc2c(N)nc(N)nc2nc1N)c1ccc(C(=O)O)cc1

Procedure:
A suitable method of synthesizing 7-NR1R2 -MTX wherein either both R1 and R2 are hydrogen, or one is hydrogen and the other is C1 -C5 alkyl, is outlined in FIGS. 1A and 1B. A suitable method of synthesizing 7-NR1R2 -MTX wherein both R1 and R2 are hydrogen comprises (a) reacting phosphorus oxychloride with 3-amino-6-(chloromethyl)-2-pyrazinecarbonitrile 4-oxide (1) to yield 3-amino-5-chloro-6-(hydroxymethyl)-2-pyrazinecarbonitrile (2); (b) reacting 3-amino-5-chloro-6-(hydroxymethyl)-2-pyrazinecarbonitrile with thionyl chloride to form 3-amino-5-chloro-6-(chloromethyl)-2-pyrazinecarbonitrile (4); (c) reacting 3-amino-5-chloro-6-(chloromethyl)-2-pyrazinecarbonitrile with ethyl 4-methylaminobenzoate (3) to form ethyl 4-[N-(2-amino-3-cyano-6-chloro-5-pyrazinylmethyl)-N-methylamino]benzoate (5); (d) reacting ethyl 4-[N-(2-amino-3-cyano-6-chloro-5-pyrazinylmethyl)-N-methylamino]benzoate with guanidine to form 4-[N-(2,4-diamino-7-chloro-6-pteridinylmethyl)-N-methylamino]benzoate (6); (e) reacting 4-[N-(2,4-diamino-7-chloro-6-pteridinylmethyl)-N-methylamino]benzoate with ammonia to form 4-[N-(2,4,7-triamino-6-pteridinylmethyl)-N-methylamino]benzoic acid (7a); and (f) coupling 4-[N-(2,4,7-triamino-6-pteridinylmethyl)-N-methylamino]benzoic acid and diethyl L-glutamate hydrochloride.
Reaction SMILES: [O:1]1[C@@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=2)[C@@H:2]1[CH2:3][OH:4].C(Cl)Cl.C(Cl)(Cl)Cl>CCCCCC.C(OCC)(=O)C>[O:1]1[C@@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:14])[F:15])[CH:7]=2)[C@@H:2]1[CH:3]=[O:4]
Reactant: OC[C@@H]1O[C@H]1c1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C[C@@H]1O[C@H]1c1cccc(C(F)(F)F)c1

Procedure:
The title compound is prepared analogously to Example 5a) from (2S,3S)-2,3-epoxy-3-(3-trifluoromethylphenyl)-propanol. Light-yellow liquid; IR (CH2Cl2): 2820, 1730, 1330, 1165, 1130, 1070 cm-1 ; [α]D20 (chloroform, 0.20%)=0.0°±5°; [α]36520 (chloroform, 0.20%)=475.0°±5.0°; Rf =0.44 (hexane/ethyl acetate 7:3).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[C:12]([C:23]#[N:24])=[N:13][N:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:8]=2[C:7]1=[O:25].[Br-].[K+].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C:29]1=[O:34].[H-].[Na+].[Br-]>CC(C)=O.CN(C)C=O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:14]2[C:8]3[C:7](=[O:25])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][C:29]4=[O:34])[CH2:11][CH2:10][C:9]=3[C:12]([C:23]#[N:24])=[N:13]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(-n2nc(C#N)c3c2C(=O)N(CCCCCl)CC3)cc1
Reactant: O=C1CCCCN1
Agent: [Br-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COc1ccc(-n2nc(C#N)c3c2C(=O)N(CCCCN2CCCCC2=O)CC3)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
Part C: 6-(4-Chloro-butyl)-1-(4-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonitrile (0.148 g, 0.412 mmol) and potassium bromide (0.982 g, 8.24 mmol) were dissolved in acetone (25 mL) and refluxed overnight. The reaction was concentrated, quenched with water (100 mL), extracted with ethyl acetate (3×100 mL), washed with brine (1×100 mL), dried over MgSO4, concentrated, and purified by flash chromatography using 0–100% ethyl acetate/hexanes gradient as eluent to afford 0.136 g (82%). 2-Piperidone (0.136 g, 0.340 mmol) was dissolved in N,N-dimethylformamide (7 mL) and the reaction was cooled to 0° C. Sodium hydride (60%, 0.040 g, 1.01 mmol) was added and the reaction was stirred at 0° C. for 30 min. The bromide intermediate (0.136 g, 0.34 mmol) dissolved in N,N-dimethylformamide (8 mL) was added, and the reaction was stirred at rt overnight. The reaction was quenched with 1N hydrochloric acid (100 mL), extracted with ethyl acetate (3×100 mL), washed with water (100 mL), washed with brine (1×100 mL), dried over MgSO4, concentrated, and purified by flash chromatography using 0–100% ethyl acetate/hexanes gradient as the eluent. Further purification by reverse-phase HPLC and freeze-drying afforded 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-butyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonitrile (0.060 g, 42%). The carbonitrile (0.060 g, 0.141 mmol), 1N sodium hydroxide (10 mL), hydrogen peroxide (30%, 10 mL), and catalytic tetrabutyl hydrogen sulfate were dissolved in methylene chloride (10 mL) and stirred overnight at rt. The reaction was quenched with 1N sodium hydroxide (20 mL), concentrated to about 10 mL of solution, water (100 mL) added, extracted with ethyl acetate (3×100 mL), washed with brine (1×100 mL), dried over MgSO4, concentrated, and purified by reverse phase HPLC and freeze-dried to afford the title compound (0.034 g, 54%): 1H NMR (CHCl3) δ 7.45 (d, j=8.8 Hz, 2H), 6.97 (d, j=8.8 Hz, 2H), 6.82 (s, 3H), 5.44 (s, 3H), 3.85 (s, 3H), 3.65 (t, j=7.0 Hz, 2H), 3.49 (t, j=7.0 Hz, 2H), 3.36 (t, j=6.8 Hz, 2H), 3.22 (t, j=7.0 Hz, 4H), 2.38–2.34 (m, 2H), 1.79–1.76 (m, 4H), 1.64–1.57 (m, 4H) ppm; Mass Spec 440.3(M+H)+.
Reaction SMILES: N[C:2](N)=[S:3].[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])CBr.[OH-].[Na+].Cl>C(O)C.C(OCC)C>[Cl:5][C:6]1[CH:7]=[C:8]([CH2:2][SH:3])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(CBr)cc1Cl
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc(CS)cc1Cl
Temperature: 80 °C
Yield: 83 %

Procedure:
Thiourea (3.04 g, 0.04 mol) was added to a solution of 3-chloro-4-methoxybenzyl bromide (4.0 g, 0.02 mol) in ethanol (200 ml) and refluxed for 16 hours. The reaction mixture was concentrated in vacuo and the residue was subsequently dissolved in aqueous sodium hydroxide solution (30 g, 0.75 mol in 300 ml water) and heated at 80° C. for one hour. The reaction mixture was cooled with an ice bath and acidified by addition of concentrated hydrochloric acid. The product was isolated by extraction three times into diethyl ether. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, to give the sub-title compound as a colourless oil in 83% yield (3.0 g).
Reaction SMILES: [C:1]([C:4]#[C:5][C:6]([OH:8])=[O:7])(O)=O.O[CH2:10][C:11]([OH:13])=[O:12]>>[C:6]([CH2:5][CH2:4][CH2:1][CH2:10][C:11]([OH:13])=[O:12])([OH:8])=[O:7]
Reactant: O=C(O)CO
Reactant: O=C(O)C#CC(=O)O
Product: O=C(O)CCCCC(=O)O

Procedure:
HOOCC≡CCOOH  B-15  HO—CH2—COOH  B-20
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:36][CH2:37][CH3:38])=[C:5]([CH:28]=[CH:29][C:30]=1[C:31]1[N:32]=[CH:33][O:34][CH:35]=1)[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]2[CH2:15][CH2:16][CH:17]([C:19]([O:21]C)=[O:20])[O:18][C:13]=2[C:12]=1[CH2:25][CH2:26][CH3:27].[OH-].[Li+].Cl.C(OCC)(=O)C>CO.C1COCC1>[CH3:1][O:2][C:3]1[C:4]([CH2:36][CH2:37][CH3:38])=[C:5]([CH:28]=[CH:29][C:30]=1[C:31]1[N:32]=[CH:33][O:34][CH:35]=1)[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]2[CH2:15][CH2:16][CH:17]([C:19]([OH:21])=[O:20])[O:18][C:13]=2[C:12]=1[CH2:25][CH2:26][CH3:27]
Reactant: CCCc1c(OCCCOc2ccc(-c3cocn3)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(-c3cocn3)c(OC)c2CCC)ccc2c1OC(C(=O)O)CC2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The compound of Example 4 (25 mg, 47.7 μmol) along with 1.0 ml of 4:I methanol/THF, and 0.09 ml of 1 N lithium hydroxide were stirred at 0° C. for thirty minutes. An additional 0.09 ml of 1 N lithium hydroxide was added and the reaction mixture was stirred at room temperature for 45 minutes. The reaction mixture was poured into 0.5 N hydrochloric acid/ethyl acetate. The ethyl acetate layer was washed with brine, dried over sodium sulfate, and concentrated under Vacuum to give the product; melting point 136-139° C. High resolution mass spectrum m/e 510.2471 (calculated for C29H36NO7 (M+H), 510.2492).
Reaction SMILES: CON(C)[C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:5].[Li][CH3:25].[Li+].[Br-]>C1COCC1>[C:11]1([C:9]2[S:10][C:6]([C:4](=[O:5])[CH3:25])=[C:7]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[N:8]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CON(C)C(=O)c1sc(-c2ccccc2)nc1N1CCCCC1
Reactant: [Li]C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)c1sc(-c2ccccc2)nc1N1CCCCC1
Yield: 72 %

Procedure:
To a solution of the above-prepared 2-phenyl-4-piperidin-1-yl-thiazole-5-carboxylic acid methoxy-methyl-amide (0.754 mmol) in THF (5 mL) was added at 0° C. MeLi.LiBr (0.83 mmol). The reaction mixture was stirred until the reaction was complete, then quenched by the addition of saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo to give a brown oil. Silica gel chromatography provided the title compound (72%) as a yellowish oil. 1H NMR (CDCl3): δ 1.6-1.8 (m, 6H), 2.45 (s, 3H), 3.5 (m, 4H), 7.4-7.5 (m, 3H), 8.0 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][S:10][C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[BrH:16]>C(O)(=O)C>[Br:16][C:11]1[S:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[N:12]=1
Reactant: Br
Reactant: N#CSCC(=O)c1cccc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Brc1cccc(-c2csc(Br)n2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 83 %

Procedure:
A suspension of 2-(3-bromophenyl)-2-oxoethyl thiocyanate (10.9075 g, 42.6 mmol), prepared in the previous step, in 64 mL of 30% hydrogen bromide in acetic acid was stirred under nitrogen at room temperature for 17 h. The yellow suspension was poured into 500 mL of 1 N NaOH (exotherm) and the mixture stirred at room temperature for 21 h. The solid present was collected by filtration, rinsed with water, ice-cold ethanol, hexane and then dried under high vacuum to give 2-bromo-4-(3-bromophenyl)-1,3-thiazole (11.3069 g, 83%) as a yellow solid, mp 88-90° C.; MS (ES) m/z 317.9 [M+H+].
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([N:13]2[CH2:18][CH2:17][O:16][C@@H:15]([CH2:19][NH2:20])[CH2:14]2)[CH3:12])[CH:7]=[CH:8][C:9]=1[Cl:10].C(N(CC)CC)C.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:30]>ClCCl>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([N:13]2[CH2:18][CH2:17][O:16][C@@H:15]([CH2:19][NH:20][C:29](=[O:30])[O:31][C:32]3[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=3)[CH2:14]2)[CH3:12])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CC(c1ccc(Cl)c(Cl)c1)N1CCO[C@@H](CN)C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(c1ccc(Cl)c(Cl)c1)N1CCO[C@@H](CNC(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C

Procedure:
Intermediate 33 (0.724 g) in dichloromethane (5 ml) was treated with triethylamine (1.14 ml), forming a slurry which was added portion-wise over 5 min to a solution of 4-nitrophenyl chloroformate (0.444 g) in anhydrous dichloromethane (5 ml) at 0° C. under nitrogen. The stirring solution was allowed to warm to room temperature over 2 h, then filtered; the filtrate was purified directly by chromatography on silica gel (Biotage 90 g column), eluting with 35–40% ethyl acetate in cyclohexane, and appropriate fractions evaporated in vacuo to give the title compound (Isomer I) as an opaque yellow film (0.202 g).
Reaction SMILES: [CH2:1]([C@@:17]1([OH:45])[C@@H:23]([CH:24](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[OH:25])[O:22][CH:19]([O:20][CH3:21])[CH2:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1CCCCC1.CCOCC>C(Cl)Cl.C1CCCCC1.C(OCC)(=O)C>[CH2:1]([C@@:17]1([OH:45])[C@@H:23]([CH2:24][OH:25])[O:22][CH:19]([O:20][CH3:21])[CH2:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC[C@]1(O)CC(OC)O[C@@H]1C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: C1CCCCC1
Solvent: CO
Product: CCCCCCCCCCCCCCCC[C@]1(O)CC(OC)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1.365 g of methyl 2-deoxy-3-n-hexadecyl-5-trityl-D-ribofuranoside in 11.1 ml of methylene dichloride were placed in a 50 ml round-bottomed flask. 11.1 ml of MeOH were added with stirring at room temperature followed by 42.7 mg of p-toluene sulfonic acid monohydrate. After 4 hours, TLC (SiO2 ; 3:1 cyclohexane/ether or 5:1 cyclohexane/ethyl acetate) indicated reaction was substantially complete. The reaction mixture was then diluted with methylene dichloride, and the organic solution extracted with an equal volume of 0.1N aqueous sodium hydroxide (pH=12.1). The sodium hydroxide extract was washed with methylene dichloride. The methylene dichloride extracts were combined, washed with brine and dried. Evaporation of the solvent yields a solid residue which was purified by chromatography over SiO2. The solid residue was loaded onto the SiO2 column as a chloroform solution, and the column was eluted with a cyclohexane containing increasing amounts of ethyl acetate (0-20%). Two major fractions were obtained. The faster moving (first to be eluted) fraction was β-methyl 2-deoxy-3-n-hexadecyl-D-ribofuranoside (349.6 mg) and the slower moving (last to be eluted) fraction was α-methyl 2-deoxy-3-n-hexadecyl-D-ribofuranoside.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][C:10]#[N:11])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH3:12]>CO>[NH2:12][C:3]([CH3:5])=[CH:2][C:1]([O:7][CH2:8][CH2:9][C:10]#[N:11])=[O:6]
Reactant: N
Reactant: CC(=O)CC(=O)OCCC#N
Solvent: CO
Product: CC(N)=CC(=O)OCCC#N
Reaction time: 8 h

Procedure:
To 10 mL of methanol was added 20 g (0.13 mole) of 2-cyanoethyl acetoacetate. The solution was cooled in ice and a slow stream of ammonia gas was passed through it for five hours. The reaction flask was stoppered and stored at 0° C. overnight. The resulting solid was collected, washed with a small amount of methanol and dried under high vacuum to give 11.1 g (0.072 mole) of 2-cyanoethyl 3-aminobut-2-enoate, 1H NMR 4.6 (s, 1H), 4.3 (t, 2H), 2.8 (t, 2H), 2.0(t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C1COCC1>[Cl:20][CH2:21][C:22]([NH:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:23]
Reactant: NCCc1ccc(F)cc1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)NCCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.05 h

Procedure:
To a solution of 4-fluorophenylethylamine (1.0 equivalent) in dried THF was added Hunig's base (DIEA) (1 equivalent). The mixture was then stirred for 3 minutes at 0° C. Thereafter, a solution of chloroacetylchloride (1.0 equivalent) in THF was added via a syringe over a period of 7 minutes. The reaction mixture was then stirred at room temperature for 1 hour after which time the reaction mixture was condensed in vacuo, quenched with water, extracted with ethyl acetate (3×) and dried over Na2SO4. After concentration in vacuo, compound 1 shown above was obtained, which was carried on further without further purification. LC/MS=M+H 216.1 at 2.18 minutes.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][NH2:8].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[C:18]1[C:22]([C:23](Cl)=[O:24])=[C:21]([CH3:26])[O:20][N:19]=1>>[CH3:2][O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][NH:8][C:23]([C:22]1[C:18]([C:12]2[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:11]=2[Cl:10])=[N:19][O:20][C:21]=1[CH3:26])=[O:24]
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Reactant: COC(=O)CCCN
Agent: Cl
Product: COC(=O)CCCNC(=O)c1c(-c2c(F)cccc2Cl)noc1C
Yield: 103.9 %

Procedure:
Methyl-4-aminobutanoate hydrochloride (668 mg, 4.34 mmol) and 3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-oyl chloride (1.19 g, 4.35 mmol) were converted to 1.60 g of the title compound by the procedure of Preparation 1 except that the residue was not treated with hexanes. (100%). EA calculated for: C16H16N2O4ClF: C, 54.17; H, 4.55; N, 7.90. Found: C, 54.41; H, 4.58; N, 7.78. MS(FD) m/z 355 (M+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br>CN(C)C=O>[CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:12])([CH3:13])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[N:3]1[CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=1[C:17]([F:16])([F:26])[F:27]
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Reactant: FC(F)(F)c1ccccc1CBr
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1ccccc1C(F)(F)F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 31 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 2-trifluoromethyl-benzyl bromide (77 μL, 0.51 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. overnight. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-1,7,8,8-tetramethyl-2-(2-trifluoromethyl-benzyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (55.3 mg, 32%) as a light yellow solid. APCI-MS (M+H) 365.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:4][C:5](=O)[C:6]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][S:9][C:7]=2[N:8]=1.P(Cl)(Cl)([Cl:21])=O>ClCCl>[Cl:21][C:5]1[C:6]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][S:9][C:7]=2[N:8]=[C:3]([CH2:2][Cl:1])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(CCl)nc2scc(-c3ccccc3)c12
Solvent: ClCCl
Product: ClCc1nc(Cl)c2c(-c3ccccc3)csc2n1
Reaction time: 18 h

Procedure:
A stirred suspension of 2-chloromethyl-5-phenyl-3H-thieno[2,3-d]pyrimidin-4-one (1.5 g, 5.42 mmol) and phosphoryl chloride (23 ml) was heated under reflux for 7 hours and then left to stand at ambient temperature for 18 hours. The excess phosphoryl chloride was removed in vacuo to give a dark residue, which was dissolved in dichloromethane (100 ml) and then washed with water (2×100 ml) followed by saturated sodium hydrogen carbonate solution (100 ml). The organic extract was dried (MgSO4) and the solvent was removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with dichloromethane gave 4-chloro-2-chloromethyl-5-phenylthieno[2,3-d]pyrimidine as a pale-yellow solid (1.42 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[N+:17]([O-])=O)[N:8]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13]([NH2:17])=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: [H][H]
Reactant: COc1ccccc1CNc1ccc2c([N+](=O)[O-])cccc2n1
Agent: [Pd]
Solvent: CO
Product: COc1ccccc1CNc1ccc2c(N)cccc2n1

Procedure:
(2-Methoxy-benzyl)-(5-nitro-quinolin-2-yl)-amine (2.2 g, 7.1 mmol) was dissolved in 100 mL methanol. Palladium on charcoal (10%, 150 mg, 0.14 mmol) was added and the reaction mixture war hydrogenated with a hydrogen balloon overnight. The palladium was filtered off and the solvent was evaporated. The title compound was obtained as a yellow solid (1.98 g, 100%), MS: m/e=280.4 (M+H+).
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH:33]([CH:37]([CH3:39])[CH3:38])[C:34](O)=[O:35]>CCOCC>[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[CH:33]([CH:37]([CH3:39])[CH3:38])[C:34]([O:15][CH2:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:13]=1)=[O:35]
Reactant: OCc1cccc(Oc2ccccc2)n1
Reactant: CC(C)C(C(=O)O)c1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)C(C(=O)OCc1cccc(Oc2ccccc2)n1)c1ccc2ccccc2c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of (6-phenoxy-2-pyridyl)methanol (0.2 g, 0.99 mmol) and triethylamine (0.14 g, 1.38 mmol) in ether (about 15 ml), under nitrogen, is added by syringe a solution of the acid chloride of 2-(2-naphthyl)-3-methylbutanoic acid (1.5 mmol) in ether. The mixture is stirred for 30 minutes and then quenched with saturated aqueous sodium bicarbonate. The ether phase is washed with aqueous sodium bicarbonate, water and brine and filtered through silica. Evaporation of solvent, followed by thin layer chromatography using a circular chromatograph, eluting with 20% ether/hexane, gives (6-phenoxy-2-pyridyl)methyl 2-(2-napthyl)-3-methyl-butanoate, MS m/e 411(M+).