Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:20][N:21]([CH3:40])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[NH:29][C:30]3[CH:36]=[C:35]([C:37]([O-])=[O:38])[CH:34]=[CH:33][C:31]=3[N:32]=2)=[CH:24][CH:23]=1>>[CH3:1][N:2]([CH3:19])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:16]=[CH:15][C:13]([NH:14][C:37]([C:35]3[CH:34]=[CH:33][C:31]4[NH:32][C:28]([C:25]5[CH:24]=[CH:23][C:22]([N:21]([CH3:40])[CH3:20])=[CH:27][CH:26]=5)=[N:29][C:30]=4[CH:36]=3)=[O:38])=[CH:12][CH:11]=2)=[O:8])=[CH:17][CH:18]=1
Reactant: CN(C)c1ccc(-c2nc3ccc(C(=O)[O-])cc3[nH]2)cc1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc(N)cc2)cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc(NC(=O)c3ccc4[nH]c(-c5ccc(N(C)C)cc5)nc4c3)cc2)cc1

Procedure:
Compound 443 was prepared from 4-(4-dimethylaminobenzamido)aniline and 2-(4-dimethylaminophenyl)benzimidazole-5-carboxylate by standard conditions. [M+H]+ calcd for C31H30N6O2: 519.24; found: 519.04.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])O1.Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:30]=[C:31]3[CH:37]=[CH:36][NH:35][C:32]3=[N:33][CH:34]=2)=[C:25]([F:38])[CH:24]=1>>[F:38][C:25]1[CH:24]=[C:23]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]([CH2:19][CH3:20])(=[O:17])=[O:18])[CH:28]=[CH:27][C:26]=1[C:29]1[N:30]=[C:31]2[CH:37]=[CH:36][NH:35][C:32]2=[N:33][CH:34]=1
Reactant: CCS(=O)(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Fc1cc(Br)ccc1-c1cnc2[nH]ccc2n1
Product: CCS(=O)(=O)Nc1ccccc1-c1ccc(-c2cnc3[nH]ccc3n2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Step C of Example 490 using N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanesulfonamide and 2-(4-bromo-2-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine. MS (ESI): mass calcd. for C20H17FN4O2S, 396.11; m/z found, 397.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 8.78 (d, J=2.6, 1H), 8.20-8.11 (m, 2H), 7.75-7.66 (m, 2H), 7.47-7.37 (m, 1H), 7.36-7.28 (m, 2H), 7.27-7.20 (m, 1H), 6.87-6.79 (m, 1H), 6.59 (s, 1H), 3.11 (q, J=7.4, 2H), 1.33-1.18 (m, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@@H:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[N:3]=1.Cl.[NH2:20][C@@H:21]1[CH2:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([OH:28])[C@H:22]1[OH:29].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C@@H:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[N:3]=[C:2]([NH:20][C@@H:21]2[CH2:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([OH:28])[C@H:22]2[OH:29])[N:7]=1
Reactant: N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Reactant: Clc1nc(Cl)nc(N[C@H]2CCc3ccccc32)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: OC[C@H]1C[C@@H](Nc2nc(Cl)nc(N[C@H]3CCc4ccccc43)n2)[C@H](O)[C@@H]1O
Temperature: 150 °C
Yield: 88 %

Procedure:
A mixture of 4,6-dichloro-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-1,3,5-triazin-2-amine (735 mg, 2.61 mmol), (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol hydrochloride (400. mg, 218 mmol), potassium carbonate (602 mg, 4.36 mmol) and 1,4-dioxane (3.60 mL) in a sealed tube was heated to 150° C. for 20 mins using MWI. Silica gel chromatography eluting with a gradient of 2 to 7% MeOH in DCM afforded the title compound as a white solid (750. mg, 88%). LC/MS: Rt=1.42 min, ES+ 392 (FA standard).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][N:7]=1)(=O)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[OH:4][CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][N:7]=1
Reactant: COc1ccnc(COC(C)=O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccnc(CO)c1C
Yield: 46 %

Procedure:
15.8 g of 2-acetoxymethyl-3-methyl-4-methoxy-pyridine was added dropwise to a 25% aqueous solution of sodium hydroxide, and the mixture was allowed to react for one hour at room temperature. Subsequently, the reaction liquid was diluted with toluene, and then the toluene phase was washed with water, dried over anhydrous magnesium sulfate, and then concentrated, to obtain 5.7 g of 2-hydroxymethyl-3-methyl-4-methoxy-pyridine as an oily matter.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>CC(C)=O>[CH3:13][O:12][C:1](=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([O:8][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][Br:20])=[C:4]([O:5][CH3:6])[CH:3]=1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCCBr)c(OC)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.4 %

Procedure:
To a solution of methyl vanillate (9.109 g, 50 mmol) in acetone (200 mL) were added K2CO3 (27.64 g, 200 mmol) and 1,5-dibromopentane (20.4 mL, 150 mmol). The resulting mixture was heated to reflux. After 6 h, TLC showed no starting material left. The mixture was cooled to rt, and the solid was removed by filtration. The filtrate was concentrated. Purification by flash chromatography (silica gel, 8:2 hexanes/EtOAc) afforded 4-(5-bromopentyloxy)-3-methoxy-benzoic acid methyl ester 15 as white solid (13.65 g, 82%): 1HNMR (300 MHz, CDCl3) δ 1.60-1.66 (m, 2H), 1.85-1.97 (m, 4H), 3.42 (t, J=5.0 Hz, 2H), 3.87 (s, 3H), 3.89 (s, 3H), 4.06 (t, J=5.0 Hz, 2H), 6.85 (d, J=6.3 Hz, 1H), 7.52 (d, J=1.5 Hz, 1H), 7.63 (dd, J=6.3, 1.5 Hz, 1H); EIMS m/z 353 and 355 ([M]++Na).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:13][N:12](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:11][NH:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CNC1
Yield: 67.1 %

Procedure:
3.4 g (9.6 mmol) of 3-(N-tert-butyloxycarbonylaminomethyl)-1benzhydryl azetidine was dissolved in 170 mL MeOH and hydrogenated over 0.30 g Pd(OH)2 at 5 MPa over night. The catalyst was filtered off and the solvent evaporated. The crude product was purified by flash chromatography using MeOH/CH2Cl2, 1/9, followed by MeOH (saturated with NH3 (g))/CH2Cl2, 1/9, as eluent to yield 1.2 g (67%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24]OS(C)(=O)=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:30][CH2:31][CH2:32][CH2:33][N:34]1[CH:38]=[CH:37][N:36]=[CH:35]1>>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][NH:30][CH2:31][CH2:32][CH2:33][N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2)=[O:5]
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: NCCCn1ccnc1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCNCCCn2ccnc2)ccc1Cl

Procedure:
Synthesized from 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 6e, 1 mg) and 1-(3-aminopropyl)imidazole according to the procedure described in Example 6f to afford the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:29]=4[CH3:35])[CH2:24][CH2:23]3)[CH:17]=1)[CH2:10][C:9]2([CH3:37])[CH3:36])=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:35][C:29]1[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:28]=1[N:25]1[CH2:26][CH2:27][N:22]([C:18]2[CH:17]=[C:16]([CH:11]3[CH2:10][C:9]([CH3:37])([CH3:36])[C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:21]=[CH:20][CH:19]=2)[CH2:23][CH2:24]1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(N3CCN(c4ccc(C)cc4C)CC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(N2CCN(c3cccc(C4CC(C)(C)c5cc(C(=O)O)ccc5N4)c3)CC2)c(C)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 95.1 %

Procedure:
A mixture of 2-{3-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-phenyl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.28 g, 0.56 mmol) in methanol (3 mL) and tetrahydrofuran (10 mL), 30% sodium hydroxide in water (1 mL). The reaction mixture was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-{3-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-phenyl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.25 g, 90%) as a white solid which was used for next step without further purification: MS (ESI) M+1=470.3.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.FC(F)(F)S(O[Si:23]([CH3:26])([CH3:25])[CH3:24])(=O)=O>C1(C)C=CC=CC=1>[CH3:24][Si:23]([N:2]([Si:23]([CH3:26])([CH3:25])[CH3:24])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:26])[CH3:25]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCN([Si](C)(C)C)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 39 h
Yield: 89.6 %

Procedure:
About 7.23 g of ethyl 3-aminopropionate hydrochloride, 15.71 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 23.00 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was stirred at room temperature for 39 hours to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 40 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding ethyl 3-[bis(trimethylsilyl)amino]propionate (3-BTMSAEP) as a colorless oil (11.03 g, 90% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 3.91 (quartet, 2 H, OCH2 protons), 3.21 (multiplet, 2 H, NCH2CH2 protons), 2.36 (multiplet, 2 H, NCH2CH2 protons), 0.91 (triplet, 3 H, CH3 protons), 0.07 (singlet, 18 H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:41][C:42]1[CH:46]=[CH:45][N:44]([CH2:47][C:48]([CH3:51])([OH:50])[CH3:49])[N:43]=1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:12])[NH:41][C:42]1[CH:46]=[CH:45][N:44]([CH2:47][C:48]([OH:50])([CH3:49])[CH3:51])[N:43]=1)[CH2:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: CC(C)(C)OC(=O)NC(CC1CCOCC1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCOCC2)NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
A solution of 2-t-butoxycarbonylamino-3-(tetrahydro-pyran-4-yl)-propionic acid (500 mg, 1.83 mmol) in dichloromethane (15 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (285 mg, 1.85 mmol) and 1-hydroxybenzotriazole (260 mg, 1.92 mmol). The reaction mixture was stirred at 25° C. for 2 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 312 mg, 2.01 mmol). The reaction mixture was then stirred for 18 h at 25° C. under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, to afford [1-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylcarbamoyl]-2-(tetrahydro-pyran-4-yl)-ethyl]-carbamic acid t-butyl ester (700 mg, 93%) as a white solid: LR-ES-MS m/z calculated for C20H34N4O5 [M]+ 410, observed [M+H]+ 411.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[C:21]#[N:22])=[O:17])[CH2:12][CH2:11]2)=[CH:2]1.[OH-].[Na+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51]Br)=[CH:49][CH:48]=1>C1COCC1>[F:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]#[N:22])=[O:17])[CH2:12][CH2:11]3)=[CH:2]2)=[CH:49][CH:48]=1
Reactant: N#Cc1cccc(C(=O)N2CCC(c3c[nH]c4ccccc34)CC2)c1
Reactant: Fc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1cccc(C(=O)N2CCC(c3cn(Cc4ccc(F)cc4)c4ccccc34)CC2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-[4-(1H-Indol-3-yl)-piperidine-1-carbonyl]-benzonitrile (0.08 g, 0.24 mmol) is dissolved in 2 ml THF, then 2 ml of 50% NaOH, 0.2 ml tetrabutyl ammonium hydroxide (1.0M in MeOH), 4-fluoro-benzyl bromide (0.055 g, 0.29 mmol) are added and the reaction mixture is stirred at RT for 1.5 hours. The layers are separated and the organic solvent is removed under the reduced pressure, purified by a silica gel flash column using heptane and ethyl acetate as the elutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:13]=[C:14]([N:18]3[CH2:22][C@@H:21]4[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C@@H:20]4[CH2:19]3)[CH:15]=[N:16][CH:17]=2)=O)[CH:5]=[C:6]([F:8])[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:13]=[C:14]([N:18]3[CH2:22][C@@H:21]4[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C@@H:20]4[CH2:19]3)[CH:15]=[N:16][CH:17]=2)=[S:42])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)Nc4cc(F)cc(F)c4)c3)C[C@@H]2C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=S)Nc4cc(F)cc(F)c4)c3)C[C@@H]2C1
Temperature: 110 °C
Reaction time: 18 h
Yield: 191.6 %

Procedure:
The product from Example 42A (60 mg, 0.14 mmol) and Lawesson's reagent (27 mg, 0.068 mmol) were combined with toluene (3 mL) and stirred at 110° C. for 18 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and purified by silica gel flash chromatography (EtOAc, Rf=0.35) to provide the title compound (60 mg, 97%). MS (APCI) m/z 387 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=1)[C:12](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>CN(C)C=O.O1CCCC1>[CH2:1]([C:8]1[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=1)[CH2:12][Cl:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Cc2ccccc2)[nH]c1=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=c1[nH]c(Cc2ccccc2)ccc1CCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 5.9 g. of 6-benzyl-1,2-dihydro-2-oxonicotinic acid in 60 ml. of tetrahydrofuran is treated with 2.04 ml. of thionyl chloride and six drops of dimethylformamide. The mixture is stirred at room temperature for 16 hours, then evaporated at reduced pressure to give a residue of 6-benzyl-1,2-dihydro-2-oxonicotinyl chloride. This acid chloride is dissolved in 90 ml. of tetrahydrofuran, the solution is cooled to 0°-5° C. and trated with an ice-cold solution of 7.59 g. of D-N-(trimethylsilyl)-2-phenylglycine trimethylsilyl ester in 60 ml. of tetrahydrofuran, then with 2.87 ml. of N-methylmorpholine. The mixture is stirred at 0°-5° C. for 1 hour, at room temperature for 2 hours, then poured into 500 ml. of water and the pH adjusted to 8.3 with saturated aqueous sodium bicarbonate. The solution is washed with several portions of ethyl acetate and the washings discarded. The solution is adjusted to pH 2.0 with 12% hydrochloric acid and extracted with several portions of ethyl acetate. The combined acetate extract is washed with water, dried and evaporated at reduced pressure to give D-(+)-N-(6-benzyl-1,2-dihydro-2-oxonicotinyl)-2-phenylglycine; m.p. 142°-145° C. after two crystallizations from acetonitrile; [α]D25 +23.0° (1.025% in tetrahydrofuran).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[O:15])OC(C)(C)C)=[C:6]([CH3:16])[CH:5]=[CH:4][N:3]=1.Cl.[CH2:18]([O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+]>CC(O)C.C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([N:30]2[C:2]3=[N:3][CH:4]=[CH:5][C:6]([CH3:16])=[C:7]3[NH:8][C:9]2=[O:15])=[CH:31][CH:32]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ccnc(Cl)c1NC(=O)OC(C)(C)C
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: Cc1ccnc2c1[nH]c(=O)n2-c1ccc(OCc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 36.2 %

Procedure:
A mixture of tert-butyl (2-chloro-4-methylpyridin-3-yl)carbamate (2.00 g), 4-(benzyloxy)aniline hydrochloride (2.91 g), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (381 mg), sodium t-butoxide (1.90 g) and Pd2(dba)3 (302 mg) in 2-propanol (6 mL) and toluene (24 mL) was stirred at 100° C. under N2 atmosphere for 24 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in MeOH, and the precipitate was removed by filtration. The filtrate was concentrated and the residue was purified by column chromatography (NH silica gel, eluted with 15%-50% AcOEt in hexane) to give 3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (988 mg) as a colorless solid.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[S:8][C:7]([NH2:9])=[N:6][N:5]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[I-].[Na+].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:10]1([CH2:2][CH2:3][C:4]2[S:8][C:7]([NH2:9])=[N:6][N:5]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: Nc1nnc(CCCl)s1
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Nc1nnc(CCN2CCOCC2)s1
Reaction time: 4 h

Procedure:
A mixture of 5-(2-chloro-ethyl)-[1,3,4]thiadiazol-2-ylamine (54a) (2.5 g, 15.3 mmol), morpholine (2.67 g, 30 mmol) and sodium iodide (0.15 g) is heated with stirring in toluene at 80° C. After adding triethylamine (2.13 ml, 15.3 mmol) heating is continued for an additional 4 hours. The solvent is removed and the residue is partitioned between water (pH 13) and n-butanol. The organic extract is dried (MgSO4) and the solid is removed to afford the titled compound as a yellow solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:14]=[C:15]([C:19]2[CH2:20][CH2:21][O:22][CH2:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([C:19]23[O:9][CH:20]2[CH2:21][O:22][CH2:23][CH2:24]3)[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1cccc(C2=CCOCC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Brc1cccc(C23CCOCC2O3)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
3-Chloroperbenzoic acid (purity: 80%, 25.1 g) was added to a solution of 4-(3-bromophenyl)-3,6-dihydro-2H-pyran (21.4 g) in dichloromethane (400 mL) in an ice bath. The mixture was stirred at the same temperature for three hours, and then warmed to room temperature and stirred for five hours. Ice and a saturated sodium bicarbonate solution were added to the reaction mixture, and the organic layer was separated. The organic layer was sequentially washed with a saturated sodium bicarbonate solution, a sodium thiosulfate solution and brine. The aqueous layers were combined and extracted with ethyl acetate, and the organic layer was sequentially washed with a sodium bicarbonate solution, a sodium thiosulfate solution and brine. The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (17.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17](=[O:26])[C:18]([CH3:25])([S:20][C:21]([F:24])([F:23])[F:22])[CH3:19]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:17](=[O:26])[C:18]([CH3:25])([S:20][C:21]([F:24])([F:23])[F:22])[CH3:19])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(SC(F)(F)F)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(SC(F)(F)F)C(=O)COc1ccc(Cl)cc1
Yield: 72.4 %

Procedure:
26 g (0.21 mol) of 4-chlorophenol and 42 g (0.3 mol) of potassium carbonate were introduced into 250 ml of acetone. 53 g (0.2 mol) of 1-bromo-3-methyl-3-trifluoromethylthio-butan-2-one in 50 ml of acetone were slowly added dropwise to the mixture, under reflux. After the end of the addition, the mixture was stirred under reflux for 12 hours and was filtered, and the filtrate was concentrated. The residue was taken up in 500 ml of methylene chloride, the solution was extracted by shaking with water and sodium bicarbonate solution, and the organic phase was dried over sodium sulphate and concentrated. The residue was distilled in vacuo. 45.3 g (73% of theory) of 1-(4-chlorophenoxy)-3-methyl-3-trifluoromethylthio-butan-2-one of boiling point 105° C./0.4 mbar were obtained. ##STR14##
Reaction SMILES: I[CH2:2][O:3][C:4]([O:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5].[Na].[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[CH2:21][NH:22][C:23]([C:25]1[C:26](=[O:41])[C:27]([OH:40])=[C:28]2[C:33](=[O:34])[N:32]3[C@@H:35]([CH3:38])[CH2:36][O:37][C@@H:31]3[CH2:30][N:29]2[CH:39]=1)=[O:24].C(=O)([O-])[O-].[K+].[K+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:11][O:10][C:8](=[O:9])[CH2:7][O:6][C:4]([O:3][CH2:2][O:40][C:27]1[C:26](=[O:41])[C:25]([C:23]([NH:22][CH2:21][C:15]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=2[F:13])=[O:24])=[CH:39][N:29]2[C:28]=1[C:33](=[O:34])[N:32]1[C@@H:35]([CH3:38])[CH2:36][O:37][C@@H:31]1[CH2:30]2)=[O:5]
Reactant: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(O)c3C(=O)N12
Reactant: COC(=O)COC(=O)OCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Product: COC(=O)COC(=O)OCOc1c2n(cc(C(=O)NCc3ccc(F)cc3F)c1=O)C[C@H]1OC[C@H](C)N1C2=O

Procedure:
The title compound was prepared from methyl ({[(iodomethyl)oxy]carbonyl}oxy)acetate (103 mg, 0.374 mmol), 1b (80 mg, 0.187 mmol), potassium carbonate (78 mg, 0.5621 mmol), and tetrabutylammonium hydrogen sulfate (64 mg, 0.187 mmol), using a similar process to that described in example 1. 1H NMR (CDCl3) δ 10.20 (m, 1H), 8.39 (s, 1H), 7.33 (m, 1H), 6.78 (m, 2H), 6.00 (d, J=6.8 Hz, 1H), 5.88 (d, J=6.8 Hz, 1H), 5.30 (dd, J=10, 4 Hz, 1H), 4.63-4.58 (m, 4H), 4.43-4.28 (m, 4H), 3.93 (m, 1H), 3.73 (s, 2H), 3.66 (m, 1H), 1.38 (d, J=6 Hz, 3H). ES+ MS: 552 (M+1).