Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=[O:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.Cl.Cl.[CH3:29][N:30]([CH3:38])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH2:37])[CH:32]=1.C(N(CC)CC)C>CN(C)C=O>[OH2:3].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([NH:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([N:30]([CH3:38])[CH3:29])[CH:32]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CN(C)c1cccc(N)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)c1cccc(NC(=O)Cn2c(-c3ccc(Cl)cc3)nc3cccnc32)c1
Product: O
Temperature: 25 °C
Yield: 5.7 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (2.03 g, 0.016 mole) was added dropwise, slowly, to a stirred and chilled solution of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) in dry dimethylformamide (60 ml). The reaction mixture was stirred at room temperature for 1.5 hr, and then an additional 0.3 ml of oxalyl chloride was added. After stirring for an additional 0.5 hr, the solution was added dropwise to a stirred mixture of N,N-dimethyl-1,3-benzenediamine dihydrochloride (3.35 g, 0.016 mole) and triethylamine (6.46 g, 0.064 mole) in dimethylformamide (130 ml). The resultant mixture was stirred at room temperature overnight and poured into 400 ml of ice water. The solid which precipitated was collected by filtration, dissolved in hot isopropyl alcohol, and filtered hot. Upon cooling to room temperature, solid precipitated. Water was added and the solid was collected by filtration and rinsed with water. A 0.5-g sample was dried under high vacuum at room temperature to give 0.34 g of title compound, mp 215°-217° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C@H:25]([CH2:26][OH:27])[CH2:24][O:23][C:22]3=[O:28])=[CH:17][C:16]=2[S:29]([CH3:32])(=[O:31])=[O:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34]I>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C@H:25]([CH2:26][O:27][CH3:34])[CH2:24][O:23][C:22]3=[O:28])=[CH:17][C:16]=2[S:29]([CH3:32])(=[O:31])=[O:30])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3CO)cc2S(C)(=O)=O)CC1
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(S(C)(=O)=O)c1
Yield: 79 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-4-[4-(4-hydroxymethyl-2-oxooxazolidin-3-yl)-2-methanesulfonylbenzoyl]piperazine-1-carboxylic acid tert-butyl ester (908 mg) described in Preparation Example 170 and methyl iodide (320 mg), the title compound (738 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]2)=[C:4]([C@H:10]([OH:17])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[CH3:26][C:27](=[CH2:29])[CH3:28].C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]2)=[C:4]([C@H:10]([O:17][C:27]([CH3:29])([CH3:28])[CH3:26])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: C=C(C)C
Reactant: Cc1nc(C)c([C@H](O)C(=O)OC(C)C)c(N2CCC(C)(C)CC2)c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C)(C)CC2)c1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.7 %

Procedure:
A stirred ice-cold yellow mixture of (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (6.7 g, 16.21 mmol) and 70% HClO4 (2.2 mL, 25.6 mmol) in dichloromethane (400 mL) was saturated with isobutylene gas by bubbling through the reaction mixture (10 min). The reaction mixture was cloudy sealed in a seal tube, stirred for 24 h at rt. The reaction mixture was recooled in a −10° C. bath, bubbled additional isobutylene (˜15 min). The reaction mixture became a clear solution at this point. The tube was sealed and stirred at rt for 16 h. LCMs at this point showed incomplete reaction. So, the reaction mixture was cooled down to −30° C. and bubbled isobutene (˜15 min). After 24 h, reaction mixture was neutralized with sat. Na2CO3 (20 mL), organic layer separated and aqueous layer was extracted with CH2Cl2 (25 mL). The combined organic layers were dried (MgSO4), filtered, concentrated and purified on a ISCO 120 g column (EtOAc/hex: 0 to 40%) to afford (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (5.43 g, 9.83 mmol, 60.7% yield) as a viscous oil. 1H NMR (500 MHz, CDCl3) δ 6.26 (br. s., 1H), 5.09-4.97 (m, 1H), 4.06 (br. s., 1H), 3.51 (br. s., 1H), 2.90 (br. s., 1H), 2.65 (s, 3H), 2.56 (s, 3H), 1.72-1.54 (m, 3H), 1.47 (br. s., 1H), 1.37 (br. s., 1H), 1.23-1.20 (m, 12H), 1.15 (d, J=6.1 Hz, 3H), 1.09 (br. s., 3H), 1.04 (br. s., 3H). LCMS (M+H)=471.3.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][C@@H:11]([NH2:14])[CH2:10]2)=[CH:6][CH:5]=1.[CH2:17]([O:19][C:20](=[O:29])[C:21]1[CH:26]=[C:25]([Cl:27])[C:24](Cl)=[N:23][CH:22]=1)[CH3:18].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[Cl:27][C:25]1[C:24]([NH:14][C@@H:11]2[CH2:12][CH2:13][N:9]([CH2:8][C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:16][CH:15]=3)[CH2:10]2)=[N:23][CH:22]=[C:21]([CH:26]=1)[C:20]([O:19][CH2:17][CH3:18])=[O:29]
Reactant: N[C@@H]1CCN(Cc2ccc(F)cc2)C1
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(N[C@@H]2CCN(Cc3ccc(F)cc3)C2)c(Cl)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of (3R)-1-(4-fluorobenzyl)-3-pyrrolidinamine dihydrochloride (3.5 g) in DMF (35 ml) was added 5,6-dichloronicotinic acid ethyl ester (3.38 ml) and K2CO3 (6.34 g), the mixture was stirred at 100° C. for 4 hours under N2 atmosphere. The mixed solution was poured into a mixture of water (250 ml) and AcOEt (250 ml). The organic layer was separated, washed with water twice and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt:hexane=1:2 to give ethyl 5-chloro-6-{[(3R)-1-(4-fluorobenzyl)-3-pyrrolidinyl]amino}nicotinate (3.75 g).
Reaction SMILES: C([NH:4][C:5]1[NH:6][C:7](=[O:14])[C:8]2[NH:9][CH:10]=[N:11][C:12]=2[N:13]=1)(=O)C.ClC(Cl)C.C(C([C@:24]([C:48](=[O:55])C1C=CC=CC=1)([C@:26](C(=O)C1C=CC=CC=1)([C@H:28]([CH2:30][O:31]C(=O)C1C=CC=CC=1)[OH:29])[OH:27])O)=O)(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>N1C=CC=CC=1.C(Cl)Cl>[CH:10]1[N:11]([C@H:30]2[O:31][C@@H:24]([CH2:48][OH:55])[C@H:26]([OH:27])[C@@H:28]2[OH:29])[C:12]2[NH:13][C:5]([NH2:4])=[N:6][C:7](=[O:14])[C:8]=2[N:9]=1
Reactant: CC(=O)Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: CC(=O)C(=O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)c1ccccc1)[C@@H](O)COC(=O)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Nc1nc(=O)c2ncn([C@H]3O[C@@H](CO)[C@H](O)[C@@H]3O)c2[nH]1
Temperature: 25 °C

Procedure:
N2-Acetylguanine (4.125 g, 21.35 mmol) was suspended in pyridine (50 mL) at 80° C. for 25 min. and then pyridine was evaporated under high vacuum. The same, procedure was repeated once. The obtained material was dried under vacuum overnight and silylated by heating with excess of HMDS (50 mL), pyridine (10 mL) and TMSCl (150 mL) under argon for 2.5 hours. After the reaction mixture was cooled to RT, the solvents were evaporated under vacuum. The residual HMDS and pyridine were coevaporated with xylene (2×40 mL). The silylated base was suspended in dichloroethane (70 mL) and combined with dichloroethane (182 mL) solution of 1-acetyl-2,3,5-O-tribezoyl-L-ribose (9.71 g, 19.22 mmol). The obtained suspension was stirred under argon at reflux temperature for 10 min. and dichloroethane (35 mL) solution of TMS-triflate (4.50 mL, 23.276 mmol) was added dropwise (20 min). The obtained reaction mixture was stirred under reflux for 1.5 h, cooled to RT and diluted with methylene chloride (500 ml). The organic solution was washed with cold NaHCO3 (5% aq., 2×150 mL), brine (150 mL), dried. (Na2SO4) and evaporated to dryness. The reaction mixture was purified by flash chromatography (400 g of silica gel, eluent: 28% EtOAc, 2% EtOH in CH2Cl2, v/v) to give 5.60 g (46%) of N2-Acetyl-2′,3′,5′-O-tribenzoyl-∃-L-guanosine 5.
Reaction SMILES: O.[NH2:2][NH2:3].C(O[CH:7]=[C:8]([C:14](=O)[C:15]([F:18])([F:17])[F:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])C>C(O)C>[F:16][C:15]([F:18])([F:17])[C:14]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][NH:3][N:2]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c[nH]nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
A solution of hydrazine hydrate (459 mg, 9.16 mol) in ethanol (5 mL) was added to a solution of ethyl 3-ethoxy-2-(trifluoroacetyl)acrylate (2.00 g, 8.33 mmol) in ethanol (15 mL) at 0° C. The reaction was allowed to warm to RT and stirred for 24 hrs. The reaction was concentrated in vacuo, dissolved in ethyl acetate (30 mL), washed with 5% citric acid (25 mL), saturated sodium bicarbonate (25 mL) and brine (25 mL), dried (Na2SO4) and concentrated in vacuo to afford ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (1.365 g, 79% yield). 1H NMR (300 MHz, DMSO-d6): δ 1.24 (t, 3 H), 4.22 (q, 2 H), 8.56 (s, 1 H); MS (ESI) m/z: 209.0 (M+H+).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C@@H:7]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[S:22][C:21]3[C:16](=[N:17][CH:18]=[CH:19][C:20]=3[O:23][C:24]3[CH:25]=[CH:26][C:27]4[C:31]([C:32](O)=[O:33])=[C:30]([CH3:35])[S:29][C:28]=4[CH:36]=3)[CH:15]=2)=[O:13])[CH2:8]1.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>ClC(Cl)C.C(Cl)Cl>[CH:37]1([NH:40][C:32]([C:31]2[C:27]3[CH:26]=[CH:25][C:24]([O:23][C:20]4[CH:19]=[CH:18][N:17]=[C:16]5[CH:15]=[C:14]([C:12]([N:9]6[CH2:10][CH2:11][C@@H:7]([O:6][CH3:5])[CH2:8]6)=[O:13])[S:22][C:21]=45)=[CH:36][C:28]=3[S:29][C:30]=2[CH3:35])=[O:33])[CH2:39][CH2:38]1
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)sc5c4)c3s2)C1
Reactant: NC1CC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Product: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)NC6CC6)c(C)sc5c4)c3s2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.4 %

Procedure:
Thionyl chloride (31 μl, 0.427 mmole) was added to a suspension of 6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid 11c (40 mg, 0.085 mmole) in dichloroethane (1 ml). The reaction mixture was heated to reflux for 90 minutes, cooled to room temperature, and concentrated in vacuo. The yellow residue was dissolved in CH2Cl2 (1 ml) and cyclopropylamine (30 μl, 0.427 mmole) was added. The resulting mixture was stirred at ambient temperature for 16 hours, diluted with CH2Cl2 (10 ml), and washed with H2O (5 ml). The aqueous layer was extracted with CH2Cl2 (2×5 ml) and the combined organics were dried (Na2SO4), filtered, and concentrated in vacuo. The crude mixture was purified by silica gel chromatography (5% MeOH/EtOAc) to afford 20 mg (46%) of a pale yellow solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.58 (1H, d, J=5.3 Hz), 8.46 (1H, d, J=4.5 Hz), 8.06 (1H, s) 7.96 (1H, d, J=2.3 Hz), 7.81 (1H, J=8.7 Hz), 7.32 (1H, dd, J=2.3, 8.7 Hz), 6.75 (1H, d, J=5.3 Hz), 4.10–3.82 (4H, m), 3.61 (2H, m), 3.27, 3.24 (3H, s), 2.91 (1H, m), 2.72 (1H, m), 2.57 (3H, s), 0.76–0.70 (2H, m), 0.50–0.55 (2H, m.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl.C(N(CC)CC)C>[F:1][C:2]1[CH:10]=[C:6]([C:7]([NH:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=2)=[O:9])[C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=C(O)c1cc(F)cnc1Oc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a stirred solution of 5-fluoro-2-(4-fluorophenoxy)nicotinic acid (step 2, 300 mg, 1.2 mmol) and methyl 4-(aminomethyl)benzoate hydrochloride (284 mg, 1.4 mmol) in dichloromethane (10 mL) were successively added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (670 mg, 3.5 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (368 mg, 2.4 mmol), and triethylamine (3 mL). After being stirred overnight, the reaction was quenched by the addition of saturated sodium bicarbonate aqueous solution (50 mL). The aqueous layer was extracted with dichloromethane (50 mL×2) and the combined organic layers were washed with brine (50 mL), dried (sodium sulfate), and evaporated. The remaining residue was purified by flush column chromatography on silica gel (50 g) eluting with hexane/ethyl acetate (3/1) to afford 407 mg (85%) of the title compounds as white solids: 1H-NMR (CDCl3) δ 8.39 (1H, dd, J=8.3, 3.1 Hz), 8.28 (1H, br.s), 8.05 (1H, d, J=3.1 Hz), 8.01 (2H, d, J=8.1 Hz), 7.42 (2H, d, J=8.1 Hz), 7.17–7.05 (4H, m), 4.76 (2H, d, J=5.9 Hz), 3.91 (3H, s); MS (ESI) m/z 399 (M+H)+, 397 (M−H)−.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:31])[NH:6][C:7]1[N:11]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH2:19][O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[CH:16]=2)[N:10]=[C:9]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:8]=1.C(C1C=C(NC([NH:54][C@@H:55]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[C@H:58]([O:65][C:66]3[CH:67]=[CH:68][C:69]4[N:70]([C:72]([N:75]5[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]5)=[N:73][N:74]=4)[CH:71]=3)[CH2:57][CH2:56]2)=O)N(C2C=CC(CO)=CC=2)N=1)(C)(C)C>>[C:27]([C:9]1[CH:8]=[C:7]([NH:6][C:5]([NH:54][C@@H:55]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[C@H:58]([O:65][C:66]3[CH:67]=[CH:68][C:69]4[N:70]([C:72]([N:75]5[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80]5)=[N:73][N:74]=4)[CH:71]=3)[CH2:57][CH2:56]2)=[O:31])[N:11]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH2:19][O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[CH:16]=2)[N:10]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cnn(CCCOC3CCCCO3)c2)n1
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(CO)cc2)n1
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cnn(CCCOC3CCCCO3)c2)n1

Procedure:
The title compound was prepared starting from Intermediate 3c and Intermediate 113c using analogous procedures to those described in Intermediate 106a. LCMS (Method 4): Rt 3.34 min, m/z 737 [MH+].
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:14]([C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:17]=1[CH2:18]Cl)[CH3:15].C(N[CH:29]([CH3:31])[CH3:30])(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[CH2:14]([C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:17]=1[CH2:18][O:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH2:21][C:20]1[C:17]([CH3:18])=[CH:16][CH:14]=[CH:15][C:31]=1[CH2:29][CH3:30])=[O:8])[CH3:15]
Reactant: CC(C)NC(C)C
Reactant: CCc1cccc(C)c1CCl
Reactant: O=C(O)c1cnc([N+](=O)[O-])c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CC#N
Product: CCc1cccc(C)c1COC(=O)c1cnc([N+](=O)[O-])c(OCc2c(C)cccc2CC)c1
Yield: 31.2 %

Procedure:
5-hydroxy-6-nitronicotinic acid (1 g, 5 mmol), 2-ethyl-6-methylbenzylchloride (1.85 g, 11 mmol), N,N-diisopropylamine (1.75 g, 14 mmol) and tetrabutylammonium iodide (0.1 g) was added to acetonitrile (10 ml) and was refluxed for 3 h. The solvent was evaporated under reduced pressure and the residue was solved in methylene chloride and washed with water. The organic layer was separated , dried and evaporated under reduced pressure. Purification of the residue by column chromatograhy on silica gel using n-hexane:methylene chloride (1:1) as eluent gave 0.7 g (29%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].I[CH2:28][C:29]([CH:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[CH2:33][CH2:32]1)=[O:30]>CS(C)=O.O1CCCC1.C(OCC)(=O)C>[CH2:40]([O:39][C:37]([N:34]1[CH2:35][CH2:36][CH:31]([C:29](=[O:30])[CH2:28][CH:9]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:16])[CH2:32][CH2:33]1)=[O:38])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C(Cc1ccncc1)c1ccc(F)cc1
Reactant: O=C(CI)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=C(CC(C(=O)c1ccc(F)cc1)c1ccncc1)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of the product of Step 1 (0.5 g (2.3 mmol)) in 5.0 ml of dry dimethyl sulfoxide was added 2.4 ml (2.4 mmol) of a 1M solution of sodium hexamethyldisilazide in tetrahydrofuran. After 10 minutes, a solution of 0.72 g (2.4 mmol) of the product of 4-(2-iodoacetyl)-1-(benzyloxycarbonyl)piperidine was added in 1 ml dimethyl sulfoxide dropwise. The reaction mixture was stirred for 2 hours, diluted with ethyl acetate (EtOAc, 20 ml) and washed with water (3×10 ml). The combined organic phases were washed with brine and dried over MgSO4. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by MPLC over silica gel eluting with 2% MeOH/CH2Cl2 to give the desired product. FAB ms: C28H27N2O4F:474; Observed: 475 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([C@@H:50]([NH2:52])[CH3:51])=[CH:46][CH:45]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:31]([NH:52][C@H:50]([C:47]2[CH:48]=[CH:49][C:44]([O:43][CH3:42])=[CH:45][CH:46]=2)[CH3:51])=[O:33])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc([C@H](C)N)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc([C@H](C)NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 119.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (70 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (33 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 75 min. Next, a solution of (1S)-1-(4-methoxyphenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (63 mg, yield 57%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH3:22][NH:23][CH3:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:22][N:23]([CH3:24])[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14]
Reactant: CNC
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with dimethylamine hydrochloride (CAN 506-59-2) in the presence of TBTU and DIEA to give the title compound as light yellow oil; MS (EI): m/e=312.4 [MH+].
Reaction SMILES: [CH3:1][C:2]([CH3:56])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:55])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:54])=[CH:11]/[CH2:12][CH2:13]/[C:14](/[CH3:53])=[CH:15]/[CH2:16][CH2:17]/[C:18](/[CH3:52])=[CH:19]/[CH2:20][CH2:21]/[C:22](/[CH3:51])=[CH:23]/[CH2:24][CH2:25]/[C:26](/[CH3:50])=[CH:27]/[CH2:28][CH2:29]/[C:30](/[CH3:49])=[CH:31]/[CH2:32][CH2:33]/[C:34](/[CH3:48])=[CH:35]/[CH2:36][CH2:37]/[C:38](/[CH3:47])=[CH:39]/[CH2:40][CH2:41]/[C:42](/[CH3:46])=[CH:43]/[CH2:44][OH:45].[C:57](Cl)(=[O:64])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>N1C=CC=CC=1.CCCCCC>[C:57]([O:45][CH2:44][CH:43]=[C:42]([CH3:46])[CH2:41][CH2:40][CH:39]=[C:38]([CH3:47])[CH2:37][CH2:36][CH:35]=[C:34]([CH3:48])[CH2:33][CH2:32][CH:31]=[C:30]([CH3:49])[CH2:29][CH2:28][CH:27]=[C:26]([CH3:50])[CH2:25][CH2:24][CH:23]=[C:22]([CH3:51])[CH2:21][CH2:20][CH:19]=[C:18]([CH3:52])[CH2:17][CH2:16][CH:15]=[C:14]([CH3:53])[CH2:13][CH2:12][CH:11]=[C:10]([CH3:54])[CH2:9][CH2:8][CH:7]=[C:6]([CH3:55])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:56])[CH3:1])(=[O:64])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Reactant: O=C(Cl)c1ccccc1
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.5 Grams of undecaprenol were dissolved in 30 ml of pyridine and the solution was added with a solution of 1.3 g of benzoyl chloride in pyridine dropwise over 30 minutes. After completion of the addition, the mixture was stirred at room temperature for one hour to complete the reaction. The reaction product was diluted with n-hexane, washed with water and concentrated. The concentrate was purified by chromatography with 50 g of silica gel in n-hexane/benzene solvent mixture as elution solvent to obtain white waxy final product. Yield: 3.6 g.______________________________________Elementary analysis as C62H94O2 : C H______________________________________Theoretical (%): 85.45 10.87Found (%): 85.43 10.86______________________________________
Reaction SMILES: BrC1C=C(Cl)C=CC=1O.C(O[CH:13](OCC)[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Br:23])C>>[Cl:22][C:19]1[CH:18]=[C:17]([Br:23])[C:16]2[O:15][CH:14]=[CH:13][C:21]=2[CH:20]=1
Reactant: CCOC(COc1ccc(Cl)cc1Br)OCC
Agent: Oc1ccc(Cl)cc1Br
Product: Clc1cc(Br)c2occc2c1

Procedure:
Beginning with 25 gm (120.5 mmol) 2-bromo-4-chlorophenol, 41.16 gm crude 2-(2-bromo-4-chlorophenoxy)-acetaldehyde diethyl acetal was prepared essentially as described in Preparation IV. A sample of this crude material was subjected to silica gel chromatography to provide an analytical sample.
Reaction SMILES: Cl[C:2](=[CH2:12])[CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[OH-].[Na+].Cl>CN(C)C=O>[C:6]1([CH:4]([CH2:3][C:2]#[CH:12])[OH:5])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=C(Cl)CC(O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C#CCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 96.3 %

Procedure:
40.00 Grams of the 2-chloroallylphenylcarbinol obtained above were disolved in 400 g of N,N-dimethylformamide, and 17.52 g of sodium hydroxide in a flake form were added. The mixture was stirred at 25° C. for 7 hours. After the reaction was completed the reaction mixture was neutralized with concentrated hydrochloric acid, and insolubles were filtered off. The filtrate was concentrated under reduced pressure, and then the concentration residue was subjected to extraction with toluene, washed with a 7% sodium carbonate aqueous solution and dried over sodium sulfate. The desiccant was filtered off, and the toluene was distilled off under reduced pressure. The resultant oily substance was distilled under reduced pressure to give 30.84 g of phenylpropargylcarbinol. The results were as follows.