Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[O:9][N:8]=1)(=O)=O.[N-:16]=[N+:17]=[N-:18].[Na+].O>CN(C=O)C>[N:16]([CH2:6][C:7]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[O:9][N:8]=1)=[N+:17]=[N-:18]
Reactant: CS(=O)(=O)OCc1cc(C(F)(F)F)on1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc(C(F)(F)F)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
To a solution of 8.7 g (5-(trifluoromethyl)isoxazol-3-yl)methyl methanesulfonate in 87 mL DMF was added 9.23 g sodium azide. The reaction mixture was stirred 3 h at RT. 80 mL water was added under cooling. The mixture was extracted with diethyl ether (3×100 mL) and the organic layers were washed with water (3×100 mL) and then with sat. NaCl solution (1×100 mL). The combined organic layer was dried over Na2SO4, filtered off and concentrated in vacuo to yield 6.26 g of the title compound as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH2:61][C:62]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)([CH3:68])[C:63]([O:65][CH2:66][CH3:67])=[O:64].C(N(CC)C(C)C)(C)C>CS(C)=O.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:61][C:62]([C:69]3[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=3)([CH3:68])[C:63]([O:65][CH2:66][CH3:67])=[O:64])=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)(N)c1ccccc1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(NC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3nc(C(C)C)ccc23)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.4 %

Procedure:
The product of Example 385E (90 mg, 0.17 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate [TBTU] (60 mg, 0.19 mmol) and ethyl 2-amino-2-phenylpropanoate (39 mg., 0.20 mmol) in DMSO (0.9 mL) was reacted with N,N-diisopropylethylamine (0.060 mL, 0.34 mmol) dropwise at room temperature then stirred at room temperature for 18 hours under N2. The mixture was poured into water (10 mL) with stirring. The resulting precipitate was extracted with ethyl acetate (50 mL) and the organic layer was washed with water (3×), saturated aqueous NaHCO3, then brine, dried over MgSO4, and concentrated. The residue was purified by silica gel chromatography (ethyl acetate:chloroform 4:1) to give the title compound as a pale yellow amorphous solid (93 mg, 78%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([C:22](=[O:39])[CH:23]([N:25]2[CH2:30][CH2:29][C:28]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)([OH:31])[CH2:27][CH2:26]2)[CH3:24])[CH:7]=[C:8]([CH3:21])[C:9]=1[O:10][Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13]>C(O)C>[CH3:3][C:4]1[CH:5]=[C:6]([C@@H:22]([OH:39])[C@H:23]([N:25]2[CH2:30][CH2:29][C:28]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)([OH:31])[CH2:27][CH2:26]2)[CH3:24])[CH:7]=[C:8]([CH3:21])[C:9]=1[O:10][Si:11]([CH:15]([CH3:16])[CH3:17])([CH:12]([CH3:13])[CH3:14])[CH:18]([CH3:19])[CH3:20]
Reactant: Cc1cc(C(=O)C(C)N2CCC(O)(c3ccc(Cl)cc3)CC2)cc(C)c1O[Si](C(C)C)(C(C)C)C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc([C@@H](O)[C@@H](C)N2CCC(O)(c3ccc(Cl)cc3)CC2)cc(C)c1O[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 0.17 h
Yield: 56.7 %

Procedure:
A mixture of sodium borohydride (0.054 g, 1.43 mmol) and ethanol (5 mL) was stirred 10 min and then 1-(3,5-dimethyl-4-triisopropylsilyloxyphenyl)-2-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-one (0.77 g, 1.42 mmol in 25 mL of ethanol) was added. The reaction was stirred at ambient temperature overnight. The white solid which precipitated was collected by filtration and dried to yield 0.44 g (56%) of (1R*,2R*)-1-(3,5-dimethy-4-triisopropylsilyloxyphenyl)-2-(4-(4-chlorophenyl)-4-hydroxypiperdin-1-yl)-propan-1-ol which was suitable for use without further purification and had: mp 211.5-212.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([CH2:13]I)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[O:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[CH:20]=1>>[O:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[CH:20]=[C:16]1[CH2:13][C@H:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]([O:11][CH3:12])=[O:10]
Reactant: Brc1cc2ccccc2o1
Reactant: COC(=O)[C@@H](CI)C(=O)OC(C)(C)C
Product: COC(=O)[C@H](Cc1cc2ccccc2o1)C(=O)OC(C)(C)C

Procedure:
The title compound was synthesized in a manner analogous to that described Example 408, using (R)-methyl 2-(tert-butoxycarbonyl)-3-iodopropanoate and 2-bromobenzofuran. (MS m/z: 220.1 (100%, M-99).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:15]4[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[CH2:16]4)[C:12]=3[CH3:14])[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.[CH:27](O)=[O:28].C(OC(=O)C)(=O)C>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:15]4[CH2:20][CH2:19][N:18]([CH:27]=[O:28])[CH:17]([CH3:21])[CH2:16]4)[C:12]=3[CH3:14])[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=CO
Reactant: Cc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1c(N2CCN(C=O)C(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 80 °C

Procedure:
1-Cyclopropyl-7-(3-methyl-1-piperazinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.4 g) is added to a mixture of formic acid (1.7 ml) and acetic anhydride (2.2 ml) at 0° C. After the addition, the mixture is heated at 80° C. for 2 hours. To the reaction mixture is added water, and the mixture is extracted with dichloromethane. After removing the solvent by concentration, the resulting residue is recrystallized from methanol to give 1-cyclopropyl-7-(4-formyl-3-methyl-1-piperazinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.13 g), as white powder, m.p. 236°-239° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10]([Cl:21])=[N:11][C:12]([C:16]2[N:20]=[CH:19][NH:18][N:17]=2)=[CH:13][C:14]=1[Cl:15].[CH:22]([NH:25]C(C)C)([CH3:24])[CH3:23]>>[Cl:21][C:10]1[C:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[C:14]([NH:25][CH:22]([CH3:24])[CH3:23])[CH:13]=[C:12]([C:16]2[N:20]=[CH:19][NH:18][N:17]=2)[N:11]=1.[Cl:15][C:14]1[CH:13]=[C:12]([C:16]2[N:20]=[CH:19][NH:18][N:17]=2)[N:11]=[C:10]([NH:25][CH:22]([CH3:24])[CH3:23])[C:9]=1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Fc1cccc(Cl)c1-c1c(Cl)cc(-c2nc[nH]n2)nc1Cl
Reactant: CC(C)NC(C)C
Product: CC(C)Nc1cc(-c2nc[nH]n2)nc(Cl)c1-c1c(F)cccc1Cl
Product: CC(C)Nc1nc(-c2nc[nH]n2)cc(Cl)c1-c1c(F)cccc1Cl

Procedure:
In a stainless steel autoclave, 700 mg (2.0 mmol) of 3-(2-chloro-6-fluorophenyl)-2,4-dichloro-6-([1,2,4]triazolyl)pyridine (Example A) and 15 g of diisopropylamine were heated at 160° C. for 12 h. The volatile components were removed under reduced pressure and the residue was chromatographed on silica gel using cyclohexane/ethyl acetate. It was possible to isolate 240 mg of 2-chloro-3-(2-chloro-6-fluorophenyl)-4-(2-propylamino)-6-([1,2,4]triazolyl)pyridine (m.p. 152° C.) and 310 mg of 4-chloro-3-(2-chloro-6-fluorophenyl)-2-(2-propylamino)-6-([1,2,4]triazolyl)pyridine (m.p. 152° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
Periodinane (18.2 g, 42.9 mmol) was added to 3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (7.10 g, 33.0 mmol) in CH2Cl2 (230 mL) and stirred for 90 min. Diethyl ether (230 mL) was added and precipitates were removed by extraction with 10% Na2S2O3/saturated NaHCO3 (1:1, 230 mL). The organic layer was washed with 0.5 M NaOH solution and brine. The organic phase was dried and concentrated under reduced pressure to yield 3-Formyl-piperidine-1-carboxylic acid tert-butyl ester (6.50 g, 93%).
Reaction SMILES: [Na].[CH:2]1([CH2:5][OH:6])[CH2:4][CH2:3]1.Cl[C:8]1[N:13]=[N:12][C:11]([NH2:14])=[CH:10][CH:9]=1>O>[CH:2]1([CH2:5][O:6][C:8]2[N:13]=[N:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: OCC1CC1
Reactant: Nc1ccc(Cl)nn1
Agent: [Na]
Solvent: O
Product: Nc1ccc(OCC2CC2)nn1
Reaction time: 23 h
Yield: 86.7 %

Procedure:
Sodium (127 mg) was added to a stirred cyclopropylmethanol (5 g). After the sodium had dissolved, 6-chloropyridazin-3-amine (0.648 g) was added and the mixture was heated to 170° in a glass pressure vessel with magnetic stirring for 23 h. The cooled reaction mixture was diluted with water and extracted with chloroform (3×50 mL). The combined extracts were dried (sodium sulfate) and evaporated to afford crude 6-cyclopropylmethoxypyridazin-3-amine (716 mg). 1H n.m.r. (CDCl3) δ 0.27-0.38, m, 2H; 0.52-0.66, m, 2H; 1.18-1.38, m, 1H; 4.18, d, 2H; 4.47 broad s, 2H; 7.78, AB q, 2H.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[N:6]=1.[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([F:20])[CH:14]=1.Cl>CCCCO>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=3[N:6]=2)=[C:15]([F:20])[CH:14]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: Cc1cccc2sc(Cl)nc12
Agent: Cl
Solvent: CCCCO
Product: Cc1cccc2sc(Nc3ccc(Br)cc3F)nc12
Temperature: 90 °C
Yield: 89.4 %

Procedure:
To a solution of 2-chloro-4-methyl-1,3-benzothiazole (0.25 g, 1.36 mmol) in n-BuOH (8 mL was added 4-bromo-2-fluoroaniline (0.52 g, 2.72 mmol) and HCl (4.0 M in dioxane, 0.5 mL). The reaction was heated at 90° C. overnight. Solvent was removed by rotary evaporation and 1 N aqueous HCl was added. The aqueous layer was separated and extracted with EtOAc. The combined organic phases were washed with 1 N aqueous HCl and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was brought up in MeOH and the precipitate was collected by filtration, washed with MeOH, and dried in a vacuum oven to give N-(4-bromo-2-fluorophenyl)-4methyl-1,3-benzothiazol-2-amine (0.41 g, 89%). 1H NMR (400 MHz, DMSO-d6) δ 2.62 (s, 3H), 7.07 (t, 1H), 7.15 (d, 1H), 7.36 (m, 2H), 7.51 (d, 1H), 8.72 (t, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)=[O:17])=[C:11]([OH:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:33](Br)Br.C(O)=O>CN1C(=O)N(C)CC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]([N:15]2[C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][C:11]=3[O:30][CH2:33]2)=[O:17])=[CH:20][C:21]=1[C:26]([F:29])([F:27])[F:28]
Reactant: BrCBr
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(OCc2ccccc2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: O=CO
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N1COc2cc(OCc3ccccc3)ccc21
Reaction time: 0.25 h

Procedure:
To a solution of 1.4 g (3.2 mMol) of 1-(4-benzyloxy-2-hydroxy-phenyl)-3-(4-chloro-3-trifluoromethyl-phenyl)-urea in 420 ml DMEU, 700 mg NaH (55% in oil; 16 mMol) are given. After 15 min, 23 ml of CH2Br2 are added and stirring is continued for 6 h. Then 1 ml of formic acid is added and the resulting mixture is evaporated in HV. The residue is dissolved in EtOAc and water. The separated aq. phase is extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; hexane/CH2Cl2 1:1→CH2Cl2) gives the title compound: m.p.: 135-136° C.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:32])(=[O:3])[CH3:2].[CH3:33][C:34]1([CH3:40])[O:38][C:37](=[O:39])[N:36]=[CH:35]1>>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:36]3[CH2:35][C:34]([CH3:40])([CH3:33])[O:38][C:37]3=[O:39])[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C)cc3C)CC2)C1=O
Reactant: CC1(C)C=NC(=O)O1
Product: CC(=O)N1CCN(c2cc(N3CC(C)(C)OC3=O)ccc2C(=O)N2CCN(c3ncc(C)cc3C)CC2)C1=O
Yield: 11.3 %

Procedure:
By reaction and treatment in the same manner as in Example 201 and using 1-acetyl-3-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (653 mg) described in Preparation Example 126 and 5,5-dimethyloxazolin-2-one (165 mg) described in Preparation Example 43, the title compound (86.5 mg) was obtained.
Reaction SMILES: NC1SC=C(C(=O)C(N[C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([CH2:34][NH:35][S:36]([C:39]5[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([OH:46])[CH:40]=5)(=[O:38])=[O:37])[N:33]=[C:29]4[N:28]=[C:27]([CH3:47])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=O)N=1.Cl.NOC(C)(C)C(NO)=O>CC(N(C)C)=O>[OH:46][C:41]1[CH:40]=[C:39]([S:36]([NH:35][CH2:34][C:32]2[N:33]=[C:29]3[N:28]=[C:27]([CH3:47])[CH:26]=[C:25]([S:24][CH2:23][C:15]4[CH2:14][S:13][CH:12]5[N:17]([C:18](=[O:19])[CH2:11]5)[C:16]=4[C:20]([OH:22])=[O:21])[N:30]3[N:31]=2)(=[O:38])=[O:37])[CH:44]=[CH:43][C:42]=1[OH:45]
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)n2nc(CNS(=O)(=O)c3ccc(O)c(O)c3)nc2n1
Agent: CC(C)(ON)C(=O)NO
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)CC3SC2)n2nc(CNS(=O)(=O)c3ccc(O)c(O)c3)nc2n1

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[2-[(3,4-dihydroxybenzenesulphonamido)methyl]-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (0.05 g) and 0.02 g of 2-(aminooxy)-N-hydroxy-2-methylpropionamide hydrochloride are stirred in 0.5 ml of dimethylacetamide for 16 hours at room temperature. The dimethylacetamide is evaporated in a high vacuum, the residue is digested with water and the precipitate formed is filtered off and dried. There is obtained 0.015 g of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[(1-hydroxycarbamoyl)-1-methylethoxy)imino]acetamido]-3-[[[2-[(3,4-dihydroxybenzenesulphonamido)methyl]-5-methyl-s-triazolo[1.5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a pale beige powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@@H:12]([O:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[C:5](/[CH:19]=[CH:20]/[C:21](OCC)=[O:22])=[C:4]([CH3:26])[N:3]=1.C1(S)C=CC=CC=1.[Na].CCCCC=CCCCCC.C(N(C(C)C)CC)(C)C>>[NH2:1][C:2]1[N:3]=[C:4]([CH3:26])[C:5]2[CH:19]=[CH:20][C:21](=[O:22])[N:8]([C@H:9]3[CH2:14][CH2:13][C@@H:12]([O:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]3)[C:6]=2[N:7]=1
Reactant: CCOC(=O)/C=C/c1c(C)nc(N)nc1N[C@H]1CC[C@@H](OCCO)CC1
Agent: CCCCC=CCCCCC
Agent: Sc1ccccc1
Agent: [Na]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N)nc2c1ccc(=O)n2[C@H]1CC[C@@H](OCCO)CC1

Procedure:
A solution of (E)-ethyl 3-(2-amino-4-(cis-4-(2-hydroxyethoxy)cyclohexylamino)-6-methylpyrimidin-5-yl)acrylate (615 mg, 1.69 mmol), thiophenol (173 ul, 1.69 mmol), benzenethiol, sodium salt (248 mg, 1.69 mmol), 1,5-diazabicyclo5,4,0)undec-5-ene (1.01 mL, 6.75 mmol) and diisopropylethyl amine (1.76 mL, 10.1 mmol) in N′,N-dimethylformamide (11.2 mL) was heated to 120° C. overnight. The reaction mixture was concentrated and the residue was partitioned between methyl tert-butylether (500 mL) and saturated sodium bicarbonate (50 mL). The organic layer was separated and washed with 50% brine, dried (Na2SO4), filtered and concentrated. The combined aqueous layers were extracted with chloroform (3×175 mL). Combined extracts were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography eluting with chloroform/7N ammonia in methanol (0-6%) to afford the title compound (411 mg, 77%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[C:21]([CH:22]=O)=[CH:20][CH:19]=[CH:18][N:17]=1.Cl.[F:25][C:26]1([F:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C.C(O)(=O)C.C([BH3-])#N>ClC(Cl)C>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[C:21]([CH2:22][N:29]2[CH2:30][CH2:31][C:26]([F:32])([F:25])[CH2:27][CH2:28]2)=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: FC1(F)CCNCC1
Reactant: O=Cc1cccnc1Oc1ccc2c(nnn2CC2CC2)c1Br
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: FC1(F)CCN(Cc2cccnc2Oc2ccc3c(nnn3CC3CC3)c2Br)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2-{[4-bromo-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]oxy}pyridine-3-carbaldehyde (13, 20 mg, 0.05 mmol, 1 equiv.) and 4,4-difluoropiperidine hydrochloride (13 mg, 0.08 mmol, 1.5 equiv) in dichloroethane (1 mL) was treated with triethylamine (14 uL, 0.10 mmol, 2 equiv) and stirred for 5 min. The mixture was treated with acetic acid (14 uL, 0.25 mmol, 5 equiv) and resin-bound MP-cyanoborohydride (50 mg, 2.08 mmol/g, 2 equiv.) and was irradiated at 110° C. in a microwave reactor for 20 min. The mixture was cooled to ambient temperature and partitioned between sodium bicarbonate (saturated aqueous, 50 mL) and ethyl acetate (3×30 mL). The combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (100:0 to 30:70; hexanes:ethyl acetate) to afford 4-bromo-1-(cyclopropylmethyl)-5-({3-[(4,4-difluoropiperidin-1-yl)methyl]pyridin-2-yl}oxy)-1H-benzotriazole (194) as a white powder, 1H NMR (400 MHz, CDCl3) δ 7.98 (dd, 1H, J=4.9, 2.0 Hz), 7.85 (br d, 1H, J=7.4 Hz), 7.56 (d, 1H, J=8.8 Hz), 7.36 (d, 1H, J=8.8 Hz), 7.04 (dd, 1H, J=7.5, 4.9 Hz), 4.52 (d, 2H, J=7.1 Hz), 3.85 (s, 2H), 2.73 (ap t, 4H, J=5.3 Hz), 2.11-2.01 (m, 4H), 1.47-1.37 (m, 1H), 0.71-0.67 (m, 2H), 0.54-0.50 (m, 2H) ppm. High resolution mass spectrometry (ES+) m/z=478.1062, [(M+H)+ calculated for C21H23BrF2N5O: 478.1049].
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])C)=O)(C)(C)C.[F:17][C:18]([F:38])([F:37])[C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:28]2[CH2:32][C@@H:31]3[C@@H:33]([NH2:36])[CH2:34][CH2:35][C@@H:30]3[CH2:29]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[CH2:39](N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)[C:40]1[CH:45]=CC=C[CH:41]=1>>[CH2:6]([NH:8][C@H:9]([C:14]([NH:36][C@@H:33]1[C@@H:31]2[C@@H:30]([CH2:29][N:28]([S:25]([C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:37])[F:38])=[CH:24][CH:23]=3)(=[O:26])=[O:27])[CH2:32]2)[CH2:35][CH2:34]1)=[O:16])[CH2:10][CH2:11][CH3:13])[C:40]([CH3:45])([CH3:41])[CH3:39]
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Product: CCC[C@H](NCC(C)(C)C)C(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting (S)-2-(neopentylamino)pentanoic acid from Step A of Example 246 for N-(tert-butoxycarbonyl)-L-leucine and (3aR,4S,6aS)-2-(4-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 256 for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.37-8.38 (bs, 1H), 8.13-8.18 (m, 3H), 7.89-7.91 (m, 2H), 4.21-4.28 (m, 1H), 3.86 (dd, J=9.9, 2.9 Hz, 1H), 3.16-3.22 (m, 3H), 2.98 (dd, J=9.6, 7.3 Hz, 1H), 2.47-2.61 (m, 2H), 2.41 (d, J=11.2 Hz, 1H), 2.32 (d, J=11.2 Hz, 1H), 1.93-2.00 (m, 1H), 1.78-1.88 (m, 2H), 1.63-1.70 (m, 1H), 1.41-1.58 (m, 3H), 1.28-1.36 (m, 1H), 0.93 (s, 9H), 0.86 (t, J=7.3 Hz, 3H); MS (ESI+) m/z 504 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:42])[C@@H:7]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:11][CH:10]=1)(C)(C)C>FC(F)(F)C(O)=O.O>[NH:26]1[CH2:25][CH2:24][CH2:23][N:22]=[C:21]1[NH:20][C:19]([CH2:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C@H:7]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:6]([OH:42])=[O:5])=[CH:10][CH:11]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(CCCOc1ccc(C[C@H](NS(=O)(=O)c2ccc(C(F)(F)F)cc2)C(=O)O)cc1)NC1=NCCCN1
Reaction time: 2 h

Procedure:
37.3 mg of (2S)-3-{4-[3-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-propoxy]-phenyl}-2-(4-trifluoromethylbenzenesulfonylamino)-propionic acid tert-butyl ester were dissolved in trifluoroacetic acid/water (95/5) and stirred for 2 hours. The solvent was removed in vacuo, and the residue was dissolved in acetic acid/water and lyophilized. Yield 27.6 mg. MS (ES+): m/e=557.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=2)[C:18]([C:20]2[CH:27]=[CH:26][C:23]([CH2:24]O)=[CH:22][CH:21]=2)=[O:19])[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])O.[Na+].[CH3:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>ClCCl.C(Cl)(Cl)Cl>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=2)[C:18]([C:20]2[CH:27]=[CH:26][C:23]([CH2:24][N:52]3[CH2:53][CH2:54][N:49]([CH3:48])[CH2:50][CH2:51]3)=[CH:22][CH:21]=2)=[O:19])[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1cccc(C(=O)c2ccc(CO)cc2)c1
Reactant: CN1CCNCC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(C)cc(C)nc2n1Cc1cccc(C(=O)c2ccc(CN3CCN(C)CC3)cc2)c1
Reaction time: 1 h
Yield: 29.9 %

Procedure:
Compound 14 (0.250 g, 0.625 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (0.131 mL, 0.939 mmol) and methanesulfonyl chloride (0.730 mL, 0.943 mmol) was added to the solution at 0° C., followed by stirring for 1 hour. The reaction mixture was added with a saturated aqueous sodium hydrogen carbonate solution, and diluted with chloroform, then washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 mL), and 1-methylpiperazine (0.208 mL, 1.87 mmol) and triethylamine (0.870 mL, 0.623 mmol) was added to the solution, followed by stirring at room temperature overnight. The reaction mixture was diluted with chloroform, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to obtain Compound 15 (0.0900 g, yield 30%).