Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:19]=2)=[O:21])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Yield: 74.1 %

Procedure:
4-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (800 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (716 mg), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (500 mg), HBTU (952 mg), and DIEA (700 uL) in DMF (5 mL).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][C:9]=1[Cl:18]>C1COCC1.CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[Cl:18]
Reactant: COC(=O)c1ccc(OCc2ccc(OC)c(OC)c2)c(Cl)c1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(C(=O)O)cc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.4 %

Procedure:
A solution of 1A (600 mg, 1.78 mmol) in THF (30 mL) and MeOH (10 mL) was treated with a solution of LiOH monohydrate (375 mg, 8.93 mmol) in water (10 mL) at room temperature. The resulting suspension was stirred at room temperature for 18 hours. The reaction was concentrated to 30 mL, diluted with water (50 mL) and cooled to 0° C. The solution was brought to pH 5 with 1 N HCl and the resulting solid was collected by vacuum filtration. Residual water was removed from the solid material using azeotrope with toluene to afford 1B as a white solid (370 mg, 65%).
Reaction SMILES: Cl[CH:2]([B:5]1[O:9][C:8]([CH2:11][CH2:12][CH:13]([CH3:22])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:10])[C:7]([CH3:24])([CH3:23])[O:6]1)[CH2:3][CH3:4].C[Si]([N-:29][Si](C)(C)C)(C)C.[Li+].FC(F)(F)C(O)=O>O1CCCC1>[NH2:29][CH:2]([B:5]1[O:9][C:8]([CH2:11][CH2:12][CH:13]([CH3:22])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:10])[C:7]([CH3:24])([CH3:23])[O:6]1)[CH2:3][CH3:4]
Reactant: CCC(Cl)B1OC(C)(C)C(C)(CCC(C)CC(=O)OC(C)(C)C)O1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCC(N)B1OC(C)(C)C(C)(CCC(C)CC(=O)OC(C)(C)C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 129.1 %

Procedure:
0.82 g (2.27 mmol) of tert-butyl 5-[2-(1(RS)-chloropropyl)-4(RS),5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate was dissolved in 10 ml of tetrahydrofuran and then cooledto -78° C. under a nitrogen atmosphere. 2.3 ml (2.3 mmol) of 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran were added dropwise. The solution was then stirred overnight while slowly warming to room temperature. The solvent was removed by evaporation and the residue was taken up in diethyl ether. Insoluble material was removed by filtration and the filtrate was cooled to 0° C. 0.52 ml (6.8 mmol) of trifluoroacetic acid was added and the solution was stirred at 0° C. for 30 minutes. The solution was evaporated and the residue was co-evaporated with toluene to give 1 g of tert-butyl 5-[2-(1(RS)-aminopropyl)-4(RS), 5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate as an oil which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[N:16]=[C:15]([NH:17]CC4C=CC(OC)=CC=4OC)[N:14]=[C:13]([N:29]4[C@H:34]([C:35]([F:38])([F:37])[F:36])[CH2:33][CH2:32][C@H:31]([C:39]([NH:41][CH:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[O:40])[CH2:30]4)[CH:12]=3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.FC(F)(F)C(O)=O.CCCCCC>CCOC(C)=O>[NH2:17][C:15]1[N:14]=[C:13]([N:29]2[C@H:34]([C:35]([F:37])([F:36])[F:38])[CH2:33][CH2:32][C@H:31]([C:39]([NH:41][CH:42]3[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]3)=[O:40])[CH2:30]2)[CH:12]=[C:11]([C:7]2[CH:6]=[C:5]3[C:10]([C:2]([NH2:1])=[N:3][NH:4]3)=[CH:9][CH:8]=2)[N:16]=1
Reactant: COc1ccc(CNc2nc(-c3ccc4c(N)n[nH]c4c3)cc(N3C[C@@H](C(=O)NC4CCCCC4)CC[C@H]3C(F)(F)F)n2)c(OC)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.3 %

Procedure:
To cis-1-[6-(3-amino-1H-indazol-6-yl)-2-({[2,4-bis(methyloxy)phenyl]methyl}amino)-4-pyrimidinyl]-N-cyclohexyl-6-(trifluoromethyl)-3-piperidinecarboxamide (250 mg, 0.38 mmol) was added trifluoroacetic acid (TFA) (6 mL). After 3 hours, LCMS analysis indicated the reaction to be completed. The reaction mixture was concentrated under vacuum, and the resulting residue was co-evaporated from toluene (2×50 mL), then from CH3CN (50 mL). To the resulting pink solid was added a saturated aqueous NaHCO3 solution and EtOAc. The organic layer was separated, and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. This material was purified by flash chromatography (gradient: 100% CH2Cl2 to 90:10:1 CH2Cl2:CH3OH:NH4OH). The cleaner fractions were combined and concentrated under vacuum to afford a yellow solid. This material was dissolved in EtOAc (˜2 mL), and the resulting solution was transfered to a microwave vial. The vial was capped, and heated to 70 C. Hexane was added dropwise until the solution became cloudy, then the mixture was allowed to cool to room temperature. A spatula was used to scrap the solid, and the mixture was filtered. The collected pink solid was washed with hexanes and a white solid precipitate from the filtrate. This white solid was collected by filtration to afford the desired product (35 mg). LC-MS (ES) m/z=503 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.05-1.34 (m, 5H), 1.56 (m, 1H), 1.63-1.85 (m, 7H), 2.07 (m, 1H), 2.33, (m, 1H), 3.06 (bs, 1H), 3.53 (m, 1H), 5.39 (s, 2H), 6.29 (s, 2H), 6.78 (s, 1H), 7.63 (dd, J=8.5, 1.1 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.99 (s, 1H), 11.54 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17]C(C)(C)C)=[O:16])=[CH:11][C:10]=2[CH3:22])=[CH:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][C:10]=2[CH3:22])=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1-c1ccc(C#N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)O)ccc1-c1ccc(C#N)cc1
Reaction time: 1 h

Procedure:
(Step 2) To a solution of the preceding ester (3.0 g, 10.2 mmol) in methylene chloride (75 mL) at 0° C. was added TFA (75 mL) dropwise over 10 min. The ice bath was removed and stirring continued for 1 h at rt. The mixture was concentrated on a rotary evaporator and then diluted with toluene and reconcentrated to afford 4′-cyano-2-methyl-1,1′-biphenyl-4-carboxylic acid. ESI-MS m/e 228.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:8][CH2:7][N:6]1[C:9](=[O:14])[C:10](=[O:13])OC)=[O:4].[CH3:15][C:16]([Mg]Cl)([CH3:19])[CH2:17][CH3:18].[Cl-].[NH4+].CCOCC>O1CCCC1.CCCCC>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:8][CH2:7][N:6]1[C:9](=[O:14])[C:10](=[O:13])[C:16]([CH3:19])([CH3:15])[CH2:17][CH3:18])=[O:4]
Reactant: CCC(C)(C)[Mg]Cl
Reactant: COC(=O)C(=O)N1CC[C@H]1C(=O)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCC(C)(C)C(=O)C(=O)N1CC[C@H]1C(=O)OC
Temperature: -78 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a cooled (about −78° C.) solution of (2S)-Methyl-1-(1,2-dioxo-2-methoxyethyl)-azetidine-2-carboxylate from Reference Example 2 (0.98 g, 4.86 mmol, 1.0 eq) in dry tetrahydrofuran (15 mL) under an argon atmosphere was added 1,1-dimethylpropylmagnesium chloride in THF (6.30 mL of 1M solution, 6.30 mmol, 1.3 eq) over about 15 minutes. After stirring the resulting homogeneous mixture at about −78° C. for about 3 hours, the mixture was poured into chilled saturated ammonium chloride and extracted into ethyl acetate (2×50 mL). The organic phase was washed with water, dried over sodium sulfate and concentrated. Flash chromatography of the residue (2:3 ether:pentane) produced 0.90 g (77% yield) of the product as a colorless oil. 1H NMR (CDCl3) δ 0.77-0.98 (m, 3H); 1.20-1.30 (series of s, 6H); 1.68-2.01 (m, 2H); 2.24-2.40 (m, 1H); 2.60-2.80 (m, 1H); 3.80-3.82 (series of s, 3H); 3.99-4.43 (series of m, 2H); 4.84 and 5.26 (series of dd, 1H, J=6.9, 9.4).
Reaction SMILES: [OH:1][CH:2]1[CH:8]([NH:9][C:10]([C@@H:12]([NH:17][C:18]([C:20]2[O:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[CH:24]=2)=[O:19])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl.CO>[C:29]([N:4]1[CH2:5][CH2:6][CH2:7][CH:8]([NH:9][C:10]([C@@H:12]([NH:17][C:18]([C:20]2[O:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[CH:24]=2)=[O:19])[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:11])[CH:2]([OH:1])[CH2:3]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CCCNCC1O
Reactant: O=C(O)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CO
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CCCN(C(=O)c2ccccc2)CC1O

Procedure:
To a solution of benzofuran-2-carboxylic acid [(S)-1-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide of Example 78c (0.2 ) in dichloromethane was added benzoic acid (0.12 g), HOBt (0.07 g) and EDC (0.99 g). The reaction was stirred until complete. Workup and column chromatography (5% methanol:dichloromethane) provided the title compound (0.2 g): 1H NMR (CDCl3): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.7 (m, 1H), 3.8 (m,1H), 4.1 (m, 1H), 4.7 (m, 2H), 5.1 (m, 1H), 7.0-7.7 (m, 10H), 8.7 (m, 1H); MS(EI): 492 (M+H+, 100%).
Reaction SMILES: CC(OC([NH:8][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][OH:11])=O)(C)C.[NH2:16][C:17]1[CH:18]=[C:19]([S:23]([OH:26])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>N1C=CC=CC=1>[NH2:8][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][O:11][C:28]([NH:16][C:17]1[CH:18]=[C:19]([S:23]([OH:26])(=[O:24])=[O:25])[CH:20]=[CH:21][CH:22]=1)=[O:30]
Reactant: Nc1cccc(S(=O)(=O)O)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Solvent: c1ccncc1
Product: COC(=O)[C@@H](N)COC(=O)Nc1cccc(S(=O)(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Boc-Ser-OMe, 110 mg (0.5 mmol), and 87 mg (0.5 mmol) of 3-aminobenzenesulfonic acid were dissolved in 1 ml of pyridine, and 50 mg of triphosgene was added to the solution. The mixture was stirred at room temperature for 2 hours and the solvent was then distilled off. The resulting residue was purified according to the purification step A to give the crude product of the protected title compound. The crude product obtained was dissolved in 1 ml of methylene chloride and 1 ml of trifluoroacetic acid. The solution was stirred for 30 minutes at room temperature. After the solvent was distilled off, the mixture was purified in accordance with the purification step A to give the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[C:7]([CH3:13])[C:6]=1[CH3:14])(=[O:3])[CH3:2].[C:15]([O:20][CH2:21][CH3:22])(=[O:19])[C:16]([CH3:18])=[CH2:17].C=O.[CH2:25](NCCCC)CCC.C(O)(=O)C>>[CH3:17][C:16]1([C:15]([O:20][CH2:21][CH3:22])=[O:19])[CH2:18][CH2:25][C:9]2[C:8](=[C:7]([CH3:13])[C:6]([CH3:14])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[C:10]=2[CH3:11])[O:12]1
Reactant: CC(=O)Oc1c(C)cc(O)c(C)c1C
Reactant: C=C(C)C(=O)OCC
Reactant: CCCCNCCCC
Agent: C=O
Solvent: CC(=O)O
Product: CCOC(=O)C1(C)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1

Procedure:
There were mixed 1.9 g (0.01 mole) of 4-acetoxy-2,3,5-trimethylphenol, 9.2 g (0.08 mole) of ethyl methacrylate, 0.3 g (0.011 mole) of paraformaldehyde, 0.13 g (0.001 mole) of dibutylamine and 0.3 g (0.005 mole) of acetic acid, and the mixture was heated under reflux for 15 hours.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)(=[O:4])=[O:3].C([CH:16]([NH2:19])[CH:17]=[O:18])C=C.[CH:20]1[CH:25]=CC=C[CH:21]=1>>[CH2:25]([N:19]([CH2:16][CH:17]=[O:18])[C:11]([NH:10][C:8]1[S:9][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6][N:7]=1)=[O:12])[CH:20]=[CH2:21]
Reactant: c1ccccc1
Reactant: CS(=O)(=O)c1nnc(N=C=O)s1
Reactant: C=CCC(N)C=O
Product: C=CCN(CC=O)C(=O)Nc1nnc(S(C)(=O)=O)s1

Procedure:
A mixture of 5-methylsulfonyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-allyl-aminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-allyl-3-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[OH:14][CH2:15][C:16]([NH:18][CH3:19])=[O:17].C(N(C(C)C)CC)(C)C>ClCCl>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:14][CH2:15][C:16]([NH:18][CH3:19])=[O:17]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNC(=O)CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 16 h
Yield: 80.3 %

Procedure:
5.93 g (29.4 mmol) of 4-nitrophenyl chloroformate are added portionwise and at room temperature to a suspension of 2.62 g (29.4 mmol) of 2-hydroxy-N-methylacetamide and 16.5 g (58.7 mmol) of supported diisopropylethylamine (Ps-DIEA from Argonaut, charge=3.56 mmol/g) in 250 ml of dichloromethane. Orbital stirring is continued at room temperature for 16 hours. The resin is filtered off and rinsed with 150 ml of dichloromethane, and the filtrate is concentrated under reduced pressure. 6 g of product are obtained in the form of a pale yellow solid (purity estimated at 70%), and are used without further purification in the following step.
Reaction SMILES: [CH3:1][C:2]([CH3:35])([O:4][C:5]([NH:7][NH:8][C:9]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:13]([CH2:33][Cl:34])[N:12]=1)=[O:10])=[O:6])[CH3:3].CN1CC([C:42]2[CH:47]=[CH:46][CH:45]=[N:44][CH:43]=2)CC1.C[N:49](C)[CH:50]=[O:51]>>[Cl-:34].[NH2:49][C:50]([C:47]1[CH:42]=[CH:43][N+:44]([CH2:33][C:13]2[C:14]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[C:11]([C:9]([NH:8][NH:7][C:5]([O:4][C:2]([CH3:35])([CH3:3])[CH3:1])=[O:6])=[O:10])[N:12]=2)=[CH:45][CH:46]=1)=[O:51]
Reactant: CC(C)(C)OC(=O)NNC(=O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(CCl)n1
Reactant: CN1CCC(c2cccnc2)C1
Reactant: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(C[n+]2ccc(C(N)=O)cc2)n1
Product: [Cl-]

Procedure:
4.98 g 6-(chloromethyl)-4,5-bis(phenylmethoxy)2-pyridinecarboxylic acid, 2-[(1,1-dimethylethoxy)carbonyl]hydrazide and 1.23 g of isonicotine acid hydrazide and 0.1 g KI and 0.1 g C-18-Crown-6 were stirred for 12 hours at 50° C. in 50 ml dimethylformamide. After filtration the dimethylformamide was distilled off in vacuo and the residue stirred with ether. A yellow solid was obtained, 6.20 g of title compound. M.P. 205°-208° C. (dec.)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:31]=1)[O:7][C:8]1[C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=[C:10]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=[NH:28])[NH2:27])[CH:21]=2)[N:9]=1)(=[NH:3])[NH2:2].[ClH:32]>>[ClH:32].[ClH:32].[C:1]([C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:31]=1)[O:7][C:8]1[C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=[C:10]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=[NH:27])[NH2:28])[CH:21]=2)[N:9]=1)(=[NH:2])[NH2:3]
Reactant: CCOC(=O)c1ccc(Oc2cccc(C(=N)N)c2)nc1Oc1cccc(C(=N)N)c1
Agent: Cl
Product: N=C(N)c1cccc(Oc2ccc(C(=O)O)c(Oc3cccc(C(=N)N)c3)n2)c1

Procedure:
In a manner similar to Example 2 above, 2,6-bis(3-amidinophenoxy)pyridine-3-carboxylic acid, ethyl ester (0.20 g, 0.31 mmol) was dissolved in 5 M HCl and heated for 2 hours at 80 IC. The solvent was removed in vacuo to give 2,6-bis(3-amidinophenoxy)pyridine-3-carboxylic acid, dihydrochloride; NMR (DMSO-d6) 9.5 (br s,4), 9.35 (br s,4), 8.45 (d,1), 7.7 (m,2), 7.6 (m,2), 7.5 (m,4), 6.95 (d,1) ppm.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:9][NH:10][C:11]1[N:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][CH:12]=1>C(Cl)Cl>[Cl:3][CH2:17][C:14]1[CH:13]=[CH:12][C:11]([NH:10][CH2:9][C:8]2[CH:19]=[CH:20][C:21]([Cl:22])=[C:6]([Cl:5])[CH:7]=2)=[N:16][CH:15]=1
Reactant: OCc1ccc(NCc2ccc(Cl)c(Cl)c2)nc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1ccc(NCc2ccc(Cl)c(Cl)c2)nc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Thionyl chloride (0.103 mL, 1.413 mmol) was added to a suspension of (6-((3,4-dichlorobenzyl)amino)pyridin-3-yl)methanol (0.1 g, 0.353 mmol) in DCM (3.5 mL) cooled to 0° C. The mixture was stirred for 18 h at room temperature. The resulting white suspension was concentrated to yield 5-(chloromethyl)-N-(3,4-dichlorobenzyl)pyridin-2-amine, used in the next step without purification. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.05 (1H, dd, J=9.29, 2.01 Hz), 7.92-8.01 (1H, m), 7.54-7.65 (2H, m), 7.36 (1H, dt, J=8.28, 1.00 Hz), 7.04-7.23 (1H, m), 4.65 (1H, s), 4.61 (2H, d, J=2.76 Hz), 4.39 (1H, s). LCMS: R.T.=2.96; [M+H]+=301.02.
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH2:6]([O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12](Cl)=[N:11][N:10]=1)[CH3:7]>CO>[CH2:6]([O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12]([S:5][CH2:2][CH:3]=[CH2:4])=[N:11][N:10]=1)[CH3:7]
Reactant: CCOc1nnc(Cl)c2c1CCCC2
Reactant: C=CCS
Agent: [Na]
Solvent: CO
Product: C=CCSc1nnc(OCC)c2c1CCCC2

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 100 ml of absolute methanol and then mixed with 0.93 ml (0.01 mol) of allylmercaptan. To this mixture was added 2.13 g(0.01 mol) of 1-ethoxy-4-chloro-5,6,7,8-tetrahydro-phthalazine obtained from Preparation 9. The reaction solution was refluxed for 3 hours and then treated according to the same manner as Example 1 to obtain the title compound as a freezing white crystal.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:7][OH:8].[N:25]1([C:31]([NH:33][C@@H:34]([CH2:38][C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=2)[C:35]([OH:37])=[O:36])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C1C=C2C(C=C(C[C@H](N)C(O)=O)C=C2)=CC=1.[N:65]1([C:71]([NH:73][C@@H:74]([CH2:78][C:79]2[C:88]3[C:83](=[CH:84][CH:85]=[CH:86][CH:87]=3)[CH:82]=[CH:81][CH:80]=2)[C:75]([OH:77])=O)=[O:72])[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>>[N:25]1([C:31]([NH:33][C@@H:34]([CH2:38][C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=2)[C:35]([OH:37])=[O:36])=[O:32])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1.[OH:8][CH2:7][C@@H:6]([N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:75]([C@@H:74]([NH:73][C:71]([N:65]1[CH2:66][CH2:67][O:68][CH2:69][CH2:70]1)=[O:72])[CH2:78][C:79]1[CH:80]=[CH:81][C:82]2[C:87](=[CH:86][CH:85]=[CH:84][CH:83]=2)[CH:88]=1)=[O:77]
Reactant: O=C(O)[C@H](Cc1cccc2ccccc12)NC(=O)N1CCOCC1
Reactant: COc1ccc(S(=O)(=O)N(CC(C)C)[C@H](CO)CCCCN)cc1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C(O)[C@H](Cc1ccc2ccccc2c1)NC(=O)N1CCOCC1
Product: COc1ccc(S(=O)(=O)N(CC(C)C)[C@H](CO)CCCCNC(=O)[C@H](Cc2ccc3ccccc3c2)NC(=O)N2CCOCC2)cc1

Procedure:
This derivative was prepared from (1S)-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-4-methoxy-benzenesulfonamide (XII) (this example, step B) as described in general procedure B using (2S)-2-[(morpholine4-carbonyl)-amino]-3-naphthalen-2-yl-propionic acid. The (2S)-2-[(morpholine-4-carbonyl)-amino]-3-naphthalen-2-yl-propionic acid derivative was prepared from L-2-naphthylalanine as described for the preparation of (2S)-2-[(morpholine-4-carbonyl)-amino]-3-naphthalen-1-yl-propionic acid (example 32, step A). The final product was obtained in 46% yield (47 mg).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[CH3:7][C:8]([CH3:10])=O.C1(C)C=CC=CC=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[C:18]([N:5]1[C:8]([CH3:10])([CH3:7])[S:6][C:3]([NH:2][CH3:1])=[N:4]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNC(=S)NN
Reactant: CC(C)=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CNC1=NN(C(=O)c2ccccc2)C(C)(C)S1

Procedure:
A 42 g. portion of 4-methylthiosemicarbazide was reacted with 23.2 g. of acetone in 500 ml. of toluene as described in Example 1, except that the mixture was heated briefly to reflux, and then cooled to 70°, before 32 ml. of pyridine was added. Then the mixture was cooled to 20°, and 56.3 g. of benzoyl chloride was added. The reaction mixture was worked-up substantially as described in Example 1 to obtain 31.8 g. of the desired product, m.p. 130°-136°.
Reaction SMILES: [I:1]I.[C:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[F:15])([CH3:6])([CH3:5])[CH3:4]>CCO.S([O-])([O-])(=O)=O.[Ag+2]>[C:3]([C:7]1[CH:12]=[C:11]([I:1])[C:10]([O:13][CH3:14])=[CH:9][C:8]=1[F:15])([CH3:6])([CH3:4])[CH3:5]
Reactant: COc1ccc(C(C)(C)C)c(F)c1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COc1cc(F)c(C(C)(C)C)cc1I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Iodine (1.24 g, 4.90 mmol) and silver sulfate (1.53 g, 4.90 mmol) were added successively to a stirred solution of 1-tert-butyl-2-fluoro-4-methoxybenzene and 3-fluororanisole (0.755 g, 4.90 mmol) in EtOH (38.3 mL) at room temperature under N2. The mixture was stirred at room temperature for 4 h, then filtered through a plug of Celite. The mixture was partitioned between 50% saturated Na2SO3 and Et2O. The aqueous layer was separated and extracted with Et2O (×2). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to remove volatile byproducts and afford 1-tert-butyl-2-fluoro-5-iodo-4-methoxybenzene. Rf=0.34 (100% hexanes). 1H NMR (600 MHz, CDCl3): δ 7.63 (d, J=9.0 Hz, 1H); 6.53 (d, J=13.8 Hz, 1H); 3.84 (s, 3H); 1.33 (s, 9H).