Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])/[C:8]([O:10]CC)=[O:9])[N:6]=1.O.[OH-].[Na+]>CO>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\OCC(=O)N1CCCCC1)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1nc(/C(=N/OCC(=O)N2CCCCC2)C(=O)O)cs1
Reaction time: 48 h
Yield: 78.1 %

Procedure:
77.2 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-[(1-piperidinecarbonyl)methoxy]imino]-acetate are dissolved in 3 l of methanol and 265 ml of water and the solution is treated with 250 ml of 1N aqueous sodium hydroxide solution. The saponification is complete after 48 hours. 500 ml of water are added thereto and the methanol is removed under reduced pressure. The aqueous solution is washed with ethyl acetate, treated with 250 ml of 1N aqueous hydrochloric acid and concentrated to half of the volume. The acid which crystallizes out is filtered off and dried. There are obtained 55.3 g of 2-(2-amino-4-thiazolyl)-2-[(Z)-[(1-piperidinecarbonyl)methoxy]imino]-acetic acid of melting point 177° C.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.C(O[CH:17]1[O:29][C@H:28]([CH3:30])[C@H:23]([O:24]C(=O)C)[C@@H:18]1[O:19]C(=O)C)(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:1][C:2]1[N:3]([C@H:17]2[O:29][C@H:28]([CH3:30])[C@H:23]([OH:24])[C@@H:18]2[OH:19])[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: CC(=O)OC1O[C@H](C)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C[C@H]1O[C@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@@H](O)[C@H]1O
Temperature: 40 °C
Reaction time: 18 h

Procedure:
2,5,6-Trichlorobenzimidazole (221 mg, 1.0 mmol) was suspended in acetonitrile (15 ml) and the mixture was stirred at 40° C. BSA (365 μl, 1.5 mmol) was added, and the reaction mixture stirred for 15 min. A solution of 3 (260 mg, 1.0 mmol) in acetonitrile (5 ml) and TMSOTf (290 μl, 1.5 mmol) was added to the clear solution, and the mixture was allowed to stand at room temperature for 18 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved with dichloromethane (50 ml). The solution was washed with a saturated aqueous solution of sodium bicarbonate (10 ml) and with water (3×10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was taken up with the minimum amount of dichloromethane and chromatographed on a silica gel column (eluent: gradient of methanol (0-1.6%) in dichloromethane). Fractions having a UV-absorbing spot that also charred under H2SO4 and heating were pooled and concentrated to a foam which was dissolved in ethanol 90 (11 ml). To the stirred solution was added sodium carbonate (216 mg, 2.0 mmol) and the reaction mixture was stirred overnight. The mixture was then evaporated under reduced pressure, dissolved in a 2:1 mixture of ethyl acetate and dichloromethane, and washed with water. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. Compound 4 crystallized from a 2% methanolic solution of dichloromethane (120 mg, 56%).
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[C:15]([OH:22])[C:14]=2[CH2:23][CH2:24][CH3:25])[C:6]=1[O:26][CH2:27][CH3:28])C.[OH-].[Na+]>>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:7]2[C:6]([O:26][CH2:27][CH3:28])=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:4]([OH:29])=[O:3])=[C:14]([CH2:23][CH2:24][CH3:25])[C:15]=1[OH:22])(=[O:21])[CH3:20]
Reactant: CCCc1c(OCc2cccc(C(=O)OCC)c2OCC)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Product: CCCc1c(OCc2cccc(C(=O)O)c2OCC)ccc(C(C)=O)c1O

Procedure:
3[(4-Acetyl-3-hydroxy-2-propylphenoxy)methyl]-2-ethoxybenzoic acid ethyl ester was allowed to react with 1.0N sodium hydroxide according to the procedure of Example 70 and the product was purified by recrystallization from methanol to give 3-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]-2- ethoxybenzoic acid, the title compound, m.p. 154°-156° in 85% yield.
Reaction SMILES: CN(C)[C:3](=O)[CH2:4][NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.Cl.ClCC[CH2:50][N:51]([CH3:53])[CH3:52]>>[CH3:50][N:51]([CH3:53])[CH2:52][CH2:3][CH2:4][NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CN(C)CCCCl
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 3-chloro-N,N-dimethylpropan-1-amine hydrochloride as the alkylating reagent in Step 1. The product was isolated as a white solid (3 mg, 0.85%). LCMS: m/e 615.75 (M+H)+, 2.24 min (method 13). 1H NMR (400 MHz, METHANOL-d4) δ 7.95 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 5.34 (s, 1H), 4.89 (s, 1H), 4.75 (s, 1H), 3.58-3.36 (m, 2H), 3.26 (br. s., 8H), 2.78 (d, J=7.5 Hz, 1H), 2.51-2.26 (m, 3H), 2.26-1.97 (m, 7H), 1.92 (m, 1H), 1.78 (m, 6H), 1.63-1.47 (m, 6H), 1.45-1.36 (m, 2H), 1.32-1.18 (m, 5H), 1.14 (s, 3H), 1.08 (s, 3H), 1.00 (s, 3H), 0.98 (s, 3H)
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.Br[CH2:13][C@@H:14]([CH3:17])[CH2:15][OH:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N>[OH:16][CH2:15][C@H:14]([CH3:17])[CH2:13][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11]
Reactant: C[C@@H](CO)CBr
Reactant: O=C1COc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[C@@H](CO)CN1C(=O)COc2ccccc21
Temperature: 40 °C
Reaction time: 48 h
Yield: 147.7 %

Procedure:
A 25 mL flask was charged with 4H-benzo[1,4]oxazin-3-one (0.100 g, 0.670 mmol), (S)-3-bromo-2-methylpropanol (0.103 g, 0.670 mmol) and cesium carbonate (0.208 g, 0.670 mmol) in MeCN (10 mL) and stirred at 40° C. for 2 days. The reaction mixture was quenched with water (5 mL), and the product extracted into EtOAc (2×10 mL). The combined organic layers were dried (Na2SO4) and evaporated to give the crude title compound (108LM40-37) (0.219 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)C(O)=O.BrC1C=NC=[C:16](C=1)[C:17]([NH2:19])=[O:18].NC1C=NC=C(Br)C=1.C(OC(=O)C)(=O)C>>[C:17]([NH:19][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:10]=1)(=[O:18])[CH3:16]
Reactant: NC(=O)c1cncc(Br)c1
Reactant: O=C(O)c1cncc(Br)c1
Agent: Nc1cncc(Br)c1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cncc(Br)c1

Procedure:
Other representative compounds include (E)-N-methyl-4-[3-(5-acetamidopyridinyl)]-3-buten-1-amine and (E)-N-methyl-4-[3-(5-carbamoylpyridinyl)]-3-buten-1-amine. These compounds may be produced according to the techniques set forth in C. V. Greco et al., J. Heterocyclic Chem. 7 (4): 761 (1970). More specifically, the commercially available starting material, 5-bromonicotinic acid is converted to both 5-bromonicotinamide and 3-amino-5-bromopyridine. The 3-amino-5-bromopyridine can be acylated with acetic anhydride to give 3-acetamido-5-bromopyridine. 3-Acetamido-5-bromopyridine may then be reacted with N-methyl-N-(tert-butoxycarbonyl)-3-buten-1-amine (prepared according to the preceeding techniques) using the Heck reaction described hereinabove and set forth in W. C. Frank et al., J. Org. Chem. 43 (15): 2947 (1978). The reaction gives (E)-N-methyl-N-(tert-butoxycarbonyl)-4-[3-(5-acetamidopyridinyl)]-3-buten-1-amine. The Heck reaction of 5-bromonicotinic acid with N-methyl-N-(tert-butoxycarbonyl)-3-buten-1-amine gives (E)-N-methyl-N-(tert-butoxycarbonyl)-4-[3-(5-carbamoylpyridinyl)]-3-buten-1-amine. The treatment of either product with aqueous acid effects the removal of the tert-butoxycarbonyl groups from these compounds, giving the 5-acetamido and 5-carbamoyl substituted metanicotinic compounds respectively.
Reaction SMILES: Cl.[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[NH2:11].[C:12]([N:15]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)[CH3:16])(=[O:14])[CH3:13].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[NH:11][S:23]([C:20]1[CH:19]=[CH:18][C:17]([N:15]([C:12](=[O:14])[CH3:13])[CH3:16])=[CH:22][CH:21]=1)(=[O:25])=[O:24]
Reactant: NC1Cc2ccccc2C1
Reactant: CC(=O)N(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)N(C)c1ccc(S(=O)(=O)NC2Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
2-Indanylamine hydrochloride (9.68 g, 57.1 mmol) was added to a suspension of the 4-(N-acetyl-N-methylamino)benzenesulfonyl chloride (12.84 g, 51.9 mmol) prepared in Preparative Example 12 and sodium acetate (18.73 g) in ethanol (100 ml). The obtained mixture was stirred at room temperature for 3 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give N-(2-indanyl)-4-(N-acetyl-N-methylamino)benzenesulfonamide as a white crystal (16.92 g, 95%). Ethanol (80 ml) and 1N aqueous sodium hydroxide (80 ml) were added to the white crystal. The obtained mixture was heated under reflux overnight, acidified with 1N aqueous hydrochloric acid, adjusted to pH 8 with sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to precipitate a crystal. This crystal was recovered by filtration and washed with ether to give the title compound as a white crystal (6.79 g, 46%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][N:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH3:11][N:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([S:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:35])=[O:34])[CH:19]=1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC[C@@H]1Cc1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reaction time: 1 h
Yield: 46.3 %

Procedure:
Sodium bis(trimethylsilyl)amide (0.25 mL, 1M in THF, 0.25 mmol) was added to a solution of (R)-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (Example 3e, 25.8 mg, 0.12 mmol) in THF (1.5 mL) at -78° C. and the mixture was stirred for 1 h. Phenylsulfonyl chloride (50 μL, 0.39 mmol) was added and the mixture stirred at room temperature for 1 h. prior to quenching with water (6 drops) and silica gel (~1 g). Purification using solid phase extraction tubes (1000 mg silica) eluting with 2M methanolic ammonia in dichloromethane (0-4%) yielded (R)-3-(1-methyl-2-pyrrolidinylmethyl)-1-phenylsulfonylindole (19.7 mg, 46%, HRMS-FAB+ for C20H22N2O2S: calculated MH+ :355.14801; found MH+ :355.14837).
Reaction SMILES: [CH2:1]([C@:3]1([OH:23])[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([O:21][CH3:22])=[CH:13][C:12]=1[CH2:11][CH2:10]3)[CH3:2].N.[Li].[Cl-].[NH4+]>CCOCC.O.C(O)C>[CH2:1]([C@:3]1([OH:23])[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH2:16][CH:15]=[C:14]([O:21][CH3:22])[CH2:13][C:12]=1[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@]1(O)CC[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@@]21C
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CC[C@]1(O)CC[C@H]2[C@@H]3CCC4=C(CC=C(OC)C4)[C@H]3CC[C@@]21C
Yield: 69.6 %

Procedure:
Add dl-17α-ethyl-3-methoxyestra-1,3,5(10)-trien-17-ol (2 g) in ether (55 ml) to distlled liquid ammonia (180 ml), and add lithium (1 g) to the stirred solution. After 45 minutes add ethanol (15 ml) and ether (15 ml) dropwise followed by ammonium chloride and water. Extract with ether, wash, dry, evaporate, and recrystallize the residue from ether to obtain dl-17α-ethyl-3-methoxyestra-2,5(10)-dien-17-ol (1.4 g), m.p. 131°-134°.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.O1CCCCC1[O:35][CH2:36][CH2:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:41]3[CH:40]=[N:39][N:38]([CH2:37][CH2:36][OH:35])[CH:42]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4cnn(CCO)c4)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. LCMS (M+H)+=402.1.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[C:19]3[C:18]([C:20]#[N:21])=[C:17]([CH3:22])[CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH3:23])=[CH:6][CH:5]=1.Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([S:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH3:22])[C:18]=3[C:20]#[N:21])[N:13]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:12]=2[CH3:23])=[CH:8][CH:9]=1
Reactant: Cc1ccc2[nH]c(C)c(Sc3ccc(Cl)cc3)c2c1C#N
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c(C#N)c(C)ccc21
Reaction time: 4 h

Procedure:
To a stirred solution of sodium hydride (96.1 mg of 60% dispersion in mineral oil) in dry tetrahydrofuran (15 ml) was added 3-[(4-chlorophenyl)thio]-2,5-dimethyl-1H-indole-4-carbonitrile (400 mg) in dry tetrahydrofuran (5 ml). After 30 minutes the reaction was treated with methyl bromoacetate (177 μl) and stirring continued for 4 hours. The solvent was removed in vacuo, the residue redissolved in ethyl acetate, washed with water, brine, dried (MgSO4), evaporated in vacuo and the residue purified by flash column chromatography eluting with 1:1 ethyl acetate and iso-hexane mixture. The sub-title compound was obtained as a yellow solid (360 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][N:32]=1)[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=[O:17].CC(C)([O:36][C:37](=[O:68])[CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH2:58][C:59]1[CH:60]=[C:61]([CH:65]=[CH:66][CH:67]=1)[C:62](O)=[O:63])C>>[CH2:9]([N:8]([CH2:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:62]([C:61]2[CH:60]=[C:59]([CH2:58][CH2:57][CH2:56][O:55][CH2:54][CH2:53][O:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][C:37]([OH:68])=[O:36])[CH:67]=[CH:66][CH:65]=2)=[O:63])=[C:3]([C:13]2[CH:14]=[C:15]([C:16](=[O:17])[NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)[CH:30]=[CH:31][N:32]=2)[CH:4]=1)[CH3:10]
Reactant: CCN(CC)c1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCOCCOCCCc1cccc(C(=O)O)c1
Product: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCOCCOCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared from 2-(2-amino-5-(diethylamino)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide 25b using the procedures described in Example 251 using 3-(2,2-dimethyl-4-oxo-3,7,10,13,16,19,22-heptaoxapentacosan-25-yl)benzoic acid 299d as the protected acid component in the coupling. MS (ES, m/z) 897.9 [M+H]+; 1H NMR (400 MHz, d6 DMSO) δ 11.77 (s, 1H), 10.60 (t, J=5.9 Hz, 1H), 8.78 (d, J=5.2 Hz, 1H), 8.50 (s, 1H), 7.81 (d, J=5.1 Hz, 1H), 7.76 (s, 2H), 7.73 (s, 1H), 7.68 (s, 1H), 7.65-7.58 (m, 3H), 7.58-7.53 (m, 2H), 7.49 (t, J=7.9 Hz, 1H), 7.36-7.26 (m, 2H), 6.99 (d, J=3.0 Hz, 1H), 6.79 (dd, J=9.0, 3.0 Hz, 1H), 4.57 (d, J=6.0 Hz, 2H), 3.56-3.30 (m, 43H), 2.68-2.58 (m, 2H), 2.07 (t, J=7.5 Hz, 2H), 1.77 (p, J=6.1 Hz, 2H), 1.09 (t, J=7.0 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:15])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].C(Cl)Cl.CCN(C(C)C)C(C)C.[Cl:28][C:29]1[C:34]([C:35](Cl)=[O:36])=[CH:33][C:32]([Cl:38])=[CH:31][N:30]=1>CN(C1C=CN=CC=1)C.CC(O)C.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:35]([C:34]2[C:29]([Cl:28])=[N:30][CH:31]=[C:32]([Cl:38])[CH:33]=2)=[O:36])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Agent: CN(C)c1ccncc1
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cc(Cl)cnc2Cl)Cc2ccccc2C1
Reaction time: 1368 h
Yield: 107.7 %

Procedure:
A 30 mL reaction vial is charged with 2-aminoindan-2-carboxylic acid ethyl ester (1 g, 4.87 mmol) and dry DCM (5 mL). A stirring bar is added and stirring is initiated. DIPEA (1.35 mL, 7.8 mmol) is added. 2,5-dichloro-pyridine-3-carbonyl chloride (1.23 g, 5.85 mmol) and DMAP (8 mg, cat.) are added. The reaction is capped. After 57 days, tlc analysis (silica, 10% iPrOH/DCM) indicates that the starting has been completely consumed. The contents of the reaction flask are transferred to a separatory funnel and diluted with EtOAc (60 mL). This is washed with water (2×25 mL), saturated aqueous NaHCO3 (2×25 mL), and brine (25 mL), and then dried over MgSO4, filtered and evaporated by pumping to constant weight yields 1.99 g of off-white solid. This is diluted with DCM (20 mL) and applied to a silica column ((80 g) on an ISCO Companion. The column is eluted with 5% EtOAc in heptanes for 3 column volumes followed by a linear gradient to 75% EtOAc in heptanes over 12 column volumes. 17 mL fractions of UV positive eluent are collected. Fraction 12-16 are combined and evaporated by pumping to constant weight to give light yellow solid (1.39 g, 75%).
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([CH2:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C(O)(=O)C>N1C=CC=CC=1.O>[CH2:19]([N:9]1[C:8]2[N:7]=[C:6]3[CH:21]=[C:2]([N:33]4[CH2:32][CH2:31][N:30]([C:27]5[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=5)[CH2:35][CH2:34]4)[C:3]([F:22])=[CH:4][C:5]3=[CH:14][C:13]=2[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]1)[CH3:20]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: O
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(c5ccc(F)cc5)CC4)cc3nc21
Yield: 67.1 %

Procedure:
1-Ethyl-7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-4-oxo-1,4-dihydrobenzo-[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 2, but from 1.75 g of 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 3.6 g of 4-(4-fluorophenyl)piperazine in 18 cm3 of pyridine. The solid obtained was taken up in 10 cm3 of water and 1.9 cm3 of 10% acetic acid were added. The suspension was brought to approximately 100° C. The solidified product was filtered off and washed 2 times with 10 cm3 of water and 2 times with 10 cm3 of warm ethanol. After recrystallizing twice from 25 cm3 of dimethylformamide on each occasion, 1.7 g of 1-ethyl-7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid were obtained in the form of a pinkish-beige solid melting at about 311-312° C.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)[C:10]1[CH:15]=[CH:14]C=[CH:12][CH:11]=1.B(F)(F)F.CCOCC>>[F:1][CH:2]([F:8])[C:3]([O:5][CH2:6][C:7]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1)=[O:4]
Reactant: CCOC(=O)C(F)F
Reactant: OCc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Product: O=C(OCc1ccccc1)C(F)F
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a dried round bottom flask was added ethyl 2,2-difluoroacetate (25 g, 0.20 mol), benzyl alcohol (62.6 mL, 0.60 mol) and boron trifluoride etherate (2.5 mL, 0.02 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 75° C. overnight. The mixture was quenched with saturated aqueous NaHCO3, and then diluted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give benzyl 2,2-difluoroacetate. 1H-NMR: 400 MHz, (CDCl3) δ 7.39-7.29 (m, 4H), 5.93 (t, J=52.8 Hz, 1H), 5.31 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([SH:19])[NH:12][C:13]=2[C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:20][C:21]([F:25])=[C:22]([F:24])[F:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([S:19][C:22]([F:24])([F:23])[CH:21]([F:25])[F:20])[NH:12][C:13]=2[C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: FC(F)=C(F)F
Reactant: Sc1nc(-c2ccc(Cl)c(Cl)c2)c(-c2cccs2)[nH]1
Product: FC(F)C(F)(F)Sc1nc(-c2ccc(Cl)c(Cl)c2)c(-c2cccs2)[nH]1

Procedure:
4-(3,4-Dichlorophenyl)-5-(2-thienyl)-1H-2-imidazolethiol (30.0 g; 92 mmoles) was reacted with 15.0 g of tetrafluoroethylene as described in Example 4 E to give, after chromatography on Silicar CC No. 7 with chloroform, 19.1 g of 4-(3,4-dichlorophenyl)-2-(1,1,2,2-tetrafluoroethylthio)-5-(2-thienyl)-1H-imidazole, m.p. 178°-180° (recrystallized from toluene).