Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](NCCN)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[C:32]([O:36][C:37]([NH:39][CH2:40][C:41]([OH:43])=O)=[O:38])([CH3:35])([CH3:34])[CH3:33].[CH:44]1([N:50]=C=NC2CCCCC2)CCCC[CH2:45]1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2=[N:15][CH2:16][N:17]([C:41](=[O:43])[CH2:40][N:39]([C:37]([O:36][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:38])[CH2:45][CH2:44][NH2:50])[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:13]2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(NCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1C1=c2ccc(=O)n(-c3c(F)cccc3F)c2=NCN1C(=O)CN(CCN)C(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
The title compound of Example 157 (168 mg, 0.0004 mol) in dry THF (2 mL) with tert-butoxycarbonylglycine (70 mg, 0.0004 mol) was treated with dicyclohexylcarbodiimide (82.4 mg, 0.0004 mol) in dry THF (2 mL). The solution was stirred 16 h at 23°; filtered and stripped to dryness. The residue was taken up in methylene chloride (5 mL) and applied to a Chromatotron™ Rotor Plate (1000 u thickness); plate eluted with methylene chloride-methanol gradient (0% to 3% MeOH). This afforded 122 mg (52%) of the title compound as a light red solid. LC MS (m/e)=583(MH+). Rt=2.12 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[NH:25][C:26]1[S:27][C:28]2[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:29]=2[N:30]=1.ClCCl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:35][C:33]2[CH:32]=[CH:31][C:29]3[N:30]=[C:26]([NH:25][C:16]4[C:15]5[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=5)[N:19]=[CH:18][N:17]=4)[S:27][C:28]=3[CH:34]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Solvent: CO
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)Nc5ccc(Cl)cc5)cc4s3)c2cc1OC

Procedure:
1-(4-Chlorophenyl)-3-[2-(6,7-dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl]urea was prepared from 4-chlorophenyl isocyanate (17.4 mg, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 3. Preparative TLC of the reaction mixture (dichloromethane:methanol=9:1) furnished a yellowish solid (33.9 mg, 67 μmol, 59%). LC/ESI-MS: m/z=507 [M(35Cl)+H]+; m/z=505 [M(35Cl)−H]−; R′, =3.50 min.
Reaction SMILES: Cl[C:2]1C=C(C=C[CH:11]=1)C(OO)=O.C(S[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:22]=[C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]2[CH:33]=1)C.[S:34]([O-:38])([O-])(=[O:36])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:34]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:15][C:16]=1[C:21]1[N:22]=[C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][N:24]2[CH:33]=1)(=[O:38])=[O:36])[CH3:11]
Reactant: CCSc1ccccc1-c1cn2cc(C(F)(F)F)ccc2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1ccccc1-c1cn2cc(C(F)(F)F)ccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
552 mg of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to a mixture of 370 mg of 2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-imidazo[1,2-a]pyridine and 5 ml of chloroform under ice cooling, and the mixture was stirred at room temperature for 2 hours. A 10% aqueous sodium thiosulfate solution was poured to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 260 mg of 2-(2-ethylsulfonylphenyl)-6-trifluoromethyl-imidazo[1,2-a]pyridine (hereinafter, referred to as Compound of Present Invention 5).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH:54]1[CH2:57][CH:56]([NH:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[CH2:55]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([C:5]([N:54]2[CH2:57][CH:56]([NH:58][C:59](=[O:65])[O:60][C:61]([CH3:63])([CH3:62])[CH3:64])[CH2:55]2)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Yield: 80.6 %

Procedure:
A solution of 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (200 mg, 0.51 mmol), prepared using procedures similar to those in U.S. Pat. No. 7,019,033, PyBOP (256 mg, 0.51 mmol), commercially available tert-butyl azetidin-3-ylcarbamate (131 mg, 0.77 mmol) and N,N-diisopropylethylamine (180 μL, 1.02 mmol) in dimethylformamide (3 mL) was stirred at room temperature for 15 hours. The reaction mixture was partitioned between 5% aqueous lithium chloride and ethyl acetate. The organic portion was washed with 20% aqueous citric acid, saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown residue which was purified by silica gel column chromatography eluting with 30% ethyl acetate in hexanes to afford 1,1-dimethylethyl [1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate (225 mg, 80% yield) as a colorless oil. 1H NMR (400 MHz, DMSO): 8.56 (s, 1H), 7.60-7.55 (m, 2H), 7.38 (d, 1H), 7.30-7.26 (m, 1H), 7.20-7.13 (m, 1H), 6.71-6.66 (m, 1H), 4.37-4.20 (m, 2H), 4.18-4.06 (m, 1H), 3.98-3.93 (m, 1H), 3.82-3.75 (m, 1H), 1.37 (s, 9H). MS (EI) C21H21N3O3F3I: 548 (MH+).
Reaction SMILES: C([O-])(O)=O.[Na+].[C:6]([OH:10])(=[O:9])[CH2:7][CH3:8].[C:11](=[O:18])([S:15][CH2:16][CH3:17])[O:12][CH2:13]I>O.C(Cl)Cl>[C:11](=[O:18])([S:15][CH2:16][CH3:17])[O:12][CH2:13][O:9][C:6](=[O:10])[CH2:7][CH3:8]
Reactant: CCSC(=O)OCI
Reactant: CCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCSC(=O)OCOC(=O)CC
Yield: 98.8 %

Procedure:
To a stirred solution of NaHCO3 (45 g, 536 mmol) in H2O (540 ml) is added TBA HSO4 (91.2 g, 268 mmol), propanoic acid (20.1 mL, 268 mmol), and CH2Cl2 (540 ml). Following stirring for 1 h at room temperature a solution of 5b (49.2 g, 200 mmol) in CH2Cl2 (100 mL) is added during 45 min keeping the temperature below 30° C. The stirring is continued for 11/2 h. The organic phase is separated, washed with H2O (200 mL), dried (MgSO4), and evaporated. The residue is stirred in Et2O (800 mL) during the night, filtered, and washed with Et2O (50 mL). The filtrate is evaporated and distilled to yield 38.0 g (98%) of 6cb, bp 71°-73° C./0.3 mbar.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][CH:5]1[CH2:10][CH:9]([CH2:11][OH:12])[CH2:8][CH2:7][N:6]1[C:13]([O:15][CH3:16])=[O:14].[Na].[OH2:20]>C(Cl)(Cl)(Cl)Cl.C(#N)C.C(Cl)Cl.[Ru](Cl)(Cl)Cl>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([OH:20])=[O:12])[CH2:8][CH2:7][N:6]1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)N1CCC(CO)CC1CCC(C)(C)C
Reactant: O
Agent: Cl[Ru](Cl)Cl
Agent: [Na]
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)N1CCC(C(=O)O)CC1CCC(C)(C)C
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 94 %

Procedure:
Methyl 2-(3,3-dimethylbutyl)-4-(hydroxymethyl)piperidine-1-carboxylate (2.44 g, 9.49 mmol) was dissolved in CCl4 (20 mL) and acetonitrile (20 mL). Sodium periodiate (6.09 g, 28.5 mmol) was added followed by water (30 mL) and ruthenium (III) chloride (43 mg, 0.21 mmol). The resulting suspension was stirred at room temperature for 3 h 50 min. The reaction mixture was diluted with DCM (100 mL) and water (100 mL). The aqueous layer was extracted with DCM (×3) and the combined organic phase passed through a phase separator and evaporated to yield crude 2-(3,3-dimethylbutyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (2.42 g, 94%) as a black solid. MS m/z 272 (M+H)+
Reaction SMILES: [CH3:1][Li].C[Si](Cl)(C)C.[Br:8][C:9]1[CH:34]=[CH:33][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=3)[C:16]([CH:25]=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:15]2[CH3:32])=[CH:11][CH:10]=1.[NH4+].[Cl-]>CCOCC.C1COCC1>[Br:8][C:9]1[CH:34]=[CH:33][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=3)[C:16]([CH:25]([CH3:1])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:15]2[CH3:32])=[CH:11][CH:10]=1
Reactant: [Li]C
Reactant: CCOC(=O)C=Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CC(C)c1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 73.1 %

Procedure:
To a 0° C. suspension of cuprous iodide (12.7 g, 67.0 mmol) in 150 mL ether was added CH3Li (1.4M in ether, 96 mL, 134 mmol). The solution was cooled to -78° C. and treated with TMSCl (8.5 mL, 67 mmol) and a solution of the unsaturated ester from Step 3 (6.79 g, 15.8 mmol) in 30 mL of THF. The yellow suspension was allowed to warm to room temperature and was stirred 2.5 h. The reaction mixture was poured into saturated NH4Cl and extracted with EtOAc. The organic extracts were washed with water and brine and dried over Na2SO4. Purification by flash chromatography (20% ethyl acetate/hexanes) provided 5.13 g of the title product as a crystaline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].ClCCl>N1C=CC=CC=1>[NH3:1].[CH2:14]([N:11]1[CH2:12][CH2:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:24]([CH3:23])(=[O:26])=[O:25])[CH:3]=2)([CH2:20][CH2:21][CH3:22])[CH2:9][CH2:10]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCN1CCC(CCC)(c2cccc(N)c2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCN1CCC(CCC)(c2cccc(NS(C)(=O)=O)c2)CC1
Product: N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 183.9 %

Procedure:
To a solution of 4-(3-aminophenyl)-N-hexyl-4-n-propylpiperidine (Preparation 70, 25 mg, 0.08 mmol) in pyridine (0.5 ml) under nitrogen was added methanesulfonyl chloride (10 ml, 0.124 mmol) and the resultant mixture was stirred overnight. Ice (2 g) was added and, after 15 min, dichloromethane (3 ml) was added and the biphasic mixture was left to stir for 15 min. The layers were separated and the aqueous layer was extracted with dichloromethane (3 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by silica (5 g) column chromatography eluting with ethyl acetate:hexane:0.880 ammonia (60:40:1 to 80:20:1) to give the title compound as a colourless oil (28 mg, 92%). The free base was dissolved in diethyl ether (3 ml) and 1.1 mol equivalents of 1N ethereal hydrogen chloride solution was added to provide a precipitate. The solvent was decanted and the solid dried in vacuo to yield the title compound as a hygroscopic solid.
Reaction SMILES: C(Cl)Cl.[OH:4][C:5]1[C:14]2[C:9](=[C:10]([F:17])[C:11]([F:16])=[C:12]([F:15])[CH:13]=2)[N:8]=[C:7]([SH:18])[C:6]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C.[C:31]([O:34][CH2:35][C:36]([CH2:38]Cl)=[O:37])(=[O:33])[CH3:32]>C(Cl)(Cl)Cl>[C:31]([O:34][CH2:35][C:36](=[O:37])[CH2:38][S:18][C:7]1[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:5]([OH:4])[C:14]2[C:9](=[C:10]([F:17])[C:11]([F:16])=[C:12]([F:15])[CH:13]=2)[N:8]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OCC(=O)CCl
Reactant: CCOC(=O)c1c(S)nc2c(F)c(F)c(F)cc2c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(SCC(=O)COC(C)=O)nc2c(F)c(F)c(F)cc2c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
To methylene chloride (500 ml) were added ethyl 4-hydroxy-2-mercapto-6,7,8-trifluoroquinoline-3-carboxylate (33 g), triethylamine (22 g) and 1-acetoxy-3-chloroacetone (16.4 g) and the mixture was stirred at room temperature for 15 minutes. Chloroform (700 ml) was added to the reaction solution and washed with 0.1N hydrochloric acid, water and a NaCl solution in this order, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (37.2 g) as colorless crystals, m.p. 175°-180° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:32])=[C:9]([C:28]([Cl:31])=[CH:29][CH:30]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)[CH3:6])=[O:4].[C:33](OC(=O)C)(=[O:35])[CH3:34].N1C=CC=CC=1>ClCCl>[C:33]([NH:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:32])=[C:9]([C:28]([Cl:31])=[CH:29][CH:30]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)[CH3:6])=[O:4])(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(-n2ccnc2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccc3c(-n4ccnc4)cc(C)nc23)c1Cl
Reaction time: 3 h
Yield: 81.1 %

Procedure:
To a stirred solution of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (60 mg) in dichloromethane (0.6 ml) were added acetic anhydride (15.6 mg) and pyridine (15.1 mg) at ambient temperature, and the mixture was stirred for 3 hours at the same temperature. The mixture was concentrated in vacuo, and the residue was purified by preparative thin layer chromatography (chloroform:methanol, 10:1, v/v) to give 8-[3-(N-(acetylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (53 mg) as colorless amorphous.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+].[CH3:21][C:22]([CH3:24])=O>>[CH3:21][C:22]1([CH3:24])[O:4][C@@H:3]2[C@@H:5]([C@@H:7]([CH2:9][OH:10])[O:8][CH:2]2[OH:1])[O:6]1
Reactant: CC(C)=O
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC1(C)O[C@@H]2[C@@H](CO)OC(O)[C@@H]2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
Into a suspension of D-ribose (50 g, 0.33 mol) in acetone (1500 mL) was added sulfuric acid (1 mL) dropwise. Reaction mixture was stirred overnight at room temperature and then neutralized with sat. aq. NaHCO3. Solution was decanted and concentrated. Oily residue was dissolved in EtOAc (1000 mL) and washed with water (300 mL). Aqueous layer was re-extracted with EtOAc (2×500 mL). Combined extracts were dried over Na2SO4 and concentrated to yield the target compound (42.3 g, 67.3%) as oil which was used as such for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17]([OH:19])=O)=[N:9]2)[CH:3]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][C@@H:52]([C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:53][OH:54]>CN(C=O)C>[OH:54][CH2:53][C@@H:52]([NH:51][C:17]([C:10]1[C:11]2[CH2:12][C@H:13]3[CH2:16][C@H:14]3[C:15]=2[N:8]([C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=2)[N:9]=1)=[O:19])[C:55]([CH3:58])([CH3:57])[CH3:56]
Reactant: CC(C)(C)[C@H](N)CO
Reactant: O=C(O)c1nn(-c2cc(Br)ccn2)c2c1C[C@H]1C[C@@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[C@@H](CO)NC(=O)c1nn(-c2cc(Br)ccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 94.6 %

Procedure:
To a solution of (1aR,5aR)-2-(4-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2.00 g, 6.25 mmol) and triethylamine (1.741 mL, 12.49 mmol) in DMF (15 mL) was added HATU (2.423 g, 6.37 mmol). The reaction was stirred at 23° C. for 5 min, then was added (S)-2-amino-3,3-dimethylbutan-1-ol (0.805 g, 6.87 mmol). The reaction was stirred at 23° C. for 1 h then concentrated. The residue was purified by silica gel column chromatography to give the title compound as a white solid (2.48 g). LCMS m/z=419.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.44 (td, J=4.6, 3.4 Hz, 1H), 1.05 (s, 9H), 1.24 (td, J=7.8, 4.9 Hz, 1H), 2.23-2.29 (m, 1H), 2.46 (t, J=5.5 Hz, 1H), 2.78-2.83 (m, 1H), 2.91 (d, J=16.7 Hz, 1H), 3.01 (dd, J=16.6, 6.3 Hz, 1H), 3.66-3.72 (m, 1H), 3.93-4.01 (m, 2H), 7.01 (d, J=8.8 Hz, 1H), 7.37 (dd, J=5.3, 1.6 Hz, 1H), 8.09 (d, J=1.6 Hz, 1H) 8.28 (d, J=5.3 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:18][CH:17]=2)[C:10]=1[N+:31]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>C1COCC1.CO.O.[Fe]>[NH2:31][C:10]1[C:11]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[CH:20][CH:21]=2)=[N:12][CH:13]=[N:14][C:9]=1[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(Nc2ncnc(N(Cc3ccccc3)Cc3ccccc3)c2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1ccc(Nc2ncnc(N(Cc3ccccc3)Cc3ccccc3)c2N)cc1
Temperature: 60 °C
Yield: 95.3 %

Procedure:
To a solution of tert-butyl 4-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)phenyl(methyl)carbamate (37) (6 g, 11.1 mmol) in THF/MeOH/H2O (100 mL/100 mL/30 mL) was added Fe powder (3.11 g, 55.5 mmol) and NH4Cl (5.94 g, 111 mmol). The reaction mixture was heated at 60° C. for 4 h under N2. After cooling to rt, the reaction mixture was filtered through a pad of Celite. The filtrate was extracted with EtOAc (100 mL×3), washed with water and brine, dried over Na2SO4, and concentrated in vacuo to afford tert-butyl 4-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)phenyl(methyl)carbamate (38) (5.4 g, yield 95%) as a yellow solid. LC-MS (ESI): m/z (M+1) 511.
Reaction SMILES: C([S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:74]=[CH:73][C:20]([C:21]([O:23][C:24]2[CH:72]=[CH:71][C:27]([C:28]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38](=[O:70])[C:39]4[CH:44]=[CH:43][C:42]([O:45][C:46](=[O:69])[C:47]5[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][S:65]C(=O)C)=[CH:49][CH:48]=5)=[CH:41][CH:40]=4)[CH:32]=3)=[O:29])=[CH:26][CH:25]=2)=[O:22])=[CH:19][CH:18]=1)(=O)C.Cl>C1COCC1.CO.O>[SH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:23][C:24]2[CH:72]=[CH:71][C:27]([C:28]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38](=[O:70])[C:39]4[CH:44]=[CH:43][C:42]([O:45][C:46](=[O:69])[C:47]5[CH:48]=[CH:49][C:50]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][SH:65])=[CH:51][CH:52]=5)=[CH:41][CH:40]=4)[CH:32]=3)=[O:29])=[CH:26][CH:25]=2)=[O:22])=[CH:73][CH:74]=1
Reactant: CC(=O)SCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)Oc3cccc(OC(=O)c4ccc(OC(=O)c5ccc(OCCCCCCCCCCCSC(C)=O)cc5)cc4)c3)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(Oc1ccc(C(=O)Oc2cccc(OC(=O)c3ccc(OC(=O)c4ccc(OCCCCCCCCCCCS)cc4)cc3)c2)cc1)c1ccc(OCCCCCCCCCCCS)cc1
Temperature: 25 °C

Procedure:
Compound BC4 (0.2 g, 0.2 mmol) was dissolved in 50:50 THF/MeOH (20 mL), and following addition of 3 mL conc. HCl to the flask, the mixture was heated to reflux for 6 hours. The mixture was let to cool to room temperature, diluted with water (10 mL), and extracted with CH2Cl2 (2×200 mL). The solvent was removed, and the residue purified by column chromatography (CH2Cl2: EtOH, 10:0.03). The product was then selectively precipitated from CH2Cl2 through dropwise addition of petroleum ether. Yield 0.11 g (60%). EA: Found: C, 69.37; H, 7.21. C56H66O10S2 requires C, 69.83; H, 6.91%. 1H NMR: δH (CDCl3; 300 MHz): 1.24-1.56 (30 H, m, CH2 / SH), 1.63 (4 H, m, S—CH2—CH2), 1.85 (4 H, m, O—CH2—CH2), 2.55 (4 H, q, 3J=7.4, SCH2), 4.07 (4 H, t, 3J=6.5 Hz, OCH2), 7.01 (4 H, d, 3J=8.9 Hz, Ar—H), 7.22 (3 H, m, Ar—H), 7.40 (4 H, d, 3J=8.7 Hz, Ar—H), 7.50 (1 H, t, 3J=8.2 Hz, Ar—H), 8.17 (4 H, d, 3J=8.9 Hz, Ar—H), 8.29 (4 H, d, 3J=8.7 Hz, Ar—H). 13C NMR: δC (CDCl3; 75 MHz): 25.1, 26.4, 28.8, 29.5, 29.7, 29.9, 29.9, 34.4, 53.8, 68.8, 114.8, 116.2, 119.7, 121.4, 122.5, 127.0, 130.3, 132.3, 132.8, 151.8, 155.9, 164.2, 164.5, 164.7. m/z (MALDI) 985.81 [M+Na]+, C56H66NaO10S2 requires 985.40.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([N:11]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:23][CH:22]=[N:21][C:20]=3[CH3:24])=[CH:15][CH:14]=2)[CH2:10][CH2:9]1.Cl[C:33]1[N:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=1>CN1CCCC1=O>[Cl:39][C:36]1[CH:35]=[N:34][C:33]([N:29]2[CH2:30][CH2:31][CH:26]([N:11]([CH:8]3[CH2:10][CH2:9]3)[C:12](=[O:25])[C:13]3[CH:14]=[CH:15][C:16]([C:19]4[O:23][CH:22]=[N:21][C:20]=4[CH3:24])=[CH:17][CH:18]=3)[CH2:27][CH2:28]2)=[N:38][CH:37]=1
Reactant: Cc1ncoc1-c1ccc(C(=O)N(C2CCNCC2)C2CC2)cc1
Reactant: Clc1cnc(Cl)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: Cc1ncoc1-c1ccc(C(=O)N(C2CC2)C2CCN(c3ncc(Cl)cn3)CC2)cc1

Procedure:
The title compound is prepared from N-cyclopropyl-4-(4-methyl-oxazol-5-yl)-N-piperidin-4-yl-benzamide trifluoroacetic acid salt and 2,5-dichloro-pyrimidine following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 6): tR=1.92 min; Mass spectrum (ESI+): m/z=438/440 (Cl) [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH2:16]O)[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:12][C@H:11]2[CH3:26])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:41]1[CH:45]=[N:44][N:43]=[N:42]1>C(Cl)Cl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@@H:14]([CH2:16][C:45]3[NH:44][N:43]=[N:42][N:41]=3)[N:13]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:12][C@H:11]2[CH3:26])=[O:9])=[CH:4][CH:3]=1
Reactant: c1nnn[nH]1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](CO)CN1C(=O)COc1ccc(Cl)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@H](Cc2nnn[nH]2)CN1C(=O)COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 13 %

Procedure:
To a solution of (2R,5R)-1-((4-chlorophenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)-5-((hydroxy)methyl)piperazine (0.17 g, 0.42 mmol) in CH2Cl2(50 mL) at 0° C. was added triethylamine (excess) and methane sulfonyl chloride (0.050 mL, 0.5 mmol). The resultant mixture was stirred at 0° C. until consumption of alcohol was observed by TLC analysis. The mixture was concentrated of volatiles in vacuo. Residue was taken up in anhydrous DMF (5 mL) and K2CO3 (excess) added, followed by tetrazole (0.050 g, 0.71 mmol). The resulting mixture was stirred at ambient temperature for 3 days and filtered. The filtrate was concentrated in vacuo and the residue taken up in ethyl acetate. This was washed with water then brine, then dried over MgSO4 and concentrated in vacuo to afford a yellow oil. Purification by flash column chromatography on silica gel afforded 25 mg of (2R,5R)-1-((4-chlorophenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)-5-((tetrazolyl)methyl)piperazine as a white solid: NMR (CDCl3) 7.3 (m, 5), 7.0 (m, 4), 4.8-4.1 (m, 5), 3.8 (m, 3), 3.2 (m, 2), 2.8 (dd, 1), 2.5 (dd, 1), 1.4 (d, 3) ppm, MS (ESI) 458.