Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([N:15]([CH2:17][CH:18](OC)OC)[CH3:16])=[O:14])=[CH:8][CH:7]=1.Cl>O>[CH3:16][N:15]1[CH:17]=[CH:18][N:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][C:4]3[CH:23]=[CH:24][C:25]([Cl:26])=[C:2]([Cl:1])[CH:3]=3)=[CH:11][CH:10]=2)[C:13]1=[O:14]
Reactant: COC(CN(C)C(=O)Nc1ccc(Oc2ccc(Cl)c(Cl)c2)cc1)OC
Agent: Cl
Solvent: O
Product: Cn1ccn(-c2ccc(Oc3ccc(Cl)c(Cl)c3)cc2)c1=O

Procedure:
N-[4-(3,4-Dichlorophenoxy)phenyl]-N'-(2,2-dimethoxyethyl)-N'-methylurea (0.02 mole), water (30 ml) and concentrated hydrochloric acid (3 ml) are changed into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. The mixture is refluxed for a period of about 30 minutes and then cooled and extracted with ethyl acetate. The extract is washed with dilute aqueous sodium bicarbonate, with two portions of water and is then dried. The ethyl acetate is removed by mild warming under reduced pressure to yield the desired product 1-methyl-3-[4-(3,4-dichlorophenoxy)phenyl]-4-imidazolin-2-one.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([NH2:11])[N:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[CH3:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=1)(=[O:16])=[O:15]>>[NH2:11][C:8]1[N:9]=[CH:10][C:5]2[S:4][CH:3]=[C:2]([C:21]3[CH:22]=[C:17]([S:14]([NH:13][CH3:12])(=[O:15])=[O:16])[CH:18]=[CH:19][CH:20]=3)[C:6]=2[N:7]=1
Reactant: Nc1ncc2scc(Br)c2n1
Reactant: CNS(=O)(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Product: CNS(=O)(=O)c1cccc(-c2csc3cnc(N)nc23)c1
Yield: 64.6 %

Procedure:
3-(2-Aminothieno[3,2-d]pyrimidin-7-yl)-N-methylbenzenesulfonamide (180 mg, 64% yield) was prepared in the same manner as Step 6 of Example 1 using 7-bromothieno[3,2-d]pyrimidin-2-amine (200 mg, 0.87 mmol) and N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (260 mg, 0.87 mmol).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.[F:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[C:32]1[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=1>>[NH2:11][C:7]1[N:8]=[CH:9][N:10]=[C:5]([O:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[C:21]2[CH:20]=[CH:19][C:18]([C:32]3[CH:37]=[N:36][C:35]([NH2:38])=[N:34][CH:33]=3)=[C:17]([F:16])[CH:22]=2)[CH:6]=1
Reactant: Nc1cc(Oc2ccccc2Br)ncn1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1cc(Oc2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)ncn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 6-(2-bromophenoxy)pyrimidin-4-amine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C20H15FN6O, 374.13; m/z found, 375.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.38 (s, 2H), 7.92 (s, 1H), 7.47 (m, 2H), 7.40 (d, J=6.4, 1H), 7.36-7.23 (m, 3H), 7.11 (d, J=7.7, 1H), 6.68 (br, 4H), 5.68 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][CH2:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]([O:42][CH3:43])=[O:41])=[N:38][CH:39]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:43][O:42][C:40]([C:37]1[CH:36]=[CH:35][C:34]([CH2:33][NH:32][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:29])=[CH:39][N:38]=1)=[O:41]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccc(CN)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cn1
Yield: 39.3 %

Procedure:
In a manner similar to the method described in Example 379, a mixture of (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (59.2 mg, 0.127 mmol) and methyl 5-(aminomethyl)picolinate (64.4 mg, 0.388 mmol) in N,N-dimethyl formamide (5 mL) were treated with DIPEA (119 mg, 0.916 mmol), HOBt (34.2 mg, 0.253 mmol) and HBTU (96.1 mg, 0.253 mmol) at room temperature to give 5-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-pyridine-2-carboxylic acid methyl ester (30.7 mg, 39%). HRMS (ES+) m/z Calcd C31H30Cl2F2N4O3+H [(M+H): 615.1736. Found: 615.1731.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:20])[CH:14]([CH3:19])[CH:15]([CH3:18])[CH2:16][CH3:17])[CH:10]=2)[N:5]=[CH:4][N:3]=1.CO[CH:23]=[C:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26].O>CN(C)C=O>[CH3:19][CH:14]([CH:15]([CH3:18])[CH2:16][CH3:17])[C:13]([NH:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:1][CH:23]=[C:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])=[O:20]
Reactant: CCC(C)C(C)C(=O)Nc1ccc2ncnc(N)c2c1
Reactant: COC=C(C(=O)OC)C(=O)OC
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)C(C)C(=O)Nc1ccc2ncnc(NC=C(C(=O)OC)C(=O)OC)c2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
A mixture of 4-amino-6-(2,3-dimethylpentanamido)quinazoline (6.75 g) and dimethyl methoxymethylene-propanedioate (6.48 g) in N,N-dimethylformamide (20 ml) was stirred at 100° C. for 1 hour and cooled to ambient temperature. Water was added to the reaction mixture. The resulting solid was separated by filtration, washed with water, and dried. There was obtained dimethyl [[6-(2,3-dimethylpentanamido)-4-quinazolinylamino]methylene]propanedioate (6.58 g). A portion of the crude product was chromatographed on silica gel with chloroform and ethyl acetate (3:1) and recrystallized from ethyl acetate to give analytically pure dimethyl [[6-(2,3-dimethylpentanamido)-4-quinazolinylamino]methylene]propanedioate (0.45 g).
Reaction SMILES: C([Li])(CC)C.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH3:22])=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH2:23]1[CH2:27][O:26][CH2:25][CH2:24]1>C1CCCCC1>[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH2:22][C:25](=[O:26])[CH2:24][CH2:23][CH3:27])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1C
Reactant: C1CCOC1
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Product: CCCC(=O)Cc1c(NC(=O)OC(C)(C)C)cccc1OC
Temperature: -60 °C
Reaction time: 1 h

Procedure:
A solution of 50 mL (65 mmol) of 1.3M sec-butyl lithium in cyclohexane was added slowly to N-tert-butoxycarbonyl-3-methoxy-2-methylaniline (7.7 g, 32.5 mmol) in 100 mL of THF keeping the temperature below −40° C. with a dry ice-ethanol bath. The bath was removed and the temperature allowed to rise to −10° C. and then the bath replaced. After the temperature had cooled to −60° C., 4.3 g (32.5 mnmol) of N-methoxy-N-methylbutanamide in an equal volume of THF was added dropwise. The reaction mixture was stirred 1 hour, the cooling bath removed and stirred an additional 22 hours. It was then poured into a mixture of 200 mL of ether and 200 mL of 0.5N HCl. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated at reduced pressure to give 9.9 g of crude 1-[2-(tert-butoxycarbonylamino)-6-methoxyphenyl]-2-pentanone. This material was dissolved in 100 mL of methylene chloride and 20 ML of trifluoroacetic acid and stirred for a total of 23 hours. The mixture was washed with water, dried (MgSO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 2.19 g of 4-methoxy-2-propyl-1H-indole as an oil.
Reaction SMILES: Cl.COC1C=CC(C[S:9][C@@H:10]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[O:16])[C@H:12]([C:28]([NH:30][C@H:31]3[CH2:35][CH2:34]N[CH2:32]3)=[O:29])[CH2:11]2)=CC=1.[N+:38]([C:41]1[CH:54]=[CH:53][C:44]([CH2:45][O:46][C:47]([NH:49][C:50](=[NH:52])[CH3:51])=[O:48])=[CH:43][CH:42]=1)([O-:40])=[O:39]>>[SH:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[O:16])[C@H:12]([C:28]([NH:30][C@H:31]2[CH2:35][CH2:34][N:52]([C:50](=[N:49][C:47]([O:46][CH2:45][C:44]3[CH:43]=[CH:42][C:41]([N+:38]([O-:40])=[O:39])=[CH:54][CH:53]=3)=[O:48])[CH3:51])[CH2:32]2)=[O:29])[CH2:11]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N[C@H]3CCNC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: CC(=N)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](NC(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Yield: 53.3 %

Procedure:
Following a procedure similar to that described in Preparations 23(iii) and 23(iv), but using 1.08 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-pyrrolidin-3-ylaminocarbonyl)pyrrolidine hydrochloride and 440 mg of N-(4-nitrobenzyloxycarbonyl)acetamidine, 608 mg of the title compound were obtained as a powder.
Reaction SMILES: CS([O:5][C:6]1[N:11]=[C:10]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Br:22])[C:13](O)=[N:14][C:9]2=[CH:8][CH:7]=1)(=O)=O.O=P(Cl)(Cl)[Cl:25]>>[Br:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:12]1[C:10]2=[N:11][C:6]([OH:5])=[CH:7][CH:8]=[C:9]2[N:14]=[C:13]1[Cl:25]
Reactant: CS(=O)(=O)Oc1ccc2nc(O)n(-c3ccccc3Br)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Oc1ccc2nc(Cl)n(-c3ccccc3Br)c2n1

Procedure:
From 3-(2-bromophenyl)-2-hydroxy-3H-imidazo[4,5-b]pyridin-5-yl methanesulfonate and POCl3, prepared in a similar manner as the one described in Example 1.136, the title compound was obtained. LCMS m/z=323.90 [M+H]+, 1H NMR (400 MHz, methanol-d4) δ ppm 6.72 (d, J=8.6 Hz, 1H), 7.57-7.65 (m, 3H), 7.90 (dd, J1=8.1 Hz, J2=1.2 Hz, 1H), 7.93 (d, J=8.6 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH2:13]([SH:16])[CH2:14][SH:15].B(F)(F)F.CCOCC>CC(O)=O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[S:16][CH2:13][CH2:14][S:15]1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: SCCS
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C1(SCCS1)C(=O)N2
Temperature: 60 °C
Reaction time: 0.42 h

Procedure:
5-methyl-1H-indole-2,3-dione (6 g, 37 mmol) was suspended in 100 ml of AcOH. The heterogenous mixture was heated at 60° C. After complete solubilisation, 1,2-ethanedithiol (3.15 ml, 37 mmol) was added and then neat BF3.OEt2 (9.5 ml, 75 mmol) was added dropwise. The reaction was stirred for 25 minutes, in which time the reaction mixture became homogenous. After 20 minutes at room temperature, the reaction was quenched by addition of water, the solid washed several times with large amounts of water and air dried affording 5′-methylspiro[1,3-dithiolane-2,3′-indol]-2′(1′H)-one 6 as a brown solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH:11]([CH2:14][CH2:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:17]3)[CH2:10][O:9]2)=[CH:4][C:3]=1[F:26].[C:27]([Cu])#[N:28]>CN1C(=O)CCC1>[C:27]([C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:13][CH2:12][C@H:11]([CH2:14][CH2:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:17]3)[CH2:10][O:9]2)=[CH:4][C:3]=1[F:26])#[N:28]
Reactant: N#C[Cu]
Reactant: CCCC[C@H]1CC[C@H](CCC2COC(c3ccc(Br)c(F)c3)OC2)CC1
Solvent: CN1CCCC1=O
Product: CCCC[C@H]1CC[C@H](CC[C@H]2CO[C@H](c3ccc(C#N)c(F)c3)OC2)CC1
Temperature: 25 °C

Procedure:
8.4 g (0.02 mol) of 2-(4'-bromo-3'-fluorophenyl)-5-[2'-(trans-4"-butylcyclohexyl)ethyl]-1,3-dioxane and 2.7 g (0.03 mol) of CuCN were refluxed in 100 cm3 of NMP for 2 hours. The product was cooled to room temperature and 4 cm3 of EDA was added. The solution was poured into 100 cm3 of ice water, extracted with hexane, and washed with an aqueous solution of EDA and water. The hexane was distilled off. The residue was treated through a silica gel column with chloroform as the solvent and the chloroform was distilled off. The residue was recrystallized from a solvent mixture of acetone and methanol to yield 3.1 g (0.008 mol) of trans-2-(4'-cyano-3'fluorophenyl)-5-[2'-(trans-4"-butylcyclohexyl)ethyl]-1,3-dioxane. The phase transition points of this compound, measured by DSC, were: ##STR49## wherein C is the crystal phase, N is the nematic phase, and I is the isotropic liquid phase.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=O)[CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([NH2:19])[N:13]=2)=[CH:6][C:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:4][N:3]=1>ClCCl.CO>[NH2:19][C:14]1[CH:15]=[C:16]([CH3:18])[CH:17]=[C:12]([CH2:11][CH2:10][C:9]2[NH:1][C:2]3=[N:3][CH:4]=[C:5]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)[CH:6]=[C:7]3[N:8]=2)[N:13]=1
Reactant: Cc1cc(N)nc(CCC(=O)Nc2cc(-c3ccc(Cl)cc3)cnc2N)c1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(N)nc(CCc2nc3cc(-c4ccc(Cl)cc4)cnc3[nH]2)c1
Yield: 17.5 %

Procedure:
36 mg of N-[2-amino-5-(4-chloro-phenyl)-pyridin-3-yl]-3-(6-amino-4-methyl-pyridin-2-yl)-propionamide (compound A9) are treated with 2 g polyphosphoric acid at 125° C. for 24 h. Subsequent workup according to the procedure described herein for example A6 yields 6 mg of the title compound as a viscous oil after chromatography (dichloromethane/methanol 8:1). ESI-MS: 364.4/366.4 (MH+, 100%/36%). TLC: Rf=0.30 (dichloromethane/methanol 8:1).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH2:11]([OH:15])[CH2:12][CH2:13][OH:14].O>C1(C)C(C)=CC=CC=1>[CH2:1]([O:14][CH2:13][CH2:12][CH2:11][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCO
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: OCCCOCc1ccccc1
Temperature: 100 °C
Yield: 65 %

Procedure:
Benzyl chloride (104 g, 1.0 m) was added dropwise to a solution of KOH (112 g, 2.0 m) in 100 ml of xylene and 304 g of 1,3-propanediol at 50° C.-60° C. The solution was then heated at 100° C. for 2 hours. Water (400 ml) was added to the cooled solution and the mixture was extracted twice with 600 ml of methylene chloride. The combined methylene chloride extracts were washed three times with 400 ml of water, dried over MgSO4, filtered and evaporated to a yellow oil which was distilled under vacuum. The 98° C.-106° C. (1.5 mm) fraction was collected to give 88.7 g of 3-benzyloxypropanol.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[N:3]=1.[CH2:12]([C:14]1[CH:15]=[C:16]([CH3:26])[C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:18][CH:19]=1)[CH3:13]>>[Br:1][C:2]1[N:3]=[C:4]([CH3:11])[C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:17]3[C:16]([CH3:26])=[CH:15][C:14]([CH2:12][CH3:13])=[CH:19][N:18]=3)[CH2:21][CH2:22]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1nc(Br)ccc1C(=O)O
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(Br)nc3C)CC2)c(C)c1
Yield: 55.3 %

Procedure:
Using 6-bromo-2-methylnicotinic acid (675 mg) and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (611 mg) described in Preparation Example 81 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (664 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[O:8][C@@H:7]1[C:9]([OH:11])=O)=[O:5])[CH3:2].[NH2:12][C@@H:13]([CH:22]([CH3:25])[CH2:23][CH3:24])[C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:15]>>[OH:15][C@@H:14]([C@@H:13]([NH:12][C:9]([C@H:7]1[O:8][C@@H:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:11])[CH:22]([CH3:25])[CH2:23][CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCC(C)[C@H](N)[C@H](O)c1ccccc1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)O
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](C(C)CC)[C@H](O)c1ccccc1

Procedure:
The procedures of Example 1a were repeated employing (2S,3S)-3-ethoxycarbonyloxirane-2-carboxylic acid and (1R,2S)-2-amino-3-methyl-1-phenyl-1-pentanol (its preparation is described in the after-mentioned Reference Example 1), to prepare the titled compound.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1OS(C(F)(F)F)(=O)=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:15][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: Nc1ccccc1
Product: Cc1ccccc1Nc1ccccc1
Yield: 95 %

Procedure:
The general procedure B using 51.7 mg (0.215 mmol) of o-tolyltriflate and 29.4 μl (0.323 mmol) of aniline gave 95% yield of N-(2-methylphenyl)aniline after sublimation (130° C., 0.1 torr).
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:19][CH3:20])[C:5](=[O:18])[CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([NH:16][CH3:17])[CH2:12][CH2:11]1)[CH3:3].CCN(C(C)C)C(C)C.[F:30][C:31]([F:43])([F:42])[C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:19]([N:4]([CH2:2][CH3:3])[C:5](=[O:18])[CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([N:16]([CH3:17])[S:38]([C:35]2[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:42])[F:43])=[CH:37][CH:36]=2)(=[O:40])=[O:39])[CH2:14][CH2:15]1)[CH3:20]
Reactant: CCN(CC)C(=O)CCCC[C@H]1CC[C@H](NC)CC1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)C(=O)CCCC[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.8 g (2.6 mmol) trans-5-(4-Methylamino-cyclohexyl)-pentanoic acid diethylamide.hydrochloride in 20 ml CH2Cl2 was treated with 1.1 ml (6.3 mmol, 2.4 eq) Huenig's base, 706 mg (2.9 mmol, 1.1 eq) 4-(Trifluoromethyl)benzenesulfonyl chloride in 10 ml CH2Cl2 and 32 mg (0.26 mmol, 0.1 eq) DMAP. The solution was stirred at RT over night. Additonal 1.1 ml (6.3 mmol) Huenig's base, 706 mg (2.9 mmol) 4-(Trifluoromethyl)benzenesulfonyl chloride in 10 ml CH2Cl2 and 32 mg (0.26 mmol) DMAP were added and stirring was continued for 3 h. The mixture was partitioned between CH2Cl2 and a saturated aqueous solution of NaHCO3. The organic phase was washed with water, 1M KHSO4 and brine, dried over Na2SO4 and evaporated. Column chromatography with EtOAc/hexane 1:1 gave 1.06 g (84%) trans-5-{4-[Methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyl}-pentanoic acid diethylamide as colorless oil, MS: 477 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2(O)[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][CH2:8]2)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=[N:3]1.COCCN(S(F)(F)[F:28])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[F:28][C:7]1([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]=2[N+:15]([O-:17])=[O:16])[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][CH2:8]1
Reactant: Cn1ncc([N+](=O)[O-])c1C1(O)CCC=CCC1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1ncc([N+](=O)[O-])c1C1(F)CCC=CCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45 %

Procedure:
To a solution of (Z)-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)cyclohept-4-enol (1.35 g, 5.70 mmol) in dry DCM (60 mL) was added dropwise a solution of deoxo-Fluor® (50% in THF, 6.2 mL, 17.1 mmol) and the reaction mixture was stirred at room temperature for 90 min. The mixture was cooled to 0° C. and saturated aqueous NaHCO3 solution (70 mL) was added, dropwise initially, and extracted with DCM (100 mL). The organic layer was separated, dried over MgSO4, and concentrated under reduced pressure. Purification via silica gel column chromatography (15-20% EtOAc/hexane) gave (Z)-5-(1-fluorocyclohept-4-enyl)-1-methyl-4-nitro-1H-pyrazole as an off-white solid (615 mg, 45%).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.C(N(CC)C(C)C)(C)C.[CH3:30][O:31][CH2:32][CH2:33][NH:34][CH2:35][C:36]1[CH:48]=[CH:47][C:39]([O:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:38]([CH3:49])[CH:37]=1>C(Cl)Cl>[CH3:30][O:31][CH2:32][CH2:33][N:34]([CH2:35][C:36]1[CH:48]=[CH:47][C:39]([O:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:38]([CH3:49])[CH:37]=1)[C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CCOC(=O)COc1ccc(CNCCOC)cc1C
Reactant: CS(=O)(=O)c1nccc(-c2ccc(C(F)(F)F)cc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(CN(CCOC)c2nccc(-c3ccc(C(F)(F)F)cc3)n2)cc1C
Temperature: 100 °C
Yield: 24.1 %

Procedure:
A mixture of 2-(methylsulfonyl)-4-[4-(trifluoromethyl)phenyl]pyrimidine (0.2 g, 0.66 mmol), N,N-diisopropylethylamine (0.11 mL, 0.66 mmol) and ethyl (4-{[(2-methoxyethyl)amino]methyl}-2-methylphenoxy)acetate (0.28 g. 0.99 mmol) was heated at 100° C. in a sealed reactivial for 20 h. The reaction mixture was then allowed to come to room temperature, and the residue dissolved in CH2Cl2 (30 mL), the organic extract was washed water (20 mL) and passed through a hydrophobic frit before concentrating in vacuo. Purification by Biotage™ chromatography (Silica, 90 g) eluting 1:9 EtOAc:cyclohexane afforded the title compound as a pale yellow oil (0.08 g).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C)=O.[NH2:19][C:20]1[CH:24]=[C:23]([CH3:25])[O:22][N:21]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15](=[O:17])[NH:19][C:20]1[CH:24]=[C:23]([CH3:25])[O:22][N:21]=1
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reactant: Cc1cc(N)no1
Solvent: Cc1ccccc1C
Product: Cc1cc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2C)no1
Temperature: 25 °C

Procedure:
To an appropriate flask equipped for reflux and/or distillation, 900 ml xylene, 40 grams (0.149 moles) methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide and 19.94 grams (0.203 moles) of 3-amino-5-methylisoxazole are added. The mixture is refluxed for 13-18 hours. At 1 hour intervals, about 3-4% of the solvent volume is distilled off. Every 4 to 5 hours fresh xylene is added, equal in amount to that distilled during this period. At the end of the heating period, the reaction is cooled to 25°C., filtered and the cake is washed with xylene. After drying, the crude product weighed 43.8 grams (88%). This material could be recrystallized from about 40-50 volumes of dioxane with an 80-85% recovery of acceptable material. An alternate procedure for the purification of crude product is as follows:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[C:11]#[N:12].I[CH2:18][CH3:19].O>CC(C)=O>[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:18][CH3:19])[C:11]#[N:12]
Reactant: N#Cc1ccc(O)c(Br)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOc1ccc(C#N)cc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Add potassium carbonate (5.2 g, 37.9 mmol) to 3-bromo-4-hydroxy-benzonitrile (5.0 g, 25.2 mmol) in acetone with stirring at room temperature. After 15 minutes, add iodoethane (2.4 mL, 130.3 mmol) and continue stirring at room temperature. After 18 hours, pour the reaction mixture into water and extract with EtOAc. Combine the organic extracts, wash with water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes to provide the title compound.