Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)C>[ClH:36].[ClH:36].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:41])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: [NH4+]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 90 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 90% of theory, Rf value: 0.17 (silica gel; dichloromethane/ethanol=4:1) C27H28N6O3 (484.6) ##EQU29##
Reaction SMILES: [CH2:1]([C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[NH:5][CH:6]=[C:7]1[C:11](=[O:12])[N:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[N:9]=[C:8]1[CH2:22][CH2:23][CH3:24])[CH3:2].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>>[CH2:29]([N:31]([CH2:32][CH3:33])[C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([N:10]2[C:11](=[O:12])[C:7](=[CH:6][NH:5][C:4]3[CH:25]=[CH:26][CH:27]=[CH:28][C:3]=3[CH2:1][CH3:2])[C:8]([CH2:22][CH2:23][CH3:24])=[N:9]2)=[CH:14][CH:15]=1)[CH3:30]
Reactant: CCCC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1=CNc1ccccc1CC
Reactant: CCNCC
Product: CCCC1=NN(c2ccc(C(=O)N(CC)CC)cc2)C(=O)C1=CNc1ccccc1CC

Procedure:
From the reaction of 4-(4-(2-ethylanilinomethylene)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-benzoic acid and diluted diethylamine solution, N,N-diethyl-4-(4-(2-ethylanilinomethylene)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-benzamide is obtained, Mp 123° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=O.[CH2:19]([NH2:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CCOCC>[CH2:19]([NH:27][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][C:9]([C:3]1[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=1[OH:1])([CH3:18])[CH3:17])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCN
Reactant: COC(=O)CCCC(C)(C)c1ccc(O)cc1O
Solvent: CCOCC
Product: CCCCCCCCNC(=O)CCCC(C)(C)c1ccc(O)cc1O

Procedure:
2.5 Parts of methyl 5-(2,4-dihydroxyphenyl)-5-methylhexanoate and 5.0 parts of n-octylamine are sealed into a glass Carius tube for 3 days at 120° C. The cooled reaction mixture is taken up in ether, washed first with dilute hydrochloric acid until free of the excess oxtylamine, and then with water. After removing the ether, the residual oil, on dilution with 40°-60° C. petroleum ether containing a little ether yields 5-(2,4-dihydroxyphenyl)-5-methylhexanoic acid-n-octylamide m.p. 110°-113° C. with the following percentage composition by weight.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br:14]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([Br:14])=[C:10]([F:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(F)cc(N)c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)c1c(C)c(N)cc(F)c1Br
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of methyl 3-amino-5-fluoro-2-methylbenzoate (1.37 g, 7.48 mmol) in acetonitrile (57 mL) was added N-bromosuccinimide (1.01 g, 5.66 mmol) under ice-cooling, and the mixture was stirred for 2 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→30/70) to give the title compound (1.33 g, yield 68%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:7]=[C:6]([CH3:17])[N:5]=1)[CH3:2].[I:18]N1C(=O)CCC1=O>CC#N>[CH2:1]([NH:3][C:4]1[N:9]=[C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:7]([I:18])=[C:6]([CH3:17])[N:5]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCNc1nc(C)cc(NC2CCCCC2)n1
Solvent: CC#N
Product: CCNc1nc(C)c(I)c(NC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
To a solution of 2-ethylamino-4-cyclohexylamino-6-methylpyrimidine (600 mg, 2.56 mmol) in CH3CN (10 mL) was added N-iodosuccinimide (NIS, 658 mg, 2.92 mmol). The reaction was stirred for 2 h at room temperature. After removal of the solvent, the residue was dissolved in EtOAc. The organic phase was then washed with sodium bisulfite, brine, and dried over Na2SO4. Purification by flash column chromatography gave 660 mg (73% yield) of 2-ethylamino-4-cyclohexylamino-5-iodo-6-methylpyrimidine.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([CH3:11])[N:5]=[C:4]([SH:12])[N:3]=1.[OH-].[Na+].C(=O)([O-])O.[Na+].Cl[CH:21]([CH3:25])[C:22](=[O:24])[CH3:23]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O.O1CCCC1.CC(=O)C>[OH:10][CH2:9][CH2:8][C:7]1[C:2](=[O:1])[NH:3][C:4]([S:12][CH:21]([CH3:25])[C:22](=[O:24])[CH3:23])=[N:5][C:6]=1[CH3:11]
Reactant: CC(=O)C(C)Cl
Reactant: Cc1nc(S)nc(O)c1CCO
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)C(C)Sc1nc(C)c(CCO)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 30 parts of 4-hydroxy-2-mercapto-6-methyl-5-pyrimidineethanol, 6.8 parts of sodium hydroxide, 15 parts of sodium hydrogen carbonate and 100 parts of 2-propanone was stirred at room temperature and there were added 180 parts of tetrahydrofuran and 170 parts of water. Then there were added at once 25 parts of 3-chloro-2-butanone and 0.2 parts of N,N,N-triethylbenzenemethanaminium chloride and the whole was stirred and heated for 1 hour at 60° C. Stirring was continued overnight at room temperature. The reaction mixture was filtered and the filtrate was salted out. The organic phase was separated, dried, filtered and evaporated, yielding 36 parts of 5-(2-hydroxyethyl)-6-methyl-2-[(1-methyl-2-oxopropyl)thio]-4(3H)-pyrimidinone as an oily residue (intermediate 6). A mixture of 36 parts of 5-(2-hydroxyethyl)-6-methyl-2-[(1-methyl-2-oxopropyl)thio]-4(3H)-pyrimidinone and 240 parts of a hydrobromic acid solution 60% in acetic acid was stirred and heated for 4 hours at 90° C. The reaction mixture was evaporated and the residue was suspended in 400 parts of 2-propanone. The solid product was filtered off, washed with 2-propanone and dried, yielding 44 parts of 6-(2-bromoethyl)-2,3,7-trimethyl-5H-thiazolo[3,2-a]pyrimidin-5-one monohydrobromide; mp. 172° C. (intermediate 7).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1>>[CH3:25][O:24][C:22]([C:21]1[CH:26]=[CH:27][C:18]([CH2:17][N:10]([N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:19][CH:20]=1)=[O:23]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1ccc(Nn2cnnc2)cc1
Product: COC(=O)c1ccc(CN(c2ccc([N+](=O)[O-])cc2)n2cnnc2)cc1

Procedure:
Starting Compounds: 4-[N-(4-nitrophenyl)amino]-4H-1,2,4-triazole and methyl 4-bromomethylbenzoate
Reaction SMILES: C(C1CC2C(=CC=C(C3N=CC(O)=CN=3)C=2)C1)CCCCCCCCC.C(C1C=CC2N=C(C3C=CC(O)=CC=3)SC=2C=1)CCCCCCC.[C:51]1([CH3:70])[CH:56]=[CH:55][C:54]([S:57]([O:60][CH2:61][CH2:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)(=[O:59])=[O:58])=[CH:53][CH:52]=1>>[C:51]1([CH3:70])[CH:52]=[CH:53][C:54]([S:57]([O:60][CH2:61][CH2:62][CH2:63][CH:64]2[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]2)(=[O:59])=[O:58])=[CH:55][CH:56]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccccc2)cc1
Agent: CCCCCCCCCCC1Cc2ccc(-c3ncc(O)cn3)cc2C1
Agent: CCCCCCCCc1ccc2nc(-c3ccc(O)cc3)sc2c1
Product: Cc1ccc(S(=O)(=O)OCCCC2CCCCC2)cc1
Yield: 56.4 %

Procedure:
An objective product was prepared in the same manner as in Example 2 except that 2-(2-decylindan-5-yl)pyrimidine-5-ol was changed to 4-(6-octylbenzothiazole-2-yl)phenol and 3-phenylpropyl p-toluenesulfonate was changed to 3-cyclohexylpropyl p-toluenesulfonate (Yield: 56.4%).
Reaction SMILES: C1(C[N:8]2[CH2:17][CH2:16][N:15]3[C@H:10]([CH2:11][O:12][CH2:13][CH2:14]3)[CH2:9]2)C=CC=CC=1.[ClH:18]>CO.[Pd]>[ClH:18].[ClH:18].[CH2:11]1[C@@H:10]2[CH2:9][NH:8][CH2:17][CH2:16][N:15]2[CH2:14][CH2:13][O:12]1
Reactant: c1ccc(CN2CCN3CCOC[C@@H]3C2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: C1CN2CCOC[C@@H]2CN1
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a solution of (9aS)-8-(phenylmethyl)octahydropyrazino[2,1-c][1,4]oxazine (assumed 38.02 g, 163.6 mmol) in MeOH (330 mL) was added 6 N aqueous HCl (55 mL, 330 mmol) and 10% Pd/C (3.80 g). The mixture was hydrogenated overnight, and then filtered through a glass fiber filter. The filter cake was washed with MeOH, and the combined solution was concentrated in vacuo and azeotroped with MeOH (4×150 mL) to provide (9aS)-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride (34.78 g, 99% yield for 2 steps) as a red oil that solidified under high vacuum. LCMS: (M+H)+: 142.9.
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]3[N:20]=[CH:21][CH:22]=[C:23]([N:24]4[CH2:28][CH2:27][C@H:26]([N:29]([CH2:37][CH3:38])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]4)[C:6]=3[C:5]=2[CH:4]=1)#[N:2].[Cl:39]N1C(=O)CCC1=O>C(#N)C.C(O)(C)C>[Cl:39][C:22]1[CH:21]=[N:20][C:7]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:19])[CH3:17])[C:9]3[CH:10]=[N:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[C:6]=2[C:23]=1[N:24]1[CH2:28][CH2:27][C@H:26]([N:29]([CH2:37][CH3:38])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:25]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCN(C(=O)OC(C)(C)C)[C@H]1CCN(c2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Solvent: CC(C)O
Solvent: CC#N
Product: CCN(C(=O)OC(C)(C)C)[C@H]1CCN(c2c(Cl)cnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Temperature: 35 °C
Reaction time: 5 h

Procedure:
A mixture of (S)-tert-butyl 1-(6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-4-yl)pyrrolidin-3-yl(ethyl)carbamate (100 mg, 0.2 mmol) and N-chlorosuccinimide (75 mg, 0.56 mmol) in acetonitrile (0.75 mL) and isopropyl alcohol (0.2 mL) was stirred at 35° C. for 5 hours. The cooled reaction mixture was quenched with saturated aqueous sodium thiosulfate, diluted with ethyl acetate (50 mL), and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 4 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as a pale yellow foam, which was used in the next step without any further purification (100 mg).
Reaction SMILES: O=[C:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][NH:3]1.F[B-](F)(F)F.C[O+](C)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=1[C:34]1[O:38][C:37]([CH3:39])=[N:36][CH:35]=1)[C:27]([NH:29][NH2:30])=O>C(#N)C>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:27]2[N:3]3[CH2:4][CH2:5][CH2:6][CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]3=[N:30][N:29]=2)[CH:31]=[CH:32][C:33]=1[C:34]1[O:38][C:37]([CH3:39])=[N:36][CH:35]=1
Reactant: CCOC(=O)C1CCCNC1=O
Reactant: COc1cc(C(=O)NN)ccc1-c1cnc(C)o1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CCOC(=O)C1CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.5 %

Procedure:
A mixture of ethyl 2-oxo-3-piperidinecarboxylate (34.6 g), trimethyloxonium tetrafluoroborate (95%, 31.5 g) and acetonitrile (600 mL) was stirred at room temperature for 16 hr. 3-Methoxy-4-(2-methyl-1,3-oxazol-5-yl)benzohydrazide (50.0 g) was added to the reaction mixture at room temperature, and the mixture was heated under reflux for 24 hr, allowed to cool to room temperature and concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, the insoluble material was filtered off through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from methanol/ethyl acetate to give the title compound (29.0 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8](/[CH:15]=[CH:16]/[CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[C:31]1[CH:36]=[C:35]([CH2:37]Cl)[CH:34]=[CH:33][C:32]=1[C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[C:31]1[C:32]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:33][CH:34]=[C:35]([CH2:37][O:1][C:2]2[CH:3]=[CH:4][C:5]([C@H:8](/[CH:15]=[CH:16]/[CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=2)[CH:36]=1)[CH2:19][CH2:20][CH3:21]
Reactant: C/C=C/[C@H](CC(=O)OCC)c1ccc(O)cc1
Reactant: CCCCOc1ccc(OC)cc1-c1cc(CCl)ccc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C/C=C/[C@H](CC(=O)OCC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3OCCCC)c2)cc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
A mixture of compound B (11 mg, 47 μmol), compound C (17 mg, 47 μmol), and cesium carbonate (23 mg, 70 μmol) in DMF (1.0 mL) was stirred for 16 hours at 23° C. The mixture was diluted with EtOAc, washed with water and brine, dried over MgSO4, and concentrated. The crude product was purified by silica gel flash chromatography (0-10% EtOAc/hexane) to afford compound 11.1 (21 mg, 81% yield) as a colorless oil. MS ESI (pos.) m/e: 576 (M+H2O), 581 (M+Na).
Reaction SMILES: [CH3:1]N(C)CCOC1C=CC=C(C)C=1[N+]([O-])=O.[CH3:17][C:18]1[C:19]([N+:32]([O-])=O)=[C:20]([CH:29]=[CH:30][CH:31]=1)[O:21][CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.N1C2C(=CC=CC=2OCCN(C)C)C=C1>>[N:24]1([CH2:23][CH2:22][O:21][C:20]2[CH:29]=[CH:30][CH:31]=[C:18]3[C:19]=2[NH:32][CH:1]=[CH:17]3)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1cccc(OCCN2CCCC2)c1[N+](=O)[O-]
Reactant: Cc1cccc(OCCN(C)C)c1[N+](=O)[O-]
Agent: CN(C)CCOc1cccc2cc[nH]c12
Product: c1cc(OCCN2CCCC2)c2[nH]ccc2c1

Procedure:
The following compound was prepared in a similar fashion, starting with dimethyl-[2-(3-methyl-2-nitro-phenoxy)-ethyl]-amine rather than 1-[2-(3-methyl-2-nitrophenoxy)-ethyl]-pyrrolidine: [2-(1H-indol-7-yloxy)-ethyl]-dimethyl-amine (69%), MS: 205 (M+H)+
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][CH2:5][NH2:6].Br[CH2:8][CH:9]1[O:14][C:13]2[CH:15]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[C:18]([F:19])[C:12]=2[CH2:11][O:10]1.FCCCN>>[F:2][CH2:3][CH2:4][CH2:5][NH:6][CH2:8][CH:9]1[O:14][C:13]2[CH:15]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[C:18]([F:19])[C:12]=2[CH2:11][O:10]1
Reactant: NCCCF
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Agent: Cl
Product: CS(=O)(=O)c1cc(F)c2c(c1)OC(CNCCCF)OC2

Procedure:
3-Fluoropropan-1-amine HCl-salt (0.178 g, 1.52 mmol) was basified on a SCX-3 ion exchange column (TEA/MeOH). 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (8.5 mg, 0.026 mmol) and 3-fluoropropan-1-amine (0.15 M in MeOH/TEA:4/1, 5 ml) was heated under microwave radiation at 120° C. for 1 h 20 min. ESIMS: m/z 322 (M+H)+.
Reaction SMILES: [N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:31])[C:10]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:11][N:12]3CC3C=CC(OC)=CC=3OC)=[C:7]([CH3:32])[C:6]=2[F:33])[CH2:4][CH2:3][CH2:2]1>FC(F)(F)C(O)=O>[N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:31])[C:10]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:11][NH:12]3)=[C:7]([CH3:32])[C:6]=2[F:33])[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CCC3)c(F)c(C)c2c1=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c[nH]c2nc(N3CCC3)c(F)c(C)c2c1=O

Procedure:
A solution of Example 5A (267 mg) in trifluoroacetic acid (11 mL) was stirred at 40° C. for 3 hours and concentrated; and the concentrate was azeotroped with toluene.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:8][CH:9]1[CH2:14][CH2:13][C:12]([F:16])([F:15])[CH2:11][CH2:10]1)(=O)=O.[CH3:25][NH2:26]>CCOC(C)=O>[F:15][C:12]1([F:16])[CH2:13][CH2:14][CH:9]([CH2:8][C@H:7]([NH:17][C:18](=[O:19])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:6][NH:26][CH3:25])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCC(F)(F)CC1
Reactant: CN
Solvent: CCOC(C)=O
Product: CNC[C@H](CC1CCC(F)(F)CC1)NC(=O)OC(C)(C)C
Temperature: 55 °C
Yield: 34.4 %

Procedure:
(S)-2-(tert-butoxycarbonylamino)-3-(4,4-difluorocyclohexyl)propyl methanesulfonate (28.8 g, 0.077 mol) was dissolved in alcoholic of methylamine solution (350 mL) and the reaction was warmed at 50-60° C. overnight. The reaction mixture was cooled to rt and the solvent was removed under reduced pressure to give an oil, which was dissolved into EtOAc, washed with water twice and brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography to afford (S)-tert-butyl 1-(4,4-difluorocyclohexyl)-3-(methylamino)propan-2-ylcarbamate (8.1 g, 34.4%). 1H NMR (400 MHz, CDCl3): 5.12 (m, 1H), 4.97 (m, 1H), 3.82 (m, 1H), 3.63 (dd, J=14.4&4.4 Hz, 1H), 3.45 (dd, J=14.4&9.2 Hz, 1H), 2.76&2.74 (s, 1H), 2.20-1.20 (m, 11H), 1.44 (s, 9H); MS (E/Z): 307 (M+H+).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)[N:22]=3)[N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:23]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=2)[N:22]=[C:21]([C:17]2[N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)n2)c1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)n2)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To N-tert-butyl-3-{6-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonamide (example 362) (0.232 g, 0.40 mmol) was added TFA (3 mL) and the reaction mixture was stirred at 23° C. for 16 h. The mixture was evaporated to dryness and partitioned between EtOAc and saturated NaHCO3 solution, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as a white solid (0.170 g, 81%). MS (ISP) 524.8 [(M+H)+]; mp 244° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([O-])=O>CO>[NH2:1][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCOc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Solvent: CO
Product: CCCCCCCCOc1cc(C(=O)OC)ccc1N
Yield: 97.2 %

Procedure:
Methyl 4-nitro-3-octoxybenzoate (8.7 g, 0.028 mol) was dissolved in 150 mL methanol to form a solution. It was stirred at room temperature in the presence of 10% Pd--C under H2 atmosphere for 29 hours. The reaction mixture was filtered through celite, concentrated to give the product methyl 4-amino-3-octoxybenzoate as an off-white solid (7.6 g, 96%). 1H NMR (300 MHz, CDCl3): 7.25 (d, J=2.1 Hz, 1H), MS calcd (C16H25NO3): 279.2; found: 279.0.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1([F:10])[CH2:7][CH:6]([CH2:8][OH:9])[CH2:5]1.Cl[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=1.Cl>C1COCC1>[Cl:18][C:17]1[C:12]([O:9][CH2:8][CH:6]2[CH2:7][C:4]([F:10])([F:3])[CH2:5]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Clc1cccnc1Cl
Reactant: OCC1CC(F)(F)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC1(F)CC(COc2ncccc2Cl)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 1.017 g, 70.6 mmol) was suspended in THF (30.0 mL) and the reaction was cooled to 0° C. under nitrogen with an ice bath. (3,3-Difluorocyclobutyl)methanol (Preparation 36, 2.95 g, 24.2 mmol) in THF (30 mL) was added dropwise to the mixture maintaining the temperature at 0° C. After stirring for 30 minutes, 2,3-dichloropyridine (3.25 g, 22.0 mmol) was added and the suspension was heated to reflux for 16 hours. An aqueous solution of HCl (1 M, 20 mL) was added and the reaction was extracted with EtOAc (2×100 mL). The combined organics were then dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage®, gradient of 0-50% EtOAc in heptane,) to afford the title compound (4.82 g, 85%).
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH2:8][CH2:9][C:10](=[O:13])[CH2:11][CH2:12][C:6]=2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N+:21]([O-])([O-:23])=[O:22].[K+].[Br-]>C(Cl)Cl>[Br:1][C:2]1[C:7]2[CH2:8][CH2:9][C:10](=[O:13])[CH2:11][CH2:12][C:6]=2[C:5]([O:14][CH3:15])=[C:4]([N+:21]([O-:23])=[O:22])[CH:3]=1
Reactant: COc1ccc(Br)c2c1CCC(=O)CC2
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: COc1c([N+](=O)[O-])cc(Br)c2c1CCC(=O)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.1 %

Procedure:
To a stirred solution of 1-bromo-4-methoxy-5,6,8,9-tetrahydro-benzocyclohepten-7-one (20.0 g, 0.0743 mol) in sulfuric acid (200 mL, 4 mol) at 0° C. under an atmosphere of nitrogen was added potassium nitrate (7.89 g, 0.0780 mol) in portions. Note: When excess potassium nitrate is added, ipso substitution of the bromide is observed. After stirring for ˜15 min., an aliquot was removed and analyzed by HPLC indicating the completion of the reaction. Mixture was poured over ice water. A gummy solid formed which was dissolved in methylene chloride. The reaction mixture was transferred to a separatory funnel and the water layer removed. The organic phase was washed with saturated aqueous bicarbonate and water, dried over magnesium sulfate, filtered and concentrated in vacuo to an orange solid. Product was purified by ISCO chromatography on silica gel (350 g column) using ethyl acetate-hexane (10-100%). Fractions corresponding to product were combined and concentrated in vacuo to give 4-Bromo-1-Methoxy-2-nitro-5,6,8,9-tetrahydrobenzocyclohepten-7-one (18 g, 77%) as an orange solid. 1H NMR (CDCl3, 400 MHz) 8.04 (s, 1H), 3.90 (s, 3H), 3.25 (m, 2H), 3.15 (m, 2H), 2.64 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.[I:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=[C:2]([N:23]3[CH:24]=[C:20]([I:19])[N:21]=[CH:22]3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Ic1c[nH]cn1
Reactant: FC(F)(F)c1cc(-c2cccc(Cl)c2)nc(Cl)n1
Product: FC(F)(F)c1cc(-c2cccc(Cl)c2)nc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(3-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example A.44) (3.12 g, 10.6 mmol) and commercially available 4-iodo-imidazole (2.27 g, 11.7 mmol) according to the general procedure IVa. Obtained as an off-white solid (4.0 g, 83%). MS (ISP) 451.0 [(M+H)+]; mp 202° C.