Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([C:10]1[NH:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)=[O:9].[H-].[Na+].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36]Cl)[CH2:31][CH2:30]1.[Cl-].[NH4+]>CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([C:10]1[N:11]([CH2:36][CH2:35][N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])[CH2:34][CH2:33]2)[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)=[O:9]
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Reactant: O=C(Nc1ccccn1)c1nc2ccccc2[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COc1ccccc1N1CCN(CCn2c(C(=O)Nc3ccccn3)nc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
In an argon atmosphere, N-(2-pyridyl)benzimidazole-2-carboxamide (1.55 g) was dissolved in DMSO (20 ml), and 60% sodium hydride (0.28 g) was added and stirred at room temperature for 1 hr. A solution (7 ml) of 2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl chloride (1.65 g) in DMSO was added dropwise and stirred at room temperature overnight. The reaction solution was poured into an aqueous solution of ammonium chloride and extracted with chloroform, and the chloroform layer was dired. The residue obtained by distilling off the solvent was purified by column chromatography on silica gel to give the title compound (1.54 g) as amorphous solid.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:30]=[CH:31][C:32]=2[O:33][CH3:34])[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:30]=[CH:31][C:32]=3[O:33][CH3:34])[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(=O)Nc1ccc(OC)c(C2CCN(CCCN)CC2)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CCCC(=O)Nc1ccc(OC)c(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 22 was prepared from diphenyl acetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methoxyphenyl}butanamide according to the procedures described in Scheme 8: ESMS m/e: 528.4 (M+H)+.
Reaction SMILES: C([N:8]1[C:12]([CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][N:10]=[CH:9]1)C1C=CC=CC=1.Cl>[Pd].C(O)C>[C:22]1([CH:13]([C:12]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(CCC(c2ccccc2)c2cncn2Cc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc(CCC(c2ccccc2)c2c[nH]cn2)cc1
Yield: 73 %

Procedure:
1-benzyl-5-(1,3-diphenylpropyl)-1H-imidazole is hydrogenated in the mixture of 2N hydrochloric acid and ethanol at 60° C. 10% Pd/C as catalyst. The product is isolated as in Example 7 b) and is purified by flash chromatography methylene chloride-methanol (9,5:0,5) as eluent. Yield 73%.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][CH2:10][CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23]I>C1COCC1>[CH2:1]([N:8]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:23])([CH3:15])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(O)CCCN(Cc1ccccc1)Cc1ccccc1
Reactant: CI
Solvent: C1CCOC1
Product: COC(C)(C)CCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
Treat a 0° C. solution of 5-(dibenzylamino)-2-methylpentan-2-ol (3 g, 10.2 mmol) in THF (25 mL), under N2, portion-wise with KH (30%, 1.5 g, 11.3 mmol), stir at 0° C. for 0.5 h, add MeI (1.6 g, 11.3 mmol) drop-wise, warm to RT and stir for 3 h. Cool to 0° C., quench with satd. NH4Cl, partially concentrate under reduced pressure, extract with EtOAc (3×), wash the combined organics with brine, dry over Na2SO4, concentrate and purify via silica gel chromatography to afford the title compound (3.1 g, 97%). 1H NMR (400 MHz, DMSO-d6): δ 7.38-7.21 (m, 10H), 3.57 (s, 4H), 3.14 (s, 3H), 2.42 (t, J=7.2 Hz, 2H), 1.58-1.52 (m, 2H), 1.43-1.39 (m, 2H), 1.11 (s, 6H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][P:5]([CH2:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:8])[O:6][CH3:7].[CH2:17]1[C@@H]2OC(C[C@@H]2[C@@H](CO)[C@@H]1O)=O.C(O)(=O)C>C1COCC1>[CH3:3][O:4][P:5]([CH2:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:17])[CH3:15])(=[O:8])[O:6][CH3:7]
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Reactant: O=C1C[C@@H]2[C@@H](CO)[C@H](O)C[C@@H]2O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)CCCC(C)C)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the suspension of sodium hydride (NaH) (60%, 250 mg) in THF (40 ml) was added dropwise dimethyl(2-oxoheptyl)phosphonate, and the reaction solution was stirred for 30 min. A THF solution (40 ml) of the aldehyde (2) previously prepared by Collins oxidization of (−)-Corey lactone (1) (2 g) was added. Reaction was maintained at room temperature overnight, and then acetic acid was added. After the usual work-up, an α,β-unsaturated ketone (3) was obtained. Yield: 1.95 g (50%).
Reaction SMILES: C[O:2][C:3](=[O:19])[C@H:4]([CH2:14][C:15]([O:17]C)=[O:16])[NH:5][C:6]([O:8][C:9]1([CH3:13])[CH2:12][CH2:11][CH2:10]1)=[O:7].CO.[OH-].[Na+].S(=O)(=O)(O)O>O>[CH3:13][C:9]1([O:8][C:6]([NH:5][C@H:4]([C:3]([OH:19])=[O:2])[CH2:14][C:15]([OH:17])=[O:16])=[O:7])[CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)C[C@H](NC(=O)OC1(C)CCC1)C(=O)OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(OC(=O)N[C@@H](CC(=O)O)C(=O)O)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 0.05 moles of aspartic acid dimethyl ester hydrochloride in 50 ml. of chloroform is cooled to 0°C. and the pH adjusted to 8 by addition of triethylamine. 1-Methylcyclobutyl chloroformate 0.10 moles prepared according to the procedure of Example 1 is added portion-wise at 0°C. and the pH of the reaction is maintained at 8 by addition of triethylamine. Upon completion of the addition, the reaction is stirred overnight at 20°-25°C. The reaction solution is washed successively with 10 ml. portions of a saturated sodium bicarbonate solution, 50% saturated solution of sodium chloride, 0.2 N sulfuric acid saturated with sodium sulfate, 50% saturated solution of sodium chloride (twice), and the chloroform solution is dried over sodium acetate. Removal of the chloroform affords N-(1-methylcyclobutyloxycarbonyl)-aspartic acid dimethyl ester. Saponification is accomplished by dissolving the ester in 50 ml. of methanol, water 50 ml. is added, and the pH is adjusted to 12 by addition of 2 N sodium hydroxide. After stirring overnight at 25°C., the pH is adjusted to 7 with 2N sulfuric acid. The methanol is removed in vacuo and saturated sodium bicarbonate solution is added to the water solution. The aqueous bicarbonate solution is washed two times with ether and then the pH is adjusted to 3 by addition of concentrated hydrochloric acid. The acidified solution is extracted three times with ethyl acetate and the organic extracts combined, washed twice with sodium chloride solution and dried over sodium sulfate. The solvent is removed in vacuo to afford N-(1-methylcyclobutyloxycarbonyl) aspartic acid.
Reaction SMILES: C(Cl)(=O)C(Cl)=[O:3].CS(C)=O.[F:11][C:12]([F:41])([F:40])[CH:13]([OH:39])[CH:14]([NH:16][C:17](=[O:38])[C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23](=[O:37])[C@H:24]([CH3:36])[NH:25][C:26](=[O:35])[C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:32](=[O:34])[CH3:33])[CH3:15].C(N(CC)CC)C>C(Cl)Cl>[F:41][C:12]([F:11])([F:40])[C:13]([OH:3])([OH:39])[CH:14]([NH:16][C:17](=[O:38])[C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23](=[O:37])[C@H:24]([CH3:36])[NH:25][C:26](=[O:35])[C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:32](=[O:34])[CH3:33])[CH3:15]
Reactant: CC(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)NC(C)C(O)C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)NC(C)C(O)(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of oxalyl chloride (72 μl, 0.83 mmol) in methylene chloride (1 ml) under an argon atmosphere and cooled in a dry ice-acetone bath was added dimethylsulfoxide (0.12 ml, 1.65 mmol) with stirring. After 5 minutes, a solution of the compound of example 57 (0.25 g, 0.55 mmol) in methylene chloride (1.5 ml) was added. The reaction mixture was stirred for 15 minutes, triethylamine (0.50 ml,3.58 mmol) then added and the reaction warmed to room temperature for 30 minutes. The reaction mixture was placed directly onto a silica gel column and eluted with methylene chloride-methanol. Trituration of the resultant oily solid with ether-hexane and filtration gave the above-named product, (50 mg, 0.11 mmol).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:16]([OH:18])=O)[CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[NH:29][C:30](=[O:45])[C@H:31]([CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[NH:32][CH3:33]>>[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[NH:29][C:30](=[O:45])[C@H:31]([CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[N:32]([C:16](=[O:18])[C@H:9]([CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:33]
Reactant: CN[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Nc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1nccs1)C(=O)O
Product: CN(C(=O)[C@H](Cc1nccs1)NC(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Nc1ccc2ccccc2c1

Procedure:
Boc-β-(2-thiazolyl)alanine and Nδ-Boc-Nα-methylornithine β-naphthylamide were coupled under the conditions described in Procedure B, afforded a glassy solid which was purified by silica gel chromatography (1 to 2% MeOH/CH2Cl2): 1H NMR (400 MHz, CDCl3) δ1.45 (s, 9H), 1.50 (s, 9H), 1.52 (m, 2H), 1.77 (m, 1H), 2.18 (m, 1H), 3.01 (s, 3H), 3.19 (m, 3H), 3.49 (m, 1H), 4.98 (m,1H), 5.36 (m, 1H), 7.12 (s, 1H), 7.43 (m, 2H), 7.59 (d, J=7.2 Hz, 1H), 7.78 (m, 3H), 8.28 (s, 1H), 8.58 (s, 1H); mass spectrum (ES+) m/e 626 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)[C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:24]2[S:20][C:21](=[O:26])[NH:22][C:23]2=[O:25])=[CH:14][CH:13]=1)[C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CN(CCOc1ccc(C=O)cc1)c1ncccn1
Reactant: O=C1CSC(=O)N1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CN(CCOc1ccc(C=C2SC(=O)NC2=O)cc1)c1ncccn1

Procedure:
A solution of 4-[2-(N-methyl-N-(2-pyrimidinyl)amino)ethoxy]benzaldehyde (1.7 g) and 2,4-thiazolidinedione (0.7 g) in toluene (100 ml) containing a catalytic quantity of piperidinium acetate was boiled under reflux in a Dean and Stark apparatus for 2 hours. The mixture was cooled and filtered to give the title compound (mp 189°-90° C.).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[CH:23]=[C:22]([CH3:36])[N:21]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:36][C:22]1[N:21]=[C:20]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[N:19]=2)[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:28][CH:27]=2)[CH:23]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)n2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3ccc(S(N)(=O)=O)s3)n2)n1
Temperature: 23 °C
Reaction time: 16 h
Yield: 85.4 %

Procedure:
To 5-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-thiophene-2-sulfonic acid tert-butylamide (example 305) (0.170 g, 0.32 mmol) was added TFA (5 mL) and the reaction mixture was stirred at 23° C. for 16 h. The mixture was evaporated to dryness and partitioned between TBME and saturated NaHCO3 solution, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as a white solid (0.130 g, 85%). MS (ISP) 476.2 [(M+H)+]; mp 243° C. (dec.).
Reaction SMILES: C(O[CH:4](SCC)[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:42])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[C:38]([O:39][CH3:40])=[CH:37][C:27]3[C:28](=[O:36])[N:29]4[CH2:35][CH2:34][CH2:33][C@H:30]4[CH2:31][NH:32][C:26]=3[CH:25]=2)=[CH:13][C:12]=1[NH2:41])C.C([O-])([O-])=O.[Ca+2].CCOC(C)=O>CC#N.O.Cl[Hg]Cl>[CH3:18][O:17][C:15]1[C:14]([O:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[C:38]([O:39][CH3:40])=[CH:37][C:27]3[C:28](=[O:36])[N:29]4[CH2:35][CH2:34][CH2:33][C@H:30]4[CH2:31][NH:32][C:26]=3[CH:25]=2)=[CH:13][C:12]2[N:41]=[CH:4][C@@H:5]3[CH2:9][CH2:8][CH2:7][N:6]3[C:10](=[O:42])[C:11]=2[CH:16]=1
Reactant: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCOc2cc3c(cc2OC)C(=O)N2CCC[C@H]2CN3)cc1N
Agent: Cl[Hg]Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1CCC[C@H]1CN3)N=C[C@@H]1CCCN1C2=O

Procedure:
A solution of the (2S)-N-{4-[3-(7-Methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one-8-yloxy)propoxy]-5-methoxy-2-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal IV (658 mg, 1 mmol), HgCl2 (794 mg, 2.93 mmol) and CaCO3 (300 mg, 3 mmol) in CH3CN/H2O (4:1, 15 mL) was stirred at room temperature for 12 h until TLC (EtOAc), indicates complete loss of starting material. Then organic layer is evaporated in vacuum and the residue is diluted with EtOAc. To this saturated NaHCO3 was added slowly at room temperature and the mixture is filtered through celite and washed with ethylacetate. The filterate is evaporated in vacuum to get crude 7-Methoxy-8-{3-[7-methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one-8-yloxy]propoxy}-(11aS)-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one of formula V, which was further purified by column chromatography on silica gel eluting with methanol:EtOAc (2:8).
Reaction SMILES: Br[CH2:2][C:3]#[CH:4].[CH:5]1([CH2:11][CH2:12][NH2:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:5]1([CH2:11][CH2:12][NH:13][CH2:4][C:3]#[CH:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: NCCC1CCCCC1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCNCCC1CCCCC1
Temperature: 80 °C

Procedure:
20 ml of 80% 3-bromopropyne are added dropwise to 30.3 ml of cyclohexylethylamine and 29.7 g of potassium carbonate in 300 ml of acetonitrile. The reaction mixture is heated at 50° C. for 12 hours and at 80° C. for 6 hours. The resulting mixture is filtered and the solvents are evaporated off under reduced pressure. Compound V.1 is purified by distillation.
Reaction SMILES: C(OC(=O)[NH:10][C@@:11]1([CH3:57])[C:15]2=[C:16]([Cl:33])[N:17]=[C:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:19](=[O:20])[N:14]2[C@H:13]([C:34](=[O:56])[NH:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]([NH:45]C(OCC3C=CC=CC=3)=O)=[NH:44])=[CH:39][CH:38]=2)[CH2:12]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:43]([C:40]1[CH:39]=[CH:38][C:37]([CH2:36][NH:35][C:34]([C@H:13]2[N:14]3[C:19](=[O:20])[C:18]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=4)=[N:17][C:16]([Cl:33])=[C:15]3[C@@:11]([NH2:10])([CH3:57])[CH2:12]2)=[O:56])=[CH:42][CH:41]=1)(=[NH:44])[NH2:45]
Reactant: [H][H]
Reactant: C[C@@]1(NC(=O)OCc2ccccc2)C[C@@H](C(=O)NCc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)n2c1c(Cl)nc(NCc1cccc(C(F)(F)F)c1)c2=O
Agent: [Pd]
Solvent: CO
Product: C[C@@]1(N)C[C@@H](C(=O)NCc2ccc(C(=N)N)cc2)n2c1c(Cl)nc(NCc1cccc(C(F)(F)F)c1)c2=O
Reaction time: 4 h
Yield: 112.3 %

Procedure:
The compound (34 mg, 0.0325 mmol) obtained from Step B was dissolved in MeOH (0.5 mL) and 10% Pd/C (7 mg) was added. A hydrogen balloon was attached and the reaction allowed to stir for approximately 4 h at which time MS indicated a complete reaction. The reaction was filtered and concentrated under vacuum to give the product as a white solid (20 mg, 79% yield). 1HNMR (300 MHz, CD3OD) δ 1.56 (s, 3H) 2.25 (m, 1H) 2.45 (m, 1H) 4.5 (m, 2H) 4.6 (m, 2H) 5.1 (m, 1H) 7.5–7.8 (m, 8H).
Reaction SMILES: Cl.[Cl-].[N:3]1[CH:8]=[CH:7][C:6]([N+:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.[CH2:16](N)[CH2:17]CCCCC.[OH-].[Na+]>C(#N)C.C(Cl)(Cl)Cl>[CH2:14]([NH:9][C:6]1[CH:5]=[CH:4][N:3]=[CH:8][CH:7]=1)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:16][CH3:17]
Reactant: c1cc[n+](-c2ccncc2)cc1
Reactant: CCCCCCCN
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CCCCCCCNc1ccncc1
Temperature: 215 °C

Procedure:
Alternatively, 4-(heptylamino)pyridine was prepared as follows: A mixture containing 229 g. (1.0 mole) of N-(4-pyridyl)pyridinium chloride hydrochloride and 228 g. (1.5 moles) of n-heptylamine hydrochloride was heated 2 hours with stirring in an oil bath at a bath temperature of 215° C. The reaction mixture was cooled to 80° C., diluted with ice-water, made alkaline with 35% aqueous sodium hydroxide and extracted successively with ether and chloroform. The organic extracts were combined and evaporated to dryness under reduced pressure. The residual viscous oil was dissolved in ether and the ethereal solution was washed with water. The aqueous wash was back-extracted with chloroform and the chloroform extracts were combined with the ethereal solution. The combined organic solutions were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Cooling the residual oil to -78° C. effected partial solidification. The semi-solid was diluted with a small amount of ether and filtered. The solid so-obtained was dissolved in a mixture of acetonitrile and chloroform, the resulting solution treated with decolorizing carbon, filtered, and the filtrate evaporated to dryness under reduced pressure. The resulting semi-solid was diluted with a small amount of ether and cooled. The solid thus-produced was collected by filtration and washed with a small volume of cold ether to give, after drying, 84.6 g. of 4-(heptylamino)pyridine, m.p. 50°-52° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][CH2:11][OH:12])=[CH:7][C:6]=2[CH:13]=1.C(N(CC)CC)C.[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:28][C:27]1[CH:29]=[CH:30][C:24]([S:21]([O:12][CH2:11][CH2:10][C:8]2[S:9][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=3[CH:7]=2)(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1cc2cc(Br)ccc2s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2cc3cc(Br)ccc3s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
The product from Example 165C (0.5 g) in methylene chloride (10 mL) was added triethylamine (0.3 g, 1.5 eq) followed by tosyl chloride (0.37 g, 1.0 ea). The solution was stirred at RT overnight and washed with 3×20 mL of water. The methylene chloride layer was concentrated to viscous oil (0.98 g, 68.1% potency, 83.5% yield). The crude product can be purified by crystallization from 20:80 EtOAc:hexane to give crystalline solid (0.48 g). 1H NMR (CDCl3, δ) 2.38 (s, 3H), 3.21 (t, 2H), 4.30 (t, 2H), 6.87 (s, 1H), 7.18 (d, 2H), 7.36 (d of d, 1H), 7.55 (d, 1H), 7.63 (d, 2H), 7.75 (d, 1H). MS (m/z): 428, 430 (M+NH4).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:15])([F:14])[F:13])[CH:6]=1)#[N:2].[Si]([N:45]=[N+:46]=[N-:47])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl>[C:1]([CH2:3][C:4]([NH:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[C:31]([C:36]([F:37])([F:39])[F:38])[CH:30]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:13])([F:14])[F:15])[CH:6]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:24])[F:25])[CH:17]=1)#[N:2].[N:2]1[NH:45][N:46]=[N:47][C:1]=1[CH2:3][C:4]([NH:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[C:31]([C:36]([F:38])([F:37])[F:39])[CH:30]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:15])([F:13])[F:14])[CH:6]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:24])([F:25])[F:26])[CH:17]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#CCC(NC(=O)c1ccc(F)c(C(F)(F)F)c1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Agent: [F-]
Solvent: ClCCl
Product: O=C(NC(Cc1nn[nH]n1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 110 °C
Yield: 72 %

Procedure:
N-(2-cyano-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-4-fluoro-3-(trifluoromethyl)benzamide was prepared as described in Procedure 11, 18, 6 and 7. LCMS: RT=4.04 min [M+H] 581.16 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). A mixture of N-(2-cyano-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-4-fluoro-3-(trifluoromethyl)benzamide (70 mg, 0.12 mmol), TMSN3 (0.025 ml. 1.6 eq) and TBAF.3H2O (19 mg, 0.5 eq) was heated in a sealed tube at 110° C. for 24 h. After allowing to cool to rt, the residue was dissolved in CH2Cl2, and purified by ISCO flash chromatography (silica gel, CH2Cl2/MeOH) to give N-(2-(2H-tetrazol-5-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-4-fluoro-3-(trifluoromethyl)benzamide (Example 280, 54 mg, yield: 72%). LCMS: RT=3.91 min [M+H] 624.06, [M+Na] 647.06 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=O)=[CH:16]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8]/[C:9](=[CH:24]\[C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:15]([CH3:14])[CH:16]=3)/[C:10](=[O:11])/[C:12](=[CH:24]/[C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:15]([CH3:14])[CH:16]=3)/[O:13][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Reactant: Cn1cc(C=O)c2ccccc21
Product: Cc1ccc2c(c1)O/C(=C\c1cn(C)c3ccccc13)C(=O)/C(=C/c1cn(C)c3ccccc13)O2

Procedure:
Calone is reacted with 1-methylindole-3-carbaldehyde analogously to the reaction conditions of Example 1, giving 7-methyl-2,4-bis[1-(1-methyl-1H-indol-3-yl)meth-(Z)-ylidene]benzo[b]-1,4-dioxepin-3-one.