Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)=O.[NH:4]1[CH2:7][CH:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5]1.CCN(CC)CC.[O:21](C(OC(C)(C)C)=O)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=O>CN(C=O)C>[C:22]([N:4]1[CH2:7][CH:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:21]
Reactant: CCOC(=O)CC1CNC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=CO
Product: CCOC(=O)CC1CN(C(=O)OC(C)(C)C)C1
Reaction time: 20 h
Yield: 39.9 %

Procedure:
A stirred solution of 131 (10.3 mmol), DMF (50 mL), and NEt3 (5.0 mL, 36.0 mmol) at 0° C. was treated with BOC2O (2.5 g, 11.3 mmol) followed by removal of the cooling bath. After 20 h, the reaction mixture was diluted with EtOAc and then washed with H2O, 5% KHSO4, sat. NaHCO3, and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 30% EtOAc/hexanes) gave 132 (1.0 g) as a colorless oil. Rf 0.44 (silica, EtOAc/hexanes). 1H NMR (300 MHz, CDCl3) δ 4.13 (q, J=7 Hz, 2H), 4.01 (m, 2H), 3.60 (dd, J=9 and 6 Hz, 1H), 2.88 (m, 1H), 2.61 (d, J=8 Hz, 2H), 1.44 (s, 9H) 1.25 (t, J=7H, 3H). ##STR57##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([OH:30])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH2:71][CH3:72])[CH2:42][CH2:43][C@@H:44]([NH:53][C:54]1[CH:59]=[CH:58][C:57]([S:60]([NH2:63])(=[O:62])=[O:61])=[CH:56][C:55]=1[S:64]([C:67]([F:70])([F:69])[F:68])(=[O:66])=[O:65])[CH2:45][S:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH2:71][CH3:72])[CH2:42][CH2:43][C@@H:44]([NH:53][C:54]1[CH:59]=[CH:58][C:57]([S:60]([NH:63][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([C@H:14]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[OH:30])[CH2:16][CH2:17]3)=[CH:22][CH:23]=2)(=[O:61])=[O:62])=[CH:56][C:55]=1[S:64]([C:67]([F:68])([F:69])[F:70])(=[O:66])=[O:65])[CH2:45][S:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)([C:34]([CH3:37])([CH3:35])[CH3:36])([CH3:33])[CH3:32]
Reactant: CCN(CCO[Si](C)(C)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Reactant: O=C(O)c1ccc(N2CCC([C@@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCN(CCO[Si](C)(C)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
(R)-4-(4-((4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 40, 2.15 g, 5.10 mmol), (R)-4-(4-((2-(tert-butyldimethylsilyloxy)ethyl)(ethyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 65, 3.41 g, 5.10 mmol), DMAP (1.87 g, 15.29 mmol) and EDC (1.954 g, 10.19 mmol) were dissolved in DCM (17 ml). The reaction mixture was stirred at r.t. overnight, diluted with DCM (50 ml) and washed with NH4Cl solution (saturated, aq., 20 ml), saturated aq. NaHCO3 (20 ml) and brine (20 ml). The collected organic layer was dried over Na2SO4 and concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO, 12 g silica gel, eluted with 0→20% MeOH in EtOAc) to provide the title compound (3.41 g, yield: 62%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([CH2:34][CH:35]=[CH2:36])[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[Cl:25])[C:21]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH2:38].C[N+]1([O-])CCOCC1.[OH2:47]>CC(C)=O.C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([CH2:34][CH:35]([OH:47])[CH2:36][OH:38])[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[Cl:25])[C:21]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O
Reactant: C=CCC1(NC(=O)OC(C)(C)C)CCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CC1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: CC(C)(C)O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC1(CC(O)CO)CCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CC1
Temperature: 25 °C

Procedure:
A solution of 100 mg (0.19 mmol) of [1-allyl-4-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester (52) in a mixture of 250 μL of water and 500 μL of acetone was treated with 36.2 mg (0.27 mmol) N-methylmorpholine oxide monohydrate and 24.0 μL (1.91 μmol) of a 2.5% solution of osmium tetroxide in tert-butanol. The mixture was stirred at room temperature until complete conversion was indicated by LCMS. The reaction was then quenched by addition of saturated aqueous sodium bisulfite, extracted with ethyl acetate, dried over magnesium sulfate and concentrated. 68 mg of crude [4-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-1-(2,3-dihydroxy-propyl)-cyclohexyl]-carbamic acid tert-butyl ester (56) could be isolated as mixture of stereoisomers. Rt=1.92 min (Method C). Detected mass: 557.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][C:4]([N:6]=[C:7]=[S:8])=[O:5].[CH3:10][NH:11][CH3:12].C1COCC1>>[CH3:10][N:11]([CH3:12])[C:7]([NH:6][C:4](=[O:5])[CH:3]=[C:2]([CH3:9])[CH3:1])=[S:8]
Reactant: CNC
Reactant: CC(C)=CC(=O)N=C=S
Solvent: C1CCOC1
Product: CC(C)=CC(=O)NC(=S)N(C)C
Yield: 84.9 %

Procedure:
Was prepared in the same manner as described in General Procedure Example 1b) using 3-methylbut-2-enoyl isothiocyanate (2 g, 14.2 mmol, Eq: 1.00) and dimethylamine solution 2M in THF (7.08 ml, 14.2 mmol, Eq: 1.00). Evaporation of the solvent afforded 1,1-dimethyl-3-(3-methyl-but-2-enoyl)-thiourea (2.239 g/84.9%) as a yellow oil which was used without further purification in the next step. MS: m/e=187.4 (M+H+)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[CH3:2].[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1.[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)Cl>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[CH3:2]
Reactant: CCOC(=O)CCc1ccccc1OC
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(C(=O)CCC(=O)O)ccc1OC
Yield: 77.6 %

Procedure:
Starting with a mixture of 3.12 g (15.0 mmol) of 2-methoxybenzenepropanoic acid ethyl ester, 1.53 g (15.3 mmol) of succinic anhydride, 4.46 g (33.5 mmol) of aluminum chloride and 20 mL of methylene chloride, the title compound (3.59 g, 77.7%) was obtained as a white solid, mp 128°-129° C. (recrystallized from ethanol), using the procedure of example 139.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](Cl)=[C:7]([N+:16]([O-:18])=[O:17])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].[CH2:20]([NH2:22])[CH3:21]>O1CCCC1>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:22][CH2:20][CH3:21])=[C:7]([N+:16]([O-:18])=[O:17])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c([N+](=O)[O-])c(Cl)c2ccccc21
Reactant: CCN
Solvent: C1CCOC1
Product: CCCCn1c(=O)c([N+](=O)[O-])c(NCC)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
3.5 g (0.013 mole) of Compound d in Reference Example 4 was dissolved in 30 ml of tetrahydrofuran, and 8.0 ml (0.13 mole) of ethylamine was added with ice cooling, followed by stirring at room temperature overnight. The solvent was evaporated under reduced pressure and ice water was added to the residue. The precipitate was collected by filtration and dried, to afford 3.5 g of Compound e (97%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)(=O)C>[CH2:29]([O:14][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[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]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOC(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
To a solution of N-benzyloxycarbonyl glycine (3 g, 14.3 mmol), tetradecylalcohol (3.07 g, 14.3 mmol) an N,N-dimethylaminopyridine (87 mg, 10.3 mmol) in ethyl acetate (100 ml) was added DCC (2.98 g, 2.34 mmol) and the resulting mixture was stirred for 2 h at room temperature. After the precipitation which appeared was filtered off, the filtrate was concentrated in vacuo. The residue was washed with ethanol to give N-benzyloxycarbonylglycine tetradecyl ester (7) (3.46 g, 59.5%) as crystal.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:31])[CH3:30])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH:35]([C:37]1([C:43]([OH:45])=[O:44])[CH2:42][O:41][CH2:40][O:39][CH2:38]1)=[CH2:36].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1.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]>[OH:32][C@@H:28]([CH:29]([CH3:31])[CH3:30])[C:27]([NH:26][C@@H:24]([CH3:25])[C:23]([N:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([C:15]([NH:14][C@@H:12]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2](/[CH:36]=[CH:35]/[C:37]4([C:43]([OH:45])=[O:44])[CH2:42][O:41][CH2:40][O:39][CH2:38]4)=[CH:3][CH:4]=3)[N:9]=2)[CH3:13])=[O:16])[NH:18]1)=[O:34])=[O:33]
Reactant: C=CC1(C(=O)O)COCOC1
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/C4(C(=O)O)COCOC4)cc3n2)N1
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (398.4 mg, 0.745 mmol), 5-vinyl-[1,3]dioxane-5-carboxylic acid (117.9 mg, 0.745 mmol), tri(o-tolyl)phosphine (45.3 mg, 0.149 mmol) and triethylamine (0.32 mL, 2.235 mmol) in 1,4-dioxane (15 mL) was degassed by bubbling nitrogen through for 5 minutes then warmed to 50° C. and treated with tris(dibenzylideneacetone)dipalladium(0) (68.2 mg, 0.074 mmol). After stirring at 100° C. for 40 minutes the reaction was cooled to room temperature, filtered through a pad of Celite, which was rinsed with ethyl acetate. The volatiles were removed in vacuo to provide crude title compound as an orange foam that was used without further purification. LCMS (m/z) 612.2 [M+H], Tr=1.70 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[N:9]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH2:8][CH2:7][C:6]=2[CH:19]=1.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([C:27]([N:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH2:30]2)=[O:28])[CH:22]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[N:9]([CH:13]3[CH2:14][CH2:15][N:16]([C:21]4[CH:22]=[C:23]([C:27]([N:29]5[C:37]6[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=6)[CH2:31][CH2:30]5)=[O:28])[N:24]=[CH:25][N:26]=4)[CH2:17][CH2:18]3)[CH2:8][CH2:7][C:6]=2[CH:19]=1
Reactant: O=C1Nc2ccc(Cl)cc2CCN1C1CCNCC1
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(N2CCC(N3CCc4cc(Cl)ccc4NC3=O)CC2)ncn1)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
110 mg (0.36 mmol) 7-chloro-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one were added to 87.6 mg (0.34 mmol) (6-chloropyrimidin-4-yl)-(2,3-dihydro-indol-1-yl)-methanone and 63 μL (0.37 mmol) DIPEA in 2.5 mL DMF. The reaction mixture was stirred overnight at RT, then concentrated by rotary evaporation using the rotary evaporator and purified by preparative HPLC. The corresponding product fractions were combined and evaporated down using the rotary evaporator. The residue was taken up in DMF and combined with methanol. The substance was precipitated, suction filtered, washed with a little methanol and dried.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.BrCCBr.[Mg].[CH3:14][Si:15]([CH3:18])([CH3:17])Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:14][Si:15]([CH3:18])([CH3:17])[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Mg]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: Cc1cccc([Si](C)(C)C)c1
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
A solution of m-chlorotoluene (12.66 g, 0.100 mol) and 1,2-dibromoethane (0.5 ml) in THF (20 ml) was added to magnesium turnings (2.67 g, 0.110 mol). The mixture was heated under reflux for 4 h, after which the heating bath was removed and trimethylchlorosilane (11.08 g, 0.102 mol) was added so that gentle reflux was maintained. The mixture was stirred for another 0.5 h and 5% NaHCO3 (100 ml) was then added. The resulting mixture was extracted with CH2Cl2 (3×50 ml), the organic phase was washed with brine and dried (MgSO4). Filtration and evaporation provided 15.05g (92%) of 36 as a pale yellow liquid. Spectroscopic data were identical to those previously reported in the literature.40
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:25])=[C:16]([CH:24]=1)[C:17]([NH:19][CH2:20][CH2:21][NH:22][OH:23])=[O:18]>N1C=CC=CC=1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:25])=[C:16]([CH:24]=1)[C:17]([NH:19][CH2:20][CH2:21][N:22]([CH:8]=[O:10])[OH:23])=[O:18]
Reactant: O=C(NCCNO)c1cc(Br)ccc1Cl
Reactant: O=CO
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: O=CN(O)CCNC(=O)c1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
A mixture of acetic anhydride (2 mL) and formic acid (1 mL) was allowed to stand at 55° C. for 2.5 h. After cooling to 0° C., the resulting mixed anhydride (0.5 mL) was added to a solution of 5-bromo-2-chloro-N-(2-hydroxyamino-ethyl)-benzamide (0.7 g, 2.4 mmol) in pyridine (6 mL) at 0° C. under an argon atmosphere. The reaction mixture was stirred for 1 h and the pyridine removed in vacuo. The residue was chased twice with water and twice with MeOH. The resulting solid was washed with ether/acetonitrile (9:1) to provide the title compound (0.42 g, 55%) as a white solid. 1H NMR* (400 MHz, CD3OD): δ 8.35 (s, 0.5H); 7.95 (s, 0.5H); 7.58 (m, 2H); 7.38 (m, 1H); 3.78 (m, 1H); 3.73 (m, 1H); 3.62 (m, 2H). * 1:1 mixture of rotamers. ESMS: M+H=321.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[S:12])([CH3:3])[CH3:2].[CH:13]([NH:16][CH2:17][C:18](O)=[O:19])([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:13]([N:16]1[CH2:17][C:18](=[O:19])[N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])[C:11]1=[S:12])([CH3:15])[CH3:14]
Reactant: CC(C)NCC(=O)O
Reactant: CC(C)c1ccccc1N=C=S
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1N1C(=O)CN(C(C)C)C1=S
Yield: 43.6 %

Procedure:
The title compound was prepared by the procedure described in Example 18 using 10.0 g of 2-isopropylphenyl-isothiocyanate, 11.9 g of N-isopropyl glycine, 12.0 g of triethyl amine, and 200 mL of chloroform. Crystallization from ethanol afforded the title compound (6.8 g) as a light pink solid, m.p. 112°-114° C. Anal. Calcd. for. C15H20N2OS: C, 65.18; H, 7.29; N, 10.13. Found: C, 65.51; H, 7.25; N, 10.32. Mass spectrum (EI, M.+) m/z 276.
Reaction SMILES: CO[CH:3](OC)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[CH:8][CH:7]=1.O>C1(C)C=CC=CC=1>[CH2:13]([O:12][C:9]1[CH:8]=[CH:7][C:6]2[O:5][CH:4]=[CH:3][C:11]=2[CH:10]=1)[CH2:14][CH3:15]
Reactant: CCCOc1ccc(OCC(OC)OC)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCOc1ccc2occc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
To a suspension of polyphosphoric acid (5.2 g) in toluene (120 ml) was added 4-(2,2-dimethoxy)ethoxy-propoxybenzene (5.0 g), and the mixture was stirred at 100° C. overnight and cooled. To the mixture was added water, and the mixture was separated. The organic layer was washed with 1N sodium hydroxide solution and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography to give brown oil of 5-propoxybenzofuran (1.7 g).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:17]=[CH:18][C:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=O>C(O)(=O)C>[C:9]1([C:7]([C:6]2[CH:5]=[N:4][N:3]3[C:19]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[CH:18][CH:17]=[N:1][C:2]=23)=[O:8])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1n[nH]cc1C(=O)c1ccccc1
Reactant: CN(C)C=CC(=O)c1cccnc1
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1cnn2c(-c3cccnc3)ccnc12

Procedure:
A reaction mixture of 1.87 g of (3-amino-1H-pyrazol-4-yl)phenyl-methanone and 1.76 g of 3-dimethylamino-1-(3-pyridinyl)-2-propen-1-one in 25 ml of glacial acetic acid was refluxed for 6 hours and then the solvent was removed in vacuo giving a crystalline residue. This residue was partitioned between saturated aqueous sodium bicarbonate and methylene chloride. The organic layer was dried with anhydrous sodium sulfate and then passed through a short pad of hydrous magnesium silicate. The addition of hexane to the refluxing eluate induced crystallization. After cooling, the desired product was collected, giving 2.45 g, mp 202°-203° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[CH3:8][CH:9]([CH3:19])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18].C(=O)([O-])[O-].[K+].[K+]>CCOCC>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][CH2:10][CH:9]([CH3:19])[CH3:8])=[O:6]
Reactant: CC(C)COc1ccccc1N
Reactant: O=C(Cl)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CC(C)COc1ccccc1NC(=O)CCCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 44 ml of 4-chlorobutyryl chloride in 350 ml of ether is added dropwise to a suspension of 60 g of 2-(2-methylpropoxy)benzenamine and 199 g of potassium carbonate in 500 ml of ether, cooled in an icebath, and the mixture is stirred overnight at room temperature. The mixture is filtered and the filtrate washed successively with 200 ml of 1 N sodium hydroxide, three times 100 ml o& water and 100 ml of saturated sodium chloride solution. The ethereal solution is dried over magnesium sulphate and the solvent evaporated off. 85.8 g of syrupy product are collected, and used without further treatment in the following stage.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:10][C:11]([NH2:15])=[C:12]([NH2:14])[CH:13]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[CH3:32])[C:26](Cl)=[O:27]>N1C=CC=CC=1>[NH2:15][C:11]1[N:10]=[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[F:1])=[CH:13][C:12]=1[NH:14][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:31]([CH3:32])=[C:23]([F:22])[CH:24]=1
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Reactant: Cc1ccc(C(=O)Cl)cc1F
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2cc(-c3ccncc3F)c(-c3cccnc3)nc2N)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
To a solution of 3″-fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1, 0.1 g, 0.356 mmol) in pyridine (2 mL), 0.15 g (0.89 mmol) of 3-fluoro-4-methylbenzoyl chloride were added. The mixture was stirred at room temperature overnight and the solvent was evaporated. The crude mixture (0.33 g) was purified by silica gel flash chromatography (95:5 dichloromethane/methanol) to give the title compound (0.12 g, 81% of yield).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@@H:5]([OH:8])[CH2:6][OH:7])[CH3:2].[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[CH3:13][C:12]([Si:9]([CH3:11])([CH3:10])[O:7][CH2:6][C@H:5]([OH:8])[CH2:4][O:3][CH2:1][CH3:2])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC[C@@H](O)CO
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC[C@@H](O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2S)-3-ethoxy-1,2-propanediol (product from step (0.50 g) in DCM (30 mL) was added tert-butyldimethylsilyl chloride (0.88 g), triethylamine (0.43 mL) and 4-(dimethylamino)pyridine (31 mg) at 0° C. The solution was then warmed to ambient temperature and stirred for 16 h. The reaction mixture diluted with H2O and extracted with EtOAc. The organic layer was washed with brine and evaporated. Purification was by column chromatography on silica gel using EtOAc/isohexane (2:8) as eluent to give the subtitle compound as an oil. Yield: 0.69 g
Reaction SMILES: [C-]#N.[Na+].[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[C:13](#[N:16])[CH:14]=[CH2:15].C(O)(=O)C>CN(C)C=O.O>[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([C:9](=[O:10])[CH2:15][CH2:14][C:13]#[N:16])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C=CC#N
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: N#CCCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of freshly ground sodium cyanide (0.75 g, 15.0 mmol) in dimethylformamide (DMF) is added, over 30 min., 4-chlorobenzaldehyde (21.0 g, 150.0 mmol) in DMF. 30 Minutes after the addition is completed, acrylonitrile (5.96 g, 7.4 ml, 112.5 mmol) is added over a period of 1 hour. The mixture is stirred at RT for 3 hours, after which acetic acid (0.99 g, 0.94 ml, 16.5 mmol) is added. After 5 min., the reaction mixture is poured into water and extracted with chloroform. The combined chloroform layers are washed with water and with brine, dried and stripped of solvent. The residue is recrystallized and filtered to give 4-(4-chlorophenyl)-4-oxobutyronitrile.
Reaction SMILES: [C:1]([C:4]1[N+:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:7][NH:6][C:5]=1[O-:19])(=[O:3])[NH2:2].[C:20]([O:23][C@@H:24]1[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@@H:28]([O:34][C:35](=[O:37])[CH3:36])[C@@H:27]([CH2:38][O:39][C:40](=[O:42])[CH3:41])[O:26][C@@H:25]1Br)(=[O:22])[CH3:21]>>[N+:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:8]2[C:4]([C:1]([NH2:2])=[O:3])=[C:5]([O:19][C@@H:25]3[O:26][C@H:27]([CH2:38][O:39][C:40](=[O:42])[CH3:41])[C@H:28]([O:34][C:35](=[O:37])[CH3:36])[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]3[O:23][C:20](=[O:22])[CH3:21])[N:6]=[CH:7]2)=[CH:15][CH:14]=1)([O-:18])=[O:17]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: NC(=O)c1c([O-])[nH]c[n+]1Cc1ccc([N+](=O)[O-])cc1
Product: CC(=O)OC[C@H]1O[C@@H](Oc2ncn(Cc3ccc([N+](=O)[O-])cc3)c2C(N)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 65.1 %

Procedure:
Following a procedure similar to that of Example 1 but using 2.622 g of 5-carbamoyl-1-(4-nitrobenzyl)imidazolium-4-olate and 8.220 g of 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide there was obtained 3.857 g of 1-(4-nitrobenzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)oxy-1H-imidazole-5-carboxamide.