Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[C:12]1([CH:18]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19](=[O:21])[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:20][C:19](=[O:21])[CH:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:22][CH:23]=[CH:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C(CC=Cc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccc(Cl)cc1)C(CC=Cc1ccccc1)c1ccccc1

Procedure:
A sodium hydroxide solution (2.5 ml., 20%) is added to a solution of p-chlorobenzaldehyde (7.0 g., 0.05 mole) and 3,6-diphenyl-5-hexen-2-one (12.5 g., 0.05 mole) in ethanol (125 ml.) with stirring. The yellowish solid that separates on continued stirring is filtered, washed with cold ethanol, and air-dried, 14.35 g., m.p. 92°-95°C. Recrystallization from hexane gives material with m.p. 95°-96.5°C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1Cl)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[N:24][CH:25]=1.O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:26][C:22]1[CH:23]=[N:24][CH:25]=[C:20]([Cl:19])[CH:21]=1)[CH3:2]
Reactant: Oc1cncc(Cl)c1
Reactant: CCOC(=O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1Oc1cncc(Cl)c1
Temperature: 25 °C
Yield: 32 %

Procedure:
A solution of 2-Chloro-nicotinic acid ethyl ester (2.07 grams, 11.2 mmole), Cesium carbonate (7.27 grams, 22.3 mmole) and 5-chloro-3-pyridinol (1.45 grams, 11.2 mmole) in dry dimethylformamide (40 ml) was stirred at 90° C. overnight. The suspension was cooled to room temperature, poured into water and extracted with diethyl ether. The combined organics were washed with water and brine, dried over MgSO4, and concentrated to a tan solid. Recrystalization from hexane gave a yellow solid (1.0 g). M.P. 65-69° C.; Anal. calcd. for C13H11ClN2O3: C, 56.03; H, 3.98; N, 10.05. Found: C, 56.14; H, 4.04; N, 10.16.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[CH:11][S:10][C:9]=12)(=[O:4])=[O:3].[CH3:13][Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.CI.[Cl-].[Na+]>C1COCC1>[CH2:1]([S:2]([C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[CH:11][S:10][C:9]=12)(=[O:3])=[O:4])[CH3:13]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CS(=O)(=O)c1ncn2ccsc12
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCS(=O)(=O)c1ncn2ccsc12
Reaction time: 0.5 h

Procedure:
A solution of 725 mg of 7-methanesulfonylimidazo[5,1-b]thiazole in 35 ml of THF was cooled in an argon atmosphere to −70° C. A 1 N-lithiumbis(trimethylsilyl)amide/THF solution (3.9 ml) was added dropwise thereto at the same temperature. The mixture was stirred for 30 min. Thereafter, 0.25 ml of methyl iodide was added thereto. The mixture was stirred at the same temperature for 70 min. A saturated aqueous sodium chloride solution was added thereto, followed by extraction four times with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol=9:1) to give 0.79 g of 7-ethanesulfonylimidazo[5,1-b]thiazole.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:4][OH:3])[CH2:7][CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C1(Cc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1(Cc2ccccc2)CCN(Cc2ccccc2)CC1
Yield: 81 %

Procedure:
Was prepared from 1,4-dibenzyl-piperidine-4-carboxylic acid ethyl ester (J. Chem. Soc., Perkin Trans. 1 1996, 20, 2545–2551.) by lithium aluminium hydride reduction in tetrahydrofurane under standard conditions in 81% yield. MS 296(M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:7]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:5])[CH3:2].[CH:29]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)([CH3:31])[CH3:30]>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:36]3[CH:37]=[CH:38][C:33]([O:32][CH:29]([CH3:31])[CH3:30])=[CH:34][CH:35]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:7]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:5])[CH3:2]
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1cccc(Cl)c1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(OC(C)C)cc3)ccc2n1-c1cccc(Cl)c1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 1-(3-chlorophenyl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (135 mg, 0.34 mmol, see step (b) Example 8) and 4-isopropoxyphenylboronic acid (91 mg, 0.50 mmol). Yield 70 mg (39%).
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[N:21]=[C:20]([S:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=3[F:39])[N:19]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:39][C:33]1[C:34]([F:38])=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][S:30][C:20]1[N:19]=[C:18]([NH:17][S:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)(=[O:15])=[O:16])[CH:23]=[C:22]([O:24][CH2:25][C:26]([F:29])([F:27])[F:28])[N:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)Nc2cc(OCC(F)(F)F)nc(SCc3cccc(F)c3F)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1cc(OCC(F)(F)F)nc(SCc2cccc(F)c2F)n1)N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[[[2-[[(2,3-difluorophenyl)methyl]thio]-6-(2,2,2-trifluoroethoxy)-4-pyrimidinyl]amino]sulfonyl]-1-piperazinecarboxylic acid-1,1-dimethylethyl ester (the product from step i) (0.21 g) in DCM (2 mL) was added trifluoroacetic acid (2 mL) and the reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was evaporated, the residue was azeotroped with Et2O (×2) and then purified by reverse phase HPLC eluting with acetonitrile/aq. 0.2% trifluoroacetic acid mixtures to give title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-])=O)=[CH:5][C:4]([C:10]2[O:11][CH:12]=[N:13][N:14]=2)=[N:3]1.[Cl-].[NH4+]>[Zn].C1COCC1.CO>[CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:10]2[O:11][CH:12]=[N:13][N:14]=2)=[N:3]1
Reactant: Cn1nc(-c2nnco2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nc(-c2nnco2)cc1N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 31 %

Procedure:
To a mixture of 2-(1-methyl-5-nitro-1H-pyrazol-3-yl)-1,3,4-oxadiazole (2.56 g, 13.1 mmol), ammonium chloride (4.91 g, 92 mmol) in a 1:1 solution of THF/MeOH (82.6 mL) at about 0° C. was added zinc dust (6.0 g, 92 mmol) portionwise. The reaction was stirred for about 10 min at about 0° C. The ice bath was removed and the reaction stirred at ambient temperature for about 16 h. The reaction mixture was filtered through a pad of Celite® rinsing with MeOH (50 mL). The filtrate was concentrated under reduced pressure. The material was partitioned between DCM (50 mL) and water (10 mL). The aqueous layer was back extracted with DCM (2×50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The aqueous layer was acidified using 1 N HCl to about pH 3 and back extracted with DCM (50 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The organic layer batches were combined to afford 1-methyl-3-(1,3,4-oxadiazol-2-yl)-1H-pyrazol-5-amine (0.67 g, 4.06 mmol, 31%, which was used without further purification). LC-MS (Table 1, Method g) Rt=0.59 min, m/z 166 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:5]=[C:6]([CH2:14][O:15][C@@H:16]2[CH2:22][CH2:21][C@@H:20]3[N:23]([CH2:24][CH2:25][OH:26])[C@@:17]2([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:18][CH2:19]3)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[F:13][C:10]([F:11])([F:12])[C:8]1[CH:7]=[C:6]([CH2:14][O:15][C@@H:16]2[CH2:22][CH2:21][C@@H:20]3[N:23]([CH2:24][CH2:25][O:26][S:43]([CH3:42])(=[O:45])=[O:44])[C@@:17]2([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:18][CH2:19]3)[CH:5]=[C:4]([C:3]([F:33])([F:2])[F:34])[CH:9]=1
Reactant: OCCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)CC2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)CC2
Temperature: 0 °C
Yield: 98.5 %

Procedure:
(1R*,2R*,5R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-8-(2-hydroxyethyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 67; 173 mg, 0.37 mmol) was dissolved in dichloromethane (2 ml) and cooled to 0° C. Triethylamine (0.062 ml, 0.44 mmol) was added followed by methanesulphonyl chloride (0.029 ml, 0.37 mmol). The mixture was extracted between water and dichloromethane (×3) and the organics dried (MgSO4) and concentrated in vacuo to give the title compound as a clear oil (201 mg, 100%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[N-:11]=[N+:12]=[N-:13].[Na+]>>[N:11]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CBr)c1ccccc1
Agent: [Na+]
Product: [N-]=[N+]=NCC(=O)c1ccccc1

Procedure:
The synthesis of 2,5-substituted thiazoles is described in Scheme 1. Reaction of alcohol R1—OH wherein R1 alkyl, aralkyl, heteroaryl, heterocyclo, or cycloalkyl with substituted 4-fluoroacetophenone 1 afforded the ether-acetophenone intermediate 2. Ether-acetophenone intermediate 2 was then converted to the corresponding bromo-acetophenone using Bu4NBr3, which, upon reaction with NaN3, provided the azido-acetophenone intermediate. Hydrogenation of the azido-acetophenone intermediate afforded amine 3, followed by coupling with orthogonally protected amino acid 4 or amino diol-carboxylic acid 5 gave amide 6. As a note, compound 4 was synthesized from (S)-2-(tert-butoxycarbonylamino)-3-hydroxy-2-methylpropanoic acid in three steps in overall 52-64% yield. A synthesis of (R)-3-(tert-butoxycarbonyl)-2,2,4-trimethyloxazolidine-4-carboxylic acid is described in Clemens, J. J.; Davis, M. D.; Lynch, K. R.; Macdonald, T. L. Bioorg. Med. Chem. Lett. 2005, 15, 3568-3572. Compound 5 was synthesized from 2-amino-2-(hydroxymethyl)propane-1,3-diol in five steps in overall 30% yield, also as described in Clemens, J. J.; Davis, M. D.; Lynch, K. R.; Macdonald, T. L. Bioorg. Med. Chem. Lett. 2005, 15, 3568-3572. Under conditions using Lawesson's reagent, amide 6 was converted to thiazole 7 in good yield. Removal of the protecting groups afforded the final alcohol 8, which upon reaction with diethyl chlorophosphate and subsequent deprotection with TMSBr gave the phosphate 9.
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:12](Cl)(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15].O>CC(N(C)C)=O>[C:1]([NH:10][NH:11][C:12](=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(Cl)c1ccccc1O
Reactant: NNC(=O)c1ccccc1O
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(NNC(=O)c1ccccc1O)c1ccccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
30.4 g of salicylic acid hydrazide are dissolved in 500 ml of dimethylacetamide and 34.8 g of salicylic acid chloride are added dropwise over the course of 70 minutes at 25° - 40° C. The yellow solution is stirred for 3 hours at room temperature and is then poured into 1 liter of water, whereupon white, fine crystals precipitate. The substance is filtered off, washed with water and dried in vacuo at 60° C. The product is purified by recrystallisation from ethylene gylcol monomethyl ether. The N,N'-bis-salicyloyl-hydrazine thus obtained (stabiliser No. 1), melts at 303° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][C:13]([C:15]2[S:22][C:21]([CH3:23])=[C:20]3[C:16]=2[CH2:17][C@H:18]2[C:24]([CH3:26])([CH3:25])[C@H:19]23)=[O:14])[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[OH:8].Br[CH2:28][CH2:29][CH2:30][OH:31]>C(O)(C)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][C:13]([C:15]2[S:22][C:21]([CH3:23])=[C:20]3[C:16]=2[CH2:17][C@H:18]2[C:24]([CH3:26])([CH3:25])[C@H:19]23)=[O:14])[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[O:8][CH2:28][CH2:29][CH2:30][OH:31]
Reactant: COc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(Cl)c1O
Reactant: OCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: COc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(Cl)c1OCCCO
Temperature: 70 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A solution of 3-(3-chloro-4-hydroxy-5-methoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (800 mg, 2.05 mmol, Intermediate 14) in isopropanol (30 mL) and 2 N aq. NaOH (10 mL) is treated with 3-bromopropanol (569 mg, 4.09 mmol). The dark red reaction mixture is stirred at 70° C. After 4.5 and 22 h another portion of 3-bromopropanol (569 mg, 4.09 mmol) is added. Stirring is continued for further 2 h after the last addition. The solvent is removed under reduced pressure and the residue is dissolved in EA and washed twice with water. The organic layer is dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 1:1 to give 3-[3-chloro-4-(3-hydroxy-propoxy)-5-methoxy-phenyl]-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (460 mg) as a yellow oil; LC-MS: tR=1.10 min, [M+1]+=449.22; 1H NMR (CDCl3): δ 676-674 (m, 1H), 6.64-6.61 (m, 1H), 4.05 (t, J=5.5 Hz, 2H), 3.90-3.85 (m, 2H), 3.77 (s, 3H), 3.01-2.85 (m, 5H), 2.72 (d, J=18.8 Hz, 1H), 2.31 (s, 3H), 1.98-1.90 (m, 2H), 1.85-1.80 (m, 2H), 1.05 (s, 3H), 0.63 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([S:20](Cl)(=[O:22])=[O:21])[N:19]=[C:6]2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:4]=1[CH3:34])#[N:2].[CH:35]1([NH2:38])[CH2:37][CH2:36]1.C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([S:20]([NH:38][CH:35]3[CH2:37][CH2:36]3)(=[O:22])=[O:21])[N:19]=[C:6]2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:4]=1[CH3:34])#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(S(=O)(=O)Cl)nc2N1c1cccc(C(F)(F)F)c1
Reactant: NC1CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(S(=O)(=O)NC3CC3)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, abs. THF (3 ml) was stirred with molecular sieve (4 Å, 30 mg) for min (7R)-6-Cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl chloride (63%, 50 mg, 62 μmol), cyclopropylamine (13 μl, 0.19 mmol, 3 eq.) and triethylamine (9 μl, 63 μmol, 1 eq.) were added, and the mixture was stirred at RT for 12 h. The reaction solution was then concentrated under reduced pressure and the residue was purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (27 mg, 82% of theory).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#[N:8])=[CH:2]1.[CH3:9][CH:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1>>[CH3:9][CH:10]1[CH2:15][CH2:14][C:13](=[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[C:7]#[N:8])[CH2:12][CH2:11]1
Reactant: N#CCc1ccsc1
Reactant: CC1CCC(=O)CC1
Product: CC1CCC(=C(C#N)c2ccsc2)CC1

Procedure:
The expected intermediate is obtained in the manner described in General Protocol A starting from 3-thienylacetonitrile and 4-methylcyclohexanone.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@@H:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[NH:22][C:21]1=[O:31]>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([NH:19][C@@H:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[NH:22][C:21]1=[O:31])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Reactant: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1

Procedure:
Prepared from 3-benzyloxycarbonylamino-3-methylbutanoic acid and 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step E) by the procedure described in Example 1, Step I. FAB-MS: calculated for C23H27N3O4 409; found 410 (M+H, 100%). 1H NMR (200 MHz, CDCl3): 1.38 (s, 3H), 1.39 (s, 3H), 1.82 (m, 1H), 2.52 s, 2H), 2.5-3.0 (m, 3H), 4.51 (m, 1H), 5.07 (br s, 2H), 5.57 (br s, 1H), 6.68 (d, 7 Hz, 1H), 6.97 (d, 8 Hz, 1H), 7.1-7.4 (m, 8H), 7.61 (br s, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[N:13]1([CH2:19][CH2:20][NH2:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([NH:21][CH2:20][CH2:19][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:10]
Reactant: NCCN1CCCCC1
Reactant: CCOC(=O)CN1CCCC1=O
Product: O=C(CN1CCCC1=O)NCCN1CCCCC1

Procedure:
From 12.8 g. of ethyl 2-oxo-1-pyrrolidineacetate and 19.2 g. of 2-(1-piperidinyl)ethylamine [Compt. rend. 233, 1121 (1951)], following the procedure of Example 1, there is obtained 2-oxo-N-[2-(1-piperidinyl)ethyl]-1-pyrrolidineacetamide; b.p. 185°-187° C./0.15 mm.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH2:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C([O:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]2[C:47]3[C:42](=[CH:43][C:44]([C:48](O)=[O:49])=[CH:45][CH:46]=3)[C:41]([CH3:51])=[C:40]2[CH3:52])=[CH:34][CH:33]=1)=[O:25])(C)(C)C>>[CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:18][C:48]([C:44]2[CH:43]=[C:42]3[C:47](=[CH:46][CH:45]=2)[N:39]([CH2:38][C:35]2[CH:34]=[CH:33][C:32]([C:27]4[C:26]([C:24]([OH:25])=[O:23])=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:37][CH:36]=2)[C:40]([CH3:52])=[C:41]3[CH3:51])=[O:49])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc([C@@H](N)Cc2ccccc2)c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](Cc3ccccc3)c3cccc(C(C)C)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(3-isopropylphenyl)-2-phenylethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 587 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[CH:12]=[CH:11][C:10]([NH2:14])=[CH:9][C:8]=2[C:7]2[N:15]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:16]=[C:17]([C:18]([NH2:20])=[O:19])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[Cl:28][C:29]1[N:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](O)=[O:32].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([N:4]1[C:13]2[CH:12]=[CH:11][C:10]([NH:14][C:31]([C:30]3[C:29]([Cl:28])=[N:37][CH:36]=[CH:35][CH:34]=3)=[O:32])=[CH:9][C:8]=2[C:7]2[N:15]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[N:16]=[C:17]([C:18]([NH2:20])=[O:19])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1Cc2c(C(N)=O)nn(-c3ccc(F)cc3)c2-c2cc(N)ccc21
Reactant: O=C(O)c1cccnc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1Cc2c(C(N)=O)nn(-c3ccc(F)cc3)c2-c2cc(NC(=O)c3cccnc3Cl)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 39 %

Procedure:
The title material from Example 24 (1.2 g, 0.0033 mol) and 2-chloro-nicotinic acid (517 mg, 0.0033 mol) were combined, under argon, in 5 mL of DMF. Diisopropyl ethyl amine (862□L, 0.00495 mol) and HATU (1.88 g, 0.00495 mol) were added and the reaction was stirred for 18 hours at room temperature. The reaction was then concentrated in vacuo, and the resulting solids were triturated with water and isolated by vacuum filtration to give the product as an off white solid. 652 mg. (MW=504.91, 39% yield). LC/MS m/z=505.7 (m+1).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([NH:11][NH2:12])[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH2:13]([O:15][C:16](=[O:20])[C:17](=O)[CH3:18])[CH3:14]>C(O)C>[CH2:13]([O:15][C:16](=[O:20])[C:17](=[N:12][NH:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=1)[CH3:18])[CH3:14]
Reactant: CCOC(=O)C(C)=O
Reactant: NNc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(C)=NNc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(3-Nitro-phenyl)-hydrazine hydrochloride salt (B-4-a) (30.2 g, 0.16 mol) and 2-oxo-propionic acid ethyl ester (22.3 g, 0.19 mol) was dissolved in ethanol (300 mL). The mixture was stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure to give 2-[(3-nitro-phenyl)-hydrazono]-propionic acid ethyl ester, which was used directly in the next step.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][NH2:20])[CH3:16].[O:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>ClCCl.O>[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][NH:20][CH:27]1[CH2:28][CH2:29][O:24][CH2:25][CH2:26]1)[CH3:16]
Reactant: CCOC(CN)OCC
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(CNC1CCOCC1)OCC
Reaction time: 18 h

Procedure:
Sodium triacetoxyborohydride (10.6 g) was added to a cooled (0° C.) solution of aminoacetaldehyde diethyl acetal (5.8 mL) and tetrahydro-4H-pyran-4-one (3.7 mL) in dichloromethane (100 mL). The reaction was stirred for 18 h, allowing the temperature to warm to ambient conditions. Water (100 mL) was added, followed by portionwise addition of sodium bicarbonate (16.8 g), causing effervescence. The mixture was stirred vigorously for 1 h, and then allowed to partition. The phases were then separated and the aqueous phase extracted with more dichloromethane (50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford the titled compound as a colourless oil. Yield 8.3 g.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([C:34]#[N:35])=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[C:30]([C:34]#[N:35])=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccc(C#N)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2cccc(C#N)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-7-cyano-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.