Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:22]([OH:24])=[O:23])[CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][Si:26]([CH:29](O)[CH3:30])([CH3:28])[CH3:27].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:22]([O:24][CH2:30][CH2:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[O:23])[CH2:13][NH:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCc1ccccc1)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[(Benzyloxy)carbonyl]-3-[(tert-butoxycarbonyl)amino]-L-alanine (1000.0 mg, 2.96 mmol) [Rane, F. Dinanath et al.; Tetrahedron Lett.; EN; 34; 20; 1993; 3201-3204] is dissolved in dichloromethane (20 ml), and trimethylsilylethanol (4.2 ml, 3.5 g, 29.55 mmol, 10 eq.), DCC (1.22 g, 5.91 mmol, 2 eq.) and DMAP (361.1 mg, 2.96 mmol, 1 eq.) are successively added to the solution at −20° C. The reaction is warmed to RT and stirred at this temperature overnight and brought to complete conversion. For the workup, the mixture is concentrated, and the residue is taken up in diethyl ether and subsequently extracted twice with water and once with a sat. aq. sodium chloride solution. The etheric phase is dried over sodium sulfate, the desiccant is removed by filtration through silica gel, and most of the solvent is removed from the filtrate on a rotary evaporator. If a precipitate separates out during the concentration, this can be removed again where appropriate through silica gel. The residue obtained is then fine purified by chromatography (method 31) and 1.1 g (86.4% of theory) of the title compound are obtained.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8]C(C1C=NC(N2CCCC2)=C(OCCC)N=1)=O)[CH2:4][CH:5]([CH3:7])[CH3:6].[CH3:26][C:27]([CH3:46])([CH3:45])[CH2:28][O:29][C:30]1[N:35]=[C:34]([C:36]([OH:38])=O)[CH:33]=[N:32][C:31]=1[N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.N[C@H](CO)CC(C)C>>[OH:1][CH2:2][C@@H:3]([NH:8][C:36]([C:34]1[CH:33]=[N:32][C:31]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[C:30]([O:29][CH2:28][C:27]([CH3:26])([CH3:46])[CH3:45])[N:35]=1)=[O:38])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Reactant: CC(C)(C)COc1nc(C(=O)O)cnc1N1CCOCC1
Agent: CC(C)C[C@H](N)CO
Product: CC(C)C[C@@H](CO)NC(=O)c1cnc(N2CCOCC2)c(OCC(C)(C)C)n1

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 6-(2,2-dimethyl-propoxy)-5-morpholin-4-yl-pyrazine-2-carboxylic-acid and (S)-leucinol (commercially available). m/z (ES+): 395.3 (M+H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:21](=[O:22])[CH2:20][C:19](=[O:23])[NH:18][C:17]3[C:24]4[C:29]([CH:30]=[CH:31][C:16]2=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:11][CH:10]=1)=[O:7].ClC1C=CC=C(C(OO)=[O:43])C=1.C(OCC)(=O)C>CN(C)C=O>[CH3:1][S:2]([C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:21](=[O:22])[CH2:20][C:19](=[O:23])[NH:18][C:17]3[C:24]4[C:29]([CH:30]=[CH:31][C:16]2=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:13][CH:14]=1)=[O:7])=[O:43]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cccc(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)c1cccc(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)c1
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
5-[4-[3-(Methylthio)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (20 mg, 0.043 mmol) obtained in Example 126 was dissolved in dimethylformamide (0.4 mL), the solution was added with m-chloroperbenzoic acid (ii mg, 0.03 mmol) at −20° C., and the mixture was stirred for 30 minutes. After completion of the reaction, the reaction mixture was added with ethyl acetate at −20° C., the organic layer was washed with saturated aqueous sodium hydrogencarbonate, water, and saturated brine. The solvent of the organic layer was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/1) to obtain the title compound (8 mg, yield 38%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[NH:4][C:5](=[O:13])[N:6]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7]=1[NH2:8].C(Cl)(Cl)Cl.[CH3:19][CH2:20]OCC>C(O)(=O)C>[CH3:19][C:20]1[NH:1][C:2]2[C:3](=[O:14])[NH:4][C:5](=[O:13])[N:6]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7]=2[N:8]=1
Reactant: CC(C)Cn1c(N)c(N)c(=O)[nH]c1=O
Reactant: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1nc2c([nH]1)c(=O)[nH]c(=O)n2CC(C)C

Procedure:
10 g of 5,6-diamino-1-(2-methylpropyl)-2,4-(1H,3H)-pyrimidine dione was refluxed in 50 ml of acetic acid for 1 hour. 30 ml of chloroform was added and ether was then added slowly. The received crystals were filtered off. Yield 10.8 g. The amide was refluxed in 30 ml of 2N NaOH for 1 hour and then neutralized with 5N HCl. The crystals were filtered off and recrystallized from 50 ml of acetic acid. Yield 3.3 g. NMR (see Table I).
Reaction SMILES: Br.Br[CH:3]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([F:19])[CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1)=O.[NH2:20][C:21]([NH2:23])=[S:22].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[F:19][C:15]1[CH:14]=[C:13]([C:3]2[S:22][C:21]([NH2:23])=[N:20][C:4]=2[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Cc1cccc(C(=O)C(Br)c2ccnc(F)c2)c1
Reactant: NC(N)=S
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2nc(N)sc2-c2ccnc(F)c2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a mixture of 2-bromo-2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone hydrobromide [synthesized according to Reference Example 19 using 2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanbne (8.46 g, 36.9 mmol) instead of 2-(2-tert-butoxycarbonylamino-4-pyridyl)-1-(3methylphenyl)ethanone] and thiourea (3.03 g, 39.8 mmol) in acetonitrile (50 mL) was added triethylamine (5.2 mL, 37.3 mmol), and the mixture was stirred at 80° C. for 2 hrs. Aqueous sodium hydrogen carbonate solution was poured into the reaction mixture and the precipitated solids were collected by filtration. The obtained solid was washed with water and dried. Crude crystals were recrystallized from ethanol to give the title compound (3.67 g, yield 35%).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:12]OC(OC)N(C)C>>[N:1]12[CH:12]3[N:4]([CH2:5][CH2:6][CH2:7][N:8]3[CH2:9][CH2:10][CH2:11]1)[CH2:3][CH2:2]2
Reactant: C1CNCCCNCCNC1
Reactant: COC(OC)N(C)C
Product: C1CN2CCCN3CCN(C1)C23
Yield: 81.8 %

Procedure:
In a manner similar to that of Example 1 (C), 5.28 g (33.6 mmol) of 1,4,8-triazacycloundecane and 4.00 g of dimethylformamide dimethyl acetal were reacted to give 4.59 g of 1,4,8-triazatricyclo[6.3.1.04,12 ]dodecane as a clear, colorless liquid, bp 80°-82° (three fractions) (1.2 mm), nD24 = 1.5182. A fraction boiling at 82° was analyzed.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[N:10]2)=[CH:5][CH:4]=1.O1CCCC1.[CH:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]=[C:38]=[S:39])([CH3:30])[CH3:29]>ClCCl>[CH:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:38]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([C:11]2[N:12]=[CH:13][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:8][CH:7]=3)[N:10]=2)=[CH:15][CH:16]=1)=[S:39])([CH3:30])[CH3:29]
Reactant: CC(C)c1ccccc1N=C=S
Reactant: Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)c1ccccc1NC(=S)Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 65 °C

Procedure:
To 4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)aniline (0.496 g, 1.63 mmol) in a 25 mL vial equipped with a stir bar, Vigreux column, and nitrogen inlet was added tetrahydrofuran (4.08 mL) followed by 1-isopropyl-2-isothiocyanatobenzene (0.826 ml, 4.89 mmol). The reaction was heated to 65° C. overnight. The reaction was cooled to room temperature. The reaction mixture was diluted with dichloromethane and washed with water. The aqueous layer was extracted with dichloromethane (2×). The organic layers were poured through a phase separator and concentrated. Purification by flash column chromatography using 0-20% ethyl acetate/B, where B=1:1 dichloromethane/hexanes as eluent provided a white solid. The solid was dried at 55° C. at about 25 in. Hg providing the title compound as a white solid (0.361 g, 46%).
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH:3]([CH3:5])[CH3:4].Cl.[CH2:9]([O:13][C:14](=[O:29])[C@H:15]([CH3:28])[NH:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:19])[CH:10]([CH3:12])[CH3:11].C(N[C@H](C(O)=O)CC1C=CC=CC=1)(OC(C)(C)C)=O.Cl.C(OC(=O)[C@H](C)N)C(C)C>CO.C(Cl)(Cl)Cl>[CH2:9]([O:13][C:14](=[O:29])[C@H:15]([CH3:28])[NH:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH:19][C:1](=[O:7])[CH2:2][CH:3]([CH3:5])[CH3:4])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)CC(=O)O
Reactant: CC(C)COC(=O)[C@H](C)NC(=O)[C@@H](N)Cc1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)[C@H](C)N
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)COC(=O)[C@H](C)NC(=O)[C@H](Cc1ccccc1)NC(=O)CC(C)C

Procedure:
Following General Procedure C and using isovaleric acid (Aldrich) and N-(L-phenylalaninyl)-L-alanine iso-butyl ester hydrochloride (prepared from N-BOC-L-phenylalanine (Sigma) and L-alanine iso-butyl ester hydrochloride (prepared as described in Example 83A above) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp=135-138° C.). The reaction was monitored by tlc (Rf=0.3 in 3% MeOH/CHCl3) and the product was purified by silica gel chromatography using 3% MeOH/CHCl3 as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].C(Cl)Cl.[C:15](Cl)(=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:24])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: CCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1Cl
Yield: 26.1 %

Procedure:
To a solution of 2.0 g (1.1×10-2 mol) of 3-chloro-4-hydroxy benzoic acid in 40 ml of dried methylene chloride containing 3.0 g (9.2×10-3 mol) of pyridine was added dropwise 3.0 g (9.2×10-3 mol) of nonanoic acid chloride, which were stirred under reflux for 7 hours. After the completion of the reaction, the solution was washed with an aqueous solution of 1 normal hydrochloric acid and further with water and dried on anhydrous magnesium sulfate. After magnesium sulfate was filtered off, the resulting product was purified through a silica gel column chromatography using methylene chloride and ethanol at 9:1 (v/v) as a developing solution and then recrystallized with 5 ml of ethanol to obtain 750 mg (yield: 25%) of a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12]1.CCN(C(C)C)C(C)C>CCO>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:12]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(c2ccncc2[N+](=O)[O-])C1
Yield: 95 %

Procedure:
The method of Example 1 was followed using 4-chloro-3-nitropyridine (1.0 eq), tert-butyl pyrrolidin-3-ylcarbamate (2.0 eq), and DIEA (2.0 eq) in EtOH yielding tert-butyl 1-(3-nitropyridin-4-yl)pyrrolidin-3-ylcarbamate (95%) LCMS (m/z): 309.1 (MH+); LC Rt=1.922 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][N:11]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C@@H:10]([CH2:29][OH:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:32].[Na+]>CC(C)=O.O.O.[Ru](=O)=O>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][N:11]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C@@H:10]([C:29]([OH:32])=[O:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COc1ccc(S(=O)(=O)N2C[C@@H](CC(C)C)N(C(=O)OC(C)(C)C)C[C@@H]2CO)cc1
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(S(=O)(=O)N2C[C@@H](CC(C)C)N(C(=O)OC(C)(C)C)C[C@@H]2C(=O)O)cc1
Reaction time: 0.67 h
Yield: 102.4 %

Procedure:
Ruthenium (IV) oxide hydrate (238 mg) was added to a solution of (2R,5R)-4-(tert-butoxycarbonyl)-2-hydroxymethyl-1-(4-methoxybenzenesulfonyl)-5-(2-methylpropyl)piperazine (5.3 g) in acetone (50 ml) and H2O (20 ml), followed by addition of sodium periodate (5.1 g) with cooling on an ice bath. After stirring at the same temperature for 40 minutes, the reaction was quenched with 2-propanol (50 ml). Insoluble matter was removed by filtration through a celite pad, and the filtrate was washed with acetone and AcOEt. The filtrate and combined washings were concentrated in vacuo, and the residue was partitioned by dissolving same in 5% aqueous sodium bisulfite and AcOEt. The organic layer was washed with saturated NaCl solution, dried over MgSO4, and concentrated in vacuo to give 5.6 g of (2R,5R)-4-(tert-butoxycarbonyl)-1-(4-methoxybenzenesulfonyl)-5-(2-methylpropyl)piperazine-2-carboxylic acid as an amorphous powder.
Reaction SMILES: [Cl:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[OH:11].[CH:12]([O:14][CH2:15][CH3:16])=[CH2:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[Cl:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[O:11][CH:12]([O:14][CH2:15][CH3:16])[CH3:13]
Reactant: O[C@@H]1c2ccccc2C[C@H]1Cl
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Product: CCOC(C)O[C@@H]1c2ccccc2C[C@H]1Cl

Procedure:
A stirrer, thermometer and reflux condenser were mounted to a 100-ml three-necked flask which was filled with 10.0 g (0.059 mol) of trans-2-chloroindan-1-ol, 13 ml of monochlorobenzene and 4.72 g (0.066 mol) of ethyl vinyl ether. While the mixture was stirred, 5.6 g (0.03 mol) of p-toluenesulfonic acid was added and stirred for 3 hours at 25° C. to form trans-2-chloro-1-(1-ethoxyethoxy)indane in the reaction system. Moreover, to the reaction liquid was added 123.4 g (0.77 mol) of a 25% aqueous solution of NaOH and 1.44 g (0.0035 mol) of tetrabutylammonium bromide and the mixture was stirred for 30 hours at 103° C. to form 1-(1-ethoxyethoxy)indene in the reaction system. The reaction liquid was separated into a monochlorobenzene layer and a water layer. To the monochlorobenzene layer were added 20 ml of water and 0.65 g (0.0065 mol) of 98% sulfuric acid and the mixture was stirred for 1 hour at 78° C. After the reaction, the reaction liquid was separated into a monochlorobenzene layer and a water layer, and the monochlorobenzene layer was rinsed twice with 100 ml of water. The monochlorobenzene layer was dried with anhydrous sodium sulfate and then vacuum-concentrated to obtain 6.93 g of a black oil of 1-indanone (giving a yield of 88.4%). The purity of this oil according to gas chromatography (GC) was 63.9% (surface area percentage). The IR spectrum of this oil matches the IR spectrum of commercial 1-indanone.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][NH2:12].O>ClCCl>[CH3:11][NH:12][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: CN
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: ClCCl
Solvent: O
Product: CNc1ccncc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a suspension of 4-chloro-3-nitropyridine (2 g, 12.6 mmol) in dichloromethane (15 mL) was cautiously added methyl amine (25% solution in water, 10 mL, 63 mmol). The reaction mixture was heated to 40° C. After stirring for 1 h, the mixture was poured into water (20 mL), and the precipitate was collected by filtration and dried in vacuo to afford the title compound (1.9 g, yield 98%) as a yellow solid. LC-MS (ESI) m/z: 154 (M+1)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([O-:25])=[O:24]>C(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([S:32]([C:29]2[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:31][CH:30]=2)(=[O:33])=[O:34])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
Diisopropylethylamine (7.8 ml, 45 mmol) was added in one portion to a stirred solution of piperazine-1-carboxylic acid tert-butyl ester (7.6 g, 41 mmol) in DCM (100 ml) at room temperature. To this mixture was added 4-nitrophenyl sulfonyl chloride (10.0 g, 45 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (50 ml) and washed with water (100 ml), saturated NaHCO3 (100 ml) and HCl (100 ml, 2M). The organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum to give the title compound (14.9 g, 89% yield) as a white solid. δH (500 MHz, DMSO) 8.45 (2H, d), 7.97 (2H, d), 3.34 (4H, obscured), 2.96-2.92 (4H, m), 1.33 (9H, s). Tr=1.91 min m/z (ES+) ([(M−100)+H]+) 272.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38]([C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:56])OC2C=CC=CC=2)=[CH:43][CH:42]=1)(=[O:40])[NH2:39]>CN(C=O)C>[CH3:30][NH:29][C:27]([NH:26][C:23]1[CH:22]=[CH:21][C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:48]([NH:47][C:44]4[CH:43]=[CH:42][C:41]([C:38]([NH2:39])=[O:40])=[CH:46][CH:45]=4)=[O:56])=[CH:7][CH:6]=3)[N:9]=2)=[CH:25][CH:24]=1)=[O:28]
Reactant: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3CCOCC3)n2)cc1
Reactant: NC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(NC(=O)Nc4ccc(C(N)=O)cc4)cc3)nc(N3CCOCC3)n2)cc1
Temperature: 90 °C
Yield: 5.3 %

Procedure:
To a solution of 1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea (0.6 g, 1.5 mmol) and triethylamine (4-5 mL) in dry DMF (10 mL), phenyl 4-carbamoylphenylcarbamate (1.15 g, 4.5 mmol).) was added at room temperature and mixture was heated to 90° C. for 10 hours under nitrogen atmosphere. After cooling to room temperature reaction mixture was quenched with ice water and resulting solid was filtered to get crude product. Crude product was purified by Preparative HPLC to give 4-({[4-(4-{4-[(methylcarbamoyl)amino]phenyl}-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzamide (45 mg, 5.3% yield).
Reaction SMILES: C([O:8][C@H:9]1[CH2:13][N:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:11](=[O:27])[C@H:10]1[O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][C:30]=1[F:39])C1C=CC=CC=1.[H][H]>CCO.[Pd]>[F:39][C:30]1[CH:31]=[C:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=[CH:34][C:29]=1[O:28][C@H:10]1[C@@H:9]([OH:8])[CH2:13][N:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:11]1=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCC(N2C[C@H](OCc3ccccc3)[C@H](Oc3ccc(S(C)(=O)=O)cc3F)C2=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N2C[C@H](O)[C@H](Oc3ccc(S(C)(=O)=O)cc3F)C2=O)CC1
Yield: 59.5 %

Procedure:
Tert-butyl 4-((3S,4S)-4-(benzyloxy)-3-(2-fluoro-4-(methylsulfonyl)phenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (160 mg, 0.284 mmol) was dissolved in EtOH (3 mL) and 100 mg 10% Pd/C was added and stirred under balloon pressure of hydrogen overnight. The reaction was filtered and concentrated to afford tert-butyl 4-((3S,4S)-3-(2-fluoro-4-(methylsulfonyl)phenoxy)-4-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (80 mg, 0.169 mmol, 59.5% yield).
Reaction SMILES: CO[C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.[NH2:32][CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:16]2[C:15]([C:13]3[N:12]=[CH:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([NH:32][CH:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[O:31])=[CH:5][N:6]=4)[CH:14]=3)=[C:19]([C:20]([F:22])([F:21])[F:23])[O:18][N:17]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1
Reactant: NC1CCOCC1
Product: O=C(NC1CCOCC1)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1
Yield: 99.7 %

Procedure:
As described for Example 38b, 6-{4-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-nicotinic acid methyl ester (100 mg, 0.23 mmol), was converted, using 4-aminotetrahydropyran (96.35 μL, 0.9 mmol) instead of cyclopropanemethylamine, to the title compound (115 mg, 99%) which was obtained as a white solid. MS: m/e=501.8 [M+H]+.