Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:26])[NH:17][C@@H:18]1[CH2:23][CH2:22][C@@H:21]([CH2:24][OH:25])[O:20][CH2:19]1)([CH3:14])([CH3:13])[CH3:12].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[C:11]([O:15][C:16](=[O:26])[NH:17][C@@H:18]1[CH2:23][CH2:22][C@@H:21]([CH:24]=[O:25])[O:20][CH2:19]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](CO)OC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C=O)OC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.1 %

Procedure:
To a solution of oxalyl chloride (3.5 ml) in DCM (25 ml) cooled to −78° C., was added drop wise a solution of DMSO (3.5 ml) in DCM (25 ml). After 15 minutes stirring, a solution of (3R,6S)-(6-hydroxymethyl-tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester (prepared as described in Eur. J. Org. Chem. (2003), 2418-2427; 3 g) in DCM (25 ml) was added drop wise. The reaction was stirred 1 h and a solution of triethylamine (15 ml) in DCM (15 ml) was added dropwise. The reaction proceeded for 1 hour, with warming to 0° C. Saturated sodium bicarbonate (50 ml) was added. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (Hex/EtOAc 1:2) to afford the title aldehyde (2.5 g) as a colorless solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[N:10]=2)[CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O:59]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1B(O)O)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>C(O)C.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:18]1([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:9]3[N:10]=[C:3]4[C:2]([C:61]5[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=5[O:59][C:66]5[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=5)=[N:7][CH:6]=[CH:5][N:4]4[N:8]=3)=[CH:13][CH:14]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: OB(O)c1ccccc1Oc1ccccc1
Reactant: Clc1nccn2nc(Nc3ccc(N4CCOCC4)cc3)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(Oc2ccccc2-c2nccn3nc(Nc4ccc(N5CCOCC5)cc4)nc23)cc1
Temperature: 120 °C

Procedure:
To a solution of (8-chloro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl-(4-morpholin-4-yl-phenyl)-amine (0.15 g, 0.45 mmol, 1 eq) in a mixture of ethanol:toluene (1:4) (10 ml) is taken in a dry pressure tube, palladium acetate (0.01 g, 0.045 mmol, 0.1 eq), anhydrous potassium carbonate (0.125 g, 0.90 mmol, 2 eq), 2-dicyclo-hexylphosphino-2′,6′-dimethoxybiphenyl, S-Phos (0.027 g, 0.06 mmol, 0.13 eq) and 2-phenoxyphenylboronic acid (0.19 g, 0.90 mmol, 2 eq) are added and the reaction mixture is degasified with nitrogen. The reaction mixture is heated to 120° C. for 1 hour. The reaction mixture is concentrated and the residue is taken in 25% methanol in dichloromethane (50 ml) and filtered through celite to remove the inorganics and the filtrate is concentrated and purified by silica column using (230-400) mesh to get the product as pale yellow solid.
Reaction SMILES: [OH:1][C@H:2]([CH2:13]O)[CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:6].BrC[C@@H](O)CNC(C1SC(Cl)=CC=1)=O.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][C:37]2=[O:42])=[CH:32][CH:31]=1>>[OH:1][C@H:2]([CH2:13][NH:29][C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][C:37]2=[O:42])=[CH:34][CH:35]=1)[CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:6]
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C(NC[C@H](O)CO)c1ccc(Cl)s1
Agent: O=C(NC[C@H](O)CBr)c1ccc(Cl)s1
Product: O=C(NC[C@H](O)CNc1ccc(N2CCOCC2=O)cc1)c1ccc(Cl)s1

Procedure:
In this case, 5-chlorothiophene-2-carbonyl chloride (IV) is reacted with (28)-3-aminopropane-1,2-diol hydrochloride (VII) to give 5-chlorothiophene-2-carboxylic acid ((S)-2,3-dihydroxypropyl)-amide (IX). Subsequently, (IX) is converted into 5-chlorothiophene-2-carboxylic acid ((S)-3-bromo-2-hydroxypropyl)amide (X), which is then reacted with 4-(4-aminophenyl)-3-morpholinone (III) to give 5-chlorothiophene-2-carboxylic acid {(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]-propyl}amide (XI). Finally, (XI) is reacted with phosgene or a phosgene equivalent to give 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide (I).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][N+:8]([O-:11])=[C:7]([CH3:12])[C:6]=1[CH3:13].[C:14]1(=[O:20])[NH:18][C:17](=[O:19])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:12][C:7]1[C:6]([CH3:13])=[C:5]([O:4][CH2:3][CH2:2][N:18]2[C:14](=[O:20])[CH2:15][CH2:16][C:17]2=[O:19])[CH:10]=[CH:9][N+:8]=1[O-:11]
Reactant: Cc1c(OCCCl)cc[n+]([O-])c1C
Reactant: O=C1CCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1c(OCCN2C(=O)CCC2=O)cc[n+]([O-])c1C
Yield: 22.7 %

Procedure:
A mixture comprising 0.40 g (2 mmol) of 4-(2-chloroethoxy)-2,3-dimethylpyridine N-oxide, 0.30 g (3 mmol) of succinimide, 0.48 g (3.5 mmol) of potassium carbonate and 30 ml of methyl ethyl ketone was heated under reflux for 2 hours, cooled by allowing to stand and filtered. The filtrate was evaporated to dryness to remove the methyl ethyl ketone. The obtained residue was purified by silica gel column chromatography (solvent: CHCl3 /MeOH=19:1) to obtain 0.12 g of 2,3-dimethyl-4-(2-succinimidoethoxy)pyridine N-oxide as a white crystal.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([Cl:15])[CH:8]=1.[Br:16][C:17]1[CH:18]=[C:19](/[C:23](/[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[C:38]#[N:39])=[N:24]\S(C(C)(C)C)=O)[CH:20]=[CH:21][CH:22]=1.Cl.CO>O1CCCC1>[Br:16][C:17]1[CH:18]=[C:19]([C:23]2([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([Cl:15])[CH:8]=3)[C:31]3[C:32](=[C:33]([F:37])[CH:34]=[CH:35][CH:36]=3)[C:38]([NH2:39])=[N:24]2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)S(=O)/N=C(\c1cccc(Br)c1)c1cccc(F)c1C#N
Reactant: COc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc1Cl
Reaction time: 0.08 h
Yield: 41.9 %

Procedure:
To tetrahydrofuran (20 mL) at −100° C. was added tert-butyllithium (1.7M in pentane, 4.30 mL, 7.31 mmol) dropwise over 5 min. 4-Bromo-2-chloro-1-methoxybenzene (0.81 g, 3.66 mmol) dissolved in tetrahydrofuran (5 mL) was added over 10 min. The mixture was stirred for 5 min then was (E)-N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (1.241 g, 3.05 mmol) in tetrahydrofuran (10 mL) added over 10 min. The reaction mixture was held at −100° C. for 20 min and then slowly allowed to reach r.t. over night. Hydrogen chloride-methanol solution (14.63 mL, 18.29 mmol) was added and the resulting mixture was stirred at r.t. for 1 h. The mixture was concentrated and purified on a silica gel column eluted with 0-10% 0.1M NH3 in MeOH in DCM to give the title compound (570 mg, 42%). MS (ES+) m/z 445, 447 [M+1]+.
Reaction SMILES: [CH2:1]([C:10]1[O:14][C:13]([C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17](O)=O)=[N:12][N:11]=1)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1>C1C=CC=CC=1.C(O)C>[CH2:1]([C:10]1[O:14][C:13]([C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[CH3:17])=[N:12][N:11]=1)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1Cc1nnc(-c2ccccc2C(=O)O)o1
Solvent: CCO
Solvent: c1ccccc1
Product: COc1ccccc1Cc1nnc(-c2ccccc2C)o1

Procedure:
2-[5-(2-Anisyl)-1,3,4-oxadiazole-2-yl] benzoic acid, M.P. 157°-160° (benzene/ethanol) wt., 1.7 g (17.9%). (Found: C, 66.22, 65.42; H, 4.46, 4.46; N, 9.68, 9.97. C16H12N2O4 requires C, 64.86; H, 4.08; N, 9.46.)
Reaction SMILES: [NH:1]([C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[CH:12][N:13]=[C:7]2[CH:6]=1)=O)[NH2:2].[CH3:29][N:30]=[C:31]=[S:32]>CCO>[SH:32][C:31]1[N:30]([CH3:29])[C:3]([C:5]2[CH:10]=[CH:9][N:8]3[C:11]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[O:22])[CH:17]=[CH:18][CH:19]=4)=[CH:12][N:13]=[C:7]3[CH:6]=2)=[N:1][N:2]=1
Reactant: NNC(=O)c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Reactant: CN=C=S
Solvent: CCO
Product: Cn1c(S)nnc1-c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Temperature: 70 °C
Yield: 31.6 %

Procedure:
To a solution of 1-[3-(7-Hydrazinocarbonyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (200 mg, 0.51 mmol) and methyl isothiocyanate (37 mg, 0.57 mmol) were dissolved in EtOH (6 ml) and heated at 70° C. overnight. The reaction mixture was allowed to cool, placed in an ice bath upon which a precipitate was formed. The solid was filtered off, washed with EtOAc and Et2O, then dried to afford the title compound (72 mg). MS: [M+H]+=448.
Reaction SMILES: CO[C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1.S1C=C(CC(O)=O)N=C1.S1C=C(C(=NOC)C(O)=O)N=C1>>[CH2:5]([O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:11][CH:12]=1)[C:4]1[CH:3]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccccc1COc1ccc(CC(=O)O)cc1
Agent: CON=C(C(=O)O)c1cscn1
Agent: O=C(O)Cc1cscn1
Product: O=C(O)Cc1ccc(OCc2ccccc2)cc1

Procedure:
4-(2-methoxybenzyloxy)phenylacetic acid; 4-(4-fluorobenzyloxy)phenylacetic acids; 2-(thiazol-4-yl)acetic acid; 2-(thiazol-4-yl)-2-methoxyiminoacetic acid;
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=1[CH3:14])=[O:5])[CH3:2].CCN(C(C)C)C(C)C.[CH2:24]([CH2:26][NH2:27])[OH:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:25][CH2:24][CH2:26][NH:27][C:11]([C:9]1[NH:10][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:14])[CH:8]=1)=[O:13]
Reactant: NCCO
Reactant: CCOC(=O)c1[nH]c(C(=O)O)cc1C
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: CCOC(=O)c1[nH]c(C(=O)NCCO)cc1C
Yield: 20.8 %

Procedure:
To a solution of 5-[(ethyloxy)carbonyl]-4-methyl-1H-pyrrole-2-carboxylic acid (0.160 g, 0.812 mmol) in DMF (4 ml) was added DIPEA (0.140 mL, 0.790 mmol). The reaction mixture was stirred and the solution was divided into four equal portions, one of which was added to a glass vial with a stir bar. To the vial was added ethanolamine (0.012 mL, 0.2 mmol) and HATU (0.075 g, 0.197 mmol) and the reaction mixture stirred overnight. Purification was accomplished by RPHPLC (water:acetonitrile with 0.1% TFA). The desired fractions were collected and lypholized to afford ethyl 5-{[(2-hydroxyethyl)amino]carbonyl}-3-methyl-1H-pyrrole-2-carboxylate (0.010 g, 48%) as an oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.63 (br. s., 1H) 8.25-8.42 (m, 1H) 6.61 (s, 1H) 4.25 (q, 2H) 3.48 (t, 2H) 3.28 (q, 2H) 2.25 (s, 3H) 1.30 (t, 3H). MS: m/z 241.4 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[NH2:22]>>[CH3:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Cc1cc(N)cc(C(F)(F)F)c1
Product: Cc1cc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-methyl-5-(trifluoromethyl)aniline (51 mg, 0.290 mmol) similar to Example 117 and isolated as a yellow solid (60 mg, 78%). 1H NMR (DMSO-d6): 10.60 (s, 1H), 9.45–9.44 (m, 1H), 8.77–8.75 (m, 1H), 8.60–8.56 (m, 1H), 8.30 (s, 1H), 7.68 (s, 1H), 7.62–7.58 (m, 1H), 7.32 (s, 1H), 7.16 (s, 1H), 2.45 (s, 3H).
Reaction SMILES: [P:1]([O:28]C)([O:26]C)([O:3][C:4]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[N:10]([CH2:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[N:9]=1)=[C:5]([CH3:7])[CH3:6])=[O:2].C[Si](Br)(C)C>C(Cl)Cl.CC#N.O>[P:1]([OH:26])([OH:28])([O:3][C:4]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[N:10]([CH2:19][C:20](=[O:25])[C:21]([CH3:23])([CH3:22])[CH3:24])[N:9]=1)=[C:5]([CH3:7])[CH3:6])=[O:2]
Reactant: COc1ccc2c(C(OP(=O)(OC)OC)=C(C)C)nn(CC(=O)C(C)(C)C)c2c1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: COc1ccc2c(C(OP(=O)(O)O)=C(C)C)nn(CC(=O)C(C)(C)C)c2c1
Reaction time: 2.5 h

Procedure:
Dissolve 120 mg 1-[1-(3,3-dimethyl-2-oxobutyl)-6-methoxy-1H-indazol-3-yl]-2-methylprop-1-en-1-yl dimethyl phosphate from Example 1 in 0.75 mL anhydrous DCM. Cool the solution in an ice bath under nitrogen. Add 108 mg trimethylsilyl bromide and let the reaction mixture sit at room temperature for 2.5 hours. Remove solvent under reduced pressure. The residue was dissolved in a mixture of MeCN and water and purified by RP-HPLC using 10-100% MeCN gradient with about 0.05% TFA to give the title compound as a colorless solid after lyophilization. This reaction can also be carried out in MeCN. The title compound can also be purified by recrystallization in anhydrous MeCN.
Reaction SMILES: [CH:1]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([C:28]([O:30]CC)=[O:29])([CH3:27])[CH3:26])[CH:19]=3)[CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CO>O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([C:28]([OH:30])=[O:29])([CH3:27])[CH3:26])[CH:19]=3)[CH2:13]2)=[O:11])=[CH:33][CH:34]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C2CCCN(C(=O)OCc3ccc(C(C)C)cc3)C2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)c1ccc(COC(=O)N2CCCC(c3cccc(OC(C)(C)C(=O)O)c3)C2)cc1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A mixture of 3-[3-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-isopropyl-benzyl ester (6.23 g, 13.32 mmol), potassium carbonate (3.68 g, 26.64 mmol), methanol (100 mL) and water (20 mL) was heated at reflux for 3 h, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (250 mL), acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to provide 5.86 g (99%) of 3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-isopropyl-benzyl ester as a clear glassy solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[S:31][CH:30]=[CH:29][C:16]=3[N:17](S(C3C=CC(C)=CC=3)(=O)=O)[N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[S:31][CH:30]=[CH:29][C:16]=3[NH:17][N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2nc(N3CCN(Cc4ccccc4)CC3)c3sccc32)cc1
Solvent: CO
Product: c1ccc(CN2CCN(c3n[nH]c4ccsc34)CC2)cc1
Temperature: 25 °C

Procedure:
To a stirred mixture of KOH(S) (56.09 g, 2.66 mol) in methly alcohol (1.33 L) is added 3-(4-benzyl-piperazin-1-yl)-1-(toluene-4-sulfonyl)-1H-thieno[3,2-c]pyrazole (241 g, 0.532 mol). The mixture is heated at reflux for 1.25 hours, cooled to room temperature and evaporated. The residue is taked up in EtOAc (1 L) washed with water (2 L), dried (MgSO4) filtered and evaporated. The residue was recrystallized from EtOAc/Heptane yielding 129 g (81%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:6][C:5]=1[N+:17]([O-])=O.[Cl-].[NH4+].O.Cl>[Fe].CO>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:6][C:5]=1[NH2:17]
Reactant: COC(=O)c1cc(OC)c(OCCCCl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(OC)c(OCCCCl)cc1N

Procedure:
A mixture of 91 g (299.6 mmol) of 4-(3-chloro-propoxy)-5-methoxy-2-nitro-benzoic acid methyl ester and 55.2 g (988.8 mmol) of iron was mechanically stirred at reflux in a mixture containing 60.1 g ammonium chloride, 500 ml water, and 1300 ml methanol for 5.5 hr. The mixture was concentrated and mixed with ethyl acetate. The organic solution was washed with water and saturated sodium bicarbonate. The solution was dried over magnesium sulfate and filtered through a short column of silica gel. The solvent was removed and the residue mixed with 300 ml of ether-hexane 2:1. After standing 73.9 g of the title compound was obtained as a pink solid: mass spectrum (electrospray, m/e): 2M−HCl+H 511.0; M+H 273.8
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].I[CH2:22][CH3:23]>CN(C=O)C>[CH2:22]([O:1][C:2]1[C:9]([O:10][C:11]([F:12])([F:13])[F:14])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:23]
Reactant: O=Cc1cccc(OC(F)(F)F)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1c(C=O)cccc1OC(F)(F)F
Temperature: 37 °C
Yield: 103.7 %

Procedure:
To a solution of 2-hydroxy-3-trifluoromethoxybenzaldehyde (1.00 g, 4.82 mmol) in DMF (10 mL), was added K2CO3 (1.46 g, 10.6 mmol) followed by iodoethane (0.57 mL, 7.24 mmol) and the mixture was heated to 37° C. for 6 h. The reaction was quenched by the addition of H2O (40 mL) and the mixture was extracted with EtOAc (3×100 mL). The combined organics were washed with brine (2×100 mL), dried (Na2SO4) and concentrated to yield the title compound (1.17 g, quant.) as an orange oil: 1H NMR (300 MHz, DMSO-d6) δ 10.31 (s, 1H), 7.77 (m, 2H), 7.38 (t, J=8.1 Hz, 1H), 4.19 (q, J=6.9 Hz, 2H), 1.36 (t, J=6.9 Hz, 3H).
Reaction SMILES: [CH2:1]([O:13][C:14]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:15]=1[F:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([Li])CCC.CCCCCC.[C:35](=[O:37])=[O:36].Cl>C1COCC1>[CH2:1]([O:13][C:14]1[C:15]([F:23])=[C:16]([F:22])[C:17]([C:35]([OH:37])=[O:36])=[C:18]([F:21])[C:19]=1[F:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C=O
Reactant: CCCCCCCCCCCCOc1c(F)c(F)cc(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCCCCOc1c(F)c(F)c(C(=O)O)c(F)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
40.1 g of the compound (12) dissolved in 250 mL of THF were cooled at −78° C. in an argon atmosphere; thereto were then dripped 95 mL of a 1.6 M/L n-butyllithium/hexane solution, with stirring for 2 hours at the same temperature. After addition of a suitable amount of crushed dry ice, the temperature was raised to room temperature, followed by stirring overnight. 200 mL of 3N hydrochloric acid were then added under ice cooling, the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, were washed with saturated brine, and were then dried over anhydrous magnesium sulfate. After evaporating the solvent, the organic layer was recrystallized from hexane to yield 37.5 g (99 mmol) of 4-dodecyloxy-2,3,5,6-tetrafluorobenzoic acid (13).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH2:29][C:30]([O:32]C)=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:18]=[N:19][CH:20]=1.O1CCCC1.[OH-].[Na+]>CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH2:29][C:30]([OH:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:18]=[N:19][CH:20]=1
Reactant: COC(=O)Cc1cccc(OCc2cncc(OCc3nc(-c4ccccc4)oc3C)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1cncc(COc2cccc(CC(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a mixture of methyl 2-[3-[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridylmethoxy]phenyl]acetate (1.35 g), tetrahydrofuran (6 mL) and methanol (6 mL) was added a 1N aqueous sodium hydroxide solution (6 mL) and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was concentrated, and water and dilute hydrochloric acid were added to acidify the residue. The precipitated solid was collected by filtration to give crystals (1.25 g, 95%) of 2-[3-[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridylmethoxy]phenyl]acetic acid. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 143-144° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][NH:8][C:9]2[C:10](=[O:29])[N:11]([CH3:28])[N:12]=[C:13]([O:15][CH2:16][C@H:17]3[CH2:19][C@@H:18]3[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=3)[CH:14]=2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:35][C:36]#[CH:37]>C1COCC1.O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:37][C:36]#[CH:35])[C:9]2[C:10](=[O:29])[N:11]([CH3:28])[N:12]=[C:13]([O:15][CH2:16][C@H:17]3[CH2:19][C@@H:18]3[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=3)[CH:14]=2)=[CH:30][CH:31]=1
Reactant: C#CCBr
Reactant: COc1ccc(CNc2cc(OC[C@H]3C[C@@H]3c3ccc(OC)cn3)nn(C)c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCN(Cc1ccc(OC)cc1)c1cc(OC[C@H]2C[C@@H]2c2ccc(OC)cn2)nn(C)c1=O
Reaction time: 0.17 h

Procedure:
To a solution of 4-(4-methoxybenzylamino)-6-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyridazin-3(2H)-one (210 mg, 0.50 mmol) in THF (20 mL) was added NaH (30 mg, 0.75 mmol) at 0° C. After stirred for 10 min, 3-bromoprop-1-yne (118 mg, 1.00 mmol) was added. The mixture was stirred for 2 h at room temperature and then diluted with H2O (20 mL) and EtOAc (50 mL). The organic phase was washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EA (4/1) to give the title compound as oil. ESI-MS: 461.2 (M+H)+. 1H NMR (400 MHz, MeOD) δ 7.95 (d, 1H), 7.21-7.18 (m, 3H), 7.07 (d, 1H), 6.78 (d, 2H), 6.19 (s, 1H), 4.50 (s, 2H), 4.10-3.94 (m, 4H), 3.75 (s, 3H), 3.74 (s, 3H), 3.72 (s, 3H), 2.61 (s, 1H), 2.00-1.96 (m, 1H), 1.68-1.63 (m, 1H), 1.11-1.00 (m, 1H), 0.95-0.97 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([C:16](=O)[CH2:17][CH3:18])[C:12](=O)[CH2:13][CH3:14].O.[NH2:27][NH2:28]>C(O)C>[Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:16]([CH2:17][CH3:18])=[N:27][NH:28][C:12]=1[CH2:13][CH3:14]
Reactant: CCC(=O)C(CCCCCCOc1ccc(OC)cc1Cl)C(=O)CC
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCc1n[nH]c(CC)c1CCCCCCOc1ccc(OC)cc1Cl

Procedure:
A mixture of 18.5 g (0.05 m) of 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-heptanedione and 5 ml of 100% hydrazine hydrate in 100 ml of absolute ethanol was heated at reflux for five hours. The reaction mixture was concentrated in vacuo, the residue dissolved in 50 ml of ethanol, and the solution made acid with hydrochloric acid. The latter solution was concentrated in vacuo and the residue crystallized twice from an isopropyl alcohol-ether mixture to give 14.5 g of 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-diethyl-1H-pyrazole in the form of its hydrochloride salt, m.p. 117°-118° C. The corresponding hydrobromide salt had the m.p. 118°-120° C.