Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][CH:31]([CH2:33]Br)[CH2:30][C:29]=2[CH:35]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][CH:31]([CH2:33][N:11]3[CH2:10][CH2:9][C:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=4)([OH:14])[CH2:13][CH2:12]3)[CH2:30][C:29]=2[CH:35]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: BrCC1Cc2cc(OCc3ccccc3)ccc2O1
Reactant: COc1ccc(CC2(O)CCNCC2)cc1
Product: COc1ccc(CC2(O)CCN(CC3Cc4cc(OCc5ccccc5)ccc4O3)CC2)cc1

Procedure:
The title compound MS: m/e=460.2 (M+H+) was prepared from 4-(4-methoxy-benzyl)-piperidin-4-ol and 5-benzyloxy-2-(RS)-bromomethyl-2,3-dihydro-benzofuran.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:7]2.N([O-])=O.[Na+].NC(N)=O.O.[BrH:25]>[OH-].[Na+]>[Br:25][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:7]2
Reactant: Nc1cccc2cc(S(=O)(=O)O)ccc12
Reactant: Br
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)c1ccc2c(Br)cccc2c1
Temperature: 25 °C
Yield: 57 %

Procedure:
5-Amino-2-naphthalenesulfonic acid (11.15 g, 50 mmol) was dissolved in 100 ml of 0.5 N NaOH solution with stirring. The dark-red solution was cooled down to 0° C. by addition of ice (~100 g). Before the ice completely dissolved, 20 ml of 40% HBr aqueous solution was added dropwise and the resulting suspension was maintained at -5° to 0° C., then 10 ml of NaNO2 (3.65 g) aqueous solution was added in 30 minutes. The mixture was stirred continuously for 30 minutes at -5~0° C. The unreacted NaNO2 was decomposed by addition of 350 mg of urea at the end of reaction. The resulting dark diazonium suspension was kept below 0° C., and added dropwise over one hour period to CuBr (7.15 g) solution in 40 ml of 40% HBr at 70° C. with vigorous stirring (the CuBr solution was in a 1000 ml flask). The dark mixture was stirred at 80° C. for 40 minutes, then cooled down to room temperature and treated with 200 ml of water. The precipitate was collected in a Buchner funnel and washed with about 50 ml of water. 13.9 g of crude product was obtained after drying under vacuum. The crude compound was refluxed in 500 ml of water for 2 hours, cooled to room temperature and filtered. The filtrate was evaporated to dryness and solid dried in vacuo to yield 8.23 g (57% yield) of pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]([CH2:16][CH3:17])[N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:35]=[C:36]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=1)[CH3:37]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:35]=[C:36]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=1)[CH3:37])[C:6]1[CH:11]([CH2:16][CH3:17])[N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1
Reactant: CC(=CBr)c1ccc(Cl)c(Cl)c1
Reactant: CCC1c2[nH]c3ccc(Cl)cc3c2CCN1C
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CCC1c2c(c3cc(Cl)ccc3n2C=C(C)c2ccc(Cl)c(Cl)c2)CCN1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.8 %

Procedure:
6-chloro-1-ethyl-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (78 mg, 0.31 mmol) was dissolved in DMF (5 mL). To this solution was added CuI (6 mg, 0.031 mmol), L-proline (7 mg, 0.063 mmol), K3PO4 (134 mg, 0.63 mmol). The reaction mixture was stirred for 10 min at room temperature followed by addition of 4-(1-bromoprop-1-en-2-yl)-1,2-dichlorobenzene (100 mg, 0.378 mmol). The reaction mixture was heated at 80° C. overnight. Solvent was evaporated under reduced pressure, the residue was diluted with brine and extracted with ethyl acetate. Organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain 36 mg of 6-chloro-9-(2-(3,4-dichlorophenyl)prop-1-enyl)-1-ethyl-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. 1H NMR (DMSO) OXALATE SALT 7.95 (s, 1H), 7.76 (d, 1H), 7.65 (m, 2H), 7.30 (s, 1H), 7.20 (m, 2H), 3.40 (m, 3H), 2.90 (m, 4H), 2.70 (s, 3H), 1.90 (s, 3H), 0.9 (t, 3H).
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.C1(C2C=CN=C(N3C4C(CCNC4)C3)N=2)C=CC=CC=1.[CH3:39][C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=1[S:47](Cl)(=[O:49])=[O:48].CC1C=CC(C)=CC=1S(Cl)(=O)=O>>[CH3:39][C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=1[S:47]([N:3]1[CH2:4][CH2:5][C@@H:6]2[C@@H:1]([N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7]2)[CH2:2]1)(=[O:48])=[O:49]
Reactant: c1ccc2nc(N3C[C@@H]4CCNC[C@@H]43)cnc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)c(C)c1
Agent: Cc1ccc(C)c(S(=O)(=O)Cl)c1
Agent: c1ccc(-c2ccnc(N3CC4CCNCC43)n2)cc1
Product: Cc1ccc(S(=O)(=O)N2CC[C@H]3CN(c4cnc5ccccc5n4)[C@H]3C2)c(C)c1

Procedure:
The title compound was prepared in a manner analogous to Example 19, substituting (1R,6S)-2-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-quinoxaline (Intermediate 3) for 8-(4-phenyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2,4-dimethyl-benzenesulfonyl chloride for 2,5-dimethyl-benzenesulfonyl chloride. MS (ESI) mass calcd. for C22H24N4O2S, 408.52; m/z found 409.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.96 (s, 1H), 7.86 (dd, J=8.2, 1.3, 1H), 7.66 (d, J=1.2, 1H), 7.58-7.52 (m, 1H), 7.49 (dd, J=8.4, 1.1, 1H), 7.43-7.37 (m, 1H), 6.62-6.48 (m, 2H), 4.69-4.61 (m, 1H), 4.22-3.95 (m, 4H), 3.85-3.74 (m, 1H), 3.69-3.59 (m, 1H), 3.41 (dd, J=14.0, 2.8, 1H), 3.05-2.89 (m, 1H), 2.42 (s, 3H), 2.30-2.14 (m, 1H), 2.09 (s, 3H), 2.05-1.92 (m, 1H).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:7]([F:19])=[C:8]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:9](O)=[O:10].C[N:21](C)C=O>>[Cl:5][C:6]1[C:7]([F:19])=[C:8]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:9]([NH2:21])=[O:10]
Reactant: O=C(O)c1cc(C(F)(F)F)cc(Cl)c1F
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cc(C(F)(F)F)cc(Cl)c1F
Temperature: 75 °C
Yield: 99 %

Procedure:
Thionyl chloride, 6.0 g (50 mmol) was added to a solution of 4.0 g (16 mmol) 3-chloro-2-fluoro-5-(trifluoromethyl) benzoic acid in 10 mL dimethylformamide. The reaction mixture was heated to 75° C. for 2 hours, cooled to room temperature and carefully added to 25 mL of ice cold ammonium hydroxide. The mixture was cooled to 0° C. and the solid product filtered, washed with water and dried to yield 3.96 g (99%) of 3-chloro-2-fluoro-5-(trifluoromethyl)benzamide.
Reaction SMILES: [CH2:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4].C(C1C=CC2C3C(=CC=CC=3)CC=2C=1)C.[C:33](OC(=O)C)(=[O:35])[CH3:34].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[C:33]([C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[C:7](=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:17][CH:16]=3)[CH2:8][C:9]=2[CH:10]=1)(=[O:35])[CH3:34]
Reactant: CCCCc1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(=O)OC(C)=O
Agent: CCc1ccc2c(c1)Cc1ccccc1-2
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCCCc1ccc2c(c1)Cc1cc(C(C)=O)ccc1-2

Procedure:
2-Butylfluorene (6.1 g.) was acetylated exactly as described for 2-ethylfluorene in the preceding Example 21, using acetic anhydride (3.08 g.) and aluminium chloride (8.66 g.) in dichloroethane. The product was recrystallised from light petroleum to give 2-acetyl-7-butylfluorene, m.p. 102°-104.5°. This product (1.98 g.) was oxidised with sodium hypobromite (from 7.23 g. of bromine and 4.52 g. sodium hydroxide in 160 ml. water) exactly as described for 2-acetyl-7-ethylfluorene in the preceding Example. The 7-butylfluorenone-2-carboxylic acid thus isolated had m.p. > 300° and was homogeneous by thin layer chromatography.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:22]=[CH:21][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([O:19][CH3:20])=[O:18])=[O:9])=[CH:6][CH:5]=1.[P:23]([O:30]CC)([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26]>>[CH2:25]([O:24][P:23]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([O:19][CH3:20])=[O:18])=[O:9])=[CH:21][CH:22]=1)([O:27][CH2:28][CH3:29])=[O:30])[CH3:26]
Reactant: CCOP(OCC)OCC
Reactant: COC(=O)c1ccccc1NC(=O)c1ccc(CCBr)cc1
Product: CCOP(=O)(Cc1ccc(C(=O)Nc2ccccc2C(=O)OC)cc1)OCC

Procedure:
A suspension of 1.07 g of 4-bromoethyl-N-(2-methoxycarbonylphenyl)benzamide in 5 ml of triethyl phosphite was stirred under heating at 140° to 150° C. for 30 minutes. After excess triethyl phosphite had been distilled off in vacuo, the residue was subjected to silica gel column chromatography (eluent; chloroform:methanol=1:1) to give 4-diethoxyphosphinylmethyl-N-(2-methoxycarbonylphenyl)benzamide. It was recrystallized from a benzene-n-hexane mixture to give 1.20 g of colorless needles.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([CH3:11])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.Br[C:14]1[S:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1>[S:18]1[C:14]([C:8]2[N:6]3[N:7]=[C:2]([Cl:1])[C:3]([CH3:12])=[C:4]([CH3:11])[C:5]3=[N:10][CH:9]=2)=[CH:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]1=2
Reactant: Cc1c(Cl)nn2ccnc2c1C
Reactant: Brc1cc2ccccc2s1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(Cl)nn2c(-c3cc4ccccc4s3)cnc2c1C
Yield: 37.5 %

Procedure:
To a solution of 6-chloro-7,8-dimethylimidazo[1,2-b]pyridazine (162 mg, 0.892 mmol, 1.0 equiv) in toluene (5.00 mL) was added 2-bromobenzo[b]thiophene (213 mg, 1.16 mmol, 1.3 equiv), potassium carbonate (247 mg, 1.78 mmol, 2.0 equiv), triphenyl phosphine (47 mg, 0.178 mmol, 0.20 equiv) and potassium acetate (20 mg, 0.0892 mmol, 0.1 equiv). The reaction mixture was heated to reflux for 24 h. Purification by column chromatography using 50% ethyl acetate in hexanes elution gave 105 mg of the white solid, 38%.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH2:17][CH2:18][OH:19])C(=O)OC(C)(C)C)[CH2:5][CH2:4]1.[ClH:21]>ClCCl>[ClH:21].[CH3:1][N:2]([CH3:20])[CH:3]1[CH2:4][CH2:5][CH:6]([NH:9][CH2:17][CH2:18][OH:19])[CH2:7][CH2:8]1
Reactant: CN(C)C1CCC(N(CCO)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Product: CN(C)C1CCC(NCCO)CC1
Temperature: 5 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
To a 100-mL round-bottom flask was added a solution of tert-butyl N-[4-(dimethylamino)cyclohexyl]-N-(2-hydroxyethyl)carbamate (3.0 g, 10.47 mmol, 1.00 equiv) in dichloromethane (50 mL). To this solution was added hydrogen chloride (gas). The resulting solution was stirred for 3 h at 0-10° C. The resulting mixture was concentrated under vacuum to give 2.0 g (86%) of 2-[[4-(dimethylamino)cyclohexyl]amino]ethan-1-ol hydrochloride as a yellow oil. MS: m/z 187 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]([CH2:14][CH2:15][C:16](O)=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C(OCC)C>[O:7]([CH2:14][CH2:15][CH2:16][OH:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)CCOc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCCCOc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
To a stirred suspension of 5.7 g (0.15 mole) of lithium aluminum hydride in 350 ml of dry ethyl ether was added dropwise (30 min) a solution of 25.0 g (0.149 mole) of 3-phenoxypropionic acid (99%, Aldrich Chem. Co.) in 250 ml of dry ethyl ether. The reaction mixture was stirred at ambient temperature for 2 hr and treated successively with 6 ml of water, 18 ml of a 15% sodium hydroxide solution, and 10 ml of water. The reaction mixture was filtered through Celite® and the filtrate was concentrated to a viscous residue. The residue was partitioned between water and ethyl ether (300 ml each). The ethereal layer was washed with two 300 ml portions of water, dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give 16.6 g (73%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[C@H:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:24])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].[C:25]1([C:31](N)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N(OCC(C)C)=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl>[CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[C@H:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11](=[O:24])[N:6]2[C:7]=1[C:8]([O:10][C:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:9]
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)CON=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1=C(C(=O)OC(c2ccccc2)(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Yield: 50 %

Procedure:
To 3-methyl-7β-phenoxyacetamidoceph-3-em-4-carboxylic acid (3.43 g., 9.5 m. moles) in dichloromethane (50 ml) was added triphenylmethylamine (4.3 g., 16.6 m. moles), isobutyl nitrite (3.43 g., 33.2 m. moles) and anhydrous sodium sulphate (5 g) and the mixture heated 2 hours at 35°. The cooled solution was washed with 5% sodium bicarbontate (30 ml) and water (30 ml). The organic solution was evaporated to a solid, the solid slurried in toluene (40 ml) cooled, filtered and slurry-washed with cold toluene (15 ml) to yield the previously unreported title compound (2.88 g. 50.0% yield based on the input acid) m.pt. 182°, pure by t.l.c. The compound possessed ν max (1% CHBr3 solution) 3380 (NHCO), 1775 (β-lactam), 1723 (αβ-unsaturated ester) 1686 - 1518 Cm-1 (amide carbonyl); τ (11% CDCl3 solution) 2.2 - 3.2 (complex, phenyl rings + phenoxy ring + --NH), 5.41 (singlet, phenoxy methylene acetamido group, H2), 4.09 (doublet of doublets J 4.5, 9 Hz, C-7, H) 4.95 (doublet, J 4.5 Hz, H), 6.51 + 6.97 (two doublets [branches of a quartet]J 18 Hz, H2), 8.08 (singlet, C-3, H3). Found C, 70.63; H, 5.16 N, 4.52. C35H30N2O5S requires C, 71.18; H, 5.09; N, 4.75%.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][CH2:27][NH2:28].CN1CCOCC1>C(Cl)(Cl)Cl>[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][CH2:27][NH:28][S:17]([C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:3]3[C:4]([CH3:7])=[N:5][NH:6][C:2]=3[NH2:1])[S:9][C:10]=2[CH:16]=1)(=[O:19])=[O:18]
Reactant: NCCc1cccs1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCCc3cccs3)cc2s1
Yield: 8.3 %

Procedure:
the title compound (8 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (75 mg, 0.23 mmol), 2-thiophen-2-ylethylamine (29 μL, 0.25 mmol) and PS-NMM (0.22 g, 0.45 mmol) in 4 mL of chloroform. MS (m/z, ES+): 420.4 (M+1, 100): 1H NMR (500 MHz, ppm, DMSO-d6): δ 11.8-12.2 (br s, 1H), 8.5 (s, 1H), 8.0 (d, 1H), 7.8 (m, 2H), 7.32 (d, 1H), 6.93 (dd, 1H), 6.86 (d, 1H), 6.0 (br s, 2H), 3.03 (q, 2H), 2.92 (t, 2H), 2.43 (br s, 3H). Yield=8%.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:20]([OH:31])[CH2:21][C@@H:22]([C:27]([OH:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.[O:36]1[CH2:41][CH2:40][N:39]([CH2:42][C:43]([NH:45][C@H:46](C(O)=O)[CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:44])[CH2:38][CH2:37]1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>>[O:36]1[CH2:37][CH2:38][N:39]([CH2:42][C:43]([NH:45][C@H:46]([C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]([CH3:34])[CH3:35])[C@@H:20]([OH:31])[CH2:21][C@@H:22]([C:27]([OH:30])([CH3:28])[CH3:29])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]2[N:12]=[CH:13][S:14][CH:15]=2)=[O:7])[CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:44])[CH2:40][CH2:41]1
Reactant: O=C(CN1CCOCC1)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CNC(=O)[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CN1CCOCC1)C(C)(C)O
Yield: 79.5 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 100 mg (0.19 mmoles) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-4-hydroxy-2-(1-hydroxy-1-methylethyl)-7-methyl-N-methyloctanamide [prepared as described in Example 16(a)], 62 mg (0.21 mmoles) of N-morpholinoacetyl-L-phenylalanine, 0.03 ml (0.20 mmoles) of diethyl cyanophosphate, and 0.08 ml (0.57 mmoles) of triethylamine were used, to obtain 104 mg (yield 78%) of the title compound as a white amorphous substance.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][NH2:8])[CH:4]=[C:3]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=1.[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17]>ClCCl>[N:1]1[CH:6]=[C:5]([CH2:7][NH:8][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])[CH:4]=[C:3]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=1
Reactant: NCc1cncc(-c2cccnc2)c1
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Product: C=C(C)C(=O)NCc1cncc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a cooled solution of C-[3,3′]Bipyridinyl-5-yl-methylamine (1.16 g, 6.2 mmol) in dichloromethane (100 mL) was added methacryloyl chloride dropwise. After stirring for 7 h at ambient temperature, the reaction was quenched with 1 M NaOH, and extracted with dichloromethane (2×100 mL). The combined organics were washed with sat. NaHCO3, brine, dried with Na2SO4, and evaporated to a yellow oil (1.65 g) which was chromatographed en silica gel (pretreated with 10% triethylamine) using a methanol gradient (0-3%) in dichloromethane to give 0.76 g of clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[CH3:28][N:29]1[CH2:34][CH2:33][C:32]2[N:35]=[C:36]([NH:38][C:39](=[O:51])[C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]4[CH2:50][CH2:49][CH2:48][NH:47]4)[CH:41]=3)[S:37][C:31]=2[CH2:30]1.CCN(CC)CC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([N:47]1[CH2:48][CH2:49][CH2:50][CH:46]1[C:42]1[CH:41]=[C:40]([CH:45]=[CH:44][CH:43]=1)[C:39]([NH:38][C:36]1[S:37][C:31]2[CH2:30][N:29]([CH3:28])[CH2:34][CH2:33][C:32]=2[N:35]=1)=[O:51])=[O:8]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: CN1CCc2nc(NC(=O)c3cccc(C4CCCN4)c3)sc2C1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCCC2c2cccc(C(=O)Nc3nc4c(s3)CN(C)CC4)c2)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.9 %

Procedure:
Stir a solution of 3,4-dimethoxybenzoic acid (49 mg, 0.265 mmol) and CDI (44 mg, 0.265 mmol) in DMF (2.5 mL) for 10 min at room temperature. Add the N-(5-Methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-3-pyrrolidin-2-yl-benzamide di-HCl (100 mg, 0.241 mmol) followed by Et3N (0.118 mL, 0.844 mmol), and stir the solution at room temperature for 24 h. Purify the crude reaction by reverse-phase prep-HPLC (10% to 90% CH3CN/water). Concentrate the fractions containing product to give the title compound as a solid (100 mg). MS, electrospray 507.5 (M+H), rt 1.13 min.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11](=[O:25])[CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][Mg]I.[Cl-].[NH4+]>CCOCC>[CH2:1]([N:8]([CH2:10][C:11]([CH3:26])([OH:25])[CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]I
Reactant: CN(CC(=O)C(c1ccccc1)c1ccccc1)Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(Cc1ccccc1)CC(C)(O)C(c1ccccc1)c1ccccc1

Procedure:
3-(N-Benzyl N-methylamino)-1,1-diphenyl-propan-2-one (10g) in dry ether (250 ml.) was added to a solution of methyl magnesium iodide (from 2.4g. magnesium and 14.2g methyl iodide) in dry ether (250 ml.) and the mixture heated at reflux for 2 hours. Saturated ammonium chloride solution was added; isolation through ether in the usual manner gave 3-(N-benzyl,N-methylamino)-2-methyl-1,1-diphenyl-propan-2-ol, purified by chromatography on alumina using progressively graded mixtures of light petroleum and ether as eluant and isolated as the hyrochloride (6.8g., 65%, m.p. 121° - 124° (from ethanol-ether).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:26]([S:29](Cl)(=[O:31])=[O:30])([CH3:28])[CH3:27]>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:29]([CH:26]([CH3:28])[CH3:27])(=[O:31])=[O:30])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NS(=O)(=O)C(C)C)cc3)cc2C1=O

Procedure:
The compound of example 95 was prepared analogous to compound of example 77 by reaction of compound of example 6 with isopropyl sulfonyl chloride. The compound of example 95 was used directly without isolation for the preparation of compound of example 96.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[NH:22]1[CH:26]=[N:25][C:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[N:23]1>>[N:30]1[CH:29]=[CH:28][C:27]([C:24]2[N:25]=[CH:26][N:22]([C:2]3[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=4)[N:3]=3)[N:23]=2)=[CH:32][CH:31]=1
Reactant: c1cc(-c2nc[nH]n2)ccn1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4ccncc4)n3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.2) (0.16 g, 0.5 mmol) and 4-(1H-[1,2,4]-triazol-3-yl)-pyridine [CAS-No. 14803-99-7] (0.075 g, 0.51 mmol) according to the general procedure IVa. Obtained as a white solid (0.096 g, 44%). MS (ISP) 437.3 [(M+H)+]; mp 248° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].N1C=CC=CC=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>ClCCl>[C:31]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(=CNc1ncnc2ccc(N)cc12)C(=O)OCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(=CNc1ncnc2ccc(NC(C)=O)cc12)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
A mixture of diethyl [(6-amino-4-quinazolinylamino)methylene]propanedioate (3.03 g), pyridine (3.63 g) and dichloromethane (93 ml) was ice-cooled. To the mixture was added acetic anhydride (1.88 g). The reaction mixture was stirred for 30 minutes under ice-cooling and then for 2 hours and 15 minutes at ambient temperature. Ice water was added to the mixture. The resultant mixture was extracted with chloroform. The organic layer was washed three times with water and with aqueous solution saturated with sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue, which was purified by a column chromatography on silica gel (developing solvent: chloroform) and recrystallized from chloroform, ethyl acetate and hexane to give crystalline diethyl [(6-acetamido-4-quinazolinylamino)methylene]propanedioate (2.2 g).