Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:41])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:24])[CH3:23])[CH2:13][CH:12]([NH:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([O:37]CC)=[O:36])[CH:30]=3)=[O:27])[C:11]2=[O:40])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+].O1CCCC1>CO>[C:1]1([CH3:41])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:24])[CH3:23])[CH2:13][CH:12]([NH:25][C:26](=[O:27])[NH:28][C:29]3[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=3)[C:35]([OH:37])=[O:36])[C:11]2=[O:40])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(C)=O)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(=O)N1CC(NC(=O)Nc2cccc(C(=O)O)c2)C(=O)N(CC(=O)c2ccccc2C)c2cc(C)ccc21
Yield: 58.2 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-acetyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (670 mg) was dissolved in methanol (32 ml), aqueous lithium hydroxide monohydrate (253 mg) solution (16 ml) and tetrahydrofuran (16 ml) were added, and the mixture was refluxed for 45 minutes, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (150 ml), the solution was washed with diethyl ether, acidified with 1N hydrochloric acid, and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, diisoproryl ether was added to the residue for trituration, collected by filtration, to thereby obtain 370 mg of the titled compound.
Reaction SMILES: CN(C=O)C.CS([O:10][CH2:11][C:12]1[O:13][C:14]([C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:37])[C:23]([F:36])([F:35])[C:24]2([OH:34])[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)=[N:15][N:16]=1)(=O)=O.[C:38]1(O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C([O-])([O-])=O.[K+].[K+]>O>[F:35][C:23]([F:36])([C:24]1([OH:34])[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]1)[C:22]([N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1[C:14]1[O:13][C:12]([CH2:11][O:10][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N:16][N:15]=1)=[O:37]
Reactant: Oc1ccccc1
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2nnc(COS(C)(=O)=O)o2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2nnc(COc3ccccc3)o2)C1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 97.6 %

Procedure:
To a DMF (1.0 mL) solution of the compound (32.5 mg) obtained in Example 9-(6) and phenol (13 mg), K2CO3 (37 mg) was added and the mixture was stirred at 50° C. for 3.5 hours. The reaction mixture was added to water (20 mL) and the organic layer extracted with AcOEt (20 mL×2) was dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by silica gel chromatography (AcOEt/hexane) to give the titled compound (31.6 mg, colorless amorphous.)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:25][C:26]([OH:28])=[O:27])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6]C=CC=1.[CH:29]1(COC2C=C(CC(O)=O)C=C(C3C=CC(C(F)(F)F)=CC=3)C=2)[CH2:31][CH2:30]1.C(O)C1C=CC=CC=1.C1(CO)CC1>>[CH:2]1([CH2:1][O:8][C:9]2[CH:10]=[C:11]([CH:25]([CH2:30][CH2:29][CH3:31])[C:26]([OH:28])=[O:27])[CH:12]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=3)[CH:14]=2)[CH2:6][CH2:7]1
Reactant: O=C(O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O=C(O)Cc1cc(OCC2CC2)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: OCC1CC1
Solvent: OCc1ccccc1
Product: CCCC(C(=O)O)c1cc(OCC2CC2)cc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
Procedure as for example 10 replacing (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid with 5-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-3-yl-acetic acid, itself made according to the procedure of example 9 replacing benzyl alcohol with cyclopropylmethyl alcohol afforded 2-(5-cyclopropylmethoxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid, LC method B, retention time 12.8 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]([C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=O>C(O)(=O)C.C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:10]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:9][C:3]=2[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1cc(Br)ccc1N
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(Br)ccc2[nH]1
Yield: 85 %

Procedure:
A solution of the compound of Example 49A in glatial acetic acid (75 mL) was warmed at 60° C. for 3 h. The mixture was cooled and diluted with toluene and concentrated in vacuo. The remainder of the acetic acid was removed by azeotroping with toluene (2×) and the residue was chromatographed over a 360 g silica gel cartridge, eluting with 25-75% ethyl acetate in dichloromethane. These procedures afforded the product (10.0 g, 85%) as a light beige rigid foam.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH:7]2[CH:3]1[CH2:4][O:5][C:6]2=[O:8].OC[C@H]1[C@H](C(O)=O)C1(C)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:9])[C@H:7]2[C@@H:3]1[CH2:4][O:5][C:6]2=[O:8]
Reactant: CC1(C)C2COC(=O)C21
Agent: CC1(C)[C@@H](CO)[C@@H]1C(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)[C@@H]2C(=O)OC[C@@H]21

Procedure:
1.46 g of a solution containing 1.20 g of 6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one (9.49 mmol, yield based on ethyl cis-3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate: 99.4%, (1R, 5S)-body had an optical purity of 92.8% ee) was obtained in the same manner as in Example 7 excepting that pH was 1 in extracting 6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one with toluene in Example 2. In this toluene solution, 0.062 g (0.43 mmol) of trans-3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid was present.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([N+:12]([O-])=O)[CH:4]=1>[Pd].CO>[NH2:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COc1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C(=O)O)c(N)c1
Reaction time: 18 h
Yield: 91.2 %

Procedure:
4-Methoxy-2-nitrobenzoic acid (3 g, 16.4 mmol) was hydrogenated over palladium on carbon (10%, 300 mg) in methanol (80 mL) at room temperature and normal pressure for 18 hours. The reaction mixture was filtered through celite and concentrated to dryness under reduce pressure to give 2.50 g (100%) of the product as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[CH:37]1([NH2:42])[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:37]1([NH:42][C:23](=[O:24])[CH:22]([N:8]2[CH2:9][CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=3[CH:7]2[CH2:6][C:5]2[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: NC1CCCC1
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NC2CCCC2)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with cyclopentylamine.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.[Cl:15][C:16]1[CH:17]=[C:18]2[C:27](=[C:28]([Cl:30])[CH:29]=1)[C:21]1([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[NH:20][C:19]2=[O:31]>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:27](=[C:28]([Cl:30])[CH:29]=1)[C:21]1([CH2:26][CH2:25][N:24]([C:10](=[O:12])[CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:14])[F:13])[CH2:23][CH2:22]1)[NH:20][C:19]2=[O:31]
Reactant: O=C(O)Cc1ccccc1C(F)(F)F
Reactant: O=C1NC2(CCNCC2)c2c(Cl)cc(Cl)cc21
Product: O=C1NC2(CCN(C(=O)Cc3ccccc3C(F)(F)F)CC2)c2c(Cl)cc(Cl)cc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 31 using 2-(2-(trifluoromethyl)phenyl)acetic acid and 5,7-dichlorospiro[isoindoline-1,4′-piperidin]-3-one. LC-MS Method 3 tR=1.246, min, m/z=457; 1H NMR (CDCl3) 1.43 (d, 2H), 2.62 (m, 1H), 2.78 (m, 1H), 2.90 (t, 1H), 3.40 (t, 1H), 3.88-4.11 (m, 3H), 4.93 (d, 1H), 7.43 (m, 2H), 7.54 (m, 2H), 7.70 (d, 1H), 7.77 (s, 1H), 8.74 (s, 1H)
Reaction SMILES: [Si]([O:8][C@@H:9]([CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=1)/[CH:10]=[CH:11]/[C@H:12]1[C@H:16]([O:17][Si](C(C)(C)C)(C)C)[CH2:15][C@H:14]([OH:25])[C@@H:13]1[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])(C(C)(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>C(O)(C)C>[OH:17][C@@H:16]1[CH2:15][C@H:14]([OH:25])[C@H:13]([CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[C@H:12]1/[CH:11]=[CH:10]/[C@@H:9]([OH:8])[CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:47])([F:48])[F:49])[CH:41]=1
Reactant: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@H](COc2cccc(C(F)(F)F)c2)O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)COc2cccc(C(F)(F)F)c2)[C@H](O)C[C@@H]1O
Yield: 99 %

Procedure:
A mixture of crude compound (11a) (10 g), 2N HCl (37 mL) and isopropanol (IPA) (100 mL) was stirred. The reaction solution was neutralized with saturated aqueous NaHCO3 and extracted twice with EtOAc (80 mL each), once with saturated aqueous NaCl (80 mL) and then the organic layer was concentrated under reduced pressure. The product was purified twice by column chromatography using mixtures of EtOAc and n-heptane to afford Travoprost (HPLC>99.0%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[H][H]>O1CCCC1.CO.[Pd]>[NH2:8][C:7]1[C:2]([CH3:1])=[C:3]([OH:11])[CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(N)cccc1O

Procedure:
2-Methyl-3-nitrophenol (70 g) in 100 ml of tetrahydrofuran and 400 ml of methanol at room temperature was hydrogenated under 5 psi of hydrogen gas using 3.5 g of 5% palladium on carbon as catalyst. After removal of catalyst by filtration, the filtrate was concentrated to give 56 g of analytically pure 3-amino-2-methylphenol. This aminophenol was then converted to the title compound (7.9 g) using the general method of Example 2, except that the hydrochloride salt was formed by adding hydrogen chloride/dioxane to a methanol solution of the free base. The nmr spectrum and elemental analysis were in agreement with those of title compound prepared by Example 3 (Method A).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.Br[C:36]1[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([CH3:43])[CH:37]=1>>[CH3:42][C:40]1[CH:41]=[C:36]([C:17]2[CH:16]=[CH:15][C:14]([C@@H:12]([N:8]3[CH2:7][CH2:6][C@:5]([CH2:4][CH2:3][CH2:2][OH:1])([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:10][C:9]3=[O:11])[CH3:13])=[CH:19][CH:18]=2)[CH:37]=[C:38]([CH3:43])[N:39]=1
Reactant: Cc1cc(Br)cc(C)n1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccccc4)OC3=O)cc2)cc(C)n1

Procedure:
The title compound was prepared from (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-2,6-dimethylpyridine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.228, m/z=445; 1H NMR (CDCl3) 1.32 (m, 1H) 1.51 (d, 3H), 1.60-1.72 (m, 1H), 1.86-2.02 (m, 2H), 2.19 (m, 1H), 2.25-2.39 (m, 2H), 2.79 (s, 6H), 2.93 (m, 1H), 3.50 (t, 2H), 5.64 (m, 1H), 7.00 (d, 2H), 7.21 (m, 2H), 7.29 (m, 2H), 7.32 (m, 3H), 7.40 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[N:15]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][C:24]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:28][CH2:27][NH:26][CH2:25]2)[CH2:17][CH2:16]1)[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:44][O:45][C:46]1[CH:54]=[CH:53][C:52]([CH2:55][N:56]2[CH:60]=[CH:59][N:58]=[N:57]2)=[CH:51][C:47]=1[C:48](Cl)=[O:49].CO.ClCCl>O1CCCC1.C(OCC)(=O)C>[CH3:44][O:45][C:46]1[CH:54]=[CH:53][C:52]([CH2:55][N:56]2[CH:60]=[CH:59][N:58]=[N:57]2)=[CH:51][C:47]=1[C:48]([N:26]1[CH2:27][CH2:28][C:24]([CH2:23][CH2:22][N:18]2[CH2:19][CH2:20][CH2:21][N:15]([C:7]3[N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=3)[CH2:16][CH2:17]2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25]1)=[O:49]
Reactant: COc1ccc(Cn2ccnn2)cc1C(=O)Cl
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(Cn5ccnn5)ccc4OC)C3)CC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Combine 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (0.48 g, 1.04 mmol), N,N-diisopropylethylamine (0.35 mL), and 2-methoxy-5-(1H-triazol-1-ylmethyl)benzoyl chloride (0.22 g, 0.94 mmol) in tetrahydrofuran (50 mL). After 18 hours, dilute the reaction mixture with ethyl acetate and extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with methanol/dichloromethane/concentrated aqueous ammonia 10/90/0.5 give the title compound: Rf=0.68 (silica gel, methanol/dichloromethane/concentrated aqueous ammonia 10/90/0.1).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[N:16]=[C:15]([NH2:17])[CH:14]=[CH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:20]I.CO>CN(C=O)C>[O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[N:16]=[C:15]([NH:17][CH3:20])[CH:14]=[CH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CI
Reactant: Nc1cccc(C2=CCC3(CC2)OCCO3)n1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CNc1cccc(C2=CCC3(CC2)OCCO3)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
6-(1,4-Dioxa-spiro[4.5]dec-7-en-8-yl)-pyridin-2-ylamine (as prepared in Example 22, Step A, 2.5 g, 10.8 mmol) in DMF (10 mL) was treated with NaH (Aldrich, 95%, 550 mg, 21.6 mmol) at 0° C. The reaction was stirred for 20 min. and MeI (Aldrich, 810 μL, 12 mmol) was slowly added. The reaction was warmed to room temperature over 2 hours. MeOH (˜1 mL) was added to quench the extra NaH. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil, which was then purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as white solid.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[CH:2].C(N(CC)CC)C.[Cl:17][CH:18]([Cl:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH:18]([Cl:22])[C:19]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:1]#[CH:2])=[CH:4][CH:5]=1)=[O:20]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: C#Cc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#Cc1ccc(NC(=O)C(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-Ethynylaniline (2.94 g, 25.1 mmol) was dissolved in anhydrous dichloromethane (20 mL) with triethylamine (4.55 mL, 32.6 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of dichloroacetyl chloride (2.42 mL, 25.1 mmol) in anhydrous dichloromethane (20 mL) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature for 12 h. The reaction mixture was then washed successively with water, 20% hydrochloric acid and saturated sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a brown solid.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([O:11][CH:8]2[CH2:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:9]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)C1CCC(O)CC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCC(C(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Into a one liter, four-necked, round bottom flask equipped with stirrer, condenser, and thermometer, 200.0 parts of pyridine and 31.75 parts of 4-t-butylcyclohexanol were mixed under a nitrogen blanket and chilled to 0° C. with an ice water bath. To this solution 47.75 parts of p-toluenesulfonyl chloride were added in portions over thirty minutes. The solution was stirred for one hour at 0° C. and then allowed to stand for twenty-four hours at 15° C. The mixture was poured into one liter of ice water and subsequently extracted with 700 parts of methylene chloride. The organic layer was washed successively with cold 6 N sulfuric acid (until the water layer was acidic to pH paper), dilute sodium bicarbonate (three times with 500 part-portions), and water (twice with 500 part-portions). It was then dried over sodium sulfate, filtered, and the solvent removed in vacuo to yield the 4-t-butylcyclohexyl para-toluenesulfonate as a pale yellow liquid which solidified on standing.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[Cl:12][CH2:13][C:14]([NH:16][C:17]1[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])[N:20]=[CH:19][CH:18]=1)=[O:15]>C(O)(=O)C>[Cl:12][CH2:13][C:14]([NH:16][C:17]1[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:31])([F:32])[F:30])=[CH:24][C:23]=2[Cl:33])[N:20]=[CH:19][C:18]=1[N+:8]([O-:11])=[O:9])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=C(CCl)Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(CCl)Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 6 h
Yield: 89 %

Procedure:
1.03 ml (0.011 mol) of acetic anhydride and 0.56 ml (0.013 mol) of 98 percent strength nitric acid are added successively to 4.2 g (0.011 mol) of 5-chloroacetamido-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-pyrazole in 20 ml of glacial acetic acid at 15° C. After stirring for 6 hours, the mixture is concentrated in vacuo, the residue is taken up in 100 ml of dichloromethane and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and freed of solvent in vacuo. 4.1 g (89% of theory) of 5-chloroacetamido-4-nitro-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole of melting point 130° C.-133° C. are obtained.
Reaction SMILES: Cl.Cl.[N:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[NH:5][CH:4]=1.C([O-])(O)=O.[Na+].[CH2:17]([O:24][C:25](ON1C(=O)CCC1=O)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOC(C)=O.CO>[N:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:25]([O:24][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:26])[CH2:7][C:6]=2[NH:5][CH:4]=1
Reactant: c1nc2c([nH]1)CNCC2
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCc2nc[nH]c2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
A mixture of 2.0 g of 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine dihydrochloride, 2.36 g of NaHCO3 and 2.45 g of N-(benzyloxycarbonyloxy)succinimide in 80 ml of dioxane/water mixture (50/50; v/v) is stirred for 16 hours at RT. The reaction mixture is extracted with EtOAc, the organic phase is washed with a saturated solution of NaHCO3, with a 0.1 M solution of HCl, with saturated NaCl solution, it is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is purified by silica gel chromatography, eluting with DCM/MeOH mixture. 1.9 g of the expected compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:22])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[N:13][CH:12]=[C:11]([C:17]([F:20])([F:19])[F:18])[C:10]=2[C:9](=O)[CH2:8]1.[C:23]([NH:26][NH2:27])([NH2:25])=[NH:24].Cl.CS(O)(=O)=O.C1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[S:3][C:4]([Cl:22])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[N:13][CH:12]=[C:11]([C:17]([F:20])([F:19])[F:18])[C:10]=2[C:9](=[N:27][NH:26][C:23]([NH2:25])=[NH:24])[CH2:8]1
Reactant: O=C1CC(c2cc(Cl)sc2Cl)Cc2nncc(C(F)(F)F)c21
Reactant: N=C(N)NN
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: c1ccccc1
Solvent: CCO
Product: N=C(N)NN=C1CC(c2cc(Cl)sc2Cl)Cc2nncc(C(F)(F)F)c21
Yield: 31.3 %

Procedure:
To a solution of 7-(2,5-dichlorothiophen-3-yl)-4-trifluoromethyl-5,6,7,8-tetrahydrocinnolin-5-one (0.443 g) and aminoguanidine hydrochloride (167 mg) in ethanol (10 ml) were added methanesulfonic acid (0.2 ml) and benzene (10 ml), and the mixture was refluxed for 1.5 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added sodium hydrogen carbonate solution to make the solution alkaline. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and concentrated under reduced pressure. The residue was washed with isopropylether and diethylether and dried to give 7-(2,5-dichlorothiophen-3-yl)-5-guanidinoimino-4-trifluoromethyl-5,6,7,8-tetrahydrocinnoline (Compound 135) (0.160 g) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8]C1C=CC=CC=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].II.C([C:23]1[CH:30]=[CH:29][C:26](C=O)=[CH:25][CH:24]=1)C(C)C>O1CCCC1>[C:23]1([CH:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[OH:8])[CH:30]=[CH:29][CH:26]=[CH:25][CH:24]=1
Reactant: Brc1ccccc1OCc1ccccc1
Reactant: CC(C)Cc1ccc(C=O)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 164.2 %

Procedure:
A Grignard reagent was prepared from 2-benzyloxybromobenzene (0.20 g), magnesium (0.026 g), a catalytic amount of iodine and tetrahydrofuran (1 mL). The obtained Grignard reagent was added to a solution of 4-isobutylbenzaldehyde (0.16 g) in tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was purified by column chromatography on aminopropyl silica gel (eluent: tetrahydrofuran) to give a diphenylmethanol compound (0.23 g). The obtained diphenylmethanol compound was dissolved in ethanol (3 mL) and concentrated hydrochloric acid (0.1 mL). To the solution was added a catalytic amount of 10% palladium-carbon powder, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/hexane=1/1) to give 2-(4-isobutylbenzyl)phenol (0.10 g).