Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=O.N#N.[BH4-].[Na+].II>C1COCC1>[F:21][C:2]([F:1])([F:20])[CH2:3][N:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: O=C(N1CCC(c2ccc([N+](=O)[O-])cc2)CC1)C(F)(F)F
Agent: II
Agent: N#N
Agent: [BH4-]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(C2CCN(CC(F)(F)F)CC2)cc1
Temperature: 0 °C

Procedure:
A solution of 1-trifluoroacetyl-4-(4-nitrophenyl)piperidine (1.42 g, 4.7 mmol) in THF (15 mL) is stirred in 25 mL 2-necked flask fitted with a condenser and pressure-equalising addition funnel. The system is flushed with N2, NaBH4 (210 mg, 5.6 mmol) is added and the flask is cooled to 0° C. A solution of iodine (600 mg, 2.3 mmol) in THF (5 mL) is then added dropwise over 20 minutes, after which the addition funnel is removed and the mixture heated at reflux overnight. The resulting pale yellow suspension is cooled to rt and MeOH (1.5 mL) is added cautiously, causing vigorous evolution of a gas. Evaporation of the solvents affords the title compound, which is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9]O)=[CH:4][N:3]=1.[CH2:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[C:14]=1[OH:21])[CH3:12].Cl>C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:17]2[CH:16]=[C:15]([CH2:19][CH3:20])[C:14]([OH:21])=[C:13]([CH2:11][CH3:12])[CH:18]=2)=[CH:4][N:3]=1
Reactant: CCc1cccc(CC)c1O
Reactant: Nc1ncc(CO)c(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCOCC
Product: CCc1cc(Cc2cnc(N)nc2N)cc(CC)c1O

Procedure:
2,4-Diamino-5-hydroxymethylpyrimidine (1.4 g.), prepared as in Example 1, and 2,6-diethylphenol (1.6 g.) in toluene-4-sulphonic acid (10 g.) containing conc. hydrochloric acid (3 ml.) were heated on the steam-bath for 6 hours. The solution was cooled, diluted with ether and the ether decanted. The residue was treated with a soln. of sodium hydrogen carbonate and the solid filtered off. Recrystallisation from aqueous ethanol gave colourless needles of 2,4-diamino-5-(3,5-diethyl-4-hydroxybenzyl)pyrimidine, m.p. 200°-202° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:7]2[C:12]([C:13]=1[CH3:14])=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=2)=O.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:6]2[C:7]3[C:12](=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3)[C:13]([CH3:14])=[C:5]2[CH2:3][OH:2])=[CH:19][CH:20]=1
Reactant: COC(=O)c1c(C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(C)c(CO)n2Cc1ccc(Cl)cc1
Reaction time: 16 h
Yield: 95.8 %

Procedure:
1.50 g 1-(4-chlorobenzyl)-3-methyl-5-methoxy-1H-indole-2-carboxylate methyl ester was dissolved in 50 ml dry THF. Diisobutyl aluminum hydride (1.5M) in THF (2 equivalents) was added at -78° C. The reaction was stirred for 16 hrs., allowed to reach room temperature and quenched with NH4Cl (aq.). The organic phase was separated, dried (Na2SO4) and evaporated to produce 1.32 g of product which was purified on column chromatography to yield the title compound of Step 2.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:49])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[C:41](Br)[CH:40]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:49])[CH2:38][C:39]1[CH:40]=[C:41]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:33])[CH2:31][CH3:32])[C:42]([O:45][CH2:46][CH3:47])=[CH:43][CH:44]=1)[CH3:35]
Reactant: CCOC(=O)Cc1ccc(OCC)c(Br)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Product: CCOC(=O)Cc1ccc(OCC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (3-bromo-4-ethoxy-phenyl)-acetic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9](=O)O[C:6](=[O:7])[C:5]2=[CH:12][C:13]=1[I:14].C(O)(=O)C.C(N)=[NH:20]>CN(C)C=O>[OH:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([F:1])=[C:13]([I:14])[CH:12]=2)[N:10]=[CH:9][N:20]=1
Reactant: N=CN
Reactant: O=c1[nH]c2cc(F)c(I)cc2c(=O)o1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Oc1ncnc2cc(F)c(I)cc12
Temperature: 110 °C
Yield: 91.2 %

Procedure:
Dimethylformamide (0.5 liters), 4-fluoro-5-iodo-isatoic anhydride (45 grams, 147 mmoles), and formamidine acetate (45.92 grams, 441 mmoles), were combined in a one liter one-neck flask fitted with a magnetic stir bar. The mixture was placed under anhydrous nitrogen and heated at 110° C. for 6 hours. The mixture was allowed to cool, followed by concentrating the reaction mixture to one third its original volume on the rotary evaporator. The resulting mixture was poured onto 3 liters of ice water. The resulting precipitated solid was collected by suction filtration. The solid was washed with an additional one liter of distilled water. The resulting solid was dried under vacuum at 70° C. to yield 38.9 grams (91%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 12.43 (s, 1H), 8.46 (d, 1H), 8.12 (s, 1H), 7.49 (d, 1H). ESI-MS m/z 291 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]([C:18](=[O:29])[CH2:19][N:20]3[N:24]=[N:23][C:22]([C:25]([F:28])([F:27])[F:26])=[N:21]3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([C:18](=[O:29])[CH2:19][N:20]3[N:24]=[N:23][C:22]([C:25]([F:26])([F:28])[F:27])=[N:21]3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(C(=O)Cn2nnc(C(F)(F)F)n2)nn1-c1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Cn1nnc(C(F)(F)F)n1)c1cc(C(=O)O)n(-c2ncccc2Cl)n1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
300 mg (0.58 mmol) of ethyl 1-(3-chloropyridin-2-yl)-3-{[5-(trifluoromethyl)-2H-tetrazol-2-yl]acetyl}-1H-pyrazole-5-carboxylate were dissolved in 4 ml of ethanol, 282 mg (3.15 mmol) of 2N aqueous sodium hydroxide solution were added and the mixture was stirred at RT for 5 d. The solvent was distilled off under reduced pressure, the residue was taken up in water and the mixture was extracted once with methyl tert-butyl ether. The aqueous phase was then acidified with 2N hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:23][O:22][C:20]([CH2:19][O:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1)=[O:21]
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1

Procedure:
A mixture of benzyl 4-hydroxybenzoate (169.0g.), methyl bromoacetate (122.4g.) and anhydrous potassium carbonate (200g.) in acetone (500ml.) (analytical grade) was stirred and heated under reflux for 16 hours. The mixture was then filtered and the filtrate evaporated in vacuo. The semi-solid residue obtained was separated by filtration. The solid thus obtained was washed with cold (0°-5° C.) petroleum ether (b.p. 60°-80° C.) (50ml.) to give benzyl 4-(methoxycarbonylmethoxy)benzoate, m.p. 63°-66° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4].[Li+].[OH-]>CO>[CH3:22][O:21][C:13]1[CH:12]=[C:11]([C:6]2[C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:16]=[C:15]([O:17][CH3:18])[C:14]=1[O:19][CH3:20]
Reactant: COC(=O)c1ccccc1-c1cc(OC)c(OC)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-c2ccccc2C(=O)O)cc(OC)c1OC
Yield: 70.5 %

Procedure:
Dissolve 3′,4′,5′-Trimethoxy-biphenyl-2-carboxylic acid methyl ester (82) (626 mg, 2.08 mmol) in MeOH (14 mL) at rt and add 1M aqu LiOH (4.2 mL, 4.20 mmol). Stir reaction mixture for 8 h under reflux. Remove solvent and partition the residue between 1M aqu. HCl and EtOAc, separate layers, extract the aqu. layer with EtOAc (3×), wash the combined organic layer with brine and dry with Na2SO4. Remove solvent and recrystallize residue from EtOAc/CyH 1+2 to obtain 3′,4′,5′-Trimethoxy-biphenyl-2-carboxylic acid (83) as a white solid (423 mg, 79%). 1H NMR (400 MHz, CD3OD: 3.84 (s, 3H); 3.89 (s, 6H); 6.68 (s, 2H); 7.42-7.49 (m, 2H); 7.57 (t, 1H, J=7.5 Hz); 7.76 (d, 1H, J=8.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:14]=2)[NH:9][N:8]=1)=[O:5].FC(F)(F)C(O)=O.[O:43]1[CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.[H-]>ClCCl>[C:19]1([S:16]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[NH:9][N:8]=[C:7]3[NH:6][C:4](=[O:5])[C:3]2[CH:25]=[CH:26][C:27]([N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)=[CH:28][C:2]=2[NH:1][CH:46]2[CH2:47][CH2:48][O:43][CH2:44][CH2:45]2)(=[O:18])=[O:17])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C1CCOCC1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(S(=O)(=O)c5ccccc5)cc34)c(N)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Agent: [H-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(S(=O)(=O)c5ccccc5)cc34)c(NC3CCOCC3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
2-Amino-N-(5-benzenesulfonyl-1H-indazol-3-yl)-4-(4-methyl-piperazin-1-yl)-benzamide (245 mg, 0.5 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (0.77 mL, 10 mmol), treated first with tetrahydro-pyran-4-one (0.055 mL, 0.6 mmol) and then with tetramethylammonium triacetoxyborohydride (197 mg, 0.75 mmol). The reaction was stirred at room temperature overnight then additional ketone (0.055 mL, 0.6 mmol) and hydride (2 portions: 197 mg first and 50 mg after a couple of hours) were added. After additional stirring overnight the volatiles were removed under reduced pressure. Dichloromethane was added and the organic phase was washed with aqueous sodium hydrogen carbonate, dried over sodium sulfate and evaporated. The crude product was purified by flash chromatography over silica gel (eluent: dichloromethane/methanol/33% NH4OH in 95:5:1 ratio) affording 186 mg of product still containing some impurities. Further purification by preparative HPLC (basic method) gave 80 mg of title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:15][C:14]([Br:16])=[C:13]([C:17]([O:19]CC)=[O:18])[CH:12]=2)[C:8]([CH3:22])=[CH:7][N:6]=1)(=[O:3])[CH3:2].Cl>CCO.[OH-].[Na+]>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:15][C:14]([Br:16])=[C:13]([C:17]([OH:19])=[O:18])[CH:12]=2)[C:8]([CH3:22])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2cc(NC(C)=O)ncc2C)oc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)Nc1cc(-c2cc(C(=O)O)c(Br)o2)c(C)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
A mixture of ethyl 5-(2-acetamido-5-methylpyridin-4-yl)-2-bromo-3-furoate (20 g, 54.6 mmol) in EtOH (240 mL) and 1M NaOH (80 mL) was allowed to stir at rt for 2 h. The reaction mixture was acidified with concentrated HCl to pH=3-4 and then filtered. The resulting solid was washed with water and dried to give 5-(2-acetamido-5-methylpyridin-4-yl)-2-bromo-3-furoic acid (10.0 g, 43%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([C:11](=[O:18])[CH2:12][NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][C:4]=1[Br:19].[BH4-].[Na+]>>[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([CH:11]([OH:18])[CH2:12][NH:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[CH:5][C:4]=1[Br:19]
Reactant: CC(C)(C)NCC(=O)c1cc(Br)c(N)c(C#N)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)NCC(O)c1cc(Br)c(N)c(C#N)c1

Procedure:
m.p. of the hydrochloride: 213°-214° C., was prepared from 4'-amino-3'-bromo-2-tert.butylamino-5'-cyano-acetophenone and sodium borohydride analogous to Example 2.
Reaction SMILES: OC1C=CC(C(=C2CCOCC2)C2C=CC(/C=C/C(OC(C)(C)C)=O)=CC=2)=CC=1.Br[C:31]1[CH:36]=[CH:35][C:34]([C:37](=[C:45]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)[C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=2)=[CH:33][CH:32]=1.[CH:52]([P:54](=[O:61])([O:58][CH2:59][CH3:60])[O:55][CH2:56][CH3:57])=[CH2:53].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[C:45]1(=[C:37]([C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=2)[C:34]2[CH:33]=[CH:32][C:31](/[CH:53]=[CH:52]/[P:54](=[O:61])([O:58][CH2:59][CH3:60])[O:55][CH2:56][CH3:57])=[CH:36][CH:35]=2)[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]1
Reactant: Oc1ccc(C(=C2CCCCCC2)c2ccc(Br)cc2)cc1
Reactant: C=CP(=O)(OCC)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCOCC2)c2ccc(O)cc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOP(=O)(/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1)OCC
Yield: 27.9 %

Procedure:
Following the procedure described for compound 47, from 4-[(4-bromophenyl)cycloheptylidene)methyl]phenol (9) (0.146 g, 0.409 mmole), diethyl vinylphosphonate (0.190 mL, 1.24 mmole), P(o-tolyl)3 (0.0123 g, 0.0404 mmole), Et3N (0.170 mL, 1.22 mmole), Pd(OAc)2 (0.0046 g, 0.0205 mmole) and DMF (1.5 mL) yielded 63 (0.0502 g, 28%) as a white solid. 1H NMR (DMSO-d6): δ 9.28 (s, 1H), 7.57 (d, J=8.3 Hz, 2H), 7.30 (dd, J=22.7, 17.6 Hz, 1H), 7.11 (d, J=8.3 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 6.65 (d, J=8.4 Hz, 2H), 6.48 (dd, J=22.7, 17.6 Hz, 1H), 4.01-3.91 (m, 4H), 2.20 (m, 4H), 1.50 (m, 8H), 1.21 (m, 6H).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[P:14]([Cl:18])(Cl)(Cl)=[O:15]>C(Cl)Cl>[CH2:1]([P:14]([Cl:18])([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCCCCCCCO
Solvent: ClCCl
Product: CCCCCCCCCCCCP(=O)(Cl)CCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.6 %

Procedure:
223.6 Grams (1.2 mol) of dodecyl alcohol and 500 ml of methylene chloride were placed in 1-liter three-necked flask equipped with a condenser and a stirrer; then 55.8 g (0.6 mol) of phosphorus oxychloride was added dropwise over 30 min, with stirring, under cooling with ice with the internal temperature kept below 10° C.; and after the completion of the addition the stirring was continued for 20 min. The temperature of this reaction mixture was elevated to room temperature, then the reaction was continued for 1 hour under reduced pressure of 80 to 120 mmHg; and after the temperature was elevated to 50° C., the reaction was continued for 3 hours under ordinary pressures. The reaction mixture was cooled to room temperature, to obtain 246.6 g (yield: 87.6%) of a transparent liquid.
Reaction SMILES: C(O[C:4](=[O:16])[CH2:5][NH:6][CH2:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:15])C.S(O)(O)(=O)=O.CS[C:24](=N)[NH2:25]>C(O)C>[CH3:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:8]=1[CH2:7][N:6]1[CH2:5][C:4](=[O:16])[NH:25][C:24]1=[N:15]2
Reactant: CSC(=N)N
Reactant: CCOC(=O)CNCc1c(C)cccc1N
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cc1cccc2c1CN1CC(=O)NC1=N2
Yield: 10.7 %

Procedure:
A mixture of N-(2-amino-6-methylbenzyl)glycine ethyl ester (0.972 g, 0.00437 mole) and 2-methyl-2-thiopseudourea sulfate (0.609 g, 0.00219 mole) in absolute ethanol (15 ml) was stirred at reflux for 16 hours. Workup as in Example 2 gave the title compound (47 mg), identical (ir) with authentic material prepared according to the procedure of J. Med. Chem., 18, 224 (1975).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.[N:17]1[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=1.Cl.Cl.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CN=1.[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52]>CO>[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52].[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:6]1[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=[C:2]1/[CH:1]=[CH:23]/[C:20]1[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=1
Reactant: O=Cc1ccncc1
Reactant: Cc1nc2ccccc2n1-c1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccn1
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CO
Product: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccncc1

Procedure:
Free base of the titled compound was prepared from 2-methyl-1-(2-pyridyl)-1H-benzimidazole and pyridine-4-carboxaldehyde according to the preparation of (E)-1-(2-pyridyl)-2-[2-(2-pyridyl)ethenyl]-1H-benzimidazole dihydrochloride (Example 44). The free base and oxalic acid were dissolved into MeOH. Concentration and recrystallization from ethyl MeOH/Et2O/n-hexane yielded the titled compound.
Reaction SMILES: C([NH:4][C:5]1[NH:6][C:7](=[O:46])[C:8]([CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:43]=[CH:42][C:25]([C:26]([NH:28][C@H:29]([C:37]([O:39]CC)=[O:38])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:27])=[CH:24][C:23]=2[O:44][CH3:45])=[C:9]([N:11](C(=O)C)C(=O)C)[N:10]=1)(=O)C.Cl>[OH-].[Na+]>[NH2:4][C:5]1[NH:6][C:7](=[O:46])[C:8]([CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:43]=[CH:42][C:25]([C:26]([NH:28][C@H:29]([C:37]([OH:39])=[O:38])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:27])=[CH:24][C:23]=2[O:44][CH3:45])=[C:9]([NH2:11])[N:10]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(NCCCc2c(N(C(C)=O)C(C)=O)nc(NC(C)=O)[nH]c2=O)c(OC)c1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)ccc1NCCCc1c(N)nc(N)[nH]c1=O
Reaction time: 0.5 h

Procedure:
A solution of diethyl N-[4-(3-(2-acetylamino-4-diacetylamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propylamino)-3-methoxybenzoyl]-(L)-glutamate (1.00 g, 1.55 mmoles) in 1.0N sodium hydroxide (25 mL) was stirred at 55° C. under nitrogen for 18 hours. The reaction mixture was chilled (ice bath) and adjusted to pH 2.5 by the gradual dropwise addition of 6N hydrochloric acid. After stirring cold 0.5 hour, the resulting precipitate was filtered, rinsed with pH 2.1 aqueous hydrochloric acid (2×25 mL), and dried to give a white solid; yield, 596 mg (83%); mp 165°-184° C. (grad. dec.); 1H-NMR (DMSO-d6) δ 1.56 (m, 2H), 1.8-2.2 (br m, 2H), 2.2-2.4 (m, 4H), 3.07 (m, 2H), 3.81 (s, 3H), 4.37 (m, 1H), 5.6 (br s, 1H), 5.74 (s, 2 H), 5.93 (s, 2H), 6.49 (d, Jo =8 Hz, 1H), 7.29 (d, Jm =2 Hz, 1H), 7.41 (dxd, Jo =8 Hz, Jm =2 Hz, 1H), 8.15 (d, 1H), 9.8 (v br s, 1H), 12.3 (v br s, 2H); uv (0.1N NaOH) 306 nm max (15100), 287 min (11700), 273 max (15200), 250 min (6500), 215 max (25800). Anal. Calcd. for C20H26N6O7.0.7H2O (Mr 475.07): C, 50.56; H, 5.81; N, 17.69. Found: C, 50.58; H, 5.85; N, 17.63.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:12]([O:16][C:17](=[O:42])[NH:18][C:19]1[C:20]([NH:31][C:32](=[O:41])[C:33]2[CH:38]=[CH:37][C:36]([CH2:39][NH2:40])=[CH:35][CH:34]=2)=[N:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C.O>C1COCC1>[CH2:5]([O:4][C:2](=[O:3])[NH:40][CH2:39][C:36]1[CH:37]=[CH:38][C:33]([C:32]([NH:31][C:20]2[C:19]([NH:18][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:42])=[CH:24][CH:23]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:21]=2)=[O:41])=[CH:34][CH:35]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1NC(=O)c1ccc(CN)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Benzyl chloroformate (0.06 ml, 0.420 mmol) was added to a flask containing tert-butyl(2-{[4-(aminomethyl)benzoyl]amino}-6-phenylpyridin-3-yl)carbamate (158 mg, 0.378 mmol) and DIPEA (0.15 ml, 0.859 mmol) in THF (5 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour. Water was added and the products were extracted into EtOAc (2×). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated. The organic product was purified by column chromatography on silica gel Biotage 25S, eluting with EtOAc/hexanes (0%-100%) to give a pale slightly yellow transparent gel. MS: cal'd 553 (MH+), exp 553 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:20]1[C:28]2[C:23](=[C:24]([CH2:29][S:30][CH3:31])[CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[CH:10]1C(=O)O[C:13](C)([CH3:17])[O:12][C:11]1=[O:19]>N1C=CC=CC=1.C(O)C.[Cu]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:20]1[C:28]2[C:23](=[C:24]([CH2:29][S:30][CH3:31])[CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[CH2:10][C:11]([O:12][CH2:13][CH3:17])=[O:19]
Reactant: CSCc1cccc2c(C(c3ccc(Cl)cc3Cl)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CC(c1ccc(Cl)cc1Cl)c1c[nH]c2c(CSC)cccc12

Procedure:
5.3 mg (0.08 mmol) of copper powder were added to 3.99 g (8.34 mmol) of the compound from Example 17A in 59 ml of pyridine and 15 ml of ethanol. The reaction mixture was heated under reflux for 1 h. It was concentrated, and the residue was taken up in ethyl acetate, washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered through silica gel and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 2.34 g (67% of theory) of the title compound.
Reaction SMILES: [CH2:1]([C:4]1([CH3:36])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6](CC2C=CC(OC)=CC=2OC)[C:5]1=[O:35])[CH:2]=[CH2:3]>C(O)(C(F)(F)F)=O>[CH2:1]([C@@:4]1([CH3:36])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:35])[CH:2]=[CH2:3]
Reactant: C=CCC1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(Cc2ccc(OC)cc2OC)C1=O
Solvent: O=C(O)C(F)(F)F
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O

Procedure:
A solution of (5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methylpiperidin-2-one (Example 71, Step C, mixture of diastereomers) (105.87 g, 202 mmol) in TFA (778 mL, 1.01E+04 mmol) was heated at 50° C. for 2 hours before concentrating the reaction mixture in vacuo. The residue was azeotroped with hexanes to remove all of the TFA. The deep purple oil containing some residue was taken up in a minimum amount of DCM, filtered and washed liberally with DCM. The filtrate was concentrated in vacuo to provide a dark purple oil. Purification (wet packed with a minimum amount of DCM) using the Biotage Isolera (Biotage, Charlotte, N.C.) with a 1.5 kg column and eluting with 25-40% EtOAc/hexanes provided the title compound as a white solid.