Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[S:31][C:11]2=[CH:12][CH:13]=[C:14]3[C:19]([N:18]=[C:17]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([S:27](=[O:30])(=[O:29])[NH2:28])[CH:22]=4)[N:16]=[CH:15]3)=[C:10]2[CH:9]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl.O>>[S:27]([C:23]1[CH:22]=[C:21]([NH:20][C:17]2[N:16]=[CH:15][C:14]3[C:19](=[C:10]4[CH:9]=[C:8]([C:6]([OH:7])=[O:5])[S:31][C:11]4=[CH:12][CH:13]=3)[N:18]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:30])(=[O:29])[NH2:28]
Reactant: CC(C)(C)OC(=O)c1cc2c(ccc3cnc(Nc4cccc(S(N)(=O)=O)c4)nc32)s1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(Nc2ncc3ccc4sc(C(=O)O)cc4c3n2)c1
Reaction time: 2.5 h
Yield: 89.5 %

Procedure:
2-(3-Sulfamoyl-phenylamino)-thieno[2,3-h]quinazoline-8-carboxylic acid tert-butyl ester (1.84 g, 4.02 mmol) was placed in a 100 mL florentine and cooled in an ice-bath. Premixed TFA/dichloromethane/water (1:4:0.1, 9 mL TFA) was added in one portion and the resultant suspension was stirred at 0° C. for 10 minutes. After a further 2.5 hours at room temperature and 1.5 hours at 40° C. the reaction was concentrated under reduced pressure. The solid obtained was azeotroped with dry dichloromethane (3×10 mL), triturated with diethyl ether and isolated by filtration. The solid obtained was washed with diethyl ether (4×5 mL) and dried in a drying pistol at 40° C. overnight to afford the title compound as a yellow powder (1.44 g, 86% yield containing 1.24 eq. TFA). MS (ES+) 400. δH (d6 DMSO) 7.2-7.4 (2H, br s), 7.5 (1H, m), 7.6 (1H, m), 8.0 (3H, m), 8.7 (1H, s), 8.8-8.9 (1H, s), 9.4 (1H, s), 10.4-10.5 (1H, s), 13.4-13.8 (1H, br s).
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([P:12](=[O:17])([O:15][CH3:16])[O:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:20][O:21][P:22]([O-:25])[O:23][CH3:24].C(NCCCC)CCC.CCCCCC>CCOCC>[CH3:19][Si:2]([CH3:1])([CH3:18])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:11])([P:22](=[O:25])([O:23][CH3:24])[O:21][CH3:20])[P:12](=[O:17])([O:15][CH3:16])[O:13][CH3:14])[CH:6]=[CH:7][CH:8]=1
Reactant: COP(=O)(OC)C(=O)Cc1cccc([Si](C)(C)C)c1
Reactant: COP([O-])OC
Solvent: CCCCCC
Solvent: CCCCNCCCC
Solvent: CCOCC
Product: COP(=O)(OC)C(O)(Cc1cccc([Si](C)(C)C)c1)P(=O)(OC)OC
Yield: 65.3 %

Procedure:
To a solution of dimethyl m-trimethylsilylphenylacetylphosphonate (1.63 g, 5.0 mmol) in Et2O (10 cm3) was added a solution of dimethylphosphite (0.83 g, 7.5 mmol), dibutylamine (0.32 g, 2.5 mmol) and hexane (10 cm3) at 0° C. A white solid began to form after a few minutes. After 20 min the mixture was filtrated to give the title compound (1.34 g, 65%) as a white solid. Recrystallization was achieved by adding water (9.5 cm3) to a solution of the title compound (0.50 g) in acetic acid (0.5 cm3) and then leaving the resulting mixture for several days in the refrigerator. Filtration afforded the bisphosphonate (0.33 g, 66%) as white crystals.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16](I)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].C1(C)C=CC=CC=1.[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)#[N:27].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:1]([C:3]1[CH:17]=[C:16]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([C:26]#[N:27])[CH:33]=2)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#Cc1cccc(-c2cc(C#N)cc3ncn(-c4ccccc4)c23)c1
Yield: 5.8 %

Procedure:
5-Cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), 3-cyanophenylboronic acid (73 mg, 0.5 mmol), ethanol (3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) were combined and the mixture was stirred at reflux overnight. The solvent was removed under reduced pressure and the crude product was purified on a 2 g silica Isolute® SPE column, eluting with dichloromethane/methanol (95:5). The eluent was concentrated under reduced pressure and the crude product was purified by reverse-phase prep LCMS to give the title compound (9.3 mg, 6%) m/z, 321.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[N:16]=2)[CH2:10][CH:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].C(N(CC)CC)C.O1CCOCC1>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:24]=3[Cl:23])[N:16]=2)[CH2:10][CH:9]1[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: CC1CC(Oc2cccc(N)n2)CCN1C(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC1CC(Oc2cccc(NC(=O)c3ccc(F)cc3Cl)n2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 4-(6-amino-pyridin-2-yloxy)-2-methyl-piperidine-1-carboxylic acid tert-butyl ester cis isomer 1 (preparation 63, 0.025 g, 0.08 mmol), 2-chloro-4-fluoro-benzoyl chloride (0.10 g, 0.52 mmol), triethylamine (0.10 mL, 0.69 mmol) and 1,4-dioxane (10 mL), stir and heat to reflux. After 3 hr., cool to ambient temperature, dilute with methanol (10 mL) and load on an SCX column (10 g). Wash with methanol (2×25 mL). Elute product with 2M ammonia/methanol (2×25 mL). Eluent concentrated to give crude title compound. Mass spectrum (electrospray): m/z=364.1 (M+1-100) loss of t-BOC from parent. Use without further characterization in next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C1CCN2C(=NCCC2)CC1.Cl[C:22]([CH3:26])([CH3:25])[C:23]#[CH:24]>C(#N)C>[CH3:25][C:22]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:26])[C:23]#[CH:24]
Reactant: C#CC(C)(C)Cl
Reactant: N#Cc1ccc(O)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C#CC(C)(C)Oc1ccc(C#N)cc1
Reaction time: 5 h

Procedure:
To a solution of 4-cyanophenol (6.55 g, 55.0 mmol) in anhydrous acetonitrile (50 mL) at ~0° C. under argon was added DBU (9.04 mL, 60.45 mmol). After the solution had cooled to ~0° C., 3-chloro-3-methyl-1-butyne (5.13 g, 50 mmol) was added followed by cupric chloride dihydrate (9.62 mg, 0.056 mmol). After stirring at ~0° C. for 5 hours, the mixture was concentrated at reduced pressure. The residue was partitioned between 1N HCl (50 mL) and toluene (300 mL). The organic fraction was washed with 1N HCl (2×50 mL), 1N NaOH (2×50 mL), and brine. After drying (magnesium sulfate), the solvent was removed at reduced pressure to give crude title compound as a nearly colorless oil. Distillation of the crude material (bulb to bulb) afforded the title compound as a colorless, low melting solid (7.25 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:11]1[C:20]([CH:21]=[O:22])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:11]1[C:20]([CH:21]=[O:22])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: O=Cc1cc2ccccc2nc1Cl
Reactant: Oc1ccc(Cl)c(Cl)c1
Product: O=Cc1cc2ccccc2nc1Oc1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared according to preparation 65 starting from 3,4-dichlorophenol and 2-chloro-3-quinoline carboxaldehyde (Aldrich Chemical Co.); δH (CDCl3, 400 MHz) 7.19 (1H, m), 7.50 (3H, m), 7.74 (2H, m), 7.91 (1H, dd), 8.75 (1H, s), 10.59 (1H, s); MS rn/z318, 320 (MH+).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([C:16]2[CH:17]=[CH:18][C:13]([Br:12])=[CH:14][CH:15]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: COC(=O)c1ccc(I)cc1
Reactant: OB(O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccc(Br)cc2)cc1
Temperature: 80 °C

Procedure:
A mixture of methyl 4-iodobenzoate, 9.38 g (35.8 mmol), 4-bromophenylboronic acid 7.18 g (35.8 mmol), Pd(PPh3)4, 2.07 g (1.79 mmol), in 180 mL of toluene and 100 mL of ethanol was heated to obtain a clear solution. To the solution was added 30 mL of 4.0M aq. Na2CO3. The reaction mixture refluxed for 4 h at 80° C. The mixture was cooled to room temperature and diluted with 300 mL ethyl acetate. The organic layer was washed with 2×300 mL portions of water, 2×300 mL portions of sat. aq. NaCl, and dried (MgSO4). After the solution was concentrated, the residue was purified by column chromatography (eluted with 7% EtOAc-Heptane) to afford the desired product in 7.8 g (78%) as a white solid. 1H NMR (CDCl3) 8.10 (d, 2H, J=9.0 Hz), 7.62 (d, 2H, J=9.0 Hz), 7.59 (d, 2H, J=9.3 Hz), 7.48 (d, 2H, J=9.3 Hz), 3.95 (s, 3H).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)[C:14]([NH2:17])=[N:15][CH:16]=1>C1COCC1>[CH3:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)[C:14]2[N:15]([CH:16]=1)[CH2:4][CH2:5][S:6](=[O:8])(=[O:7])[N:17]=2
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1cnc(N)c(-c2ccc(Oc3ccccc3)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=CN2CCS(=O)(=O)N=C2C(c2ccc(Oc3ccccc3)cc2)=C1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 229 mg) in THF (dry) (10 mL) was added 2-chloroethanesulfonyl chloride (0.361 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 5-methyl-3-(4-phenoxyphenyl)pyridin-2-amine (316 mg) in THF (dry) (20 mL) was added at 0° C. and the mixture was stirred at room temperature for 30 min. The mixture was quenched with water. Water and EtOAc were added and the extracted organic layer was washed with brine. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) to give 7-methyl-9-(4-phenoxyphenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (158.2 mg) as a white solid. Platinum(IV) oxide (30.0 mg) was added to a solution of 7-methyl-9-(4-phenoxyphenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (141 mg) in THF (dry) (15 mL) and MeOH (15 mL) and the mixture was stirred at 50° C. under hydrogen overnight. Platinum(IV) oxide (30.0 mg) was added and the mixture was stirred at 50° C. under hydrogen for 1 day. The insoluble material was removed by filtration, silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and crystallized from THF/IPE to give the title compound (35.4 mg) as colorless crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:17])[CH2:12][C:13](=O)[CH2:14][CH3:15])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.[NH2:27][C:28]([NH2:30])=[O:29].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>CC#N.O>[CH2:14]([C:13]1[NH:30][C:28](=[O:29])[NH:27][CH:23]([C:22]2[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=2)[C:12]=1[C:11]([NH:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[CH:3]2)=[O:17])[CH3:15]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCC(=O)CC(=O)Nc1ccc2[nH]ncc2c1
Reactant: NC(N)=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: O
Product: CCC1=C(C(=O)Nc2ccc3[nH]ncc3c2)C(c2ccc(F)cc2)NC(=O)N1
Yield: 67.7 %

Procedure:
The product of Step (a) (126 mg, 0.545 mmol, 1 equiv), 4-fluorobenzaldehyde (0.058 mL, 0.545 mmol, 1 equiv), urea (49 mg, 0.818 mmol, 1.5 equiv), and ytterbium triflate (37 mg, 0.06 mol, 0.10 equiv) were combined in CH3CN (2 mL) and heated to reflux for 4.5 hours. The reaction was diluted with water and the resulting precipitate was collected by filtration. The solid was washed with water, CH3CN, and Et2O. 140 mg (68%) of the product was isolated as a pale grey solid. MS (ES+) m/e 380 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1([CH3:24])[C:8](=[O:9])[NH:7][C:6]([C:10]2[C:18]3[N:17]=[C:16]([CH3:19])[N:15]([CH3:20])[C:14]=3[CH:13]=[CH:12][C:11]=2[C:21]([OH:23])=O)=[N:5]1)([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH:1]([C:4]1([CH3:24])[C:8](=[O:9])[N:7]2[C:21](=[O:23])[C:11]3[CH:12]=[CH:13][C:14]4[N:15]([CH3:20])[C:16]([CH3:19])=[N:17][C:18]=4[C:10]=3[C:6]2=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc2c(C3=NC(C)(C(C)C)C(=O)N3)c(C(=O)O)ccc2n1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: Cc1nc2c3c(ccc2n1C)C(=O)N1C(=O)C(C)(C(C)C)N=C31
Reaction time: 3 h
Yield: 23.6 %

Procedure:
A mixture of 4-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-1,2-dimethyl-5-benzimidazolecarboxylic acid (0.942 g, 2.87 mmol), dicyclohexylcarbodiimide (0.590 g, 2.87 mmol) and tetrahydrofuran is stirred for 3 hours at reflux temperature, cooled and concentrated in vacuo. The residue is chromatographed (silica gel, ethyl acetate eluent) to afford the title product as a white powder (0.210 g, 23.6%), mp 258°-263° C.
Reaction SMILES: [C:1]12([NH:11][C:12](=[O:24])[C:13]3[CH:18]=[CH:17][C:16](Cl)=[N:15][C:14]=3[S:20][CH2:21][CH2:22][CH3:23])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:26]1.Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)CCC.CCOC(C)=O>[C:1]12([NH:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([N:25]4[CH2:30][CH2:29][CH2:28][C@@H:27]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:26]4)=[N:15][C:14]=3[S:20][CH2:21][CH2:22][CH3:23])=[O:24])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CCCSc1nc(Cl)ccc1C(=O)NC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)C[C@@H]1CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCC#N
Product: CCCSc1nc(N2CCC[C@@H](CC(=O)OC)C2)ccc1C(=O)NC12CC3CC(CC(C3)C1)C2
Yield: 44 %

Procedure:
N-adamantan-1-yl-6-chloro-2-(propylthio)nicotinamide (0.365 g, 1 mmol) was added to (S)-methyl 2-(piperidin-3-yl)acetate.HCl (0.194 g, 1 mmol) and potassium carbonate (0.415 g, 3 mmol) in butyronitrile (4 mL) was heated at 150° C. for 2 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (20 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in hexane. Pure fractions were evaporated to dryness to afford methyl {(3S)-1-[5-(adamantan-1-ylcarbamoyl)-6-(propylthio)pyridin-2-yl]piperidin-3-yl}acetate (0.215 g, 44%) as a white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:25]=[N:26][CH:27]=C([CH:31]=2)C#N)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:32].[K+].Cl.[O:35]1[CH2:40][CH2:39]OCC1>O>[CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:25]=[N:26][CH:27]=[C:39]([CH:31]=2)[C:40]([OH:35])=[O:32])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: N#Cc1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Reactant: C1COCCO1
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)c1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 100 °C
Yield: 59.7 %

Procedure:
5-(4-(Benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinonitrile (prepared as in Example 11) (0.800 g, 1.99 mmol) was dissolved in dioxane (3 mL), and KOH (0.892 g, 15.9 mmol) was added. The reaction mixture was heated to 100° C. for 14 h. The reaction mixture was allowed to cool and concentrated under reduced pressure to remove dioxane. The residue obtained was diluted with water (10 mL) and neutralized with dilute HCl to pH 6. The solid was filtered and air dried. The solid was purified by preparative HPLC (Condition B-67 as described in general methods) to obtain 5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinic acid (0.500 g, 59.7%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.83 (d, J=5.6 Hz, 2H), 6.66 (t, J=5.6 Hz, 1H), 6.83 (d, J=2.8 Hz, 1H), 7.26-7.56 (m, 10H), 7.96 (d, J=2.8 Hz, 1H), 8.99 (dd, J=1.6 Hz, J=2.0 Hz, 1H), 9.14 (d, J=2.0 Hz, 1H), 9.53 (d, J=1.6 Hz, 1H), 13.61 (br s, 1H). LCMS Condition B-44: retention time 1.54 min, [M+1]=422.2. HPLC Condition B-31: retention time 10.72 min, Purity 97.70%.
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4][C:5]([O:7]CC)=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[N:13]=1.P(=O)(O)(O)O.N>>[NH2:18][C:14]1[CH:15]=[CH:16][C:17]2[C:12](=[N:11][C:5]([OH:7])=[CH:4][C:3]=2[CH2:2][Cl:1])[N:13]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Nc1cccc(N)n1
Agent: N
Agent: O=P(O)(O)O
Product: Nc1ccc2c(CCl)cc(O)nc2n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 54.4 %

Procedure:
32.9 g (0.2 mol) of ethyl 4-chloroacetoacetate is dripped into a suspension of 21.8 g (0.2 mol) of 2,6-diaminopyridine in 100 ml of 85% strength phosphoric acid. The reaction mixture is stirred for 3 hours at 90° C., cooled and poured into ice water, followed by neutralization with concentrated aqueous ammonia solution. The precipitate is suction filtered, stirred into water again and finally boiled with acetonitrile. 22.8 g (54%) of the title compound is obtained; m.p.: >280° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Li+].O1CCOCC1.Cl>O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)[C@H](Cc1ccnc(OC)c1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: COc1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-methoxypyridin-4-yl)propanoate (1.42 g, 4.58 mmol) was mixed with methanol (10.0 mL) and a solution of lithium hydroxide (0.66 g, 14 mmol) in water (5.0 mL). The mixture was stirred at rt for 1 h. The mixture was then acidified with 4 N HCl dioxane solution and condensed under vacuum directly to give the white solid mixture, which was used directly in the next step. LC-MS found: 297.1 (M+H)+.
Reaction SMILES: IC1C=CC(C2NC([C@@H](N3C(=O)[C@@H](CCC(O)=O)NC3=O)C(C)C)=NC=2)=CC=1.[Cl:29][C:30]1[CH:35]=[C:34]([I:36])[CH:33]=[CH:32][C:31]=1I.C(O[C:43](=[O:66])[NH:44][C@H:45]([C:54]1[NH:55][C:56](C2C=CC=CC=2F)=[CH:57][N:58]=1)[C@H:46]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH3:47])(C)(C)C.ClN1C(=O)CCC1=O.C([O:79][C:80]([NH:82][C@H:83]([C:87]1[CH:92]=[CH:91][C:90]([O:93][CH2:94][C:95](=[O:99])N(C)C)=[CH:89][CH:88]=1)C(O)=O)=O)(C)(C)C.N[C@H](C1C=CC(OCCO)=CC=1)C(N[C@H](C1NC(C2C=CC(I)=CC=2Cl)=CN=1)[C@H](C1C=CC=CC=1)C)=O>>[Cl:29][C:30]1[CH:35]=[C:34]([I:36])[CH:33]=[CH:32][C:31]=1[C:57]1[NH:58][C:54]([C@@H:45]([N:44]2[C:43](=[O:66])[C@@H:83]([C:87]3[CH:88]=[CH:89][C:90]([O:93][CH2:94][CH2:95][OH:99])=[CH:91][CH:92]=3)[NH:82][C:80]2=[O:79])[C@H:46]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH3:47])=[N:55][CH:56]=1
Reactant: Clc1cc(I)ccc1I
Reactant: CN(C)C(=O)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)c1ncc(-c2ccccc2F)[nH]1
Agent: CC(C)[C@@H](c1ncc(-c2ccc(I)cc2)[nH]1)N1C(=O)N[C@H](CCC(=O)O)C1=O
Agent: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)c1ccc(OCCO)cc1)c1ncc(-c2ccc(I)cc2Cl)[nH]1
Agent: O=C1CCC(=O)N1Cl
Product: C[C@@H](c1ccccc1)[C@@H](c1ncc(-c2ccc(I)cc2Cl)[nH]1)N1C(=O)N[C@H](c2ccc(OCCO)cc2)C1=O

Procedure:
Prepared by the same method as described in example 1 except that (i) in step 35-A 2-chloro-1,4-diiodo-benzene was used in place of 2-fluoro-1,4-diiodo-benzene; (ii) chlorination of the 5-position of the imidazole ring with N-chlorosuccinimide in step F was omitted; and (iii) cyclization of (R)-2-amino-N-{(1S,2S)-1-[5-(2-chloro-4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-2-[4-(2-hydroxy-ethoxy)-phenyl]-acetamide in step 35-H was performed as described in example 34. HR-MS: calcd for C29H26ClIN4O4 [M+H+] 657.07600. Found 657.0757.
Reaction SMILES: [F:1][CH2:2][C:3]([NH2:17])([CH2:6][CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]#[N:5].C(N(CC)CC)C.[C:25](Cl)(=[O:35])[C:26]1[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:28](Cl)=[O:29].C1(=O)NC(=O)C2=CC=CC1=C2>ClCCl>[F:1][CH2:2][C:3]([N:17]1[C:28](=[O:29])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]2[C:25]1=[O:35])([CH2:6][CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]#[N:5]
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: N#CC(N)(CF)CCCOCc1ccccc1
Agent: O=C1NC(=O)c2cccc1c2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CC(CF)(CCCOCc1ccccc1)N1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 47.2 %

Procedure:
To a stirred mixture of 2-fluoromethyl-2-amino-5-benzyloxy-valeronitrile (74.8 g), triethylamine (100 g), and dry dichloromethane (450 ml), cooled in an ice bath, a solution of phthaloyldichloride (58 g) in dichloromethane (300 ml) is added slowly. Stirring is continued at room temperature overnight. The mixture is extracted with 2 N HCl (2×750 ml), washed with water (2×750 ml), dried carefully (Na2SO4), and evaporated to give a brown oil which, according to NMR analysis, contains some iso-phthalimide. The oil is dissolved in dry dichloromethane (500 ml), triethylamine (100 g) is added, and the mixture is refluxed for 3 hours. Work-up as described above gives an oil which is purified by flash-chromatography on silica (2 kg, petroleum ether/ethyl acetate 4:1). Crystallisation from ether gives the title compound (49.4 g).
Reaction SMILES: [C:1]1([C:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([CH2:27][O:28][NH2:29])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:48](Cl)(=[O:50])[CH3:49].Cl>ClCCl.C(OCC)(=O)C>[C:36]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([CH2:27][O:28][NH:29][C:48](=[O:50])[CH3:49])[CH2:10]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NOC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)NOC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.42 h
Yield: 88 %

Procedure:
To a solution of (2S,4S)-4-triphenylmethylthio-2-aminooxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (6), prepared above as A (6) in dichloromethane are added pyridine (93 μl) and acetyl chloride (66 μl), and the mixture is stirred for 25 minutes. To the reaction mixture are added 1N-hydrochloric acid (1 ml) and ethyl acetate. The organic layer is taken, washed with water, aqueous sodium hydrogen carbonate, and brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by silica gel chromatography to give (2S,4S)-4-triphenylmethylthio-2-acetylaminooxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (7: 385 mg) as a pale yellow foam. Yield: 88%.