Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[C:11]2[CH2:15][C@H:16]([NH:18][CH2:19][C@@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[OH:21])[CH3:17])=[O:5])C.[O:31]1CCOCC1>Cl>[Cl:28][C:24]1[CH:23]=[C:22]([C@@H:20]([OH:21])[CH2:19][NH:18][C@H:16]([CH3:17])[CH2:15][C:11]2[C:10]3[C:14](=[C:6]([C:4]([OH:31])=[O:5])[CH:7]=[CH:8][CH:9]=3)[NH:13][CH:12]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CCN(CC)C(=O)c1cccc2c(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)c[nH]c12
Reactant: C1COCCO1
Agent: Cl
Product: C[C@H](Cc1c[nH]c2c(C(=O)O)cccc12)NC[C@H](O)c1cccc(Cl)c1
Temperature: 150 °C
Yield: 30 %

Procedure:
A solution of 3-{(2 R)-2-[2-(3-chlorophenyl)-(2R)-2-hydroxyethyl-amino]propyl}-1H-indole-7-carboxylic acid diethylamide (175 mg, 0.41 mmol) in 1,4-dioxane (7 mL) and 6N hydrochloric acid (7 mL) is stirred with heating at 150° C. for 7 hours in a closed system. After cooling, the mixture is evaporated under reduced pressure to remove dioxane, and the resultant is neutralized with an aqueous Na2CO3 solution. The precipitates are filtered, and purified by reversed phase column (octa-decylsilyl, methanol/water=1/1→3/1) to give the desired 3-{(2R)-2-[2-(3-chlorophenyl)-(2R)-2-hydroxyethylamino]propyl}-1H-indole-7-carboxylic acid (45 mg, yield: 30%).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[CH2:9]([C@@:12]1([CH3:37])[CH2:17][C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[C@@H:15]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N+:14]2[C@@H:32]([CH2:35][CH3:36])[CH2:33][O:34][C:13]1=2)[CH:10]=[CH2:11].[Na+].[CH:39]1([S:42]([O-:44])=[O:43])[CH2:41][CH2:40]1>C(#N)C>[CH2:9]([C@@:12]1([CH3:37])[CH2:17][C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[C@@H:15]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[N:14]([C@@H:32]([CH2:35][CH3:36])[CH2:33][S:42]([CH:39]2[CH2:41][CH2:40]2)(=[O:44])=[O:43])[C:13]1=[O:34])[CH:10]=[CH2:11]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)[N+]2=C1OC[C@@H]2CC
Reactant: O=S([O-])C1CC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CS(=O)(=O)C2CC2)C1=O
Temperature: 90 °C
Reaction time: 24 h

Procedure:
To a solution of (3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium trifluoromethanesulfonate (75 mg, 0.130 mmol; Example 339, Step A) in acetonitrile (1.3 mL) was added cyclopropanesulfinic acid sodium salt (50 mg, 0.39 mmol) at 25° C. After being stirred at 90° C. for 1 day, the reaction was quenched with sat. aq. NH4Cl solution, extracted (2×EtOAc) and the combined organic layers wer washed with brine (2×), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (12 g SiO2, 35% and 45% EtOAc/hex) provided the title compound as a colorless liquid.
Reaction SMILES: [C:1]1(O)[C:5](=[O:6])[C:3](=O)[C:2]=1[OH:7].[OH:9][CH2:10][CH2:11][NH:12][CH:13]1[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][C:15]([CH3:22])([CH3:21])[CH2:14]1>CC(C)=O>[OH:9][CH2:10][CH2:11][N:12]([C+:1]1[C:2]([O-:7])=[C:3]([N:12]([CH:13]2[CH2:14][C:15]([CH3:22])([CH3:21])[NH:16][C:17]([CH3:20])([CH3:19])[CH2:18]2)[CH2:11][CH2:10][OH:9])[C+:5]1[O-:6])[CH:13]1[CH2:14][C:15]([CH3:22])([CH3:21])[NH:16][C:17]([CH3:20])([CH3:19])[CH2:18]1
Reactant: CC1(C)CC(NCCO)CC(C)(C)N1
Reactant: O=c1c(O)c(O)c1=O
Solvent: CC(C)=O
Product: CC1(C)CC(N(CCO)c2c([O-])[c+](N(CCO)C3CC(C)(C)NC(C)(C)C3)[c+]2[O-])CC(C)(C)N1
Yield: 66.8 %

Procedure:
5.7 g of quadratic acid (0.05 mole) and 50.1 g of 97.7% strength 4-(2-hydroxyethyl)amino-2,2,6,6-tetramethylpiperidine (0.244 mole) were heated for five hours to 200° C. After cooling, the reaction product was boiled with 150 cc of acetone and, after another cooling step, vacuum-filtered and washed with acetone, thus obtaining 16.0 g. Yield: 66.8% of theory, mp 309°-311° C. Extinction (g/l.cm) at 336 nm: 97.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH:38]1[CH2:43][CH2:42][CH:41]([C:44]([OH:47])([CH3:46])[CH3:45])[CH2:40][CH2:39]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30][N:38]4[CH2:43][CH2:42][CH:41]([C:44]([OH:47])([CH3:46])[CH3:45])[CH2:40][CH2:39]4)=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:15][CH2:16][C@@H:17]([NH:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:19]2)=[O:7])=[CH:32][CH:33]=1
Reactant: CC(C)(O)C1CCNCC1
Reactant: CC(C)C(=O)N[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)C(=O)N[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCC(C(C)(C)O)CC4)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.3 %

Procedure:
To a 0° C. cooled solution of (E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-isobutyramidocyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (75 mg, 0.166 mmol) in DCM (5 mL) was added thionyl chloride (0.060 mL, 0.829 mmol) dropwise. The resulting mixture was stirred at 0° C. for 30 minutes. After 30 minutes, the solvent was removed, and the residue was suspended in ACN (5 mL) and re-concentrated to remove residual thionyl chloride. The residue was resuspended in ACN (3 mL), cooled to 0° C., and 2-(piperidin-4-yl)propan-2-ol (95 mg, 0.663 mmol) was added. The reaction was stirred overnight at RT. After 16 hours, the reaction mixture was concentrated and partitioned between EtOAc and water. The organic layer was concentrated and the residue was purified by column chromatography, eluting with 0-100% (90:9:1 DCM/MeOH/NH4OH) in DCM to provide (E)-4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-isobutyramidocyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide as a white powder (30 mg, 31.3% yield). MS, m/z (C33H44FN5O3): calcd, 577.3. found, 578.1 [M+H].
Reaction SMILES: C(O)(C(F)(F)F)=O.O[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:27])[N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1.[SH:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>>[N:32]1[CH:33]=[CH:34][C:29]([S:28][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:27])[N:19]([CH3:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][CH:12]=2)=[CH:30][CH:31]=1
Reactant: Sc1ccncc1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)Oc1ccc(CCSc2ccncc2)cc1)c1ccccc1
Yield: 5 %

Procedure:
The title compound was prepared as its TFA salt in 5% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 4-mercaptopyridine. NMR (400 MHz; CDCl3): δ 3.07 (t, 2H), 3.36 (t, 2H), 3.44 (br s, 3H), 7.06 (br d, 2H), 7.20 (d, 2H), 7.25-7.43 (m, 7H), 8.51 (d, 2H); HPLC-MS: m/z=365.2 (M+1); Rt=2.53 min.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[CH:18]1[CH:19]=[CH:20][N:21]=[C:22]([NH:24][S:25]([C:28]2[CH:29]=[CH:30][C:31]([NH2:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:23]=1.C(O)C>O>[O:17]=[C:6]1[C:5](=[CH:4][NH:34][C:31]2[CH:30]=[CH:29][C:28]([S:25]([NH:24][C:22]3[CH:23]=[CH:18][CH:19]=[CH:20][N:21]=3)(=[O:27])=[O:26])=[CH:33][CH:32]=2)[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7]1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Reactant: Nc1ccc(S(=O)(=O)Nc2ccccn2)cc1
Solvent: CCO
Solvent: O
Product: O=C1Nc2ccc3ncsc3c2C1=CNc1ccc(S(=O)(=O)Nc2ccccn2)cc1
Reaction time: 18 h
Yield: 71 %

Procedure:
To a 25 ml round bottom flask was added a stir bar, 246 mg (1.00 mmol) of 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one. 249 (1.00 mmol) of sulfapyridine and 10 ml of ethanol. The flask was fitted with a water-cooled reflux condenser, and the mixture was heated to reflux using an oil bath with stirring for 18 h. The reaction was allowed to cool and was filtered. The precipitate was washed with excess ethanol and dried under vacuum to yield 321 mg (71%) of the title compound: 1H NMR (DMSO-d6): δ 11.9 (br s, 1H), 11.2 (d, 1H), 10.9 (s, 1H), 9.3 (s, 1H), 8.1 (d, 2H), 7.9 (m 3H) 7.8 (m, 1H), 7.6 (d, 2H), 7.2 (d, 1H), 7.2 (d, 1H), 6.9 (t, 1H); C21H15N5O3S2: APCI−MS m/z 450 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([N+:18]([O-])=O)=[CH:12][C:11]=2[CH3:21])[CH2:6][CH2:5]1)[CH3:3].NN.C>CO.[Fe](Cl)(Cl)Cl>[CH3:21][C:11]1[C:10]([N:7]2[CH2:6][CH2:5][N:4]([CH:2]([CH3:3])[CH3:1])[CH2:9][CH2:8]2)=[CH:15][C:14]([O:16][CH3:17])=[C:13]([CH:12]=1)[NH2:18]
Reactant: COc1cc(N2CCN(C(C)C)CC2)c(C)cc1[N+](=O)[O-]
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CO
Product: COc1cc(N2CCN(C(C)C)CC2)c(C)cc1N
Temperature: 60 °C
Yield: 93.7 %

Procedure:
To a solution of 1-(1-methylethyl)-4-[2-methyl-5-(methyloxy)-4-nitrophenyl]piperazine (1.78 g, 6.08 mmol) in methanol (75 mL) was added hydrazine (1.33 mL, 7.0 mmol), iron (III) chloride (0.200 g, 1.22 mmol) and activated charcoal (2 g). The resulting slurry was warmed to 60° C. and maintained overnight. The next morning the slurry was filtered and concentrated to a residue. The residue was partitioned between ethyl acetate and sat. NaCl(aq). The organic layer was washed twice with saturated brine, dried over sodium sulfate, and taken to a residue under reduced pressure to afford 5-methyl-4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)aniline (1.50 g, 94% yield) of sufficient purity for use directly in the next step. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98 (d, J=6.60 Hz, 6 H), 2.04 (s, 3 H), 2.52 (s, 4 H), 2.64 (dt, J=12.92, 6.55 Hz, 1 H), 2.68-2.72 (m, 4 H), 3.69 (s, 3 H), 4.28 (s, 2 H), 6.41 (s, 1 H), 6.55 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.CN(C)[CH:16]=[O:17]>C(OCC)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH:16]=[O:17])=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 39.1 %

Procedure:
To a diethyl ether (500 mL) solution of 2,5-dibromopyridine (25 g, 110 mmol) was added dropwise n-butyl lithium (2.67 M n-hexane solution, 45 mL, 120 mmol) at −76° C., which was stirred for 25 minutes. To this solution was added dropwise N,N-dimethylformamide (9.0 mL, 120 mmol) at −76° C. Upon completion of this addition, the reaction solution was gradually cooled to room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=8:1) to obtain the title compound (8.0 g, 41%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1O[CH:5]=[CH:6][C:7](=[O:9])[CH:8]=1.[OH-].[NH4+:13]>CO>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][N:13]=1
Reactant: O=c1ccoc(C(F)(F)F)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Oc1ccnc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 10 h
Yield: 80.6 %

Procedure:
To a solution of 2-(trifluoromethyl)-4H-pyran-4-one (350 mg, 2.13 mmol) in MeOH (15 mL) was added ammonium hydroxide (14.8 mL, 107 mmol) at 25° C. The reaction mixture was stirred at 90° C. for 10 h, then concentrated, diluted with water and extracted with ethyl acetate. Combined organic portions were dried over Na2SO4, filtered and concentrated. Purification via Biotage Spla HPFC system (C18, mobile phase: 0.01% NH4HCO3, CH3CN/water, 10˜95%, 9.5 min, 30 mL/min) afforded the title product (280 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1.[CH3:29]CN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.CO>C(Cl)Cl>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]([CH3:21])([CH3:20])[C:17]([O:19][CH3:29])=[O:18])=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1
Reactant: CC(C)(Oc1ccc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2c1)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(C)(C)Oc1ccc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a solution of 2-((4-(2-fluoro-4-nitrophenoxy)quinolin-7-yl)oxy)-2-methylpropanoic acid (3 g, 7.75 mmol), EDCI (1.8 g, 9.3 mmol) and HOAT (0.2 g, 1.6 mmol) in CH2Cl2 (60 mL) was added CH3OH (5 mL). The reaction mixture was stirred at room temperature for 1 hour and then diluted with 20 mL of CH2Cl2. The organic phase was separated, washed with water (20 mL) and concentrated in vacuo. The crude product was purified by a column chromatography on silica gel (PE/EtOAc=2:1) to afford the title compound as a yellow oil (3 g, 96.5%).
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O[CH:22](N(C)C)[N:23]([CH3:25])[CH3:24])(C)(C)C>>[CH3:22][N:23]([CH3:25])[CH:24]=[C:3]([C:2](=[O:1])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)c1cccc(C#N)c1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cccc(C#N)c1

Procedure:
Ethyl 3-oxo-3-(3-cyano-phenyl)-propionate (109 mg, 0.5 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 28a) to give crude title compound (85 mg) as a yellow oil which was used directly in the next step.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[CH2:30]([NH:32][CH2:33][CH2:34][OH:35])[CH3:31]>CN(C)C(=O)C>[CH2:30]([N:32]([CH2:33][CH2:34][OH:35])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1)[CH3:31]
Reactant: CN(C[C@H]1CC[C@H](COC/C=C/CBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCNCCO
Solvent: CC(=O)N(C)C
Product: CCN(C/C=C/COC[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1)CCO

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with ethyl-(2-hydroxy-ethyl)-amine in N,N-dimethylacetamide at room temperature to yield trans-N-(4-{4-[ethyl-(2-hydroxy-ethyl)-amino]-(E)-but-2-enyloxymethyl}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide as light yellow solid, MS: 507 (MH+).
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=3)=[C:16]([CH3:29])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[I-].[Na+].Br[CH2:33][CH:34]1[CH2:36][CH2:35]1.O>CN(C)C=O>[CH:34]1([CH2:33][N:15]2[C:16]([CH3:29])=[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:21][CH:20]=3)[C:13]([O:12][C@@H:1]3[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]3[OH:3])=[N:14]2)[CH2:36][CH2:35]1
Reactant: Cc1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OC(C)C)cc1
Reactant: BrCC1CC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cc2ccc(OC(C)C)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1CC1CC1
Reaction time: 72 h
Yield: 60 %

Procedure:
To a suspension of 3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (0.050 g) cesium carbonate (0.20 g) and a catalytic amount of sodium iodide in N,N-dimethylformamide (1 mL) was added bromomethylcyclopropane (0.050 g) at 50° C., and the mixture was stirred for 3 days. Water was added to the reaction mixture, and the mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol), and successively by column chromatography on silica gel (eluent: dichloromethane/methanol=8/1) to give 1-(cyclopropylmethyl)-3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (0.034 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH:17](OC)OC)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8].[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH2:36][N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[CH:35][C:30]=2[O:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:40]2[CH2:41][CH2:42][N:37]([CH2:36][C:34]3[CH:33]=[CH:32][C:31]4[O:27][CH2:28][O:29][C:30]=4[CH:35]=3)[CH2:38][CH2:39]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8]
Reactant: COC(CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O)OC
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCN(Cc3ccc4c(c3)OCO4)CC2)C1

Procedure:
Compound 749 was prepared from 1-(2,2-dimethoxy-ethyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide and 1-benzo[1,3]dioxol-5-ylmethyl-piperazine using the method described for compound 747. The title compound was isolated as a white solid (0.0068 g, 17% yield). HRMS (M+H) calcd for C27H31N4Cl2O5: 561.16716. found: 561.1674.
Reaction SMILES: Cl.Cl.[C:3]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[C:22]1[N:23]([CH3:35])[C:24](=[O:34])[CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][N:29]=2)[N:27]=1.C(N(CC)CC)C>O1CCCC1>[C:3]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([C:22]2[N:23]([CH3:35])[C:24](=[O:34])[CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][N:29]=3)[N:27]=2)[CH2:13][CH2:14]1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: c1ccc(-c2ccccc2N2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCN(c3ccccc3-c3ccccc3)CC2)nc(-c2ccncn2)cc1=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 64.7 %

Procedure:
To a solution of 1-biphenyl-2-yl-piperazine dihydrochloride (311 mg, 1.0 mmol) and 2-chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (202 mg, 0.91 mmol) in tetrahydrofuran (20 mL) was added triethylamine (404 mg, 4.0 mmol). The mixture was stirred at 90° C. for 4 h. The solvent was evaporated off in vacuo and the residue treated with water and chloroform. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. Recrystallization from ethyl acetate gave 2-[4-(biphenyl-2-yl)piperazin-1-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (250 mg, 65%) as colorless crystals.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([F:18])[CH:10]=1)(=[O:7])[CH3:6].[CH3:19][CH:20](O)[CH2:21][CH2:22][CH3:23]>N1C=CC=CC=1>[C:5]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][CH:20]([CH3:19])[CH2:21][CH2:22][CH3:23])=[O:14])=[C:11]([F:18])[CH:10]=1)(=[O:7])[CH3:6]
Reactant: CCCC(C)O
Reactant: CC(=O)Oc1ccc(C(=O)O)c(F)c1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCCC(C)OC(=O)c1ccc(OC(C)=O)cc1F

Procedure:
Thionyl chloride in an amount of 60 ml was added to 10.8 g (0.06 mol) of 4-acetoxy-2-fluoro-benzoic acid, and the mixture was allowed to react under reflux for 7 hours. Then, excessive thionyl chloride was distilled off, and then 10 ml of pyridine and 3.5 g (0.0402 mol) of 2-pentanol were dropwise added.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([I:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].[CH2:15]([O:17][P:18]([C:23]([C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)([O:26][CH2:27][CH3:28])[PH2:24]=[O:25])(=[O:22])[O:19][CH2:20][CH3:21])[CH3:16].CCN(C(C)C)C(C)C>CCO>[CH2:15]([O:17][P:18]([C:23]([O:26][CH2:27][CH3:28])([C:29]1[CH:30]=[CH:31][C:32]([NH:35][C:2]2[N:10]=[C:9]([I:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]([CH3:14])[CH3:13])=[CH:33][CH:34]=1)[PH2:24]=[O:25])(=[O:22])[O:19][CH2:20][CH3:21])[CH3:16]
Reactant: CC(C)n1cnc2c(Cl)nc(I)nc21
Reactant: CCOC([PH2]=O)(c1ccc(N)cc1)P(=O)(OCC)OCC
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC([PH2]=O)(c1ccc(Nc2nc(I)nc3c2ncn3C(C)C)cc1)P(=O)(OCC)OCC
Temperature: 105 °C

Procedure:
6-Chloro-2-iodo-9-isopropyl-9H-purine (1.7 g, 5.2 mmol), [(4-amino-phenyl)-ethoxy-phosphinoylmethyl]-phosphonic acid diethyl ester (2.6 g, 7.7 mmol), and DIPEA (2.7 mL, 15.5 mmol) were dissolved in EtOH (27 mL) and heated in a sealed tube at 105° C. for 48 h. After cooling, the EtOH was evaporated. The residue was poured into water and extracted with EtOAc. The combined extracts, were washed with water, sat'd NaCl, then dried over MgSO4 and filtered. Concentration yielded an oil which was purified by silica gel chromatography (11% MeOH/EtOAc) to a glassy solid (1.8 g, 53%): MS [M+H]+ 621.
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[C:6]([O:8][CH2:9][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])(=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([C:1]([O:13][CH2:14][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])=[O:12])=[CH:3][CH:4]=1
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1ccc(C(=O)OCCCCCCCCCCCCCCCCCC)cc1
Temperature: 130 °C
Yield: 96.2 %

Procedure:
To a 2 L Buchi reactor equipped with a double turbine agitator and distillation apparatus was charged Dimethyl terephthalate (315.8 grams), Stearyl Alcohol (879.7 grams) and heated to 130° C. under Nitrogen purge for 1 hour, after which stirring was commenced followed by the addition of Tyzor catalyst (3.0 grams, available from Dupont). The reaction mixture was then heated to 145° C., followed by slowly ramping the temperature to 190° C. over a 3-4 hour period such that the evolution of methanol is distilled in a controlled manner. The reaction temperature was maintained at 190° C. for an additional 16 hours until >96% conversion to the product was achieved as determined by 1H NMR spectroscopy. The product was discharged as a low viscosity liquid which solidified on cooling to give a 1050 gram of a white solid (96.2% yield). The product was shown to be pure by 1H NMR spectroscopy with trace amounts of the mono-ester. Physical properties of this compound are shown in Table 2.