Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[C:13]2[C:8](=[C:9]([C:16]([F:19])([F:18])[F:17])[C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:20])[CH3:4].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](O)[CH:22]=1>>[CH3:20][C:6]1[N:5]([C@H:3]([CH3:4])[CH2:2][O:1][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)[C:13]2[C:8]([CH:7]=1)=[C:9]([C:16]([F:19])([F:17])[F:18])[C:10]([C:14]#[N:15])=[CH:11][CH:12]=2
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1[C@H](C)CO
Reactant: Oc1cccnc1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1[C@H](C)COc1cccnc1

Procedure:
Synthesized as described in Example 139C using 1-[(1R)-2-hydroxy-1-methylethyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 329) and 3-pyridinol: MS (ES) m/z 360 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:26]1[C:31]([CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[N:30][CH:29]=[CH:28][N:27]=1>CN1CCCC1=O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:26]2[C:31]([CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[N:30][CH:29]=[CH:28][N:27]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: Clc1nccnc1C1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(Oc2nccnc2C2CCCC2)cc1)c1nc2ccccc2[nH]1
Temperature: 140 °C

Procedure:
A mixture of (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.98 g, 4.11 mmol), cesium carbonate (1.34 g, 4.11 mmol), and 2-chloro-3-cyclopentylpyrazine (0.38 g, 2.05 mmol) in 1-methyl-2-pyrrolidinone (2 mL) under argon was heated to 140° C. for 24 h. The mixture was cooled to room temperature and then partitioned between ethyl acetate and water. The resulting layers were separated and the organic layer was washed with 1N aqueous sodium hydroxide (2×), saturated aqueous sodium chloride (1×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography to give (1H-benzo[d]imidazol-2-yl)(4-(3-cyclopentylpyrazin-2-yloxy)phenyl)methanone. MS (ESI, pos. ion) m/z: 385.2 (M+1). IC50 (uM) ++++.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:15]=[C:16]([I:17])[C:3]=12.CS(C)=[O:29]>[OH-].[Na+]>[I:17][C:16]1[C:3]2[C:2]([OH:29])=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:6]=[N:5][C:4]=2[N:14]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[N:15]=1
Reactant: CN1CCN(CCn2nc(I)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Reactant: CS(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(CCn2nc(I)c3c(O)c(-c4ccccc4)nnc32)CC1
Temperature: 50 °C

Procedure:
A suspension of 4-chloro-3-iodo-1-(2-(4-methylpiperazin-1-yl)ethyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (140 mg, 0.29 mmol) in DMSO (3 mL) and NaOH aqueous solution (4 M, 3 mL) was heated to 50° C. for 2.5 h. The mixture was left to cool to rt, then neutralised to pH 2-3 before loading on an SCX (10 g) cartridge. The cartridge was eluted with MeOH then CH2Cl2/MeOH (1:1) and finally the product was released with 10% methanolic ammonia (7 N) in CH2Cl2/MeOH (1:1). Evaporation of the solvent gave the title compound (100 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([I:9])=[CH:4][N:3]=1.[NH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[C:5]([I:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: CC(=O)NCCN
Product: CC(=O)NCCNc1nc(Cl)ncc1I
Yield: 71 %

Procedure:
In analogy to GP 2 reaction of 2,4-dichloro-5-iodopyrimidine (1.0 g, 3.6 mmol) with N-(2-aminoethyl)acetamide (e.g. ABCR, Aldrich) (0.42 mL, 3.9 mmol) provided the desired product in 71% yield (878 mg) after trituration of the crystals obtained with diethyl ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:38]1[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]([CH3:45])[CH:39]=1>>[CH3:45][C:40]1[CH:39]=[C:38]([C:20]2[CH:21]=[CH:22][C:17]([C@@H:15]([N:11]3[CH2:10][CH2:9][C@@:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)([CH2:32][C:33]([OH:36])([CH3:34])[CH3:35])[O:13][C:12]3=[O:14])[CH3:16])=[CH:18][CH:19]=2)[CH:43]=[C:42]([CH3:44])[N:41]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Reactant: Cc1cc(Br)cc(C)n1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccc(F)cc4)OC3=O)cc2)cc(C)n1

Procedure:
The title compound was prepared (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-2,6-dimethylpyridine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.001, m/z=477.1; 1H NMR (CDCl3) 1.05-1.23 (d, 6H), 1.49 (d, 3H), 2.10-2.23 (m, 4H), 2.31-2.42 (m, 1H), 2.56 (s, 6H), 2.89 (m, 1H), 5.67 (m, 1H), 6.92-7.07 (m, 4H), 7.08 (s, 2H), 7.22 (m, 2H), 7.33 (d, 2H).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])[CH:3]([CH3:5])[CH3:4].C([O-])([O-])=O.[Na+].[Na+].[C:20](Cl)([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21]>O.O1CCOCC1>[CH:35]1[C:36]2[CH:24]([CH2:23][O:22][C:20]([NH:1][C@@H:2]([CH:3]([CH3:5])[CH3:4])[C:6]([NH:8][C@@H:9]([CH3:10])[C:11]([OH:13])=[O:12])=[O:7])=[O:21])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
H-Val-Ala-OH 11 (1.0 g, 5.313 mmol, 1.0 eq.) and Na2CO3 (1.42 g, 13.282 mmol, 2.5 eq.) were solubilised in distilled H2O (40 mL) and the mixture was cooled to 0° C. before dioxane (40 mL) was added. Partial precipitation of the amino acid salt occurred. A solution of Fmoc-Cl (1.44 g, 5.579 mmol, 1.05 eq.) dissolved in dioxane (40 mL) was added dropwise with vigorous stirring over 10 minutes. The resulting mixture was stirred at 0° C. for 2 hours before the ice bath was removed and the stirring maintained for 16 hours. The solvent was evaporated under reduced pressure and the solid remaining dissolved in water (450 mL). The pH was adjusted to 2 with 1N HCl (25 mL) and the aqueous layer was subsequently extracted with EtOAc (3×250 mL). The combined organics were washed with brine (100 mL), dried over MgSO4, filtered and the volatiles removed under reduced pressure to afford pure HO-Ala-Val-Fmoc 12 as a white solid (2.06 g, 94%). LC/MS (2.758 min (ES+)), m/z: 411.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.47 (br s, 1H), 8.20 (d, 1H, J=6.7 Hz), 7.89 (d, 2H, J=7.5 Hz), 7.75 (t, 2H, J=6.8 Hz), 7.43-7.38 (m, 3H), 7.34-7.30 (m, 2H), 4.31-4.16 (m, 4H), 3.88 (dd, 1H, J=8.8, 7.2 Hz), 1.98 (m, 1H), 1.26 (d, 3H, J=7.3 Hz), 0.89 (d, 3H, J=6.8 Hz), 0.86 (d, 3H, J=6.8 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@@H:10]([OH:37])[CH2:11][C@H:12]([NH:26]C(=O)OCC1C=CC=CC=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>CO.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[NH2:26][C@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:16][CH:15]=1)[CH2:11][C@H:10]([OH:37])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](N)Cc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.7 %

Procedure:
A solution of the product from Example 1D (2.6 g, 4.4 mmol) in a mixture of methanol (22 mL) and ethyl acetate (22 mL) was treated with Pd(OH)2 on carbon (0.8 g, 20% Pd by wt.) and HCl solution (1.0 mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloon pressure) at 25° C. for 16 hours, filtered through celite®, rinsed with methanol and concentrated to give the title product (1.7 g) as the hydrochloride salt.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCc1ccccc1
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Ic1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A reaction mixture composed of 21.40 g (95.3 mmol) of 98% 4-iodophenol, 12.19 g (95.3 mmol) of 99% benzyl chloride, 20.73 g (150 mmol) of potassium carbonate and 250 ml of acetone was heated to reflux temperature and heated to boiling for 30 hours. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated and then cooled in an ice bath, in the course of which a solid precipitated out. This was removed by means of a blue-band filter and then dried. The crude product (23.22 g) was recrystallized from 70 ml of ethanol. 17.20 g (58% of theory) of colorless microcrystals having an m.p. of 61-62° C. (lit. 62° C.) were obtained.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH:25][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CN(C)CCCN
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\CCCCCCCCNCCCN(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.9 %

Procedure:
A solution of (9Z,12Z)-octadeca-9,12-dienal (1.06 g, 4.0 mmol) and N,N-dimethylpropane-1,3-diamine (408 mg, 4.0 mmol) in anhydrous tetrahydrofuran (15 mL) was stirred under nitrogen for 15 minutes then sodium triacetoxyborohydride (1.7 g, 8.0 mmol). The solution was stirred for 2 hours at room temperature. Upon completion, the solution was diluted with ethyl acetate (20 mL) and washed with sodium bicarbonate (2×15 mL) and brine (15 mL). The ethyl acetate layer was dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The oil was purified by column chromatography on silica gel (eluted with 100% CH2Cl2 to 1/5/94 NH4OH/MeOH/CH2Cl2) to afford N,N-dimethyl-N′-((9Z,12Z)-octadeca-9,12-dienyl)propane-1,3-diamine as a colorless oil (420 mg, 30%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:37][NH:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:47]=[N:48][CH:49]=[N:50][CH:51]=2)=[CH:42][CH:41]=1>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:38]([CH3:37])[CH2:39][C:40]3[CH:41]=[CH:42][C:43]([C:46]4[CH:51]=[N:50][CH:49]=[N:48][CH:47]=4)=[CH:44][CH:45]=3)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CNCc1ccc(-c2cncnc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(-c4cncnc4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (75 mg, 0.21 mmol), CDI (41 mg, 0.25 mmol) and N-methyl-1-[4-(pyrimidin-5-yl)phenyl]methanamine (42 mg, 0.21 mmol) in THF (4.5 mL) and DMF (0.6 mL). The crude product was purified using prep method A.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].CC1(C)C(C)(C)OB([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)O1>>[NH2:35][C:34]1[CH:36]=[CH:37][C:31]([C:2]2[C:3]([F:22])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])=[CH:32][CH:33]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)cc3)c(F)cn2c1=O
Yield: 93.9 %

Procedure:
Ethyl 8-(4-amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.54 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (439 mg, 2.00 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (550 mg, 93%). ESI-MS m/z: 381 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C(O)(=O)/C=C/C(O)=O.[NH2:29][CH2:30][CH2:31][C:32]#[N:33]>>[C:30]([CH2:31][CH2:32][NH:33][C:14]([C:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:16])#[N:29]
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: N#CCCN
Agent: O=C(O)/C=C/C(=O)O
Solvent: O=S(Cl)Cl
Product: Cc1ccc(-c2ccccc2C(=O)NCCC#N)cc1
Yield: 84335.3 %

Procedure:
4'-Methylbiphenyl-2-carboxylic acid (50.0 g, 0.24 mmol) was converted into the corresponding acid chloride as described in Example 89, Part B using thionyl chloride. This acid chloride was subsequently reacted with 3-aminopropionitrile fumarate (30.25 g, 0.24 mmol) under Schotten-Baumann reaction conditions described in Example 209, Part B to yield 53.50 g of white powder after recrystallization from methylcyclohexane/butylchloride; m.p. 102.0°-103.5° C.; NMR (200 MHz, CDCl3): δ7.68 (d, 1H, J=7 Hz); 7.56-7.19 (m, 7H); 5.65 (bm, 1H); 3.43 (d of t, 2H, J=7,7 Hz); 2.39 (t, 2H, J=7 Hz). Anal. calcd. for C17H16N2O: C, 77.25; H, 6.10; N, 10.60. Found: C, 77.42; H, 6.40; N, 10.68.
Reaction SMILES: [N+:1]([C:4]1[CH:32]=[CH:31][C:7]([CH2:8][O:9]C(=O)[C@H](CC2C=CC=CC=2)NC(OCC2C=CC=CC=2)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(#N)C>C(O)C(N)(CO)CO.CS(C)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][OH:9])=[CH:31][CH:32]=1)([O-:3])=[O:2]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)OCc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Agent: NC(CO)(CO)CO
Solvent: CS(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(CO)cc1

Procedure:
To a solution of antibody 7G12 in 50 mM Tris-buffered solution, pH 8.0 (90 μL), was added a solution of a substrate compound, N-(benzyloxycarbonyl)-L-phenylalanine 4-nitrobenzyl ester (L-1) (R=PhCH2), synthesized in Preparation 3, in 2mM DMSO solution (10 μL) at 25° C., and they were mixed with stirring to obtain the reaction mixture containing 10.8 μM antibody and 200 μM substrate. By means of HPLC (YMCAM-303: C-18, 10 mm in diameter×250 mm in length, an aqueous solution of acetonitrile/0.1% trifluoroacetic acid=35/65 (0-7 minutes), 35/65-90/10 (7-15 minutes), 90/10 (15-17 minutes), 1.0 mL/minute, 278 nm), the amount of 4-nitrobenzyl alcohol (retention time: 5.9 minutes) produced in the reaction mixture was traced in time course for the purpose of determing initial rate. Next, the same procedure as mentioned above was repeated using N-(benzyloxycarbonyl)-D-phenylalanine 4-nitrobenzyl ester (D-1) (R=PhCH2) instead of N-(benzyloxycarbonyl)-L-phenylalanine 4-nitrobenzyl ester (L-1) (R=PhCH2) to determine the initial rate. Background hydrolytic reaction rate was also determined based on the amount of 4-nitrobenzyl alcohol produced by spontaneous degradation in the reaction solution free from antibody 7G12.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[C:20]3[C:19](=[O:21])[NH:18][C:17]([NH2:22])=[N:16][C:15]=3[NH:14][CH:13]=2)=[CH:6][CH:5]=1.CO.O1CCCC1.Cl>[OH-].[Na+]>[NH2:22][C:17]1[NH:18][C:19](=[O:21])[C:20]2[C:12]([CH2:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:23])=[O:2])=[CH:5][CH:6]=3)=[CH:13][NH:14][C:15]=2[N:16]=1
Reactant: COC(=O)c1ccc(CCc2c[nH]c3nc(N)[nH]c(=O)c23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc2[nH]cc(CCc3ccc(C(=O)O)cc3)c2c(=O)[nH]1
Reaction time: 4 h
Yield: 87.5 %

Procedure:
A mixture of 3.17 g (10.15 mmol) of 4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5yl)ethyl]benzoic acid methyl ester, prepared in Example 3, in 30 ml of 1N aqueous sodium hydroxide and 5 ml methanol was stirred for 20 hours at room temperature. Tetrahydrofuran (5 ml) was added and the mixture was stirred for 4 hours then neutralized with 30 ml of 1N aqueous hydrochloric acid. The resulting precipitate was separated by filtration, washed with water (20 ml) and dried in a vacuum oven at 50° C. to obtain 2.65 g of the above product in a yield of 87 percent. 1H NMR (DMSO-d6) δ2.45 (m, 2H), 2.91 (m, 2H), 5.99 (s, 2H), 6.27 (d, J=2.0 Hz, 1H), 7.27 (d, J=8.2 Hz, 2H), 7.79 (d, J=8.2 Hz, 2H), 10.14 (s, 1H), 10.59 (d, J=2.0 Hz, 1H), 13.2 (bs, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:50][C:51]1[CH:52]=[C:53]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[NH:63][C:64](=[O:66])[CH3:65])[CH:54]=[CH:55][CH:56]=1>CN(C=O)C>[C:64]([NH:63][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=1[C:53]1[CH:54]=[CH:55][CH:56]=[C:51]([NH:50][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])[CH:52]=1)(=[O:66])[CH3:65]
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: CC(=O)Nc1ccccc1-c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccccc4NC(C)=O)c3)c(=O)oc12
Temperature: 25 °C
Yield: 70.7 %

Procedure:
DIEA (0.013 mL, 0.073 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.015 g, 0.066 mmol) and HATU (0.028 g, 0.073 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, N-(3′-Amino-biphenyl-2-yl)-acetamide (0.015 g, 0.066 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.020 g of product in 69% yield: LCMS (ESI) m/z 429 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[CH3:10][S:11]([O:8][CH2:7][CH:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)(=[O:13])=[O:12]
Reactant: CC1(C)OCC(CO)O1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OCC(COS(C)(=O)=O)O1
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
To (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (400 mg, 3.03 mmol) in DCM (6 mL) at 0° C. was added methanesulfonyl chloride (381 mg, 3.33 mmol) and triethylamine (368 mg, 3.63 mmol. The cold bath was removed and the reaction mixture was stirred for 30 minutes. The mixture was diluted with DCM (5 mL). The organic phase was washed with water (4 mL) and brine (2 mL), and dried (Na2SO4). The solution was concentrated under reduced pressure to give the product (642 mg).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)=[N:5][CH:4]=1)=[O:2].Cl.C(OCC)C>C(Cl)Cl>[NH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]1[S:7][C:3]([CH:1]=[O:2])=[CH:4][N:5]=1
Reactant: CC(C)(C)OC(=O)NCCCNc1ncc(C=O)s1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: NCCCNc1ncc(C=O)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 137.1 %

Procedure:
To a solution of material from Example 60 (400 mg, 1.402 mmol) in CH2Cl2 (75 mL) is added HCl, 1.0M in diethyl ether (25 mL, 25.00 mmol) and the resulting pale yellow solution is stirred at room temp for 18 h. The solvent is removed in vacuo to give 356 mg (98%) of the title compound as a bis HCl salt by weight. LC/MS (Condition A): ret. T=0.522 min, (M+H)+ 186.11.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14](Cl)=[O:15])[C:5]([CH2:11][O:12][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH3:17]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([NH2:17])=[O:15])[C:5]([CH2:11][O:12][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: N
Reactant: COCc1cc([N+](=O)[O-])c(Cl)cc1C(=O)Cl
Solvent: CCOCC
Product: COCc1cc([N+](=O)[O-])c(Cl)cc1C(N)=O
Reaction time: 0.25 h

Procedure:
A sample of 4-chloro-α-methoxy-5-nitro-o-toluoyl chloride (1.5 g.) is added to 100 ml of ether saturated with ammonia. During the addition and for 15 minutes thereafter, the reaction temperature is kept below 20°. The precipitate solid is collected and washed well with water. The crude product (0.9) has an infrared compatible with the desired structure.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[NH:18][CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]Br>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[N:18]([CH2:36][C:35]3[CH:38]=[CH:39][CH:40]=[C:33]([F:32])[CH:34]=3)[CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1cccc(CBr)c1
Reactant: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3[nH]ccc23)ccc2c1CCCO2
Solvent: CC#N
Solvent: O
Product: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2cccc(F)c2)ccc2c1CCCO2

Procedure:
The title compound was prepared in a manner similar to that described in Example 41 from 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetic acid and 3-fluorobenzyl bromide and was isolated by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) on an achiral column. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.29-7.38 (m, 2H) 6.91-7.10 (m, 4H) 6.67-6.81 (m, 1H) 5.74-5.95 (m, 2H) 5.18-5.50 (m, 1H) 4.12-4.30 (m, 2H) 3.62-3.74 (m, 3H) 2.61-2.77 (m, 2H) 2.07-2.17 (m, 2H) 1.93-2.08 (m, 3H) 1.05 (s, 9H); LCMS (m/z) ES+=533 (M+1).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Br)[CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:22]=1
Reactant: O=C(C#Cc1ccccc1)Nc1ccccc1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.8 %

Procedure:
3-Phenyl-propynoic acid phenylamide (951.4 mg, 4.3 mmol), 3-bromomethyl-benzoic acid methyl ester (1.2 g, 5.16 mmol) and Cs2CO3 (2.1 g, 6.45 mmol) were dissolved in DMF (20 ml). The mixture was stirred at room temperature for 16 h. The mixture was poured into water and extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification was by flash column chromatography on silica gel, eluting with hexanes-EtOAc (6:1 and then 4:1) afforded 3-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl ester 1.03 g (65%).