Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>C(O)(C)C>[CH2:7]1[CH2:6][CH2:5][CH:4]([CH2:3][C@H:2]([NH2:1])[C:10]([OH:12])=[O:11])[CH2:9][CH2:8]1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: N[C@@H](CC1CCCCC1)C(=O)O
Temperature: 55 °C
Reaction time: 7 h

Procedure:
20 g (121 mmol) L-phenylalanine are dissolved or suspended in 200 ml deionised water, 200 ml isopropanol and 12.2 ml (146 mmol) 37% hydrochloric acid. After addition of 2 g of the Pt/Rh catalyst, 4% Pt+1% Rh on activated carbon (water content approx. 50%, corresponding to approx. 5 wt. % catalyst relative to L-phenylalanine used), the reaction mixture is introduced into a 1 l hydrogenation autoclave. After being rendered inert with nitrogen three times, it is rinsed with hydrogen twice, then a hydrogen overpressure of 8-10 bar is established and the reaction solution heated to 50-60° C. After approximately 6 to 8 hours, hydrogen uptake is completed (theoretical amount of H2 8.1 l). The hydrogenator is depressurised and once again rendered inert with nitrogen three times. The still hot reaction solution is extracted with a nutsch filter and the catalyst is washed with 50 ml deionised water. The filtrate is first concentrated to low volume in vacuo (the isopropanol largely removed), the residue then adjusted to a pH of 5-6 with 50% sodium hydroxide solution. It is cooled to a temperature of 0-10° C., the product is extracted with a nutsch filter, rinsed with 50 ml deionised water and dried in a drying oven in vacuo at 50-70° C.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OC)=O.CCCCCC.[C:44]([O:47]CC)(=[O:46])[CH3:45]>C(Cl)Cl>[C:44]([OH:47])(=[O:46])/[CH:45]=[CH:1]/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCC/C=C/C=O
Reactant: CCOC(C)=O
Agent: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCCCCCC/C=C/C=C/C(=O)O
Reaction time: 2 h

Procedure:
To a solution of trans-2-dodecenal (4.5 g) dissolved in methylene chloride (80 ml ) was added (carbomethoxymethylene)triphenylphosphorane (8.3 g), and the mixture was stirred for 2 hours. The reaction mixture was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 100:1 to 20:1) to give the methyl ester of trans,trans-2,4-tetradecadienoic acid (5.4 g). To a solution of potassium hydroxide (6.5 g) in a mixed solvent of ethanol-water (1:1) (100 ml) was added the methyl ester of trans,trans-2,4-tetradecadienoic acid (5.4 g), and the mixture was stirred at 60° C. for 40 minutes. The reaction mixture was cooled, and acidified to a weak acidic range of pH with citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give trans,trans-2,4-tetradecadienoic acid (4.3 g). To the tetradecadienoic acid dissolved in N,N-dimethylformamide (DMF, 50 ml) was added para-nitrophenol (2.67 g) and N,N'-dicyclohexylcarbodiimide (3.9 g), and the mixture was stirred for 12 hours. After precipitates produced were removed by filtration and DMF was evaporated, the residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 200:1 to 50:1) to give the active ester of trans,trans-2,4-tetradecadienoic acid (5.1 g). To the active ester (500 mg) dissolved in DMF (30 ml) were added 6-(4'-N-glycyl-septaminyl-amino)purine hydrochloride (560 mg) and triethylamine (1.5 ml), and the mixture was stirred for 18 hours. The solvent was evaporated, and the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPT241 in the yield of 271 mg.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:15]=[C:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(N(CC)CC)C>C1COCC1.O>[Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:15]=[C:14]([C:16]3[N:17]=[N:18][N:19]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:20]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)CBr
Reactant: Fc1ccc(Br)c(OC2CCN(c3cc(-c4nnn[nH]4)on3)CC2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Cn1nnc(-c2cc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)n1

Procedure:
A mixture of 4-(2-bromo-5-fluorophenoxy)-1-[5-(1H-tetrazol-5-yl)isoxazol-3-yl]piperidine (1.2 g, 2.93 mmol), ethyl bromoacetate (0.45 mL, 4.04 mmol) and triethylamine (0.75 mL, 5.38 mmol) in THF (12 mL) was heated at reflux temperature for 2 h. After cooling, the mixture was diluted with water and extracted with EtOAc. The EtOAc extract was washed with water, dried (Na2SO4) and concentrated. Combi-Flash chromatography (40 g, 25-40% EtOAc in hexanes for 20 min, 35 mL/min, 18 mL/fraction) gave the title compound as a colorless gum, containing about 20% of 1-alkylated isomer.
Reaction SMILES: [Li+].[BH4-].CON(C)[C:6](=[O:41])[CH:7]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:19]=2)=[CH:13][C:12]=1[Cl:32].O.[CH2:44]1COCC1>C(O)C>[CH2:25]([O:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][CH2:8][CH:7]([NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH:6]([OH:41])[CH3:44])=[C:12]([Cl:32])[CH:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)C(CCCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1Cl)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CCO
Product: CC(O)C(CCCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1Cl)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
LiBH4 (50 mg) was added to the compound of Example 130 in a mixture of THF (15 mL) and ethanol (3 mL). The mixture was stirred at room temperature for 1 hour. Following addition of water, the mixture was extracted with ethyl acetate and the extract was washed sequentially with water and a saturated aqueous solution of sodium chloride. The organic phase was then dried over anhydrous sodium sulfate. The solvent was concentrated and the residue was purified on a silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product as a colorless oil (320 mg).
Reaction SMILES: O[C:2]1[N:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:4](=[O:14])[CH:3]=1.P(Cl)(Cl)([Cl:17])=O.C(=O)([O-])O.[Na+]>O>[Cl:17][C:2]1[N:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:4](=[O:14])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(O)ncn1C1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=c1cc(Cl)ncn1C1CCOCC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 6-hydroxy-3-(tetrahydro-2H-pyran-4-yl)pyrimidin-4(3H)-one obtained in Reference Example 25 (210 mg) and phosphorus oxychloride (6 mL) was stirred at 100° C. for 2 hr. The mixture was allowed to be cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was subjected to azeotropy with toluene to give a residue. The residue was dissolved in water (10 mL), and the solution was basified with saturated aqueous sodium hydrogen carbonate solution (30 mL) under ice-cooling. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a residue. The residue was purified by chromatography (hexane/ethyl acetate) to give the title compound (125 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=[O:5])C>CO.[OH-].[Na+]>[CH3:12][N:9]1[CH2:8][CH2:7][C:6]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:20][CH:21]=2)(=[O:15])=[O:14])([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C)CC2)cc1

Procedure:
1-Methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (7.6 g, 20 mmol) dissolved in methanol (300 ml and 10 N NaOH (35 mL). The resulting reaction mixture was worked up outlined in example 83. Yield 6.0 g (84%); white solid; mp 195° C.; MS: 356.4 (M+H)+
Reaction SMILES: [NH:1]([C:3]([NH:5][C:6]1[S:7][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=1)=[O:4])[NH2:2].[CH:17](OCC)(OCC)OCC>>[CH3:11][C:9]1[N:10]=[C:6]([N:5]2[C:3](=[O:4])[NH:1][N:2]=[CH:17]2)[S:7][C:8]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1sc(NC(=O)NN)nc1C
Reactant: CCOC(OCC)OCC
Product: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Temperature: 95 °C
Yield: 80 %

Procedure:
To a 2-neck round bottom flask (1 L) equipped with a mechanical stirrer was added ethyl 2-(hydrazinecarboxamido)-4-methylthiazole-5-carboxylate (42.00 g, 172.00 mmol) in anhydrous triethyl orthoformate (393 mL). The yellow reaction mixture was heated at 95° C. for 2 h, and then cooled to ambient temperature. The precipitate was filtered and washed with cold methanol (100 mL) to afford the title compound as a colourless solid (34.9 g, 80%): mp 165-167° C.; 1H NMR (300 MHz, DMSO-d6) δ 12.94 (br, 1H), 9.09 (s, 1H), 4.64 (t, J=7.1 Hz, 2H), 2.98 (s, 3H), 1.67 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.3, 157.1, 154.5, 152.3, 133.6, 118.4, 61.9, 17.7, 14.9; MS (ES+) m/z 255.0 (M+1).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]([N:12]2[C:15](=[O:16])[C@H:14]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=3)[C@H:13]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C>[C:1]1([C@H:7]([NH:9][C:10]([N:12]2[C:15](=[O:16])[C@H:14]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=3)[C@H:13]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:11])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)[C@@H]1[C@@H](Sc2cccc([N+](=O)[O-])c2)C(=O)N1C(=O)N[C@H](C)c1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)[C@@H]1[C@@H](Sc2cccc(N)c2)C(=O)N1C(=O)N[C@H](C)c1ccccc1
Temperature: 50 °C
Yield: 70.8 %

Procedure:
To a solution of compound 85a (18 mg, 41 umol) in ethyl acetate (1 mL) was added tin chloride monohydrate (2.5 eq.) and the solution was heated to 50° C. After 1 h the solution was concentrated in vacuo. The residue was purified by column chromatography using a gradient of hexane/ethyl acetate 20-100% as eluent to yield 86 (12 mg, 72%). Product MS: 414.1 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:11]=1[C:12]#[C:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[SH:30].C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30][CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:11]=1[C:12]#[C:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1
Reactant: Sc1ccccn1
Reactant: FC(F)(F)c1cccc(C#Cc2c(CCl)nc3ccccn23)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: FC(F)(F)c1cccc(C#Cc2c(CSc3ccccn3)nc3ccccn23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
150 mg (0.421 mmol) of 2-(chloromethyl)-3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2-a]pyridine were dissolved in 5 ml of acetonitrile followed by the addition of 96 mg (0.842 mmol) of pyridine-2-thiol and 274 mg (0.842 mmol) of cesium carbonate. The solvent was stirred at r.t. for 2 h 30 min. The mixture was then poured into 40 ml of water, and then extracted 3 times with 15 ml of ethyl acetate. The collected organic phases were washed with 30 ml of a saturated sodium hydrogencarbonate solution, with 30 ml of brine and then were dried on Na2SO4 which was then removed by filtration and the obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: heptane/ethyl acetate gradient, 80% to 70% of heptane, v/v). 129 mg (yield=74%) of 2-((pyridin-2-ylthio)methyl)-3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo-[1,2-a]pyridine were obtained as a beige solid. LC-MS: m/z=410 (MH+) UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.70 (d, J=6.7 Hz, 1H), 8.52-8.37 (m, 1H), 8.02 (s, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.71 (dd, J=41.7, 4.5 Hz, 4H), 7.43 (s, 2H), 7.13 (d, J=1.1 Hz, 2H), 4.73 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([NH2:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[C:12]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)(=O)[CH3:13].C([BH3-])#N.[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:15]1([CH:12]([NH:11][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:10])[CH3:13])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)c1cccc2ccccc12
Reactant: COc1cccc(C(C)N)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Product: COc1cccc(C(C)NC(C)c2cccc3ccccc23)c1

Procedure:
In a similar fashion equal molar amounts of 1-(3-methoxyphenyl)ethylamine, 1′-acetonaphthone and 1.25 equivalents of titanium(IV) isopropoxide were mixed and the resulting intermediate imine was reduced with ethanolic sodium cyanoborohydride. Work-tip and chromatography yielded N-1-(1-naphthyl)ethyl-1-(3-methoxyphenyl)ethylamine, 6E, as a clear, colorless oil; m/z (rel. int.) 305 (M+, 10), 290 (30), 170 (43), 155 (100), 135 (69), 115 (9), 105 (15), 91 (14), 77 (18).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][C:20]#[N:21])[CH2:14][CH2:13]2)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[OH:22][C@H:23]([CH3:27])[C:24](O)=[O:25].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>C(Cl)Cl>[C:20]([CH2:19][CH2:18][C@H:15]1[CH2:14][CH2:13][C@H:12]([NH:11][C:3]2[C:2]([NH:1][C:24](=[O:25])[C@H:23]([OH:22])[CH3:27])=[CH:7][N:6]=[C:5]3[CH:8]=[CH:9][S:10][C:4]=23)[CH2:17][CH2:16]1)#[N:21]
Reactant: C[C@@H](O)C(=O)O
Reactant: N#CCC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](O)C(=O)Nc1cnc2ccsc2c1N[C@H]1CC[C@H](CCC#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-{trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}propanenitrile (0.048 g, 0.16 mmol) and (R)-2-hydroxypropanoic acid (0.019 g, 0.21 mmol) in methylene chloride (0.96 mL) was added N,N-diisopropylethylamine (60 μL, 0.35 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (66 mg, 0.17 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was washed with water. The organic layers were concentrated and purified on silica gel (eluting with 0 to 10% MeOH in dichloromethane) to give (2R)—N-(7-{[trans-4-(2-Cyanoethyl)cyclohexyl]amino}thieno[3,2-b]pyridin-6-yl)-2-hydroxypropanamide. LCMS calculated for C19H25N4O2S (M+H)+: m/z=373.2. Found: 373.0. A solution of the amide intermediate in acetic acid (0.3 mL) was stirred at 105° C. for 5 h. The solvent in the reaction mixture was removed in vacuo, diluted with MeOH and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (6 mg, 10%). LCMS calculated for C19H23N4OS (M+H)+: m/z=355.2. Found: 355.1.
Reaction SMILES: [C:1]1([C:7]2([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[NH:22][C:21]4=[O:29])[CH2:16][CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:33]>CN(C=O)C.C(Cl)Cl>[CH3:33][N:22]1[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:20]([CH:17]2[CH2:18][CH2:19][N:14]([C:7]3([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)[CH2:15][CH2:16]2)[C:21]1=[O:29]
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(=O)n(C2CCN(C3(c4ccccc4)CCCCCC3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a stirred suspension of 1-[1-(1-phenylcycloheptyl)-4-piperidyl]-1,3-dihydro-2H-1,3-benzimidazol-2-one (116 mg, 0.298 mmol) in DMF (1 ml) was added NaH (60% oil suspension, 18 mg, 0.447 mmol) at rt. After 30 min stirring at rt, iodomethane (22.3 μl, 0.358 mmol) was added to the reaction mixture at rt. After 15 min stirring at rt, the reaction mixture was diluted with CH2Cl2, washed with water and brine, dried (Na2SO4), filtered, and concentrated to give pale yellow solid, which was purified by column chromatography (silica gel:5 g, hexane/ethyl acetate:5/1-3/1) to give 83 mg (69%) of white solid.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:13])[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:29][C@H:30]1[CH2:34][C@@H:33]([N:35]2[CH:43]=[N:42][C:41]3[C:36]2=[N:37][C:38]([Cl:45])=[N:39][C:40]=3[Cl:44])[C@H:32]([OH:46])[C@@H:31]1[OH:47]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][C@H:9]([CH3:13])[C:10]([NH:29][C@H:30]1[CH2:34][C@@H:33]([N:35]2[CH:43]=[N:42][C:41]3[C:36]2=[N:37][C:38]([Cl:45])=[N:39][C:40]=3[Cl:44])[C@H:32]([OH:46])[C@@H:31]1[OH:47])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: C[C@@H](OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
The title compound is prepared by dissolving (R)-2-benzyloxy-propionic acid (1 equivalent) in dichloromethane with 1,3-dicyclohexylcarbodiimide (1 equivalent) and a catalytic amount of 4-dimethylaminopyridine, stirring for five minutes, then adding (1S,2R,3S,5R)-3-amino-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol (Intermediate J5; 1-equivalent) in dichloromethane. The reaction is stirred at room temperature until determined to be complete, the solvent is removed under reduced pressure, and the title compound purified by column chromatography/crystallisation.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:34])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:22]3[N:23]=[CH:24][CH:25]=[C:26]([C:27]([O:29]C(C)(C)C)=[O:28])[C:21]3=[N:20][N:19]=2)=[CH:14][CH:13]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:34])[NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:22]3[N:23]=[CH:24][CH:25]=[C:26]([C:27]([OH:29])=[O:28])[C:21]3=[N:20][N:19]=2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1ccnn2c(-c3ccc(NC(=O)Nc4ccccc4C(F)(F)F)cc3)nnc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(-c2nnc3c(C(=O)O)ccnn23)cc1)Nc1ccccc1C(F)(F)F
Yield: 96.1 %

Procedure:
A solution of tert-butyl 3-(4-(3-(2-(trifluoromethyl)phenyl)ureido)phenyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate (66G) (58 mg, 0.12 mmol) in a mixed solvent of TFA (0.5 mL) and CH2Cl2 (0.5 mL) was stirred at room temperature for 3 h. Analysis by LC/MS indicated the starting material was consumed. The reaction was concentrated under reduced pressure, chased with CH2Cl2 (2×) and dried in high vacuum for 2 h to afford 51 mg of the title compound as a yellow solid. HPLC/MS (Method B): retention time=2.81 min, [M+H]+=443.3.
Reaction SMILES: Cl.CC1(C)[O:8][CH2:7][CH:6]([CH2:9][N:10]([CH2:12][C:13]2[C:17]3[N:18]=[CH:19][NH:20][C:21](=[O:22])[C:16]=3[NH:15][CH:14]=2)[CH3:11])[CH2:5][O:4]1>CO>[OH:4][CH2:5][CH:6]([CH2:7][OH:8])[CH2:9][N:10]([CH2:12][C:13]1[C:17]2[N:18]=[CH:19][NH:20][C:21](=[O:22])[C:16]=2[NH:15][CH:14]=1)[CH3:11]
Reactant: CN(Cc1c[nH]c2c(=O)[nH]cnc12)CC1COC(C)(C)OC1
Agent: Cl
Solvent: CO
Product: CN(Cc1c[nH]c2c(=O)[nH]cnc12)CC(CO)CO
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
Hydrochloric acid 30% (10.00 μl, 326 μmol) was added to a solution of 7-((((2,2-dimethyl-1,3-dioxan-5-yl)methyl)(methyl)amino)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (100 mg, 326 μmol) in methanol (13.21 μl, 326 μmol) and the resulting reaction left to stand for 30 min. The reaction was concentrated in vacuo to afford a solid. The solid was redissolved in methanol and absorbed onto silica. Chromatography eluting with 20% 7N NH3 in MeOH to afford the title compound as a solid (80 mg, 92% yield). 13C NMR (D2O) δ155.1, 144.4, 143.3, 132.1, 118.0, 104.4, 61.3 (2×CH2), 56.7, 50.5, 40.9, 38.3.
Reaction SMILES: [Na+].[I-].C([O-])([O-])=O.[K+].[K+].C([CH:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1)CCC.Cl[CH2:20][CH2:21][CH2:22][N:23]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH2:25][C:24]1=[O:33]>C(#N)C.CO>[CH2:14]([CH:18]1[CH2:13][CH2:14][N:15]([CH2:20][CH2:21][CH2:22][N:23]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH2:25][C:24]2=[O:33])[CH2:16][CH2:17]1)[CH2:13][CH2:18][CH3:17]
Reactant: CCCCC1CCCNC1
Reactant: O=C1COc2ccccc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: CCCCC1CCN(CCCN2C(=O)COc3ccccc32)CC1
Temperature: 60 °C
Reaction time: 13 h

Procedure:
NaI (1.33 g, 8.87 mmol), K2CO3 (1.23 g, 8.90 mmol), and 4-(3-butylpiperidine (0.66 g, 4.71 mmol) in acetonitrile (10 mL) were stirred at rt. 4-(3-chloropropyl)-4H-benzo[1,4]oxazin-3-one (1.0 g, 4.43 mmol) in acetonitrile (15 mL) was added via a syringe. The reaction was stirred at 60° C. for 13 hours and then at 80° C. for another 5 hours under nitrogen atmosphere and concentrated in vacuo. Water (150 mL) was added and the reaction mixture was extracted with ethyl acetate (3×150 mL). The combined organic phases were dried (Na2SO4) and concentrated in vacuo to give 1.58 g of crude. The crude product was subjected to CC[eluent:EtOAC:MeOH(100:1-5%)] to give the pure title compound. Yield 0.82 g 56.0% HPLC-MS [M+H]+331 (UV/MS (%)=100/99. 1H NMR (CDCl3): d 0.88 (t, 3H), 1.21 (m, 6H), 1.26 (m, 3H), 1.66 (d, 2H), 1.86 (m, 4H), 2.37 (t, 2H), 2.86, (d, 2H), 3.97 (t, 2H), 4.58 (s, 2H), 6.99 (m, 3H), 7.11 (d, 1H), 13C NMR (CDCl3): d 14.22, 23.04, 24.90, 29.17, 32.68, 35.95, 36.46, 39.74, 54.31, 56.02, 67.77, 115.26, 117.15, 122.83, 123.83, 128.78, 145.50, 164.34.
Reaction SMILES: [OH:1][CH:2]([C:9]([OH:11])=[O:10])[C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[OH:1][CH:2]1[C:9](=[O:10])[O:11][C:4](=[O:6])[C:3]1([CH3:7])[CH3:8]
Reactant: CC(C)(C(=O)O)C(O)C(=O)O
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1(C)C(=O)OC(=O)C1O
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
(3RS)-3-Hydroxy-2,2-dimethyl-succinic acid [Tetrahedron Letters (2002), 43 (52), 9513-9515](120 mg, 0.74 mmol) was suspended in CH2Cl2 (2 ml) and cooled to 0-5° C. Trifluoroacetic anhydride (260 μl, 1.85 mmol) was added and the reaction mixture stirred for 2 hours at room temperature. The reaction mixture was evaporated to dryness and used without any further purification in the next step.