Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:24][C:25]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([Br:37])=[CH:29][CH:28]=1)=[O:26]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:24][C:25]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([Br:37])=[CH:29][CH:28]=1)=[O:26])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: O=C(CBr)c1ccc(Br)c2ccccc12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)OCC(=O)c1ccc(Br)c2ccccc12
Reaction time: 1.5 h
Yield: 96.2 %

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (4.85 g) was dissolved in acetonitrile (65 mL), and triethylamine (3.09 mL) was added. A solution of 2-bromo-1-(4-bromonaphthalen-1-yl)-ethanone (6.60 g) in acetonitrile (35 mL) was added. Reaction mixture was stirred 90 minutes and evaporated under vacuum. Oil was dissolved in DCM (50 mL), extracted once with water (20 mL) and once with NaHCO3 solution (20 mL), and evaporated under vacuum to a concentrated liquid. Solution was purified by chromatography (0-50% ethyl acetate:hexane) and evaporated under vacuum, giving pyrrolidine-1,2-dicarboxylic acid 2-[2-(4-bromonaphthalen-1-yl)-2-oxo-ethyl]ester 1-tert-butyl ester (8.95 g, 95%) as a tan solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[S:19][C:17]=2[N:18]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(Cl)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)c1

Procedure:
Following the procedure of Example 1, the reaction of 3-nitrobenzylamine with 2,4-dichloro-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-nitro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([CH2:14][O:15][CH3:16])[N:8]=[CH:9]2)=[C:2]=[S:3].[OH:17][CH2:18][CH2:19][CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21]1>C(O)C>[OH:17][CH2:18][CH2:19][CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][N:21]1[C:2](=[S:3])[NH:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([CH2:14][O:15][CH3:16])[N:8]=[CH:9]2
Reactant: COCc1cc2c(N=C=S)cccc2cn1
Reactant: OCCC1Cc2ccccc2CN1
Solvent: CCO
Product: COCc1cc2c(NC(=S)N3Cc4ccccc4CC3CCO)cccc2cn1
Temperature: 20 °C
Reaction time: 24 h
Yield: 64.9 %

Procedure:
5-Isothiocyanato-3-methoxymethylisoquinoline (18.2 g) is added to a solution of (RS)-3-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline (14 g) in ethanol (250 cc). The mixture is stirred for 24 hours at a temperature of about 20° C. The precipitate formed is filtered off and washed with ethanol (2×10 cc) and diethyl ether (2×10 cc). (RS)-3-(2-Hydroxyethyl)-N-(3-methoxymethylisoquinol-5-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbothioamide (20.9 g), m.p. 152° C., is thus obtained.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:14])[CH2:12][NH2:13].[CH:15]1[C:20]2[C:21]3[C:32](=O)[C:31]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:22]=3[O:23][C:24](=[O:25])[C:19]=2[CH:18]=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[O:25]=[C:24]1[C:19]2[C:20](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:21]2[C:22](=[O:23])[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=3[C:32]=2[N:13]1[CH2:12][C:11]([O:10][CH3:9])=[O:14]
Reactant: O=C1c2ccccc2-c2oc(=O)c3ccccc3c21
Reactant: COC(=O)CN
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)Cn1c2c(c3ccccc3c1=O)C(=O)c1ccccc1-2
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Triethylamine (2.7 mL, 19.4 mmol) was added to a stirred solution of glycine methyl ester hydrochloride (1.57 g, 12.5 mmol) in chloroform (30 mL). After 1 h, benz[d]indeno[1,2-b]pyran-5,11-dione (2) (1.24 g, 5.0 mmol) was added to the mixture. The red mixture stirred an additional 4 h before CHCl3 (100 mL) was added and the mixture washed with H2O (3×50 mL) and brine (1×50 mL), dried (MgSO4), and concentrated under reduced pressure to give an orange-red solid (1.48 g, 92%): mp 248-251° C.; IR (thin film) 2956, 1735, 1667, 1609, 1502, 1426, 1227, 981 cm−1; 1H NMR (CDCl3, 300 MHz) δ8.68 (d, 1H, J=8.0 Hz), 8.32 (d, 1H, J=8.2 Hz), 7.73 (td, 1H, J=7.1, 1.3 Hz), 7.61 (m, 1H), 7.47 (td, 1H, J=7.1, 1.1 Hz), 7.37 (m, 2H), 7.26 (m, 1H), 5.34 (s, 2H), 3.79 (s, 3H); CIMS m/z (relative intensity) 320 (MH+, 100). Anal. Calcd for C19H13NO4: C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([OH:12])([CH3:11])[CH2:9][OH:10])[C:5]([F:13])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([OH:12])([CH3:11])[CH2:9][O:10][S:22]([CH3:21])(=[O:24])=[O:23])[C:5]([F:13])=[CH:4][N:3]=1
Reactant: CC(O)(CO)c1cc(Br)ncc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(O)(COS(C)(=O)=O)c1cc(Br)ncc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-(2-bromo-5-fluoro-pyridin-4-yl)-propane-1,2-diol (17.45 g, 69.8 mmol) and triethylamine (19.45 ml, 14.12 g, 140 mmol) in DCM (350 ml) at 0° C. was added dropwise methanesulfonyl chloride (5.71 ml, 8.39 g, 73.3 mmol) over a period of 10 min. The reaction mixture was stirred at 0° C. for 30 min, then quenched with 1M aq. NaHCO3 soln. The phases were separated, the aq. phase was twice reextracted with DCM and the combined org. phases were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography on silica gel (gradient heptane: EtOAc 0-5 min 88:12, 5-37.5 min 24:76) yielded the title compound as a clear oil. HPLC RtH4=0.76 min; ESIMS: 328, 330 [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): δ 8.22 (d, 1H), 7.82 (d, 1H), 4.58-4.47 (m, 2H), 3.04 (s, 3H), 3.00 (s, 1H), 1.64 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[C:22]1([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[OH:4][CH:3]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1
Yield: 87 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-phenyl-3-(4-(trifluoromethyl)phenyl)-1-propanol (500 mg, 1.69 mmol) in ethyl acetate (15 ml) were added 3-phenylpropionyl chloride; (377 ml, 2.54 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (628 mg, 87%).
Reaction SMILES: [C:1]([C:5]1[CH:47]=[CH:46][C:8]([O:9][C@@H:10]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][N:31]=[C:32]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=4)=[CH:36][CH:35]=3)[CH3:33])=[CH:23][CH:22]=2)[C:11]([O:13]CC[Si](C)(C)C)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C@@H:10]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][N:31]=[C:32]([C:34]3[CH:35]=[CH:36][C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=4)=[CH:38][CH:39]=3)[CH3:33])=[CH:23][CH:22]=2)[C:11]([OH:13])=[O:12])=[CH:46][CH:47]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=NOCCOc1ccc(C[C@H](Oc2ccc(C(C)(C)C)cc2)C(=O)OCC[Si](C)(C)C)cc1)c1ccc(-c2ccccn2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=NOCCOc1ccc(C[C@H](Oc2ccc(C(C)(C)C)cc2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1
Yield: 68.6 %

Procedure:
The reaction was carried out according to Reference example 7 using 2-trimethylsilylethyl (S)-2-(4-t-butylphenoxy)-3-[4-[2-[[1-[4-(2-pyridyl)phenyl]ethylidene]aminoxy]ethoxy]phenyl]propionate (310 mg) obtained from Reference example 12 and a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.7 ml). The resulting residue was purified by chromatography on a silica gel column (eluant; methylene chloride/methanol=24/1˜19/1), and then the obtained compound was filtered off and washed with isopropyl ether and hexane to afford the target compound (180 mg) as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[Cl:12][C:13]1[CH:14]=[C:15]([NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31](I)[CH:30]=2)[CH:16]=[CH:17][C:18]=1[CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([C:2]#[C:1][C:3]3[N:7]4[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=[N:5][CH:4]=3)[CH:30]=2)[CH:16]=[CH:17][C:18]=1[CH2:19][N:20]1[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]1
Reactant: C#Cc1cnc2cccnn12
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(Cl)c2)cc1I
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(Cl)c2)cc1C#Cc1cnc2cccnn12

Procedure:
The title compound was synthesized according to Example 14, from 3-ethynylimidazo[1,2-b]pyridazine and N-(3-chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-iodo-4-methylbenzamide. The product was obtained as a solid: 499 m/z (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>CCOCC>[CH2:9]([O:8][C:7]1[C:2]([NH:1][C:25]([NH:24][C:21]2[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:27])[F:28])=[CH:23][CH:22]=2)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(NC(=S)Nc2ncccc2OCc2ccccc2)cc1

Procedure:
A mixture of 2-amino-3-benzyloxypyridine (2.34 g, 0.0117 mol), 4-trifluoromethylphenyl isothiocyanate (2.85 g, 0.014 mol) and toluene (10 ml) was refluxed for 3.5 hours, then cooled and treated with ether to induce crystallisation of the product. Yield 3.06 g (65%), m.p. 165°-167 ° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:21][NH:22][S:23](Cl)(=[O:25])=[O:24].[BH4-].[Na+]>N1C=CC=CC=1>[F:20][C:16]1[CH:15]=[C:14]([CH:12]2[C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[N:10][CH:9]=[CH:8][CH:7]=4)[C:2]=3[NH:1][S:23](=[O:25])(=[O:24])[N:22]2[CH3:21])[CH:19]=[CH:18][CH:17]=1
Reactant: Nc1c(C(=O)c2cccc(F)c2)ccc2cccnc12
Reactant: CNS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1C(c2cccc(F)c2)c2ccc3cccnc3c2NS1(=O)=O
Yield: 38.3 %

Procedure:
In a similar fashion using route 27 general procedure 70, (8-amino-quinolin-7-yl)-(3-fluoro-phenyl)-methanone (Intermediate 374) (100 mg, 0.38 mmol), N-methylsulfamoyl chloride (Intermediate 213) (146 mg, 1.13 mmol) and NaBH4 (14 mg, 0.38 mmol) in pyridine (3 ml) gave the title compound (50 mg, 39%) after purification by preparative HPLC (acidic conditions 1).
Reaction SMILES: [CH3:1][N:2]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[NH2:3].Cl[CH2:12]/[CH:13]=[CH:14]\[CH2:15]Cl>>[N:3]1([N:2]([CH3:1])[C:4](=[O:5])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:15][CH:14]=[CH:13][CH2:12]1
Reactant: ClC/C=C\CCl
Reactant: CN(N)C(=O)OC(C)(C)C
Product: CN(C(=O)OC(C)(C)C)N1CC=CC1
Yield: 86.3 %

Procedure:
Using tert-butyl 1-methylhydrazinecarboxylate (5.00 g, 34.2 mmol) and (2Z)-1,4-dichloro-2-butene (3.6 ml, 34.2 mmol), and according to the method of Reference Example 35, step A, the title compound (5.85 g, yield 86%) was obtained as a yellow oil.
Reaction SMILES: [CH:1]1([C@:4]([OH:28])([CH3:27])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12](Br)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.[C:29]([C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)#[CH:30]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]1([C@:4]([OH:28])([CH3:27])[CH2:5][NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12]([CH2:30][CH2:29][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: C#Cc1cccnc1
Reactant: C[C@](O)(CNC(=O)c1cnc(Br)c(-c2ccc(OC(F)(F)F)cc2)n1)C1CC1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@](O)(CNC(=O)c1cnc(CCc2cccnc2)c(-c2ccc(OC(F)(F)F)cc2)n1)C1CC1

Procedure:
To a solution of 0.1 g 5-bromo-6-(4-trifluoromethoxy-phenyl)-pyrazine-2-carboxylic acid ((R)-2-cyclopropyl-2-hydroxy-propyl)-amide in 2.0 ml of TEA is added at room temperature 0.015 g of bis(triphenylphosphine) palladium(II) chloride, 0.002 g cuprous iodide and 0.034 g meta-ethynylpyridine. The mixture is treated at 100° C., 1½ hours at the microwave. The starting material is consumed, as evidenced by HPLC. To the mixture is 1N HCl solution in water and ethyl acetate. The organic layer is washed with sodium bicarbonate and sodium chloride 10% solution in water. The residue is purified by chromatography in silica gel. The intermediate was hydrogenated under a hydrogen atmosphere in the presence of palladium on charcoal to yield after filtration and evaporation of the solvent the title compound as off-white oil, MS (ISP) 487.3 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[CH:27]=[C:26]([C:28]5[O:29][C:30]([C:33]67OCC(C)(C[O:38]6)C[O:34]7)=[CH:31][CH:32]=5)[N:25]=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:42]>C1COCC1.O>[ClH:42].[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[CH:27]=[C:26]([C:28]5[O:29][C:30]([C:33]([OH:38])=[O:34])=[CH:31][CH:32]=5)[N:25]=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC12COC(c3ccc(-c4cc5c(Nc6ccc7c(cnn7Cc7ccccc7)c6)ncnc5cn4)o3)(OC1)OC2
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2cc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3cn2)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(1-Benzylindazol-5-yl)-(6-(5-(4-methyl-2,6,7-trioxa-bicyclo[2,2,2]oct-1-yl)-furan-2-yl]-pyrido-[3,4-d]pyrimidin-4-yl)-amine (0.445 g, 0.81 mmol) was suspended in a mixture of THF (15 ml) and dilute HCl (15 ml) and stirred at room temperature for 18 hours. The mixture was diluted with water to preciptate the intermediate (partial hydrolysis) which was collected by filtration and washed with water. This solid was suspended in a mixture of THF (10 ml) and NaOH (1M, 10 ml) and stirred at room tmperature for 18 hours. The THF was removed in vacuo and the residue was acidified to pH1 with dilute HCl to give the product as an orange solid, which was collected by filtration (0.322 g, 0.645 mmol, 79%); δH [2H6]DMSO 10.63(1H,s), 9.19(1H,s), 8.89(1H,s), 8.64 (1H,s), 8.17-8.22 (2H,m), 7.67-7.80 (2H,m), 7.46 (1H,s), 7.23-7.39 (6H,m), 5.70 (2H,s); m/z (M+1+) 463.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:38])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]2[C:29]3[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=3)[N:23]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[C:22]=2[CH3:37])[CH:15]=1)[CH3:10].IC>C1COCC1>[CH2:9]([O:11][C:12](=[O:38])[CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]2[C:29]3[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=3)[N:23]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[C:22]=2[CH3:37])[CH:15]=1)[CH3:1])[CH3:10]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)Cc1cccc(Sc2c(C)n(-c3cccnc3)c3cc(Cl)ccc23)c1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1cccc(Sc2c(C)n(-c3cccnc3)c3cc(Cl)ccc23)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of lithium diisopropylamide (10.7 mmol) in THF (10 mL), freshly prepared at −78° C., was added to a solution of ([3-(6-Chloro-2-methyl-1-pyridin-3-yl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid ethyl ester (0.256 g, 0.586 mmol) in THF (5 mL) at −78° C. The reaction was stirred at −78° C. for 2 hours then iodomethane (0.044 mL, 0.71 mmol) was added and the reaction was allowed to warm to 0° C. After stirring at 0° C. for 30 minutes the reaction was submitted to standard aqueous workup then purified by silica gel chromatography (0-30% EtOAc in hexanes) to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[C:7]2=[O:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][C:51](O)=[O:52])=[CH:45][CH:44]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:16][N:15]([CH3:17])[CH2:14][CH2:13][N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:51](=[O:52])[CH2:50][CH2:49][C:46]2[CH:47]=[CH:48][C:43]([CH3:42])=[CH:44][CH:45]=2)[C:7]1=[O:12]
Reactant: CN(C)CCn1ccc2c(N)cccc2c1=O
Reactant: Cc1ccc(CCC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(CCC(=O)Nc2cccc3c(=O)n(CCN(C)C)ccc23)cc1
Yield: 40 %

Procedure:
5-Amino-2-(2-dimethylamino-ethyl)-2H-isoquinolin-1-one (50 mg, 0.2 mmol), HATU (99 mg, 0.26 mmol), 3-(4-methylphenyl)propionic acid (42 mg, 0.26 mmol) and DIPEA (110 mg, 0.86 mmol) were stirred in methylene chloride (3 mL) at room temperature for 16 hours. The mixture was purified via flash chromatography (12 g of silica gel, 0-10% MeOH/CH2Cl2 gradient) gave N-[2-(2-Dimethylamino-ethyl)-1-oxo-1,2-dihydro-isoquinolin-5-yl]-3-p-tolyl-propionamide as a white solid (31 mg, 0.08 mmol, 40%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10]I)[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:6]=1)=[O:4].[CH3:28][NH:29][CH3:30]>CO>[CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10][N:29]([CH3:30])[CH3:28])[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:6]=1)=[O:4]
Reactant: CNC
Reactant: COC(=O)c1nc(CI)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Solvent: CO
Product: COC(=O)c1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of 12.90 g (0.025 mole) of 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(iodomethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester [see Example 13(b)] and 11 ml of 33% ethanolic dimethylamine solution in 250 ml of methanol is stirred for 7 hours at room temperature. The reaction solution is thereupon concentrated in vacuo; water is added to the residue and the whole is extracted twice with methylene chloride. The organic phase is washed twice with water and once with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo to dryness. The amorphous residue is dissolved in 130 ml of ether; the solution is allowed to stand and the reaction product then crystallises out. It is filtered off with suction and washed with ether. After drying there is obtained 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carboxylic acid methyl ester, m.p. 131°-134°.
Reaction SMILES: [CH3:1][C:2]([CH3:44])([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[C:10]2[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:31][C:9]=2[N:8]=1)[C:3]([OH:5])=[O:4].Br[C:46]1[CH:47]=[N:48][O:49][CH:50]=1>>[O:49]1[CH:50]=[C:46]([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][N:11]3[C:10]4[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]5[CH:43]=[CH:42][C:41]6[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=6)[N:35]=5)=[CH:31][C:9]=4[N:8]=[C:7]3[CH2:6][C:2]([CH3:44])([CH3:1])[C:3]([OH:5])=[O:4])=[CH:14][CH:15]=2)[CH:47]=[N:48]1
Reactant: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)O
Reactant: Brc1cnoc1
Product: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(-c2cnoc2)cc1)C(=O)O

Procedure:
The title compound was prepared with similar methods to those in Example 147 using 2,2-dimethyl-3-(5-(quinolin-2-ylmethoxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazol-2-yl)propanoic acid and 4-bromoisoxazole. MS (ESI): mass calcd. for C32H28N4O4, 532.21; m/z found, 533.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 9.18 (d, J=7.8, 1H), 9.08 (s, 1H), 8.82 (s, 1H), 8.42 (d, J=8.6, 1H), 8.35 (d, J=8.2, 1H), 8.24-8.17 (m, 2H), 7.98 (t, J=7.4, 1H), 7.67-7.64 (m, 4H), 7.45 (d, J=8.0, 1H), 7.34 (d, J=7.0, 2H), 5.88 (s, 4H), 3.59 (s, 2H), 1.44 (s, 6H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].[C:9](Cl)(=[O:12])[CH:10]=[CH2:11].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH:10]=[CH2:11])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccccc1
Reactant: C=CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccc(CC)cc1

Procedure:
Ethylbenzene (0.5 mL), acryloyl chloride (120 mg), and aluminium chloride (199 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (110 mg).
Reaction SMILES: C([O:3][C:4](=[O:24])[C@H:5]([CH3:23])[NH:6][C:7](=[O:22])[C@H:8]([CH3:21])[NH:9][C:10](=[O:20])[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)C.[Li+].[OH-]>O1CCOCC1.O>[F:18][C:16]1[CH:17]=[C:12]([CH2:11][C:10]([NH:9][C@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:24])=[O:3])[CH3:23])=[O:22])[CH3:21])=[O:20])[CH:13]=[C:14]([F:19])[CH:15]=1
Reactant: CCOC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reaction time: 3 h

Procedure:
The title compound was prepared by dissolving 1.98 g (0.006 mols) of N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl ester (from Example 85 below) in 60 mL dioxane and 15 mL of H2O and adding LiOH (0.25 g, 0.006 mol) that has been dissolved in 15 mL of H2O. After stirring for 3 hours, the dioxane was removed under reduced pressure and the residue diluted with EtOAc, the layers were separated and the aqueous layer acidified to pH 2. The aqueous layer was back extracted with EtOAc (4×100 ml), and the combined organics were dried over Na2SO4 and the solvent was removed under reduced pressure after filtration. The residue was recrystallized from EtOAc/isooctane giving 1.7 g (90%). C,4H,6F2N2O4 requires C, 53.50 H, 5.13 N, 8.91. Anal found C, 53.30 H, 5.26 N, 8.98.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(OCC)(=O)C>[C:3]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: Nc1ccccc1-c1ccccc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
5.08 g (30 mmol) of 2-aminobiphenyl, 50 ml of ethyl acetate, and 3.1 g (30 mmol) of triethylamine were placed in a flask, to which 4.1 g (30 mmol) of ethyl chloroglyoxylate was added dropwise under ice cooling. The reaction mixture was stirred at room temperature for three hours, and then 50 ml of ethyl acetate was added thereto. The organic layer was washed with 30 ml of 1N hydrochloric acid and 30 ml of brine one by one, and then was dried with anhydrous sodium sulfate. The solvent was removed by evaporation to obtain 6.8 g (24 mmol, yield 85%) of ethyl N-biphenyl-2-yloxamate as colorless crystals.