Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](B(O)O)=[CH:11][N:10]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:9]=2)=[CH:4][CH:3]=1.Br[C:36]1[CH:37]=[CH:38][C:39]2[N:40]([C:42]([C:45]3[S:46][C:47]([S:50][CH3:51])=[CH:48][CH:49]=3)=[CH:43][N:44]=2)[CH:41]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:36]3[CH:37]=[CH:38][C:39]4[N:40]([C:42]([C:45]5[S:46][C:47]([S:50][CH3:51])=[CH:48][CH:49]=5)=[CH:43][N:44]=4)[CH:41]=3)=[CH:11][N:10]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1-c1ccc(F)cc1
Reactant: CSc1ccc(-c2cnc3ccc(Br)cn23)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)s1
Yield: 64.3 %

Procedure:
736 mg 3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolylboronic acid (compound in Production Example 25), 550 mg 6-bromo-3-[5-(methylsulfanyl)-2-thienyl]imidazo[1,2-a]-pyridine (compound in Production Example 58) and 100 mg tetrakis (triphenylphosphine)palladium were stirred at 80° C. for 3 hours in a solution mixture of 5 mL toluene, 5 mL ethanol and 2.5 mL of 2 N aqueous sodium carbonate under nitrogen atmosphere. The reaction solution was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, the solvent was removed, and the resulting residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) to give 685 mg of the title compound (pale greenish yellow crystals; recrystallization solvent, ethyl acetate/methanol).
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH2:6](OC(C(OCC)=O)=CC=[N+](C)C)[CH3:7].[CH3:20][N:21]([CH3:33])[CH:22]=[CH:23][C:24](=[O:32])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].F[B-](F)(F)F.C([O+](CC)CC)C>ClCCl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH2:6]([O:32][C:24]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])=[CH:23][CH:22]=[N+:21]([CH3:20])[CH3:33])[CH3:7]
Reactant: CCOC(=O)C(=CC=[N+](C)C)OCC
Reactant: CN(C)C=CC(=O)C(=O)OC(C)(C)C
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=CC=[N+](C)C)C(=O)OC(C)(C)C

Procedure:
The procedure is as in Example 2 for the preparation of N-(3-ethoxy-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate, starting with t-butyl 4-dimethylamino-2-oxo-3-butenoate (3.3 g) and triethyloxonium tetrafluoroborate (3.62 g) in dichloromethane (20 cc). The solution of N-(3-ethoxy-3-t-butyloxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate in methylene chloride thereby obtained is stored under an argon atmosphere and used immediately in the subsequent syntheses.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C(=O)(O)[O-].[Na+].[C:15](Cl)(Cl)=[S:16].[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>C(Cl)(Cl)Cl>[CH2:19]([NH:23][C:15]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1)=[S:16])[CH2:20][CH2:21][CH3:22]
Reactant: S=C(Cl)Cl
Reactant: CCCCN
Reactant: N#Cc1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCNC(=S)Nc1cccc(C#N)c1
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To a 250 mL flask was added 3-aminobenzonitrile (0.59 g, 5.0 mmol), CHCl3 (25 mL) and saturated sodium bicarbonate (25 mL). To the well-stirred mixture was added dropwise thiophosgene (0.39 mL, 5.1 mmol). After 2 h butylamine (0.50 mL, 5.1 mmol) was added dropwise and stirred 1 h. The reaction mixture was then extracted with CHCl3, concentrated under reduced pressure, and chromatographed (silica gel, 2:98 MeOH/DCM) to yield 1-butyl-3-(3-cyanophenyl)thiourea (1.02 g, 87%) as a white solid: TLC (2:98 MeOH/DCM Rf 0.47).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH:15]([CH3:17])[CH3:16])[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+].CO>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH:15]([CH3:17])[CH3:16])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=NOC(C)C)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)ON=C(C(=O)O)c1csc(N)n1
Yield: 64.1 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-iso-propoxyiminoacetate (syn isomer, 26.8 g.), 1N aqueous solution of sodium hydroxide (156 ml.), methanol (156 ml.) and tetrahydrofuran (100 ml.) were treated in a similar manner to that of Example D-(4) to give 2-(2-aminothiazol-4-yl)-2-iso-propoxyiminoacetic acid (syn isomer, 15.3 g.), mp. 151° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.[N:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[O:19][C:20]1[CH:21]=[C:22]([C@@H:26]([NH2:28])[CH3:27])[CH:23]=[CH:24][CH:25]=1>>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([NH:28][C@H:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([O:19][C:14]2[N:13]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:21]=1)[CH3:27])=[O:8]
Reactant: C[C@H](N)c1cccc(Oc2ncccn2)c1
Reactant: O=C(O)C=Cc1ccccc1F
Product: C[C@H](NC(=O)C=Cc1ccccc1F)c1cccc(Oc2ncccn2)c1

Procedure:
The title compound was prepared from 2-fluorocinnamic acid following the general procedures as described for Example 1 with the exception that (S)-1-[3-(pyrimidin-2-yloxy)-phenyl]-ethylamine was used.
Reaction SMILES: N1CCC[C@@H]1C(N)=O.C(N(CC)CC)C.[CH3:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1.C(O)=O.C(N(CC)CC)C>C(Cl)Cl.C[Ir-4](Cl)(C)(C)(C)(C)C1C=CC=C1.[Ir](Cl)(Cl)Cl>[CH3:16][CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18]1
Reactant: Cc1ccc2ccccc2n1
Agent: C[Ir-4](C)(C)(C)(C)(Cl)C1C=CC=C1
Agent: Cl[Ir](Cl)Cl
Agent: NC(=O)[C@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: ClCCl
Product: CC1CCc2ccccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
To 10 ml of methylene chloride, 55.6 mg of a pentamethylcyclopentadienyl iridium(III) chloride dimer ([Cp*IrCl2]2), 16.7 mg of (R)-prolinamide and 15.6 mg of triethylamine were added, and the mixture was stirred under argon atmosphere at room temperature for about 30 minutes to give a catalyst-containing mixture. In 60 ml of methylene chloride, 1.00 g of 2-methylquinoline was dissolved, and a 1/10 amount of the catalyst-containing mixture (equivalent to 0.1 mol % as an iridium chloride dimer) was added. After cooling to −10° C., 8.4 ml of a mixed solvent of formic acid/triethylamine (molar ratio: 5/2) was added dropwise, and the mixture was stirred at the same temperature for 2 days to give 2-methyl-1,2,3,4-tetrahydroquinoline (degree of conversion: 67.4%). The R-enantiomer was in excess and the optical purity was 85.4% ee.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH3:25].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH3:25]
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Reactant: CCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.61 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 0.45 ml (5.0 mmol) of n-butyraldehyde in 50 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate) to yield 1.89 g (quant, light yellow oily substance) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17](=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]([O:29][Si](C)(C)C)=[C:26]([CH3:28])[CH3:27]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:22])([CH2:18][CH:19]([CH3:20])[CH3:21])[C:26]([CH3:28])([CH3:27])[C:25]([O:24][CH3:23])=[O:29])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: CC(C)CC(=O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(O)(CC(C)C)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 94.7 %

Procedure:
1-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-3-methylbutan-1-one (220 mg, 0.742 mmol) was dissolved in 10 mL of dry DCM and 1-methoxy-2-methyl-1-(trimethylsiloxy)propene (0.162 mL, 0.8 mmol) was added. The reaction mixture was cooled to 0° C. and TiCl4 (0.8 mL of 1.0 M DCM solution, 0.8 mmol) was added portionwise and then stirred 12 h. The reaction was quenched with aqueous sodium bicarbonate and extracted 2×DCM. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified SiO2 chromatography eluting with 1:1 EtOAc/hexane to give 280 mg (95% yield) of methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-hydroxy-2,2,5-trimethylhexanoate. MS found: (M+H)+=399.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15](O)=[O:16].C[Si](C=[N+]=[N-])(C)C.[BH4-].[Na+]>CO.C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][CH2:15][OH:16]
Reactant: Cc1oc(-c2ccccc2)nc1CCC(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1CCCO
Reaction time: 4 h
Yield: 71.3 %

Procedure:
Acid 1-3 (4.6 g, 20 mmol) was dissolved in 300 mL of a 1:1 mixture of methanol/toluene at 23° C. under N2 atmosphere. Trimethylsilyl diazomethane (20 mL, 40 mmol), added dropwise until color persisted and stirred for an additional 4 hours. Solvent was removed in vacuo and residue dried under vacuum for 1 hour. Residue was then redissolved in 300 mL methanol and placed under N2 atmosphere. NaBH4 (10 g, 264 mmol)and the reaction stirred for 4 hours. When complete, solvent was removed in vacuo and residue taken up in ethyl acetate and washed with water, brine and dried over MgSO4. SiO2 chromatography with 40% EtOAc/Hexanes gave 3.1 g of the product 1-4 as white crystals (71%) M.P. NMR CDCl3 (δ): 8.01 (2H, m); 7.44 (3H, m); 3.75 (2H, t, J=5.8, 11.4 Hz); 2.68 (2H, t, 6.8, 13.7 Hz); 2.35 (3H, s); 1.91 (2H, m).
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([O:8][CH2:9][CH2:10][NH2:11])([O-:7])=[O:6].[CH2:12]([CH:19]1[S:23][C:22](=[O:24])[NH:21][CH:20]1[C:25](O)=[O:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[N+:5]([O:8][CH2:9][CH2:10][NH:11][C:25]([CH:20]1[CH:19]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[S:23][C:22](=[O:24])[NH:21]1)=[O:26])([O-:7])=[O:6]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C1NC(C(=O)O)C(Cc2ccccc2)S1
Solvent: O=[N+]([O-])O
Product: O=C1NC(C(=O)NCCO[N+](=O)[O-])C(Cc2ccccc2)S1
Yield: 64.2 %

Procedure:
A procedure similar to that described in Example 1 was repeated, but using 210 mg of N-(2-nitrooxyethyl)amine nitrate and 250 mg of 5-benzyl-2-oxothiazolidine-4-carboxylic acid, to obtain 220 mg of the title compound as pale yellow columnar crystals, melting at 123°-124° C. (after recrystallization from ethanol).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].O.[OH-].[K+].[C:13](#[N:16])[CH:14]=[CH2:15]>O1CCOCC1>[C:13]([CH2:14][CH2:15][O:1][CH2:2][C:3]([CH2:8][O:9][CH2:15][CH2:14][C:13]#[N:16])([CH2:6][O:7][CH2:15][CH2:14][C:13]#[N:16])[CH2:4][O:5][CH2:15][CH2:14][C:13]#[N:16])#[N:16]
Reactant: C=CC#N
Reactant: OCC(CO)(CO)CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N#CCCOCC(COCCC#N)(COCCC#N)COCCC#N
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Pentaerythritol (6.84 g, 50 mmol) was dissolved in 20 ml dioxane and 2 ml water and mixed up with 40% aqueous potassium hydroxide solution (w/v, 1 ml). After cooling to 0° C. in an ice bath, acrylonitrile (16.2 g, 300 mmol) was added and the mixture stirred for 48 h at room temperature. Solvents were evaporated, the remaining oil was diluted in 100 ml dichloromethane and washed with 10% aqueous sodium chloride solution (w/v, 50 ml). After re-extraction of the aqueous layer with dichloromethane (2×25 ml), the combined organic layers were dried over sodium sulfate and intensively evaporated. The nitrile was obtained as a colorless syrup: yield: 14.32 g (41 mmol, 82%). 1H-NMR (400 MHz, CDCl3) δ 2.60 (t, 8 H,—CH2CN), 3.50 (s, 8 H, —CqCH2O—), 3.65 (t, 8 H, —OCH2—). 13C-NMR (100 MHz, CDCl3) δ 18.86 (—CH2CN), 45.68 (Cq), 65.88 (—OCH2—), 68.82 (CqCH2O—), 118.22 (CN).
Reaction SMILES: N#N.[C:3]([SiH2:7][O:8][C:9]([CH3:18])([CH3:17])[C:10]1[O:14][N:13]=[C:12]([CH2:15][OH:16])[CH:11]=1)([CH3:6])([CH3:5])[CH3:4]>C(C#N)(C)=O.O=[Mn]=O>[C:3]([SiH2:7][O:8][C:9]([CH3:18])([CH3:17])[C:10]1[O:14][N:13]=[C:12]([CH:15]=[O:16])[CH:11]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CO)no1
Agent: O=[Mn]=O
Agent: CC(=O)C#N
Agent: N#N
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(C=O)no1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(tert-butyl-dimethyl-silanyloxymethyl)-isoxazol-3-yl]-methanol (2.94 g, 12.08 mmol) in AcCN (120.0 mL) was treated at rt with MnO2 (8.17 g, 84.56 mmol) and the reaction mixture was stirred for 24 h at rt before being filtered through Celite. The solvent was removed under reduced pressure to give the title compound as a yellow oil: TLC:rf (9:1 hept-EA)=0.32. LC-MS-conditions 02: tR=0.92 min.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([NH:14][NH2:15])=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[Cl-].[CH3:25][O:26][C:27](=[O:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1.O>O1CCCC1>[CH2:1]([O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:14][NH:15][C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([C:27]([O:26][CH3:25])=[O:37])=[CH:36][CH:35]=2)=[O:13])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CCCCCCOc1ccc(C(=O)NN)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCOc1ccc(C(=O)NNC(=O)c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.7 %

Procedure:
To a solution of 4-n-Hexyloxybenzoylhydrazine (1.96 g) and pyridine (0.74 ml) in tetrahydrofuran (20 ml) was added a solution of terephthalic acid monomethyl ester chloride (1.56 g) in tetrahydrofuran (15 ml) dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 hours, and poured into water. The precipitate was collected by filtration and washed with acetonitrile. The residue was dried under reduced pressure to give 1-(4-n-Hexyloxybenzoyl)-2-(4-methoxycarbonylbenzoyl)hydrazine (2.99 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:20]([C:16]2[CH:15]=[C:14]([O:13][C:12]3[CH:11]=[CH:10][C:9]([NH:8][C:6]4[CH:5]=[C:4]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:3]=[C:2]([NH2:1])[N:7]=4)=[CH:24][CH:23]=3)[CH:19]=[CH:18][N:17]=2)=[O:22])[CH2:34][CH2:33]1
Reactant: CN1CCNCC1
Reactant: Nc1nc(Nc2ccc(Oc3ccnc(C(=O)O)c3)cc2)cc(-c2ccccc2)n1
Product: CN1CCN(C(=O)c2cc(Oc3ccc(Nc4cc(-c5ccccc5)nc(N)n4)cc3)ccn2)CC1

Procedure:
This material is prepared by a method analogous to that described for Example 21, starting from 4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy} pyridine-2-carboxylic acid (Example 20) and 1-methylpiperizine. 1H NMR (DMSO-d6) δ 10.85 (s, 1H), 10.19 (s, 1H), 8.42 (d, 1H), 7.90 (m, 2H), 7.74 (m, 3H), 7.59 (m, 4H), 7.22 (m, 3H), 7.06 (m, 2H), 6.60 (s, 1H), 4.51 (m, 1H), 4.08 (m, 1H), 3.45 (m, 3H), 3.17 (m, 3H), 2.78 (s, 3H); MS ES 482 (M+H)+, calcd 482, RT=1.86 min.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][CH2:9][CH2:8]2)[CH:2]=[CH2:3].Br[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.[H-].[Na+].O>CN(C)C=O>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][CH2:17][N:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[CH:6]=3)[C:11]2=[O:15])=[CH:21][CH:22]=1
Reactant: Fc1ccc(CCCBr)cc1
Reactant: C=CCOc1ccc2c(c1)CCNC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc2c(c1)CCN(CCCc1ccc(F)cc1)C2=O

Procedure:
To a solution of 6-allyloxy-1-oxo-1,2,3,4-tetrahydroisoquinoline (10.6 g, 52 mmol) and 1-bromo-3-(4-fluorophenyl)-propane (17 g, 78 mmol) and KI (430 mg, 2.6 mmol) in dimethyl formamide (DMF) (125 mL) is added NaH (3.1 g, 78 mmol). After 4 hours the reaction mixture is poured into H2O (500 mL) and the resulting suspension is extracted with EtOAc (3×300 mL). The combined organic extracts are washed with H2O (5×200 mL), saturated NaCl solution (2×200 mL), dried over MgSO4 and concentrated in vacuo. The residue is chromatographed (silica gel, 1:1 EtOAc/hexane) to yield 2-[3-(4-fluorophenyl)-propyl]-6-allyloxy-1-oxo-1,2,3,4-tetrahydroisoquinoline as a brown oil.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[C:5]([C@@H:10]([C@H:12]([C:14]([O:16]CC)=O)[OH:13])[OH:11])([O:7]CC)=O.O>CO>[CH2:1]([NH:4][C:5](=[O:7])[C@@H:10]([C@H:12]([C:14]([NH:4][CH2:1][CH2:2][CH3:3])=[O:16])[OH:13])[OH:11])[CH2:2][CH3:3]
Reactant: CCCN
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Solvent: CO
Solvent: O
Product: CCCNC(=O)[C@H](O)[C@@H](O)C(=O)NCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
N,N′-Di-n-propyl L-tartaramide was prepared by the reaction of n-propyl amine with diethyl L-tartrate. Diethyl L-tartrate (20.027 g, 1.0 eq) and HPLC grade methanol (40 mL) were weighed into a 250 mL round-bottomed flask equipped with a teflon coated magnetic stir bar. n-Propyl amine (12.038 g, 2.0 eq) was slowly poured into the stirring diethyl L-tartrate solution. Some fuming and a color change from water-white to pale yellow were observed. Additional methanol (10 mL) was used to rinse all of the amine into the reaction flask. After stirring the solution for 30 min at ambient temperature, the product began to crystallize from solution. The reaction mixture was allowed to sit at ambient temperature for two hours. The flat, white crystals were filtered, washed with methanol (2×50 mL), washed with diethyl ether (2×30 mL), and dried under vacuum. The first crop of product was obtained in 35% yield (7.977 g, 34.34 mmole). Subsequently, a second crop of crystals (1.80 g, 7.75 mmole) was isolated from the mother liquor.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[CH3:17][NH2:18]>CCO>[CH3:17][NH:18][CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Reactant: CN
Solvent: CCO
Product: CNCC1OCc2ccc(S(C)(=O)=O)cc2O1
Temperature: 145 °C
Yield: 74.7 %

Procedure:
A mixture of 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (0.4 g, 1.30 mmol), methanamine (33% in EtOH, 2.0 ml, 16.1 mmol) and EtOH (3.0 ml) was heated in a micro wave oven at 145° C. for 30 min. The volatiles were evaporated in vacuum and the crude product was chromathographed twice on a silica column using EtOAc/MeOH (4:1) as eluent. Collection of the fractions containing pure product and evaporation of the solvent afforded the title compound (0.25 g, 74%). The amine was converted into hydrochloric acid salt and crystallized from EtOH/MeOH/DEE. M.p. 225° C. MS m/z (rel. intensity, 70 eV) 257 (M+, 1), 123 (76), 78 (35), 77 (bp), 51 (97).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])[O:28][C:29](Cl)(Cl)Cl)Cl.[CH3:35][O:36][C:37]1[CH:38]=[C:39](CO)[CH:40]=[CH:41][CH:42]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:28][CH2:29][C:41]2[CH:40]=[CH:39][CH:38]=[C:37]([O:36][CH3:35])[CH:42]=2)=[CH:18][CH:17]=1
Reactant: COc1cccc(CO)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cccc(COC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)c1
Yield: 85.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (151 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (3-methoxyphenyl)methanol (71 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (133 mg, yield 79%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([CH2:11][CH2:12][N:13]1[CH2:19][CH2:18][CH2:17][C:16]2[CH:20]=[CH:21][C:22]([C:24]#[C:25][CH2:26][CH2:27][CH2:28][NH2:29])=[CH:23][C:15]=2[C:14]1=[O:30])([OH:10])=[O:9].[C:31](S(O)(=O)=O)([NH2:33])=[NH:32]>C(O)(=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([CH2:11][CH2:12][N:13]1[CH2:19][CH2:18][CH2:17][C:16]2[CH:20]=[CH:21][C:22]([C:24]#[C:25][CH2:26][CH2:27][CH2:28][NH:29][C:31]([NH2:33])=[NH:32])=[CH:23][C:15]=2[C:14]1=[O:30])([OH:10])=[O:9]
Reactant: N=C(N)S(=O)(=O)O
Reactant: NCCCC#Cc1ccc2c(c1)C(=O)N(CCC(=O)O)CCC2
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NCCCC#Cc1ccc2c(c1)C(=O)N(CCC(=O)O)CCC2
Reaction time: 2 h
Yield: 15.2 %

Procedure:
A solution of 2-(2-carboxyethyl)-8-(5-aminopentynyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one trifluoracetate (20 mg, 0.063 mmol) in saturated aqueous KHCO3 (1 mL) was treated with formamidine sulfonic acid (80 mg, 1.0 mmol), and the resulting mixture stirred for 2 hours. The mixture was then treated with acetic acid, and the volatiles were removed. The residue was purified by HPLC (1/2' C-18 reverse-phase column) eluting with a gradient of 3:7 methanol (0.1% trifluoroaceate)/water (0.1% trifluoroaceate), time 0 to 10 min, to 7:3 methanol(0.1% trifluoroaceate)/water(0.1% trifluoroaceate), time 10 to 40 min, to yield 4.5 mg (15%) of 2-(2-carboxyethyl)-8-(5-guanidinopentynyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one trifluoracetate as a light brown solid; 1H NMR(D2O) d7.40(s, 1H), 7.25(dd, J=3, 6 Hz, 1H), 7.15(d, J=6 Hz, 1H), 3.80(t, J=6 Hz, 2H), 3.30(m, 4H), 3.15(t, J=6 Hz, 2H), 2.00(t, J=6 Hz, 2H), 1.80(m, 2H); MS(FAB) m/z=357.1(MH+).