Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([O:13]C)=[O:12])[CH2:7][N:6]1[S:15]([CH3:18])(=[O:17])=[O:16])=[O:4].[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[CH2:7][N:6]1[S:15]([CH3:18])(=[O:17])=[O:16])=[O:4]
Reactant: COC(=O)C1CCC(C(=O)OC)N(S(C)(=O)=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)C1CCC(C(=O)O)CN1S(C)(=O)=O
Reaction time: 0.75 h
Yield: 38 %

Procedure:
To a solution of (2RS,5RS)-1-methanesulfonyl-piperidine-2,5-dicarboxylic acid dimethyl ester (46.5 g) in methanol (850 ml) and water (85 ml) was added 1 molar sodium hydroxide (166 ml) within 20 minutes at reflux temperature. The reaction mixture was stirred for 45 minutes at reflux, cooled and concentrated. The residue was taken up in water (300 ml) and washed with Et2O. The aqueous phase was acidified with 1 molar HCl (166 ml) and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulphate and concentrated. The residue was crystallized from acetone/Et2O to obtain (2RS,5RS)-1-methanesulfonyl-piperidine-2,5-dicarboxylic acid 2-methyl ester (16.8 g) as a colourless solid, mp 130-133° C., MS: 206 (M+-59).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:10]([C:19]([OH:21])=[O:20])=[CH:11][C:12]2[O:16][CH:15]=[N:14][C:13]=2[C:17]=1[F:18].C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C>[Br:29][C:6]1[CH:5]=[CH:4][C:3]([NH:8][C:9]2[C:10]([C:19]([OH:21])=[O:20])=[CH:11][C:12]3[O:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)c1cc2ocnc2c(F)c1Nc1ccccc1Cl
Solvent: CN(C)C=O
Product: O=C(O)c1cc2ocnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
To a solution of 5-((2-chlorophenyl)amino)-4-fluorobenzo[d]oxazole-6-carboxylic acid (12.31 g, 40.14 mmol) in DMF (100 mL) was added NBS (7.86 g, 44.15 mmol). After stirring for 4 h at ambient temperature, the reaction was quenched by water and the precipitate was filtered. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 50:1, v/v) and gave the desired product (pale brown solid, 10.82 g, 69.9% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 9.42 (s, 1H), 8.96 (s, 1H), 8.27 (s, 1H), 7.82 (d, J=12.0 Hz, 1H), 7.37 (m, 1H), 6.65 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[C:12]2[S:11][N:10]=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:13]Br>C(Cl)(Cl)Cl>[Br:13][CH2:2][C:1]([C:4]1[C:12]2[S:11][N:10]=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1cccc2nnsc12
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1cccc2nnsc12
Reaction time: 2 h

Procedure:
0.9 g of 7-acetylbenzo-1,2,3-thiadiazole is dissolved in 20 ml of chloroform, and 0.88 g of bromine is added dropwise at room temperature. Stirring is then continued for 2 hours at the same temperature, during which process a yellow precipitate forms. This precipitate is filtered off, washed with hexane and dried. The title compound which is thus obtained melts at 155°-157° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[N:7]=[C:6]([NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:12]([O:11][CH3:10])[CH:13]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc(N)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: COc1cccc(Nc2ncc(F)c(Nc3cccc(OC)c3)n2)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-methoxyaniline were reacted to yield N2,N4-bis(3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.96 (d, 1H, J=5.4 Hz), 7.24 (m, 6H), 7.06 (t, 1H, J=2.4 Hz), 7.00 (dt, 1H, J=1.2 Hz), 6.79 (m, 1H), 3.72 (s, 3H), 3.70 (s, 3H); 19F NMR (CD3OD): δ −46112; LCMS: ret. time: 23.46 min.; purity: 99%; MS (m/e): 341 (MH+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH2:7][CH2:6]1.[NH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31]>>[ClH:1].[F:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][N:26]3[C:27](=[O:30])[CH2:28][CH2:29][NH:24][C:25]3=[O:31])[CH2:6][CH2:7]2)=[C:12]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH:13]=1
Reactant: O=C1CCNC(=O)N1
Reactant: Fc1ccc(N2CCN(CCCCl)CC2)c(OCC(F)(F)F)c1
Product: Cl
Product: O=C1CCNC(=O)N1CCCN1CCN(c2ccc(F)cc2OCC(F)(F)F)CC1

Procedure:
substituting 1-chloro-3-{4-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propane and 5,6-dihydro-2,4(1H,3H)-pyrimidinedione and recrystallizing from a solution of hydrochloric acid in alcohol gave 3-(3-{4-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-5,6-dihydro-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 186°-189° C.; Anal.: Calcd. for C19H24F4N5O3.(HCl)2 : C, 44.10; H, 5.06; N, 10.83%; Found: C, 43.99; H, 5.16; N, 10.78%; and
Reaction SMILES: [S:1]1[C:12]2[C:4](=[CH:5][CH:6]=[C:7]3[C:11]=2[CH2:10][C:9](=[O:13])[NH:8]3)[N:3]=[CH:2]1.[C:14]([O:17][CH:18](OCC)OCC)(=O)[CH3:15]>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[CH2:14]([O:17][CH:18]=[C:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]3[C:12]=2[S:1][CH:2]=[N:3]3)[NH:8][C:9]1=[O:13])[CH3:15]
Reactant: O=C1Cc2c(ccc3ncsc23)N1
Reactant: CCOC(OCC)OC(C)=O
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: CCOC=C1C(=O)Nc2ccc3ncsc3c21

Procedure:
To a 250-ml round bottom flask was added a stir bar, 6.8-dihydro-1-thia-3,6-diaza-as-indacen-7-one (4.0 g, 0.021 mol), 40 mL of glacial acetic and diethoxymethyl acetate (17.0 g, 0.105 moles). The flask was fitted with a reflux condensor and charged with nitrogen. The reaction was heated to reflux for 8 h. The flask was cooled, the stir bar was removed and the reaction was concentrated to a wet solid. The solid was triturated with a solution of ether and ethanol. The mixture was filtered, the solid was washed with an ethanol-ether solution, and the solid was dried under vacuum to yield 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one: 1H NMR (DMSO-d6): δ 10.5 (s, 1H), 9.1 (s, 1H), 7.8 (d, 1H), 7.7 (s, 1H), 7.0 (d, 1H), 4.5 (q, 2H), 1.4 (t, 3H); APCI-MS m/z 245 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:15]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl.[O:46]1[CH:50]=[CH:49][N:48]=[C:47]1[CH2:51][NH2:52]>CC(O)C>[C:1]([C:5]1[N:10]=[C:9]([NH:52][CH2:51][C:47]2[O:46][CH:50]=[CH:49][N:48]=2)[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:15]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ncco1
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2Cl)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2NCc2ncco2)CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 15 h
Yield: 85.2 %

Procedure:
To a solution of 1-tert-butyl 3-methyl (3R,5S)-5-{[(2-tert-butyl-4-chloropyrimidin-5-yl)carbonyl](isobutyl)amino}piperidine-1,3-dicarboxylate (0.55 g) and diisopropylethylamine (0.87 ml) in 2-propanol (5 ml) was added 2-oxazolylmethylamine hydrochloride (0.34 g), and the mixture was stirred at 80° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography, and the fraction eluted with hexane to ethyl acetate-hexane (1:2) was concentrated under reduced pressure to give the object compound (525 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([O:35]C)[CH:34]=1)[O:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([CH3:31])([CH3:30])[CH2:12][CH2:13][C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([NH2:17])=[O:16])[CH2:7]1.B(Br)(Br)Br>>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([OH:35])[CH:34]=1)[O:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([CH3:30])([CH3:31])[CH2:12][CH2:13][C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15]([NH2:17])=[O:16])[CH2:7]1.[NH3:8]
Reactant: COc1cc(F)cc(O[C@H]2CCN(C(C)(C)CCC(C(N)=O)(c3ccccc3)c3ccccc3)C2)c1
Agent: BrB(Br)Br
Product: CC(C)(CCC(C(N)=O)(c1ccccc1)c1ccccc1)N1CC[C@H](Oc2cc(O)cc(F)c2)C1
Product: N
Reaction time: 2 h

Procedure:
The title compound was prepared from the product of example 45, using the same method as that described for example 34, with the addition of further boron tribromide (1M in dichloromethane, 4 eq) after 3 hours, and subsequent stirring for 2 hrs. Crude material was purified by column chromatography on silica gel, eluting with ethyl acetate:methanol:0.88 ammonia, 98:2:0.2 to 94:6:0.6 to afford a white foam in 35% yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]([OH:22])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:5]=[CH:4][C:3]=1[C:23]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH:37]([OH:49])[CH2:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[CH:31][C:30]=2[OH:50])[N:26]=[C:25]([C:51]2[CH:56]=[CH:55][C:54]([S:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:53][CH:52]=2)[N:24]=1.ClC1C=C(C=CC=1)C(OO)=[O:69].CCCCCCC.C(OCC)(=O)C>C(Cl)(Cl)Cl>[C:58]1([S:57]([C:54]2[CH:53]=[CH:52][C:51]([C:25]3[N:26]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH:37]([OH:49])[CH2:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[CH:31][C:30]=4[OH:50])[N:28]=[C:23]([C:3]4[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH:10]([OH:22])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:7][C:2]=4[OH:1])[N:24]=3)=[CH:56][CH:55]=2)=[O:69])[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: CCCCCCCCCOCC(O)COc1ccc(-c2nc(-c3ccc(Sc4ccccc4)cc3)nc(-c3ccc(OCC(O)COCCCCCCCCC)cc3O)n2)c(O)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCOCC(O)COc1ccc(-c2nc(-c3ccc(S(=O)c4ccccc4)cc3)nc(-c3ccc(OCC(O)COCCCCCCCCC)cc3O)n2)c(O)c1

Procedure:
Following the general procedure of Example 7, 1.55 g (1.76 mmol) of 2,4-bis-[2-hydroxy-4-(2-hydroxy-3-nonyloxypropoxy)phenyl]-6-[4-(phenylthio)phenyl]-s-triazine are dissolved in 30 mL of chloroform. To the stirred solution at room temperature are added 0.606 g (1.76 mmol) of m-chloroperoxybenzoic acid (50-60%) all at once. After several minutes, the chloroform is removed under reduced pressure and the residue is redissolved in ethyl acetate. The solution is then washed five times with saturated sodium bicarbonate solution, once with water and once with brine and finally dried over anhydrous magnesium sulfate. The solvent is removed to give a yellow oil which is subjected to medium pressure liquid chromatography with 1:3 heptane:ethyl acetate. The title compound is isolated as a yellow glassy solid in a yield of 0.43 g (27%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[CH2:14][N:15]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[C:16]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[O:17])[CH2:9]1)=O)(C)(C)C.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[CH:10]12[CH:11]([CH2:14][N:15]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[C:25]([F:35])[CH:24]=3)[C:16]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[O:17])[CH:12]1[CH2:13][NH:8][CH2:9]2
Reactant: CC(C)(C)OC(=O)N1CC2C(C1)C2CN(C(=O)c1cccs1)c1ccc(N2CCOCC2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cccs1)N(CC1C2CNCC21)c1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 6-{[(3-Fluoro-4-morpholin-4-yl-phenyl)-(thiophene-2-carbonyl)-amino]methyl}-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester prepared above (640 mg, 1.28 mmol) in 6 mL of CH2Cl2 at room temperature was added 6 mL of TFA. The reaction stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, taken up in toluene and concentrated again to yield 854 mg of the desired product. 400 MHz 1H NMR (CDCl3) δ 9.06 (brs, 1H), 8.62 (brs, 1H), 7.33-7.35 (m, 1H), 7.21-7.25 (m, 1H), 6.94-7.11 (m, 2H), 6.88-6.92 (m, 1H), 6.81-6.84 (m, 1H), 3.89-3.91 (m, 4H), 3.72 (d, J=7.05 Hz, 2H), 3.39-3.46 (m, 4H), 3.16-3.18 (m, 4H), 1.77 (brs, 2H), 1.35-1.37 (m, 1H); MS (M+1) 402.1
Reaction SMILES: [Br:1][C:2]1[C:3]([F:23])=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17](N(OC)C)=[O:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][Mg+].[Br-]>C1COCC1>[C:17]([C:10]1[C:11](=[O:16])[C:12]([O:14][CH3:15])=[CH:13][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[C:3]=2[F:23])[N:9]=1)(=[O:18])[CH3:24]
Reactant: C[Mg+]
Reactant: COc1cn(-c2cccc(Br)c2F)nc(C(=O)N(C)OC)c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2cccc(Br)c2F)nc(C(C)=O)c1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To a solution of 1-(3-bromo-2-fluorophenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (4.22 g, 10.9 mmol) in THF (218 mL) was added MeMgBr (1.0 M in THF, 16.4 mL, 16.4 mmol) at −78° C. under N2. The mixture was stirred at −78° C. for 2 h. The reaction was quenched with saturated NH4Cl aqueous solution at −78° C. The mixture was diluted with NaHCO3 aqueous solution, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (EtOAc/MeOH=100/0 to 50/50) to yield the title compound (3.48 g, 93% yield) as a yellow solid: 1H-NMR (DMSO-d6, 300 MHz): δ ppm 2.50 (3H, s), 3.80 (3H, s), 7.36-7.46 (1H, m), 7.77-7.85 (1H, m), 7.89-7.99 (1H, m), 8.57 (1H, d, J=1.9 Hz).
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C([O-])(=O)C.[Na+].[F:9][C:10]([F:23])([F:22])[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1)=O>O.C(O)C>[F:9][C:10]([F:23])([F:22])[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1)=[N:3][OH:2]
Reactant: CSc1ccc(C(=O)CC(F)(F)F)cc1
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CSc1ccc(C(CC(F)(F)F)=NO)cc1
Yield: 59.4 %

Procedure:
Hydroxylammonium chloride (1.07 g, 15.4 mmol) and sodium acetate (1.85 g, 22.5 mmol) are dissolved in 10 ml of water. To this solution are added 2.35 g (10.0 mmol) of 3,3,3-trifluoro-1-(4-methylsulfanyl-phenyl)-propan-1-one in 30 ml of ethanol. The reaction mixture is heated to reflux for 6.5 hr. The reaction mixture was concentrated by rotary evaporation and poured into water. The product is extracted with CH2Cl2, and the organic layer is washed with water, followed by drying over anhydrous MgSO4. After evaporation of the solvent, the product is purified by column chromatography on silica gel with CH2Cl2-Hexane (2:1) as eluent. 1.48 g of white solid melting at 106-107° C. are obtained (59%). 1H NMR (CDCl3), δ[ppm]: d 2.51 (s, 3H), 3.73 (q, 2H), 7.26 (d, 2H), 7.57 (d, 2H), 8.23 (s, 1H).
Reaction SMILES: [CH:1]1([N:4]2[C:8]([N:9]3[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:11][CH2:10]3)=[C:7]([N+:23]([O-])=O)[CH:6]=[N:5]2)[CH2:3][CH2:2]1.[C:26]([O:30][C:31]([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[F:46][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]([F:45])[C:39]=1[C:37]1[S:38][C:34]([NH:33][C:31](=[O:32])[O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[C:35]([C:47](=[O:48])[NH:23][C:7]2[CH:6]=[N:5][N:4]([CH:1]3[CH2:3][CH2:2]3)[C:8]=2[N:9]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:11][CH2:10]2)[N:36]=1
Reactant: O=C(N[C@@H]1CCCN(c2c([N+](=O)[O-])cnn2C2CC2)CC1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Product: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnn(C2CC2)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Yield: 73 %

Procedure:
Following the procedure for Example 517 starting with (R)-N-(1-(1-cyclopropyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid gave (R)-tert-butyl 2-(2,6-difluorophenyl)-4-(1-cyclopropyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a cream solid (142 mg, 73%). 1H-NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.76 (s, 1H), 7.87 (s, 1H), 7.41-7.34 (m, 1H), 7.10-7.00 (m, 2H), 6.39 (d, J=8 Hz, 1H), 4.25-4.15 (m, 1H), 3.45-3.36 (m, 3H), 3.35-3.15 (m, 2H), 2.25-2.12 (m, 1H), 2.10-1.70 (m, 5H), 1.55 (s, 9H), 1.35-1.15 (m, 2H), 1.10-1.00 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[Cl-].[CH2:9]([O:11][C:12]1([NH3+:15])[CH2:14][CH2:13]1)[CH3:10].[C:16](Cl)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O1CCCC1>[CH2:9]([O:11][C:12]1([NH:15][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13]1)[CH3:10]
Reactant: CCOC1([NH3+])CC1
Reactant: CCCCCC(=O)Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCC(=O)NC1(OCC)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (2.22 g, 22 mmol) is added dropwise (15 min) with vigorous stirring at 0° to a solution of 1-ethoxycyclopropylammonium chloride (1.37 g, 10 mmol) and caproyl chloride (1.34 g, 10 mmol) in dry tetrahydrofuran (30 ml) and the mixture is stirred at room temperature for 1 hr. The precipitate is filtered off and the filtrate is evaporated in vacuo. The crystalline residue (1.85 g) is dissolved in petroleum ether (20 ml) and the solution is filtered through a short silica-gel column (2 cm × 10 cm). After evaporation the residue (1.30 g) is recrystallised from petroleum ether (at low temperature) yielding pure N-(1-ethoxycyclopropyl)-caproic amide, mp 47°-48.5° (1.0 g, 50%); NMR (60 MHz): δCDCl 3 = 0.7-1.9 (m, 16H), 2.0-2.4 and 2.4-2.8 (2 m, total 2H), 3,57 and 3.63 (2q, J=7.2 Hz, total 2H), 6.7 (br. s, 1H), (two rotamers).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][C:8]([F:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]>C1COCC1.C(O)C.[Ni]>[NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([F:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1cc(F)cc([N+](=O)[O-])c1N
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: NC(=O)c1cc(F)cc(N)c1N
Reaction time: 5 h

Procedure:
To a solution of EXAMPLE 45C (11.2 g) in a mixture of THF (50 mL) and ethanol (50 mL) was added Raney nickel (50% in water, 11.0 g). The mixture was stirred under hydrogen (60 psi) for 5 hours. Solid material was filtered off and the filtrate was concentrated.
Reaction SMILES: CCN(C(C)C)C(C)C.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]([NH:28][S:29]([C:32]2[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=2)(=[O:31])=[O:30])=[O:27])[CH2:22][CH2:21]1.Cl>CS(C)=O>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:20]1[CH2:25][CH2:24][CH:23]([C:26]([NH:28][S:29]([C:32]2[CH:33]=[C:34]([C:42]([F:43])([F:44])[F:45])[CH:35]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:37]=2)(=[O:30])=[O:31])=[O:27])[CH2:22][CH2:21]1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: O=C(NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCNCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCN(c2ccccc2[N+](=O)[O-])CC1
Reaction time: 18 h

Procedure:
0.13 g of DIEA and 0.07 g of 1-fluoro-2-nitrobenzene are added to a solution of 0.22 g N-(piperidine-4-carbonyl)-3,5-bis-trifluoromethyl-benzenesulfonamide in the form of a hydrochloride in 4 ml of DMSO. The mixture obtained is stirred for ca. 18 h at 80°, solvent is evaporated and the evaporation residue is subjected to flash chromatography on silica gel (eluent: EtAc). N-[1-(2-Nitro-phenyl)-piperidine-4-carbonyl]-3,5-bis-trifluoromethyl-benzenesulfonamide is obtained.
Reaction SMILES: [CH:1]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[C:6]1[CH:5]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:3][C:2]2=1.[H-].[Na+].Br[CH2:19][C:20]#[N:21].O>CN(C=O)C>[C:20]([CH2:19][N:3]1[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][C:6]2[CH:7]3[CH2:10][CH:1]([CH2:9][CH2:8]3)[C:2]1=2)#[N:21]
Reactant: N#CCBr
Reactant: CCOC(=O)c1cc2c([nH]1)C1CCC2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2c(n1CC#N)C1CCC2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
To a solution of 334c (3.0 g, 14.6 mmol) in anhydrous DMF (30 mL) was added NaH (880 mg, 22 mmol). The mixture was stirred at room temperature for 30 minutes. 2-Bromoacetonitrile (3.5 g, 29.3 mmol) was added and the resulting mixture was heated at 65° C. for 1 hour. It was then cooled to room temperature and stirred for overnight. After reaction water (30 mL) was added and the reaction mixture was extracted with ethyl acetate (3×200 mL). The organic phase was evaporated to dryness. The residue was purified by column chromatography eluting with 20:1 methylene chloride/methanol to give 334d as a brown solid (2.6 g, 72%). MS: [M+H]+ 245.
Reaction SMILES: [C:1]12([CH3:11])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=O.[C:12]1([NH2:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.Cl.C1(N)C2C(=CC=CC=2)C=CC=1.C([BH3-])#N.[Na+]>CO>[C:1]12([CH3:11])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:2]2[NH:22][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cccc2ccccc12
Reactant: CC12CCC(CC1=O)C2(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC1(C)C2CCC1(C)C(Nc1cccc3ccccc13)C2
Reaction time: 48 h

Procedure:
Camphor (10 gm), 9.4 gm α-naphthylamine, 0.1 gm α-naphthylamine-HCl and 30 gm 1 Å molecular sieves were added to 40 ml anhydrous methanol. Sodium cyanoborohydride (2.5 gm) was added dropwise and stirred under N2 for 48 hours. The sieves were removed by filtration and 5 drops of concentrated HCl were added to the filtrate until it was acidic (pH>7). The solvent was stripped by boiling and 10 gm potassium hydroxide was added to the remaining mixture. The aqueous phase was extracted with ether over potassium carbonate. The extractions were filtered to remove the potassium carbonate. After the ether was evaporated, the mixture was distilled under high vacuum. The material boiling at 120° C. and 0.1 mm of mercury was collected. IR spectra verified that this material was the product.