Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8]>C(OC(=O)C)(=O)C>[C:2]([O:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[O:8][C:14](=[O:15])[CH3:13])(=[O:1])[CH3:7]
Reactant: O=C(C=Cc1cc(O)c(O)c([N+](=O)[O-])c1)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cc(C=CC(=O)c2ccccc2)cc([N+](=O)[O-])c1OC(C)=O

Procedure:
A solution containing 1.0 g of the product obtained in Example 8 in 5.0 ml of acetic anhydride was refluxed for 2 h. After cooling the product was filtered and washed with ether. Yield 0.73 g (68%), m.p. 183°-185° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6](N)[C:5]=1[C:11]([O:13][CH3:14])=[O:12].Cl.N([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].[C:27]([Cu])#[N:28].[C-]#N.[K+]>O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:27]#[N:28])[C:5]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cccc(N)c1C(=O)OC
Reactant: N#C[Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: COC(=O)c1cccc(C#N)c1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a stirred suspension of methyl-3-amino-2-(methoxycarbonyl)benzoate (17.0 g, 81 mmol) in a mixture of concentrated HCl (44 ml) and water (440 ml) at 4° C. was added a solution of NaNO2 (6.73 g, 97 mmol) in water (25 ml) dropwise at 4-5° C. Stirring was continued for 30 min at 4° C. The mixture was then carefully neutralized with sat. sodium carbonate to pH 6. A stirred solution of CuCN (9.46 g, 105 mmol) and KCN (6.38 g, 105 mmol) in water (150 ml) was warned to 6° C. The cold neutralized diazonium solution was then added in small portions at a time with vigorous stirring. The mixture was stirred at 60° C. for 1 hour and then cooled to room temperature. The mixture was extracted with dichloromethane (4×150 ml) and the combined dichloromethane extracts were washed with water (2×100 ml), brine (100 ml) and dried. The solvent was removed in vacuo and the product was purified by chromatography (dichloromethane) to afford 12.36 g (65%) of the product as a light yellow solid: 1 H NMR (CDCl3) δ 8.19 (d, J=7.9 Hz, 1H), 7.8.9 (d, J=7.4 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 4.03 (s, 3H), 3.94 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]([CH3:16])([CH3:15])[C:12](O)=[O:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH2:23][C:24]1[S:25][CH:26]=[N:27][N:28]=1>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]([CH3:16])([CH3:15])[C:12]([NH:23][C:24]3[S:25][CH:26]=[N:27][N:28]=3)=[O:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C(=O)O)C(c1ccccc1)c1ccc2[nH]ncc2c1
Reactant: Nc1nncs1
Product: CC(C)(C(=O)Nc1nncs1)C(c1ccccc1)c1ccc2[nH]ncc2c1

Procedure:
The title compound was prepared from 3-(1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid (Example 29(d)) (44 mg, 0.15 mmol) and 2-amino-1,3,4-thiadiazole using General Coupling Method A to give 29 mg (51% yield) of Example 30. MS found: (M+H)+=378.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][OH:7].[CH3:8][C:9]([CH3:16])([CH3:15])[C:10](=O)[CH2:11][C:12]#[N:13].[OH-].[Na+]>O>[C:9]([C:10]1[CH:11]=[C:12]([NH2:13])[O:7][N:6]=1)([CH3:16])([CH3:15])[CH3:8]
Reactant: NO
Reactant: CC(C)(C)C(=O)CC#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1cc(N)on1
Temperature: 25 °C

Procedure:
Hydroxylamine sulfate (27.575 g, 0.168 mol) is added to a stirred solution of 4,4-dimethyl-3-oxopentanenitrile (20 g; 0.160 mol) and sodium hydroxide (26.24 g; 0.656 mol) in water (160 mL). The mixture is heated at reflux for 2 hours, then allowed to cool to room temperature and extracted with methylene chloride. The combined organics are washed with water, dried (Na2SO4), filtered and concentrated in vacuo to afford title compound as a white solid. ESI m/z 141 [M+H]+
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[O:15][CH2:16][CH2:17][NH:18][C:19]=2[N:20]=1)CCC.[OH-].[Na+].Cl>CO>[O:15]1[CH2:16][CH2:17][NH:18][C:19]2[N:20]=[C:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:21])=[O:5])[CH:12]=[CH:13][C:14]1=2
Reactant: CCCCOC(=O)CCCCc1ccc2c(n1)NCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCc1ccc2c(n1)NCCO2

Procedure:
A solution of 4-6 (0.223 mmol) and 1.0 N NaOH solution (0.268 mL, 0.268 mmol) in MeOH (1.5 mL) was stirred overnight. The reaction was neutralized by adding 1.0 N HCl solution (0.268 mL, 0.268 mmol) then concentrated and used in Step G without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.C(O)(C)C.[CH3:16][S:17]([OH:20])(=[O:19])=[O:18]>O.[Pd]>[CH3:16][S:17]([OH:20])(=[O:19])=[O:18].[F:11][C:8]([F:9])([F:10])[CH:6]1[CH2:5][CH2:4][NH:3][C:2]([NH2:1])=[N:7]1
Reactant: Nc1nccc(C(F)(F)F)n1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: NC1=NC(C(F)(F)F)CCN1
Yield: 96 %

Procedure:
A mixture of 6 g of 10% Pd/C and 60 g (370 mmol) of 2-amino-4-(trifluoromethyl)pyrimidine dissolved in 80 mL of water, 250 mL of isopropanol and 24 mL (370 mmol) of methanesulfonic acid is hydrogenated at 5 bar, at 40° C., for 5 hours in an autoclave. The resulting mixture is then filtered and rinsed with isopropanol and with water. The filtrate is then concentrated under reduced pressure and the residue obtained is dried under vacuum to give 93.5 g of 4-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine methanesulfonate in the form of a white solid. The white solid is dissolved in 250 mL of methyl isobutyl ketone. 100 mL of 10 N sodium hydroxide are then added. The mixture is stirred at room temperature for 15 minutes. The phases are separated by settling and the aqueous phase is re-extracted with methyl isobutyl ketone. The organic phases are combined and then evaporated under vacuum. 59.50 g of 4-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine are thus obtained, the characteristics of which are as follows:
Reaction SMILES: C([O:4][C@H:5]1[C@@H:28]2[O:29][C@@H:27]2[C@@:26]2([CH3:30])[C:7](=[CH:8][CH:9]=[C:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:21][CH2:20][CH2:19][O:18]2)[CH3:16])[CH2:6]1)(=O)C.C(O[C@H]1[C@@H]2O[C@@H]2[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C2OCC(C)(C)CO2)C)C1)(=O)C>>[O:18]1[CH2:19][CH2:20][O:21][CH:17]1[CH:15]([C@@H:14]1[C@:22]2([CH3:31])[C@H:11]([C:10]3[C@H:25]([CH2:24][CH2:23]2)[C@:26]2([CH3:30])[C:7]([CH2:6][C@@H:5]([OH:4])[C@@H:28]4[O:29][C@@H:27]42)=[CH:8][CH:9]=3)[CH2:12][CH2:13]1)[CH3:16]
Reactant: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Agent: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Product: CC(C1OCCO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Yield: 90.3 %

Procedure:
The procedure of Example 23 was repeated except that 4.5 mg (0.0106 mmole) of 20-(1,3-dioxolan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate was used in lieu of 5 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate to give 3.7 mg of 20-(1,3-dioxolan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-ol (yield: 90%).
Reaction SMILES: C(N[C:6]([NH:8][S:9]([C:12]1[C:20]2[N:19]=[N:18][N:17]([CH3:21])[C:16]=2[CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10])=[O:7])CCC.N12CCN(CC1)CC2.C(Cl)(Cl)=O>>[CH3:21][N:17]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([S:9]([N:8]=[C:6]=[O:7])(=[O:11])=[O:10])[C:20]=2[N:19]=[N:18]1
Reactant: CCCCNC(=O)NS(=O)(=O)c1cccc2c1nnn2C
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: Cn1nnc2c(S(=O)(=O)N=C=O)cccc21
Yield: 48.3 %

Procedure:
To a stirred mixture of N-[(butylamino)carbonyl]-1-methyl-1H-benzotriazole-4-sulfonamide (8.25 g), 1,4-diazabicyclo[2,2,2]octane (catalytic amount), and xylenes (175 mL), heated at reflux under a nitrogen atmosphere, was added phosgene (2 mL) in small portions over 1 hour. The resulting suspension was heated an additional 0.5 hours and was cooled prior to filtering off the insoluble material. The filtrate was evaporated to give 3.05 g of the title compound as a pale yellow solid. IR (nujol) 2260 cm-1. The compound was immediately diluted to 100 mL with dry acetonitrile and stored under nitrogen to give a 0.125M solution of the title compound for further use.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=3)[N:24]=[CH:23][CH:22]=2)[C:17](OC)=[O:18])[CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[OH:18][CH2:17][CH:16]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=2)[N:24]=[CH:23][CH:22]=1)[CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:3])([CH3:4])[CH3:1])[CH2:10][CH2:11]1
Reactant: COC(=O)C(CN1CCC(NC(=O)OC(C)(C)C)CC1)c1ccnc2ccc(OC)nc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2nccc(C(CO)CN3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Yield: 37.7 %

Procedure:
To a solution of methyl 3-[4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-piperidinyl]-2-[6-(methyloxy)-1,5-naphthyridin-4-yl]propanoate (1.70 g, 3.83 mmol) in tetrahydrofuran (40 ml) at −78° C. was added lithium aluminium hydride (1M in diethyl ether, 4.59 ml, 4.59 mmol). The reaction was then stirred at −78° C. for 0.5 h before water (10 ml), then 2M NaOH solution (10 ml) and finally water (10 ml) was added and the mixture warmed to ambient temperature and then filtered and evaporated. The residue was subjected to column chromatography on silica gel using a 0-5% methanol in dichloromethane gradient affording the desired compound as a white solid (601 mg, 38%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][C@@H:35]1[CH3:47])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][C@@H:35]3[CH3:47])(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and (S)-tert-butyl 4-((2-bromophenyl)sulfonyl)-3-methylpiperazine-1-carboxylate. MS (ESI): mass calcd. for C26H30FN5O4S, 527.20; m/z found, 528.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=[C:4]([N+:13]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:13][C:4]1[CH:3]=[C:2]([Br:1])[N:7]=[CH:6][C:5]=1[NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11]
Reactant: C[C@@H](CO)Nc1cnc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: C[C@@H](CO)Nc1cnc(Br)cc1N
Temperature: 80 °C
Yield: 62.9 %

Procedure:
Iron powder (0.101 g, 1.811 mmol) was added to a solution of (S)-2-(6-bromo-4-nitropyridin-3-ylamino)propane-1-ol (0.050 g, 0.181 mmol) and ammonium chloride (2.422 mg, 0.045 mmol) in ethanol (2.0 mL) and water (0.7 mL). The reaction mixture was heated at 80° C. for 2 h. The mixture was cooled to room temperature and filtered through celite (washing with methanol). The filtrate was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford (S)-2-(4-amino-6-bromopyridin-3-ylamino)propane-1-ol (0.028 g, 63%) as a purple solid. MS (ESI, pos. ion) m/z 246, 248.
Reaction SMILES: [H-].[Na+].COP([CH:9]([CH3:20])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(OC)=O.[Si]([O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[C:31]([Cl:37])[CH:30]=1)(C(C)(C)C)(C)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.O>[Cl:37][C:31]1[CH:30]=[C:29]([OH:28])[CH:36]=[CH:35][C:32]=1/[CH:33]=[C:9](\[CH3:20])/[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11]
Reactant: COP(=O)(OC)C(C)C(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)c(Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C/C(=C\c1ccc(O)cc1Cl)C(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
To a solution of 55% sodium hydride (128 mg) in tetrahydrofuran (15.0 mL) was added benzyl 2-(dimethoxyphosphoryl)propanoate (796 mg) under ice-cooling, followed by stirring for 30 minutes under ice-cooling. Subsequently, a solution of 4-{[tert-butyl(dimethyl)silyl]oxy}-2-chlorobenzaldehyde (720 mg) in tetrahydrofuran (3.00 mL) was added thereto, followed by stirring at room temperature for 4 hours. To the reaction mixture were added a saturated aqueous ammonium chloride solution, water, and ethyl acetate, and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a solution of the residue in tetrahydrofuran (10.0 mL) was added a 1 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (2.70 mL) under ice-cooling, followed by stirring for 30 minutes under ice-cooling. After completion, to the reaction mixture were added a saturated aqueous ammonium chloride solution, water, and ethyl acetate, and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain benzyl (2E)-3-(2-chloro-4-hydroxyphenyl)-2-methylacrylate (587 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([OH:43])=[N:41][CH:42]=1.[CH2:44]([N:51]1[CH2:56][CH2:55][CH:54]([CH:57](O)[CH3:58])[CH:53]([C:60]2[CH:65]=[CH:64][C:63]([Cl:66])=[CH:62][CH:61]=2)[CH2:52]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C1COCC1>[CH2:44]([N:51]1[CH2:56][CH2:55][CH:54]([CH:57]([O:43][C:40]2[CH:39]=[CH:38][C:37]([Cl:36])=[CH:42][N:41]=2)[CH3:58])[CH:53]([C:60]2[CH:65]=[CH:64][C:63]([Cl:66])=[CH:62][CH:61]=2)[CH2:52]1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CC(O)C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Reactant: Oc1ccc(Cl)cn1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1ccc(Cl)cn1)C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Temperature: 2.5 °C
Reaction time: 0.33 h

Procedure:
In a 50 mL three-necked round bottom flask (flame dried) charged with a magnetic stirrer and under inert atmosphere to 1080 mg polymer bound triphenylphosphine (3 mmol/g) in 10 mL THF was added 502 mg (2.18 mmol) di-tert-butyl azodicarboxylate in 5 mL THF and 265 mg (2.04 mmol) 5-chloro-2-hydroxypyridine in 10 mL THF at 0-5° C. The brownish suspension was stirred for 20 min at 0-5° C. 450 mg (1.36 mmol) (RS)-1-[(3SR,4SR)-1-benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanol in 5 mL THF was added and the ice bath was removed and the reaction was stirred for 63 h at room temperature. The suspension was filtered over a Dicalit-filter. The filtrate was concentrated under vacuum and the residue was purified by chromatography over silica eluting with a gradient formed from i-propanol and heptane to yield after evaporation of the product containing fractions 480 mg (80%) of the title compound as yellow viscous oil. MS (m/e): 441.2 [(M+H)+].
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:31])[CH2:15][CH2:16][C@@:17]34[CH2:23][C@:22]53[CH2:24][CH2:25][C@H:26]([OH:30])[C:27]([CH3:29])([CH3:28])[C@@H:21]5[CH2:20][CH2:19][C@H:18]4[C@:13]2([CH3:32])[CH2:12][CH2:11]1)[CH2:3][CH2:4][C:5]([CH3:9])=[C:6]([CH3:8])[CH3:7].[N+:33]([C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39](Cl)=[O:40])([O-:35])=[O:34]>N1C=CC=CC=1>[CH3:1][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:31])[CH2:15][CH2:16][C@@:17]34[CH2:23][C@:22]53[CH2:24][CH2:25][C@H:26]([OH:30])[C:27]([CH3:29])([CH3:28])[C@@H:21]5[CH2:20][CH2:19][C@H:18]4[C@:13]2([CH3:32])[CH2:12][CH2:11]1)[CH2:3][CH2:4][C:5]([CH3:9])=[C:6]([CH3:7])[CH3:8].[N+:33]([C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39]([O-:30])=[O:40])([O-:35])=[O:34]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: CC(C)=C(C)CC[C@@H](C)[C@H]1CC[C@@]2(C)[C@@H]3CC[C@H]4C(C)(C)[C@@H](O)CC[C@@]45C[C@@]35CC[C@]12C
Solvent: c1ccncc1
Product: O=C([O-])c1cccc([N+](=O)[O-])c1
Temperature: 20 °C

Procedure:
Cyclobranol (18 g, 0.04 mole) dissolved in pyridine (200 ml) was stirred and cooled in a bath of ice water, and to it was added m-nitrobenzoyl chloride (9.85 g, 0.053 mole). Then the mixture was warmed to 20° C. and continued to stir for 12 hours. After the reaction is complete the mixture was evaporated under reduced pressure. Ice cold water (200 ml) was added to the residue and crystals begans to appear. The crude crystals were separated by filtration and recrystallized from acetone-water (1:1, V/V), giving cyclobranol-m-nitrobenzoate (20.1 g), in a 83% yield. m.p. 206°-207° C.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:21][C:22]([F:54])([C:50]([F:53])([F:52])[F:51])[C:23]([F:49])([F:48])[C:24]([F:47])([F:46])[O:25][C:26]([F:45])([F:44])[C:27]([F:43])([F:42])[O:28][C:29]([F:41])([F:40])[CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br>O>[CH2:1]([O:7][C:8]1[CH:13]=[N:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][O:31][CH2:30][C:29]([O:28][C:27]([F:42])([F:43])[C:26]([F:44])([F:45])[O:25][C:24]([F:46])([F:47])[C:23]([F:48])([F:49])[C:22]([F:21])([F:54])[C:50]([F:52])([F:53])[F:51])([F:41])[F:40])=[CH:18][CH:19]=2)=[N:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(COCCCCCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: O
Product: CCCCCCOc1cnc(-c2ccc(OCCCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as described in Example 1 by combining 5-hexyloxy-2-(4-hydroxyphenyl)pyrimidine (3.0 g, 11.0 mmol) and 7-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromoheptane (7.7 g, 12.0 mmol; prepared by combining 1,7-dibromoheptane with 2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethanol). Product was isolated by addition of water (50 mL) to the resulting mixture, followed by filtration and recrystallization from ethanol. The recrystallized precipitate was dried at about 130° C., and the resulting product was further purified by Kugelrohr distillation (b.p. 210-222° C. at 0.03 torr; yield 7.3 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[N:10]=[CH:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7]1)=[S:5])[CH3:2].I[CH3:16]>CO>[CH3:16][S:5][C:4]([N:6]1[N:10]=[CH:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7]1)=[N:3][CH2:1][CH3:2]
Reactant: CCNC(=S)N1CC2(C=N1)CCCC2
Reactant: CI
Solvent: CO
Product: CCN=C(SC)N1CC2(C=N1)CCCC2
Temperature: 45 °C
Yield: 0.3 %

Procedure:
0.55 g (1 mol equiv.) 2,3-Diazaspiro[4.4]non-3-ene-2-carbothioic acid ethylamide was dissolved in 15 mL MeOH, 3.4 mL (21 mol equiv.) iodomethane was added and the magnetically stirred reaction mixture was heated at 45° C. for 2 hours. Volatiles were removed in vacuo. The residue was taken up in dichloromethane (DCM) and extracted with 5% aqueous NaHCO3. The organic layer was washed twice with water, dried over Na2SO4, filtered and evaporated to dryness to give 0.57 g (97%) N-ethyl-2,3-diaza-spiro[4.4]non-3-ene-2-carboximidothioic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 1.16 (t, J=7.3 Hz, 3H), 1.64-1.80 (m, 8H), 2.46 (s, 3H), 3.54 (q, J=7.3 Hz, 2H), 3.57 (s, 2H), 6.72 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Br:18])=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[N:13]=[C:12]2[CH3:29])[CH:5]=1.[OH-].[Na+]>O1CCCC1>[Br:18][C:15]1[C:16](=[O:17])[N:11]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[CH3:10])[C:3]([OH:30])=[O:2])[C:12]([CH3:29])=[N:13][C:14]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-[5-bromo-4-(2,4-difluoro-benzyloxy)-2-methyl-6-oxo-6H-pyrimidin-1-yl]-4-methyl-benzoic acid methyl ester from Step B (50 mg, 1.04 mmol) in tetrahydrofuran (3 mL) was added 1N sodium hydroxide (2 mL) and the solution was stirred at ambient temperature for four hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH=2 using 1M HCl. The solution was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The slurry was filtered and concentrated to a light yellow semi-solid (470 mg, 97%). MS (M, M+2): 465, 467
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH3:36])[CH:31]=[CH:30][C:29]=4[F:37])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:41]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][N:35]5[CH2:2][CH2:3][O:5][CH2:41][CH2:36]5)[CH:31]=[CH:30][C:29]=4[F:37])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNC)ccc4F)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CN5CCOCC5)ccc4F)cc23)CC1
Yield: 64.3 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole-7-carboxamide trifluoroacetate, substituting morpholine (45 μL, 0.524 mmol) for methanamine to afford 15 mg of the title compound (64.3%)
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[N+]([O-])([O-])=O.[NH4+].[Ce].[Ce].[Br:17]Br>C(#N)C>[Br:17][C:7]1[C:3]([C:2]([F:9])([F:8])[F:1])=[N:4][NH:5][CH:6]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: BrBr
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Product: FC(F)(F)c1n[nH]cc1Br
Yield: 169.9 %

Procedure:
An acetonitrile solution (20 ml) of 3-trifluoromethyl-1H-pyrazole (1.0 g), dicerium ammonium nitrate (2.0 g) and bromine (0.7 g) was refluxed for 2 hours. After cooling, the reaction solution was washed with saturated aqueous solution of sodium thiosulfate and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure to obtain 4-bromo-3-trifluoromethyl-1H-pyrazole (1.6 g).