Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:27]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42](Cl)=[O:43])=[CH:37][CH:36]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:41][C:42]([NH:21][C:18]2[C:17]([C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:43])=[CH:39][CH:40]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3ccsc3)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2ccsc2)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 69 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(thiophen-3-yl)pyrazin-2-amine (7g) (450 mg, 1.17 mmol) and 4-(dimethylamino)pyridine (15.5 mg, 127 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 15 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (200 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11g (512 mg, 809 μmol, 69.0%) as a yellow solid. Rf=0.22 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.16 (s, 6H), 0.20 (s, 6H), 0.92 (s, 9H), 0.94 (s, 9H), 3.56 (s, 2H), 6.72-6.82 (AA′BB′, 2H), 6.93-7.02 (AA′BB′, 2H), 7.12-7.22 (AA′BB′, 2H), 7.50 (dd, 1H, J=2.9, 5.0 Hz), 7.59 (d, 1H, J=5.0 Hz), 7.81 (d, 1H, J=2.9 Hz), 8.04-8.12 (AA′BB′, 2H), 8.91 (s, 1H), 10.50 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.6 (4C), 17.90, 17.95, 25.50 (3C), 25.54 (3C), 41.9, 119.6 (2C), 120.3 (2C), 125.7, 126.0, 127.7, 127.9, 128.2 (2C), 128.8, 130.5 (2C), 137.1, 138.2, 142.0, 143.5, 148.0, 153.9, 156.8, 169.9; IR (KBr, cm−1) 517, 669, 712, 741, 781, 806, 839, 914, 1007, 1082, 1105, 1169, 1261, 1341, 1362, 1441, 1472, 1508, 1605, 1665, 2857, 2886, 2930, 2955, 3057, 3227; HRMS (ESI+) m/z 654.2618 ([M+Na]+, C34H45N3NaO3Si2+ requires 654.2612).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:35]C)=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:16]=2[NH:24][C:25](=[O:34])[CH2:26][C:27]2[N:31]([CH2:32][CH3:33])[N:30]=[N:29][N:28]=2)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[Cl-].[Li+].Cl.C(OCC)(=O)C.C[N:47](C)C=O>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:35])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:17][C:16]=2[NH:24][C:25](=[O:34])[CH2:26][C:27]2[N:31]([CH2:32][CH3:33])[N:30]=[N:29][N:28]=2)(=[O:10])=[O:11])[CH:8]=1)(=[NH:47])[NH2:2]
Reactant: CN(C)C=O
Reactant: CCn1nnnc1CC(=O)Nc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CCn1nnnc1CC(=O)Nc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C(=N)N)ccc1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 0.112 g of N-[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenyl]-2-(1-ethyl-1H-tetrazol-5-yl)acetamide and 28 mg of lithium chloride in 0.65 mL of N,N-dimethylformamide was stirred at 140° C. for 4 hours. To the reaction mixture were added 1 mol/L hydrochloric acid and ethyl acetate, and the mixture was separated. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined. After the organic layer was washed with water, and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in 2.5 mL of 39% hydrogen chloride-ethanol solution, and the solution was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 1.0 mL of ethanol. To the solution was added 66 mg of ammonium acetate, and the mixture was stirred at room temperature for 14 hours. To the reaction mixture were added water, ethyl acetate, and hexane, and the precipitate was collected by filtration to give 42 mg of N-[2-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenyl]-2-(1-ethyl-1H-tetrazol-5-yl)acetamide.
Reaction SMILES: Cl[C:2]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([CH3:22])=[N:19][CH:18]=4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[N:9][N:10]=[C:3]12.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:32]=1[F:38].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O.C(OCC)(=O)C>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:2]2([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6][CH2:5][N:4]3[C:8]([C:11]4[CH:16]=[CH:15][C:14]([C:17]5[O:21][C:20]([CH3:22])=[N:19][CH:18]=5)=[C:13]([O:23][CH3:24])[CH:12]=4)=[N:9][N:10]=[C:3]23)=[CH:33][C:32]=1[F:38]
Reactant: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reactant: Oc1ccc(Cl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Oc2ccc(Cl)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
A mixture of ethyl 8-chloro-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (200 mg), 4-chloro-3-fluorophenol (73.8 mg), potassium carbonate (199 mg) and DMF (2 mL) was stirred at 100° C. for 30 min, and allowed to cool to room temperature. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (127 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[CH2:17]O)=[CH:3][N:2]=1.P(Br)(Br)[Br:20].O>ClCCl>[Br:20][CH2:17][C:8]1[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=1[C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(C(F)(F)F)cc1-c1ccnnc1
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)c1ccc(CBr)c(-c2ccnnc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
[2-Pyridazin-4-yl-4-(trifluoromethyl)phenyl]methanol (Preparation 32, 46 mg, 0.18 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0° C. Phosphorus tribromide (1.0 M in dichloromethane, 199 μL, 0.20 mmol) was added and the reaction stirred for 30 minutes. Water (2 mL) was added dropwise to the reaction at 0° C. before the organics were separated and dried using a phase separation cartridge. The organics were concentrated in vacuo to afford the title compound as a residue which was re-dissolved in THF (1 mL) and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([O:32][P:33]([O:38][CH2:39]C)([O:35][CH2:36]C)=[O:34])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.ClC1C=CC(C2C=CC=CC=2[C@H](O)C2CCN(C3C=CC(C(OCC)=O)=CC=3)CC2)=CC=1.P(OC)(OC)OC>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([O:32][P:33]([O:35][CH3:36])([O:38][CH3:39])=[O:34])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(N2CCC([C@@H](OP(=O)(OCC)OCC)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Agent: CCOC(=O)c1ccc(N2CCC([C@@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Agent: COP(OC)OC
Product: CCOC(=O)c1ccc(N2CCC([C@@H](OP(=O)(OC)OC)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Yield: 67 %

Procedure:
A similar procedure to that described for INTERMEDIATE 119 utilizing (R)-ethyl 4-(4-((4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoate (INTERMEDIATE 11A, 600 mg, 1.33 mmol) and trimethyl phosphite (0.473 ml, 4.0 mmol) as starting material was followed, with subsequent purification by column chromatography (ISCO, 0→100% EtOAc/hexane over 24 minutes) to give the title compound (500 mg, yield: 67%). The title compound was used in the preparation of INTERMEDIATE 122 without further purification.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]([C:24]([NH:26][CH2:27][C@@H:28]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:25])[CH2:19][CH2:20][C:21]([NH2:23])=[O:22])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C)C=O>[C:44]([O:43][C:41](=[O:42])[NH:40][C@H:28]([CH2:27][NH:26][C:24](=[O:25])[C@@H:18]([NH2:17])[CH2:19][CH2:20][C:21]([NH2:23])=[O:22])[CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])([CH3:45])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)[C@H](CCC(N)=O)NC(=O)OCC1c2ccccc2-c2ccccc21)NC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)[C@@H](N)CCC(N)=O)NC(=O)OC(C)(C)C

Procedure:
A solution of 33 mg (0.05 mmol) of 9H-fluoren-9-ylmethyl{(1S)-4-amino-1-[({(2S)-2,5-bis[(tert-butoxycarbonyl)amino]pentyl}amino)carbonyl]-4-oxobutyl}carbamate (Example 129A) in 1 ml of dimethylformamide is stirred after the addition of 4 mg (0.05 mmol) of piperidine at room temperature for 45 min. The solvent is evaporated and the crude product is reacted without further purification.
Reaction SMILES: [CH2:1]1[C:3]([NH2:7])([C:4]([OH:6])=[O:5])[CH2:2]1.Cl[Si](C)(C)C.CCN(C(C)C)C(C)C.Cl[C:23]([O:25][CH:26](Cl)[CH:27]([CH3:29])[CH3:28])=[O:24].[C:31]([OH:41])(=[O:40])/[CH:32]=[CH:33]/[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)(Cl)Cl>[C:34]1(/[CH:33]=[CH:32]/[C:31]([O:41][CH:26]([O:25][C:23]([NH:7][C:3]2([C:4]([OH:6])=[O:5])[CH2:2][CH2:1]2)=[O:24])[CH:27]([CH3:29])[CH3:28])=[O:40])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: CC(C)C(Cl)OC(=O)Cl
Reactant: NC1(C(=O)O)CC1
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(OC(=O)/C=C/c1ccccc1)OC(=O)NC1(C(=O)O)CC1
Yield: 4.8 %

Procedure:
Following the general procedure for the one pot synthesis, ACPC (2.5 g, 24.6 mmol) was reacted with chlorotrimethylsilane (6.25 mL, 49.2 mmol) in anhydrous chloroform (25 mL) in the presence of DIEA (9.1 mL, 49.4 mmol). Subsequent reaction of the intermediate with 1-chloro-2-methylpropyl chloroformate (5.0 mL, 37 mmol) followed by a mixture of DIEA (9.1 mL, 49.4 mmol) and trans-cinnamic acid (7.1 g, 48 mmol) provided 0.406 g (12.2% yield) of the title compound (18) as a light-yellow solid after aqueous work-up and mass-guided preparative HPLC purification. M.p: 147.8-150.2° C. 1H NMR (CDCl3, 400 MHz): δ=7.72-7.68 (d, 1H, J=15.6), 7.51 (br s, 2H), 7.37 (m, 3H), 6.71 (d, 1H), 6.42 (d, 1H, J=16), 5.51 (s, 0.3H), 5.31 (s, 0.7H), 2.11 (m, 1H), 1.58 (m, 2H), 1.24 (m, 2H), 1.02 (d, 6H). MS (ESI) m/z 345.98 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH:15]([CH3:17])[CH3:16])([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][N:23]([CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27])[CH:24]=1.C(O)(=O)C>C(O)C>[ClH:1].[C:13]([C@@:10]1([CH:15]([CH3:17])[CH3:16])[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]3[CH:21]=[N:22][N:23]([CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27])[CH:24]=3)[N:7]=2)[C:9]1=[O:18])#[N:14]
Reactant: CC(C)[C@]1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Reactant: CN(C)C(=O)Cn1cc(N)cn1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)[C@]1(C#N)CCN(c2ccnc(Nc3cnn(CC(=O)N(C)C)c3)n2)C1=O
Product: Cl
Yield: 100.1 %

Procedure:
A solution of (3S)-1-(2-chloropyrimidin-4-yl)-3-isopropyl-2-oxopyrrolidine-3-carbonitrile (55 mg) obtained in Step A of Example 9, 2-(4-amino-1H-pyrazol-1-yl)-N,N-dimethylacetamide (42 mg) and acetic acid (13 μL) in ethanol (2 mL) was stirred in a microwave reactor at 150° C. for 1 hr, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, ethyl acetate/methanol). To a solution of the residue (80 mg) in ethanol (3 mL) was added 1M hydrochloric acid (200 μL), and the solvent was evaporated under reduced pressure. The residue was recrystallized (diisopropyl ether/ethanol) to give the title compound (90 mg).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[NH:10]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:19]=[O:20])[C:13]=2[CH:12]=[CH:11]1>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:11]1[NH:10][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:19]=[O:20])[C:13]=2[CH:12]=1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: BrCc1ccccc1Br
Product: O=Cc1cccc2[nH]c(Cc3ccccc3Br)cc12
Yield: 96.6 %

Procedure:
The same procedures used in Example 1 were repeated except for using 3.78 g of o-bromobenzyl bromide and 2.00 g of indole-4-carbaldehyde as a starting material to give 4.18 g of (2-bromobenzyl) indole-4-carbaldehyde as pale yellow crystals. The yield thereof was found to be 97%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]2[C:25]([O:26]C)=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:23]([CH3:34])[C:22]=2[CH3:35])=[O:20])[CH2:11][CH2:10]1.B(Br)(Br)Br.C(Cl)Cl>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]2[C:25]([OH:26])=[C:24]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:23]([CH3:34])[C:22]=2[CH3:35])=[O:20])[CH2:13][CH2:14]1
Reactant: COc1c(C(=O)NCCCN2CCN(c3cccc(Cl)c3Cl)CC2)c(C)n(C)c1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(C(=O)NCCCN2CCN(c3cccc(Cl)c3Cl)CC2)c(O)c(-c2ccccc2)n1C
Temperature: 0 °C
Yield: 24.3 %

Procedure:
To a solution of N-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)-4-methoxy-1,2-dimethyl-5-phenyl-1H-pyrrole-3-carboxamide (375 mg, 0.60 mmol) was added BBr3 (0.77 ml, 17% in DCM) slowly at 0° C. After stirring at 0° C. for 2˜3 hours, the mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM (50 mL) MeI (2.13 mL, 34.2 mmol). The organic phase was dried over MgSO4 and evaporated under vacuum. The residue was further purified by prep HPLC (Gilson, C18 column) to provide title compound (73 mg, 20%).
Reaction SMILES: N1CCCCC1.[CH2:7]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=O)[CH2:8][CH2:9][CH2:10][C:11]#[CH:12].C([CH2:27][C:28]([NH:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34])=[O:29])(O)=O.Cl>C1(C)C=CC=CC=1>[CH2:7]([O:13][C:14]1[CH:15]=[C:16](/[CH:17]=[CH:27]/[C:28]([NH:30][C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33]([OH:35])=[O:34])=[O:29])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:8][CH2:9][CH2:10][C:11]#[CH:12]
Reactant: C#CCCCCOc1cc(C=O)ccc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: C#CCCCCOc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OC
Yield: 67.8 %

Procedure:
Piperidine (0.26 mL, 2.6 mmol) was added to a suspension of 3-(hex-5-ynyloxy)-4-methoxybenzaldehyde (0.60 g, 2.6 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.52 g, 2.4 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1M HCl. The crude product was recrystallised from EtOH/water providing (E)-2-[[3-(3-(hex-5-ynyloxy)-4-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.64 g, 70%) as a pale yellow crystalline solid; mp 135-137° C.; δH (400 MHz, DMSO-d6) 1.62 (p, J=7.2 Hz, 2H, CH2), 1.82 (p, J=7.2 Hz, 2H, CH2), 2.25 (dt, J=7.2, 2.4 Hz, 2H, CH2CCH), 2.78 (t, J=2.4 Hz, 1H, CCH), 3.80 (s, 3H, OCH3), 4.05 (t, J=7.2 Hz, 2H, OCH2), 6.77 (d, J=15.6 Hz, 1H, CH═CHCO), 6.99 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.23 (d, J5′,6′=8.0 Hz, 1H, H6′), 7.37 (s, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.61 (d, J5,6=8.0 Hz, 1H, H6), 11.27 (s, 1H, NH), 13.58 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 18.1, 25.3, 28.5, 56.3, 68.4, 72.1, 85.0, 112.3, 112.5, 117.3, 120.5, 121.0, 123.3, 127.9, 131.8, 134.7, 141.7, 142.3, 149.0, 151.5, 164.8, 170.1; HRMS (ESI) calculated for C23H23NO5 [M+H]+ 394.1649. found 394.1650; vmax 753, 1257, 1512, 1586, 1675, 2941, 3242, 3536 cm−1.
Reaction SMILES: [NH2-].[Na+].CC1C=CC=CC=1.[C:10]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3(C#N)[CH2:33][CH2:32][C:27]4([O:31][CH2:30][CH2:29][O:28]4)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CO>CC1C=CC=CC=1C>[C:10]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:33][CH2:32][C:27]4([O:28][CH2:29][CH2:30][O:31]4)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#CC1(c2ccc(OCc3ccccc3)cc2)CCC2(CC1)OCCO2
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Solvent: CO
Product: c1ccc(COc2ccc(C3CCC4(CC3)OCCO4)cc2)cc1
Reaction time: 24 h
Yield: 87 %

Procedure:
To a stirred and heated (±65° C.) mixture of 60 parts of sodium amide solution 50% in dimethylbenzene and 315 parts of methylbenzene are added portionwise 33.5 parts of 8-[4-(phenylmethoxy)phenyl]-1,4-dioxaspiro[4,5]decane-8-carbonitrile. Upon completion, stirring is continued for 24 hours at reflux. The reaction mixture is cooled, about 16 parts of methanol are added dropwise and the whole is poured onto ice-water. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 27 parts (87%) of 8-[4-(phenylmethoxy)phenyl]-1,4-dioxaspiro[4,5]decane as a residue.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]([NH2:28])=O)=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.S(Cl)(Cl)=O>>[CH2:1]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]#[N:28])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C#CC(N)=O)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCCCNc1ccc(C#CC#N)cc1

Procedure:
As described in Example 33, a sample of 4-hexadecylaminophenylpropiolamide is treated successively with hydrogen chloride gas and refluxing thionyl chloride to afford 4-(hexadecylamino)phenylpropiolnitrile. Similarly prepared is 4-(4-hexadecylaminophenyl)butyronitrile.
Reaction SMILES: COP([CH2:7][C:8]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9])(=O)OC.[H-].[Na+].[C:18]([O:21][CH:22]1[CH2:29][CH2:28][CH:27]2[CH:23]1[CH2:24][CH2:25][CH:26]2[CH:30]=O)(=[O:20])[CH3:19].C(O)(=O)C>O1CCCC1.C(OCC)C.O1CCOCCOCCOCCOCCOCC1>[C:18]([O:21][CH:22]1[CH2:29][CH2:28][CH:27]2[CH:23]1[CH2:24][CH2:25][CH:26]2/[CH:30]=[CH:7]/[C:8]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)=[O:9])(=[O:20])[CH3:19]
Reactant: COP(=O)(CC(=O)C1CCCCC1)OC
Reactant: CC(=O)OC1CCC2C(C=O)CCC12
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)OC1CCC2C(/C=C/C(=O)C3CCCCC3)CCC12
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Dimethyl(2-cyclohexyl-2-oxoethyl)phosphonate (3.3 g) was added to a stirred suspension of sodium hydride (0.34 g) and 1,4,7,10,13,16-hexaoxacyclooctadecane (10 mg) in dry tetrahydrofuran (90 ml) in an atmosphere of argon and the mixture was stirred for 12 hours. The mixture was then cooled to 0° C. and treated dropwise with 6-acetoxy-2-formylbicyclo[3,3,0]octane (1.05 g; prepared as described in Reference Example 21 and predominantly in the 2β-configuration). The reaction mixture was allowed to warm to room temperature and then it was stirred for a further period of 24 hours. A solution of glacial acetic acid (400 mg) in diethyl ether (1 ml) was then added and the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (10 ml) and the resulting solution was washed with water (10 ml) and then with saturated aqueous sodium chloride solution (10 ml), dried over magnesium sulphate, and concentrated in vacuo. The resulting oil was treated with acetic anhydride (1 ml) and pyridine (4 ml) at 20° C. and left to stand for 12 hours. Concentration at 0.01 mmHg gave an oil, which was subjected to chromatography on a silica gel column, eluting with mixtures of ethyl acetate and hexane (1:6 v/v and then 1:1 v/v), to give (E)- 6-acetoxy-2-(3-cyclohexyl-3-oxoprop-1-enyl)bicyclo[3,3,0]octane (0.84 g), predominantly in the 2β-configuration.
Reaction SMILES: [F:1][C:2]1[C:3]([O:26][CH3:27])=[CH:4][C:5]([CH3:25])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](OS(C(F)(F)F)(=O)=O)[C:9]=2[N+:22]([O-:24])=[O:23])[CH:7]=1.[CH:28]1([C@H:31]([NH2:34])[CH2:32][CH3:33])[CH2:30][CH2:29]1>>[CH:28]1([C@H:31]([NH:34][C:10]2[C:9]([N+:22]([O-:24])=[O:23])=[C:8]([C:6]3[CH:7]=[C:2]([F:1])[C:3]([O:26][CH3:27])=[CH:4][C:5]=3[CH3:25])[CH:13]=[CH:12][N:11]=2)[CH2:32][CH3:33])[CH2:30][CH2:29]1
Reactant: CC[C@@H](N)C1CC1
Reactant: COc1cc(C)c(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])cc1F
Product: CC[C@@H](Nc1nccc(-c2cc(F)c(OC)cc2C)c1[N+](=O)[O-])C1CC1
Yield: 38.8 %

Procedure:
Trifluoro-methanesulfonic acid 4-(5-fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl ester (0.5 g, 1.22 mmol), prepared substantially as described in Part C of Example 19a, and (R)-1-cyclopropyl-propylamine (0.33 g, 2.44 mmol) were treated substantially as described in Part C of Example 19a to produce 0.17 g (43%) of crude (R)-(1-Cyclopropyl-propyl)-[4-(5-fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-amine.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=2[N:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:22]2[CH:27]([CH2:28][N:29]([C@@H:37]([C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=[CH:41][CH:40]=3)[CH3:38])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.O>CS(C)=O>[C:32]([O:31][C:30]([N:29]([CH2:28][CH:27]1[CH2:26][CH2:25][N:24]([C:2]2[NH:6][C:5]3[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=3[N:3]=2)[CH2:23][CH:22]1[C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[CH:17]=1)[C@@H:37]([C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][CH:40]=1)[CH3:38])=[O:36])([CH3:33])([CH3:34])[CH3:35]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc2nc(Cl)[nH]c2c1
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(N3CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c4cccc5ccccc45)C(c4cccc(F)c4)C3)[nH]c2c1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
A solution of 313 mg of methyl 2-chloro-1H-benzimidazole-6-carboxylate and 100 mg of tert-butyl {[3-(3-fluorophenyl)piperidin-4-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate in 2.00 mL of DMSO was stirred at 130° C. for 9 hours. The reaction mixture was cooled to room temperature, and water was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 48 mg of methyl 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-1H-benzimidazole-6-carboxylate as a pale yellow solid. ESI+: 637