Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:24])=[C:11]([N:15]4[CH2:18][CH:17]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:25])[C:6]([C:26]([O:28]CC)=[O:27])=[CH:5]2)[CH2:3][CH2:2]1>[OH-].[Na+].C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:24])=[C:11]([N:15]4[CH2:16][CH:17]([O:19][S:20]([CH3:23])(=[O:21])=[O:22])[CH2:18]4)[C:12]=3[F:14])[C:7](=[O:25])[C:6]([C:26]([OH:28])=[O:27])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC(OS(C)(=O)=O)C3)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)OC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1

Procedure:
A solution of 0.2 g (0.4 mmole) of ethyl 1-cyclopropyl-6,8-difluoro-7-(3-mesyloxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate (example 3) in 6 ml of 0.5N sodium hydroxide and 1 ml of ethanol is refluxed for 1 hour. It is evaporated under vacuum, and acetic acid is added. Filtering and washing yield 0.18 g (96%) of 1-cyclopropyl-6,8-difluoro-7-(3-mesyloxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid melting at 240°-4° C.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.B1(O)[O:29][CH2:28][C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2>C1COCC1.C(Cl)Cl.CCCCCC>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:27]=4[CH2:28][OH:29])[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1
Reactant: OB1OCc2ccccc21
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1NC(=O)c2c1c(-c1ccccc1CO)cc1[nH]c3ccc(O)cc3c21
Yield: 57 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 2-(hydroxymethyl)benzeneboronic acid cyclic monoester according to the procedure described in example 8 gave 9-Hydroxy-4-[2-(hydroxymethyl)phenyl]pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (503) (I; Ar=2-(hydroxymethyl)phenyl) in a 57% yield, mp (THF/CH2Cl2/hexane) 270–280° C. (dec). 1H NMR [(CD3)2SO] δ 11.76 (br s, 1H), 10.96 (br s, 1H), 9.25 (br s, 1H), 8.32 (d, J=2.4 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.47 (s, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.43 (td, J=7.6, 1.2 Hz, 1H), 7.31 (td, J=7.4, 0.9 Hz, 1H), 7.23 (dd, J=7.5, 1.0 Hz, 1H), 7.06 (dd, J=8.7, 2.5 Hz, 1H), 5.00 (t, J=5.4 Hz, 1H), 4.33 (dd, J=13.6, 5.2 Hz, 1H), 4.24 (dd, J=13.5, 5.3 Hz, 1H). Found: C, 68.41; H, 4.29; N, 7.59. C21H14N2O4,1/2H2O requires C, 68.66; H, 4.12; N, 7.63.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][C@H:27]([N:31]([S:36]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH2:32][CH:33]([CH3:35])[CH3:34])[C:28]([OH:30])=[O:29])=S)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:46]#[C:47][NH2:48]>CO.[NH4+].[Cl-]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@H:12]([C:20]([NH:48][C:47]#[N:46])=[N:22][CH2:23][CH2:24][CH2:25][CH2:26][C@H:27]([N:31]([S:36]([C:39]2[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=2)(=[O:37])=[O:38])[CH2:32][CH:33]([CH3:34])[CH3:35])[C:28]([OH:30])=[O:29])[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: N#CN
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=S)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)NC#N)cc1
Yield: 57 %

Procedure:
To a stirred solution of the thioamide, Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-[N′α-(4-methylbenzenesulfonyl)-L-thiophenylalanyl]-L-lysine, (227 mg, 0.33 mmol, example 72) in MeOH (3 mL) was added cyanamide (28 mg, 0.66mmmol). The mixture was stirred for 5 mim, then mercuric acetate (209 mg, 0.66 mmol) was added. The reaction was stirred for 3 h then diluted with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with brine and concentrated then rediluted with THF/MeOH (2 mL/1 ML) and treated with 1N NaOH (0.8 mL). After stirring for 4 h, the reaction was acidified with 1N HCl and extracted with EtOAc. The organic layer was dried over MgSO4, concentrated and purified by column chromatography to give 128 mg (57%) of the final product.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.[CH2:27]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:34]1[CH2:39][CH2:38][N:37]([CH2:12][C:9]2[C:10](=[O:11])[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:6]=[C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)[CH:8]=2)[CH2:36][CH2:35]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Reactant: c1ccc(CN2CCNCC2)cc1
Product: COc1ccc(-c2cc(CN3CCN(Cc4ccccc4)CC3)c(=O)n(CC3CC3)n2)cc1F
Yield: 97.7 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methane-sulfonyloxymethyl-2H-pyridazin-3-one and 1-benzylpiperazine were reacted to yield the title compound as a yellow oil (yield: 97.7%).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>CC(C)=O>[C:22]([O:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([S:9](=[O:11])(=[O:12])[NH2:10])=[CH:8][C:4]=2[CH:3]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: NS(=O)(=O)c1cc2cc(O)ccc2s1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc2sc(S(N)(=O)=O)cc2c1
Temperature: -5 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
A solution of 5-hydroxy-2-sulfamoylbenzo[b]thiophene (4.00 g, 0.017 m) in acetone (70 ml) was cooled to -5° C., triethylamine (1.92 g, 0.019 m) was added, followed by the dropwise addition of a solution of acetyl chloride (1.48 g, 0.019 m) in acetone (10 ml) over 15 minutes, maintaining the temperature at -5° to -3° C. After stirring at -5° C. for 21/4 hours, the mixture was filtered and the solid was washed with acetone. The combined filtrate and washings were concentrated under reduced pressure, the residue was dissolved in ethyl acetate (7.5 ml) washed with water (2×20 ml), dried and evaporated under reduced pressure. The residue was crystallized from 1,2-dichloroethane to yield 4.01 g (87%) of product melting at 129°-132° C. An analytical sample melted at 131.5°-133° C. after recrystallization from 1,2-dichloroethane.
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Br[C:19]1[CH:20]=[CH:21][C:22]([CH:25]2[CH2:27][CH2:26]2)=[N:23][CH:24]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[CH:25]1([C:22]2[N:23]=[CH:24][C:19]([C:2]#[C:1][N:3]3[C:11]4[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=4[C:5]4[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]3=4)=[CH:20][CH:21]=2)[CH2:27][CH2:26]1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: Brc1ccc(C2CC2)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccc(C3CC3)nc2)CCN(C)C1
Temperature: 80 °C
Yield: 6.9 %

Procedure:
A mixture of 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (102 mg, 0.45 mmol), 5-bromo-2-cyclopropyl-pyridine (75 mg, 0.38 mmol), dichlorobistriphenylphosphine palladium(II) (7 mg, 0.0114 mmol) and TBAF.3H2O (359 mg, 1.14 mmol) was heated at 80° C. for min by microwave. After completion of reaction (monitored by TLC), the mixture was poured into water (10 mL) and extracted with EtOAc (2×20 mL). The organic layer was dried over sodium sulfate, concentrated under vacuum to obtain crude product, which was purified by reverse phase chromatography to obtain 9 mg of 5-(6-cyclopropyl-pyridin-3-ylethynyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, free base) δ (ppm): 8.58 (s, 1H), 7.62 (d, 1H), 7.40 (d, 1H), 7.18 (s, 1H), 7.08 (m, 2H), 3.65 (s, 2H), 2.90 (m, 4H), 2.60 (s, 3H), 2.42 (s, 3H), 2.05 (m, 1H), 1.05 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.[Br:11]Br>C(Cl)(Cl)Cl>[BrH:11].[Br:11][C:8]1[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([CH3:10])[C:6]=1[NH2:7]
Reactant: COc1ccc(N)c(C)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Br
Product: COc1cc(C)c(N)c(Br)c1
Yield: 170.9 %

Procedure:
4-Methoxy-2-methylaniline (9.30 ml, 72.9 mmol) in chloroform (250 ml ) at 0° C. was added a solution of bromine (3.76 ml, 72.9 mmol) in chloroform (60 ml) dropwise over ca. 3 h. The reaction mixture was concentrated, diluted with dichloromethane and concentrated, diluted again with diethyl ether and concentrated, and dried under high vacuum to give 18.5 g of 2-bromo-4-methoxy-6-methylaniline hydrobromide (85%). LC/MS (HPLC method 3): tR=1.395 min, 216.03(MH)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[CH:5][CH:4]=1)#[CH:2].[H][H]>[Pd].N1C=CC=CC=1>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[CH2:2])=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: C#Cc1ccc(-c2ccccc2F)cc1
Agent: [Pd]
Solvent: c1ccncc1
Product: C=Cc1ccc(-c2ccccc2F)cc1

Procedure:
1-Ethynyl-4-(2-fluorophenyl)benzene, 29.6 g., was reduced in a Parr Instrument Company Series 3910 Low-Pressure Shaker-Type Apparatus, using 450 ml. of pyridine, and 0.3 g. of 5 percent palladium on barium sulfate; reduction was carried out at room temperature for 30 minutes and at an initial hydrogen pressure of 30 psig. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was vacuum distilled to give 20.5 g. of solid which was recrystallized from methanol to give 4-(2-fluorophenyl)-1-vinylbenzene, mp 38° . The material contained traces of pyridine and 1-ethyl-4-(2-fluorophenyl)benzene, as shown by nuclear magnetic resonance analysis. The following elemental analysis was obtained:
Reaction SMILES: C([NH:9][CH2:10][C:11]1[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=1)(=O)C1C=CC=CC=1.Cl.Cl.[N:22]1([C:27]2[CH:38]=[CH:37][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])=[CH:29][CH:28]=2)[CH:26]=[CH:25][N:24]=[CH:23]1.[OH-].[Na+].Cl>ClCCl.O>[NH2:9][CH2:10][C:11]1[S:15][C:14]([S:16]([NH:36][CH2:35][CH2:34][CH2:33][CH2:32][O:31][C:30]2[CH:37]=[CH:38][C:27]([N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)=[CH:28][CH:29]=2)(=[O:17])=[O:18])=[CH:13][CH:12]=1
Reactant: O=C(NCc1ccc(S(=O)(=O)Cl)s1)c1ccccc1
Reactant: NCCCCOc1ccc(-n2ccnc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: NCc1ccc(S(=O)(=O)NCCCCOc2ccc(-n3ccnc3)cc2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3.0 g of 5-benzoylaminomethyl-2-thiophenesulfonyl chloride, in 100 ml of dichloromethane, is added to a stirred mixture of 3.0 g of 4-[4-(1H-imidazol-1-yl)phenoxy]butaneamine dihydrochloride (Example 2) and 3.5 ml of 10N NaOH in 100 ml of water. The mixture is stirred at room temperature for 3 hours, a tacky precipitate being formed. The precipitate is mixed with 100 ml of concentrate HCl, and the mixture is stirred at reflux for 12 hours, solution taking place. The solution is taken to dryness in vacuo, and the dihydrochloride salt of the title compound was recrystallized from aqueous ethanol, m.p. 230°-232° C. (dec.); yield, 0.5 g.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].CN([CH:27]=[O:28])C>O>[CH2:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH:27]=[O:28])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: c1ccc(Cc2ccc3[nH]ccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2ccc(Cc3ccccc3)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
Freshly distilled POCl3 (0.122 ml) was added dropwise to cooled (ice bath) dry DMF (0.4 ml). The mixture was stirred 0.5 h at 0° C., then a solution of 5-benzylindole (0.24 g, 1.2 mmol) in DMF (0.14 ml) was added dropwise, during which time the temperature was maintained below 10° C. Once the solution was well mixed, the temperature was brought to 35° C. The syrup was stirred efficiently at this temperature for 1 h. At the end of the reaction period 0.4 g of crushed ice was added to the paste with careful stirring. The cherry-red solution was transferred with H2O (0.13 ml) to a flask containing 0.28 g of crushed ice. A solution NaOH (0.53 g, 13 mmol) in H2O (1.4 ml) was added dropwise; the suspension was heated to reflux, allowed to cool to room temperature, and was placed in a refrigerator overnight the precipitate was collected by filtration, washed well with H2O and air-dried to provide 0.15 g (56%) of 5-benzyl-3-formylindole.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][CH2:29][NH2:30])[CH2:25][CH:26]=2)=[CH:17][CH:16]=1.CC1C=CC=C2C=1N[C:39](=[O:42])NC2=O.[K+].[Br-]>>[Cl:13][C:10]1[C:11]([CH3:12])=[C:2]2[C:3]([C:4](=[O:6])[N:30]([CH2:29][CH2:28][CH2:27][N:24]3[CH2:23][CH:22]=[C:21]([C:18]4[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=4)[CH2:26][CH2:25]3)[C:39](=[O:42])[NH:1]2)=[CH:8][CH:9]=1
Reactant: NCCCN1CC=C(c2ccc(Cl)cc2)CC1
Reactant: COC(=O)c1ccc(Cl)c(C)c1N
Reactant: Cc1cccc2c(=O)[nH]c(=O)[nH]c12
Agent: [Br-]
Agent: [K+]
Product: Cc1c(Cl)ccc2c(=O)n(CCCN3CC=C(c4ccc(Cl)cc4)CC3)c(=O)[nH]c12

Procedure:
The same general procedure was followed as in Example 7 with starting materials, 2-amino-3-methyl-4-chloro-benzoic acid, methyl ester and 3-[4-(4-Chloro-phenyl)-3,6-dihyro-2H-pyridin-1-yl]-propylamine to yield 7-Chloro-3-{3-[4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-propyl{-8-methyl-1H-quinazoline-2,4-dione. The maleate salt of the compound has the following was found to have: Mp. 208-210° C.; 1H NMR DMSO-d6 δ 10.90 (s, 1H), 9.44 (brd s, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.46 (dd, J=8.7, 20.5 Hz, 4H) 7.28 (d, J=8.5 Hz, 1H), 6.20 (brd s, 1H), 6.00 (s, 2H), 3.98 (t, J=6.4 Hz, 2H), 3.84-3.54 (m, 2H), 3.38-3.26 (m, 2H), 3.25-3.10 (m, 2H), 2.75-2.624(m, 2H), 2.39 (s, 3H), 2.10-1.99 (m, 2H); IR (KBr) 3351, 3226, 3071 2965, 2728, 2603, 1904, 1714, 1656, 1612, 1596, 1448, 1353, 1321, 1294, 1261, 1205, 1152, 1134, 1094, 1011, 989, 950, 922, 866, 836, 811, 763, 729, 706, 682, 645, 579, 523, 511, 499, 468, 441, 404; Analysis calculated for C23H23Cl2N3O2.C4H4O4: C, 57.86; H, 4.86; N, 7.50. Found: C, 57.55; H, 4.79; N, 67.36.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[C:24]2[NH:26][N:27]=[C:28](I)[C:23]2=[CH:22][N:21]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][N:41]([CH:43]([CH3:46])[C:44]#[N:45])[CH:42]=2)O1>>[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[C:24]2[NH:26][N:27]=[C:28]([C:38]3[CH:39]=[N:40][N:41]([CH:43]([CH3:46])[C:44]#[N:45])[CH:42]=3)[C:23]2=[CH:22][N:21]=1
Reactant: CC(C#N)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4cnn(C(C)C#N)c4)n[nH]c3n2)c1F

Procedure:
This compound was prepared as a TFA salt by using procedures analogous to those described for the synthesis of Example 7, Step 3 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile. LCMS (M+H)+=412.0.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:19][CH2:18][CH:17]([N:20]2[C:25]3[N:26]=[C:27]([NH2:31])[N:28]=[C:29]([CH3:30])[C:24]=3[CH:23]=[C:22]([C:32]3[CH:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)[C:21]2=[O:40])[CH2:16]1)=O)(C)(C)C>ClCCl>[NH2:31][C:27]1[N:28]=[C:29]([CH3:30])[C:24]2[CH:23]=[C:22]([C:32]3[CH:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)[C:21](=[O:40])[N:20]([CH:17]3[CH2:18][CH2:19][NH:15][CH2:16]3)[C:25]=2[N:26]=1
Reactant: COc1ccc(-c2cc3c(C)nc(N)nc3n(C3CCN(C(=O)OC(C)(C)C)C3)c2=O)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2cc3c(C)nc(N)nc3n(C3CCNC3)c2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
The TFA (0.56 ml, 10 eq.) was added into the solution of 3-[2-Amino-6-(6-methoxy-pyridin-3-yl)-4-methyl-7-oxo-7H-pyrido[2,3-d]pyrimidin-8-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (328 mg, 0.725 mmol) in 2 ml dichloromethane at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction was complete and the solvent was removed. The residue was partitioned in EA/sat. sodium bicarbonate. The EA layer was dried and concentrated to obtain the title compound as a solid (237 mg, 92.8% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]1[CH2:17][CH2:16][CH:15]([C@H:18]([NH2:22])[C:19](O)=[O:20])[CH2:14][CH2:13]1.C1C([C@@H](N)C(O)=O)=CC=C(O)C=1.N[C@@H](C(O)=O)CCSC.N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:22][C@@H:18]([CH:15]2[CH2:16][CH2:17][CH2:12][CH2:13][CH2:14]2)[CH2:19][OH:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: N[C@H](C(=O)O)C1CCCCC1
Agent: CSCC[C@@H](N)C(=O)O
Agent: N[C@@H](C(=O)O)c1ccc(O)cc1
Agent: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: O=S(=O)(N[C@H](CO)C1CCCCC1)c1ccc(Br)cc1

Procedure:
The following compounds (Examples 16-19, Table 3) were prepared using 4-bromobenzensulfonyl chloride with L-cyclohexylglycine, D-4-hydroxyphenylglycine, D-methionine, and L-tryptophan and following the procedure outlined in Example 16.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11](Cl)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:25][CH2:26][NH2:27])=[O:21])([CH3:18])([CH3:17])[CH3:16]>C(N(CC)CC)C>[C:15]([O:19][C:20]([NH:22][CH2:23][CH:24]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:25][CH2:26][NH:27][S:11]([C:6]1[C:5]2[CH:4]=[CH:3][N:2]=[CH:1][C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:13])=[O:12])=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC(CCN)c1ccccc1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(CCNS(=O)(=O)c1cccc2cnccc12)c1ccccc1
Yield: 82.5 %

Procedure:
The same procedure as described in Referential example 3 were repeated using 4.0 g of 5-isoquinolinesulfonyl chloride, 6.95 g of 4-t-butoxycarbonylamino-3-phenylbutylamine and 2.66 g of triethylamine, and there were obtained 6.6 g of N-(4-t-butoxycarbonylamino-3-phenylbutyl)-5-isoquinolinesulfonamide in a yield of 83%.
Reaction SMILES: C[Si]([N:5]=[N+:6]=[N-:7])(C)C.C([Sn](=O)CCCC)CCC.[CH2:18]([C:22]1[N:23]=[C:24]([CH3:52])[N:25]([C:44]2[N:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][N:45]=2)[C:26](=[O:43])[C:27]=1[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=2[C:37]#[N:38])=[N:33][CH:34]=1)[CH2:19][CH2:20][CH3:21]>C1(C)C=CC=CC=1>[NH:5]1[C:37]([C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=2[C:32]2[N:33]=[CH:34][C:29]([CH2:28][C:27]3[C:26](=[O:43])[N:25]([C:44]4[N:45]=[CH:46][C:47]([O:50][CH3:51])=[CH:48][N:49]=4)[C:24]([CH3:52])=[N:23][C:22]=3[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:30][CH:31]=2)=[N:38][N:7]=[N:6]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCCc1nc(C)n(-c2ncc(OC)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)nc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCCCc1nc(C)n(-c2ncc(OC)cn2)c(=O)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Temperature: 95 °C
Reaction time: 24 h
Yield: 79.4 %

Procedure:
Process 4: Trimethylsilyl azide (8.68 g, 75.3 mmol) and dibutyltin oxide (55 mg, 0.221 mmol) were added to toluene (20 mL) solution of 2-{5-{[4-butyl-1-(5-methoxypyrimidin-2-yl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}pyridin-2-yl}benzonitrile (200 mg, 0.43 mmol) and stirred for 24 hours at 95° C. under argon atmosphere. The residues obtained by removing the reaction solvent by distillation was separated and purified by silica gel column chromatography (chloroform:methanol=100:1) to give 5-{{6-[2-(1H-tetrazol-5-yl)phenyl]pyridin-3-yl}methyl}-6-butyl-3-(5-methoxypyrimidin-2-yl)-2-methylpyrimidin-4(3H)-one (174 mg, 80%) as yellow oil.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:7][C:8](=[O:35])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=3)[C:19]2=[O:34])=[CH:13][CH:12]=1)[CH3:6]>C(O)C.O.[Fe]>[CH2:5]([O:7][C:8](=[O:35])[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][N:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([C:25]3[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=3)[C:19]2=[O:34])=[CH:15][CH:16]=1)[CH3:6]
Reactant: CCOC(=O)CCc1ccc(Cn2cc(Cl)cc(-c3ccc([N+](=O)[O-])cc3)c2=O)cc1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)CCc1ccc(Cn2cc(Cl)cc(-c3ccc(N)cc3)c2=O)cc1
Temperature: 25 °C

Procedure:
Acetic acid (1 mL) followed by iron (160 mg, 2.9 mmol) were added to a solution of 3-(4-[5-chloro-3-(4-nitrophenyl)-2-oxo-2H-pyridin-1-ylmethyl]phenyl}-propionic acid ethyl ester (0.31 g, 0.72 mmol) in ethanol (10 mL) and water (5 mL) with stirring. The mixture was then heated at reflux for 2 hours and allowed to cool to room temperature. After basification with aqueous ammonia the mixture was filtered through a pad of celite (Diatomaceous Earth) and the filtrate evaporated to dryness. The residue was taken up in aqueous sodium bicarbonate/ethyl acetate and the organic layer washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. After purification by chromatography on silica gel with a gradient of 30-50% ethyl acetate in hexane the title compound was obtained as an oil.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)(=O)=O.[O:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].CN(C)C(N(C)C)=N>O1CCCC1.CN(C)C=O>[O:26]=[C:21]1[N:22]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[C:23](=[O:25])[CH2:24][O:20]1
Reactant: O=C1COC(=O)N1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN2C(=O)COC2=O)CC1

Procedure:
A suspension of 13.60 g (46.36 mmol) of 1,1-dimethylethyl 4-{[(methylsulphonyl)oxy]methyl}piperidine-1-carboxylate, prepared in step 2.1., 9.37 g (92.72 mmol) of 1,3-oxazolidine-2,4-dione and 16.02 g (139.08 mmol) of 1,1,3,3-tetramethylguanidine in a mixture of 180 ml of tetrahydrofuran and 30 ml of dimethylformamide is heated at reflux for 24 hours. It is allowed to return to ambient temperature and is concentrated under reduced pressure. The residue is taken up in dichloromethane and water and the aqueous phase is separated off and extracted twice with dichloromethane. The combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulphate. Following evaporation of the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 98/2 then 95/5 mixture of dichloromethane and methanol.