Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH3:7][O:8][N:9]=[CH:10][C:11]1[CH:16]=[C:15]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[NH:19][C:18]2=O)[C:14]([F:29])=[CH:13][C:12]=1[Cl:30].CI.O>CN(C)C=O>[CH3:7][O:8][N:9]=[CH:10][C:11]1[CH:16]=[C:15]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[N:19]([CH3:18])[C:1]2=[O:4])[C:14]([F:29])=[CH:13][C:12]=1[Cl:30]
Reactant: CON=Cc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CON=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 20 °C
Reaction time: 20 h

Procedure:
First, 117.1 g (0.85 mol) of potassium carbonate were added to a solution of 281.6 g (0.77 mol) of 2-chloro-4-fluoro-5-(6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl)benzaldehyde (O-methyl)oxime in 0.8 l of dimethylformamide, whereupon a solution of 120.2 g of methyl iodide (0.85 mol) in 0.1 l of dimethylformamide was added dropwise in the course of 1 hour. The reaction mixture was subsequently stirred for 20 hours at approximately 20° C., and 0.9 l of water was subsequently added dropwise with ice-cooling. The product of value was extracted from the resulting solution using 1 l of dichloromethane. The extract was washed three times using 300 ml of water, dried over sodium sulfate and finally concentrated. Yield: 241 g; m.p.: 141-142° C. (diisopropyl ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[C:11]([C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])=[O:17])#[N:12].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>>[C:11]([C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:17])#[N:12]
Reactant: COc1ccc(CCl)cc1
Reactant: N#Cc1cccc(C(=O)Nc2ccccc2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccccc2NC(=O)c2cccc(C#N)c2)cc1

Procedure:
Using a procedure similar to Example 32A except starting from 4-methoxybenzyl chloride and N1-(3-cyanobenzoyl)-2-hydroxyaniline and using K2CO3/DMF in place of potassium t-butoxide/THF, the title compound was obtained as a solid (27%); MS(FD): 359.
Reaction SMILES: [CH2:1]([NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-])=O)[C:12]=1[OH:21])(=[O:10])=[O:9])[C@H:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[H][H]>[Pd]>[CH2:1]([NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([NH2:18])[C:12]=1[OH:21])(=[O:9])=[O:10])[C@H:2]1[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC[C@@H]2CCCO2)c1O
Reactant: [H][H]
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)NC[C@@H]2CCCO2)c1O
Yield: 92.1 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, N-((2S)-tetrahydrofurfuryl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (270 mg, 0.80 mmol) was reduced with hydrogen and Pd/C (140 mg) to form the desired product (226 mg, 94%). EI-MS m/z 305(M-H)−.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][NH2:14]>>[O:1]1[CH:5]=[CH:4][C:3]([C:10]2[CH:11]=[C:12]([CH2:13][NH2:14])[CH:15]=[CH:16][CH:17]=2)=[CH:2]1
Reactant: NCc1cccc(Br)c1
Reactant: OB(O)c1ccoc1
Product: NCc1cccc(-c2ccoc2)c1
Yield: 76 %

Procedure:
Using the same method as in Example 19-(ii), 3-furanboronic acid was reacted with the 3-bromobenzyl amine to give 1-[3-(furan-3-yl)phenyl]methanamine (yield: 76%).
Reaction SMILES: N[C:2](N)=[S:3].[CH3:5][O:6][C:7]1[CH:18]=[CH:17][C:10]([CH2:11][O:12][CH2:13][CH:14]2CO2)=[CH:9][CH:8]=1>CO>[CH3:5][O:6][C:7]1[CH:18]=[CH:17][C:10]([CH2:11][O:12][CH2:13][CH:14]2[CH2:2][S:3]2)=[CH:9][CH:8]=1
Reactant: COc1ccc(COCC2CO2)cc1
Reactant: NC(N)=S
Solvent: CO
Product: COc1ccc(COCC2CS2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Thiourea (0.935 g, 12.28 mmol) was added to a solution of 2-(((4-methoxybenzyl)oxy)methyl) oxirane (1.084 g, 5.58 mmol) in methanol (30 mL) and the mixture stirred at room temperature for 16 hours, then evaporated under vacuum. Purification by chromatography on silica, eluting with 0-10% EtOAc/hexane, afforded the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].C1C(=O)N([Br:25])C(=O)C1>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Br:25])[CH:13]=3)[NH:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2c(c1)[nH]c1ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(c1)[nH]c1ccc(Br)cc12
Reaction time: 5 h

Procedure:
To a solution of 9H-carbazol-2-yl acetate (500 mg, 2.2 mmol) in DCM (40 mL) was added a solution of NBS in 25 mL of DCM dropwise at rt. The reaction mixture was stirred in the dark for 5 h. It was washed with water (3×50 mL) and dried over MgSO4 and concentrated. The crude product was purified by silica chromatography (EtOAc/hexane) to afford 6-bromo-9H-carbazol-2-yl acetate (WZ02025) as an off-white solid (250 mg, containing 17% dibrominated product). MS (ESI) m/z 305 (M+H+).
Reaction SMILES: [Br: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.[NH:13]1[C:17]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([NH:24][NH2:25])=[O:23])=[CH:20][CH:19]=2)=[N:16][N:15]=[N:14]1>C(O)(=O)C>[Br: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=[N:25][NH:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:18]([C:17]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:19][CH:20]=1
Reactant: NNC(=O)c1ccc(-c2nnn[nH]2)cc1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(Br)cc2C1=NNC(=O)c1ccc(-c2nnn[nH]2)cc1
Temperature: 100 °C
Yield: 53 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-bromo-1H-indole-2,3dione in acetic acid was added 4-(1H-tetrazol-5-yl)benzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 29 mg of the title compound (53%) as a orange Solid in 89.1% purity by HPLC (Rt: 3.29, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)=[CH:10][C:4]=2[S:3]1.[C:17]1([CH3:30])[CH:22]=[CH:21][C:20]([O:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1>C(OCC)C>[O:15]=[C:13]([N:27]1[CH2:28][CH2:29][CH:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([CH3:30])=[CH:18][CH:19]=2)[CH2:25][CH2:26]1)[C:12]([NH:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2](=[O:1])[S:3][C:4]=2[CH:10]=1)=[O:16]
Reactant: Cc1ccc(OC2CCNCC2)cc1
Reactant: O=C(O)C(=O)Nc1ccc2[nH]c(=O)sc2c1
Solvent: CCOCC
Product: Cc1ccc(OC2CCN(C(=O)C(=O)Nc3ccc4[nH]c(=O)sc4c3)CC2)cc1

Procedure:
The title compound is prepared from N-(2-oxo-2,3-dihydro-benzothiazol-6-yl)-oxalamic acid (Example 61b) and 4-p-tolyloxy-piperidine according to the method described in Example 1c. Melting Point: 215-217° C. (diethylether)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:40])[C@@H:12]1[CH2:19][N:18]2[C:20]3[CH:21]=[C:22]([C:33](O)=[O:34])[CH:23]=[CH:24][C:25]=3[C:26]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[C:17]2[C:16]2[CH:36]=[CH:37][CH:38]=[CH:39][C:15]=2[O:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[CH3:45][O:46][CH:47]([O:55][CH3:56])[CH2:48][N:49]([CH3:54])[S:50]([NH2:53])(=[O:52])=[O:51].S(N)(N)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH:27]1([C:26]2[C:25]3[CH:24]=[CH:23][C:22]([C:33]([NH:53][S:50]([N:49]([CH2:48][CH:47]([O:46][CH3:45])[O:55][CH3:56])[CH3:54])(=[O:52])=[O:51])=[O:34])=[CH:21][C:20]=3[N:18]3[C:17]=2[C:16]2[CH:36]=[CH:37][CH:38]=[CH:39][C:15]=2[O:14][CH2:13][C@H:12]([N:11]([CH3:40])[CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:19]3)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COC(CN(C)S(N)(=O)=O)OC
Reactant: CN(CCNC(=O)OC(C)(C)C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Agent: CN(C)c1ccncc1
Agent: NS(N)(=O)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCNC(=O)OC(C)(C)C)COc1ccccc1-3)OC
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 44 %

Procedure:
To a solution of (7R)-7-[{2-[(tert-butoxycarbonyl)amino]ethyl}(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid (0.15 M) in DCM were added sequentially EDC (1.8 eq), N-(2,2-dimethoxyethyl)-N-methylsulfamide (1.8 eq) (prepared as described in Step 1) and DMAP (1.2 eq). The mixture was stirred at 40° C. for 1.5 hours. Further EDC (0.48 eq) and sulfamide (0.5 eq) were introduced and heating continued for 1 h. The reaction was left to cool with stirring overnight. The reaction was diluted with EtOAc and washed with 1N HCl (aq). The aqueous was extracted with EtOAc and the organics combined, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to leave a brown gum. The residue was purified by RP-HPLC (Waters Xterra column; MeCN/H2O/0.1% TFA gradient). Fractions containing the pure compound were combined and lyophilized to afford the product as a white powder (44%). MS (ES+) m/z 728 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C@@H:11]1[CH2:16][C@H:15]([N:17]([CH:19]([CH3:21])[CH3:20])[CH3:18])[CH2:14][CH2:13][C@@H:12]1[NH:22][C:23](=[O:36])[CH2:24][NH:25]C(=O)OCC1C=CC=CC=1)([CH3:10])[CH3:9]>CO.[Pd]>[NH2:25][CH2:24][C:23]([NH:22][C@H:12]1[CH2:13][CH2:14][C@@H:15]([N:17]([CH:19]([CH3:20])[CH3:21])[CH3:18])[CH2:16][C@H:11]1[CH:8]([CH3:10])[CH3:9])=[O:36]
Reactant: CC(C)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)CNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)CN
Reaction time: 3 h
Yield: 122.6 %

Procedure:
A solution of benzyl 2-((1S,2S,4R)-2-isopropyl-4-(isopropyl(methyl)amino)cyclohexylamino)-2-oxoethylcarbamate trifluoroacetate (188 mg) in MeOH (10 mL) was charged with 10% Pd/C, Degussa (30 mg). The reaction flask was evacuated and then back-filled with hydrogen; this was repeated three more times. The reaction was stirred under 1 atm of H2 for 3 h and then filtered and concentrated to afford 2-amino-N-((1S,2S,4R)-2-isopropyl-4-(isopropyl(methyl)amino)cyclohexyl)acetamide (120 mg). MS found: (M+H)+=270.3.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[CH2:15]([O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21])[CH2:16][CH3:17]>CO>[CH2:15]([O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1)[CH2:16][CH3:17]
Reactant: CCCOc1ccccc1N
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Solvent: CO
Product: CCCOc1ccccc1Nc1ncc(C(=O)OCC)c(=O)[nH]1
Temperature: 120 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
A mixture of ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (4.2 g) and 2-propoxyaniline (3.5 g) is heated with stirring without a solvent at 120° C. for 1 hour. After cooling, methanol is added to the reaction mixture in order to pulverize the solid, and then the product is collected by filtration and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-2-(2-propoxyanilino)-6-oxo-5-pyrimidinecarboxylate (4.5 g). M.p. 198°-200° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH2:13])=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([O:16][C:17](=[O:28])[C:18](=[CH:24]OCC)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:15]>>[CH2:14]([O:16][C:17](=[O:28])[C:18](=[CH:24][NH:13][C:12]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:9]=[CH:10][CH:11]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:15]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccnn1Cc1ccccc1
Product: CCOC(=O)C(=CNc1ccnn1Cc1ccccc1)C(=O)OCC
Temperature: 120 °C
Yield: 75 %

Procedure:
To 2-benzyl-2H-pyrazol-3-ylamine (5.0 g, 0.0289 mol) was added 2-ethoxymethylene-malonic acid diethyl ester (5.78 mL, 0.0289 mol) and the mixture was heated at 120° C. for 4 hours. After cooling down to RT, the crude mixture was purified by column chromatography (SiO2, EtOAc/Heptane 1/1) to give 7.44 g (75%) of the title compound as a light yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])C3C(=CC=CC=3)[C:7](=[O:19])[C:6]=2[C:5]=1[N+]([O-])=O)([O-:3])=[O:2].[N+:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([O-:25])=[O:24]>>[N+:23]([C:26]1[C:31]2[C:7](=[O:19])[C:6]3[C:15](=[CH:16][CH:17]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14](=[O:18])[C:30]=2[CH:29]=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: O=C1c2ccccc2C(=O)c2c1ccc([N+](=O)[O-])c2[N+](=O)[O-]
Reactant: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)c2c1cccc2[N+](=O)[O-]

Procedure:
100 g of dinitroanthraquinone mixture of the composition described in Example 1 (A) are employed and stirred with B ml of nitrobenzene at C° C. for A hours and the precipitate is filtered off at C° C., washed with 50 ml of nitrobenzene and dried. D g of 1,7-dinitro-anthraquinone of the composition E are obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:45][C:46](=[O:50])[CH2:47][CH2:48][NH2:49])C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:49][CH2:48][CH2:47][C:46]([OH:45])=[O:50])=[O:36])=[CH:38][CH:39]=2)=[CH:40][CH:41]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)NCCC(=O)O)cc2)cc1

Procedure:
The product from Example 233 and beta-alanine ethyl ester hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ11.91-12.41 (br.s, 1 H), 8.94 (s, 1 H), 7.90 (m, 1 H), 7.22 (m, 7 H), 6.88-7.09 (m, 7 H), 6.82 (d, 2 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.92 (t, 2 H), 3.24 (dd, 2 H), 2.91 (s, 3 H), 2.38 (s, 3 H), 2.37 (t, 2 H), 2.21 (t, 2 H), 1.91 (m, 2 H); MS (ESI+) m/z 646 (M+H)+.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2]1.[NH:24]1[CH:31]=[CH:30][C:28]([NH2:29])=[N:27][C:25]1=[O:26].C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>CN(C)C=O>[OH:1][CH:3]([CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2][N:24]1[CH:31]=[CH:30][C:28]([NH2:29])=[N:27][C:25]1=[O:26]
Reactant: Nc1cc[nH]c(=O)n1
Reactant: CCCCCCCCCCCCCCCCCCOCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOCC(O)Cn1ccc(N)nc1=O
Temperature: 25 °C
Yield: 37.3 %

Procedure:
rac-1,2-Epoxy-3-octadecyloxypropane (2.0 g, 6.13 mmol) is added to a mixture of cytosine (1.0 g, 9.0 mmol) and anhydrous potassium carbonate (40 mg) in dimethyl formamide (25 mL) over a 30 minute period under a nitrogen atmosphere. The resultant mixture is stirred at 80°-90° C. (oil bath temperature) for 48 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo to leave a residue. The residue is stirred with chloroform (50 mL). The undissolved material is filtered in vacuo, and the filtrate is concentrated in vacuo, purified by chromatography and dried in vacuo to afford 1.0 g (37%) of 1-[2'-hydroxy-3'-octadecyloxypropyl]-cytosine (CPR 1149): Thin-layer Chromatography (TLC; 4×8 cm silica gel 60, 0.25 mm thickness): 10:2:0.2 (v/v/v) CHCl3 -CH3OH-30% aqueous ammonia (Rf value=0.66); mp 153°-154° C.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:5]=2[N:4]([CH2:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([O:30][CH2:31][CH3:32])[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=2)[CH2:3]1.O.[OH-].[Li+]>>[CH3:1][CH:2]1[O:7][C:6]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:5]=2[N:4]([CH2:13][CH2:14][CH2:15][NH:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH:24]([O:30][CH2:31][CH3:32])[C:25]([OH:27])=[O:26])=[CH:21][CH:22]=2)[CH2:3]1
Reactant: CCOC(=O)C(Cc1ccc(NCCCN2CC(C)Oc3cc(F)ccc32)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCOC(Cc1ccc(NCCCN2CC(C)Oc3cc(F)ccc32)cc1)C(=O)O
Yield: 63.4 %

Procedure:
Ethyl 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate (320 mg, 1 eq, 0.72 mmol) obtained in example 52, was hydrolyzed using lithium hydroxide monohydrate (46 mg, 1.5 eq, 1.08 mmol), in methanol-THF-water at RT till all the starting material is consumed (4 to 5 h). The reaction mixture was diluted with water, acidified (pH ˜4-5) with dil. HCl and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on rotary evaporator. The residue was chromatoghaphed using methanol and chloroform to afford the title compound (190 mg, yield 64%) as viscous liquid.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:8][CH:7]=1)(=[NH:4])[CH2:2][CH3:3].Br.Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)=O>>[CH2:2]([C:1]1[N:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:8][CH:7]=2)[CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[N:4]=1)[CH3:3]
Reactant: CCC(=N)Nc1ccc(CCNC(=O)OC(C)(C)C)cc1
Reactant: O=C(CBr)c1ccccn1
Agent: Br
Product: CCc1nc(-c2ccccn2)cn1-c1ccc(CCNC(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 4 of Example 26 from tert-butyl 2-[4-(propanimidoylamino)phenyl]ethylcarbamate and 2-bromo-1-(2-pyridinyl)ethanone hydrobromide (J. Org. Chem., 1996, 61, 4623). MS (ESI) m/z 393 [M+H]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:34][C@H:35]([C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=1)[C@H:36]([NH:40][C:41](=[O:54])[C@@H:42]([NH:44][C:45](=[O:53])[CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)[CH3:43])[C:37](O)=[O:38].[NH2:63][C@@H:64]([CH2:71][CH:72]1[CH2:76][CH2:75][CH2:74][CH2:73]1)[C:65]([C@@:67]1([CH3:70])[CH2:69][O:68]1)=[O:66]>CN(C=O)C>[CH:72]1([CH2:71][C@H:64]([NH:63][C:37](=[O:38])[C@@H:36]([NH:40][C:41](=[O:54])[C@@H:42]([NH:44][C:45](=[O:53])[CH2:46][N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[CH3:43])[C@H:35]([OH:34])[C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=2)[C:65]([C@@:67]2([CH3:70])[CH2:69][O:68]2)=[O:66])[CH2:73][CH2:74][CH2:75][CH2:76]1
Reactant: C[C@]1(C(=O)[C@@H](N)CC2CCCC2)CO1
Reactant: COc1ccc([C@@H](O)[C@H](NC(=O)[C@H](C)NC(=O)CN2CCOCC2)C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([C@@H](O)[C@H](NC(=O)[C@H](C)NC(=O)CN2CCOCC2)C(=O)N[C@@H](CC2CCCC2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
Sequentially HATU (1.84 g, 4.80 mmol) and DIEA (0.63 mL, 20 mmol) were added to a 0° C. solution of (2S,3R)-3-hydroxy-3-(4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanoic acid (1.65 g, 4.00 mmol) and (S)-2-amino-3-cyclopentyl-1-((R)-2-methyloxiran-2-yl)propan-1-one (1.2 g, 4.0 mmol) in DMF (30 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 30 min. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=2:1 to EtOAc) to afford (2S,3R)-N-((S)-3-cyclopentyl-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-hydroxy-3-(4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanamide (1.45 g, 61% yield) as a colorless solid. 1H NMR (300 MHz, CDCl3): δ 7.40 (d, J=5.7 Hz, 1H), 7.32-7.22 (m, 2H), 7.06-6.99 (m, 2H), 6.82 (d, J=8.7 Hz, 2H), 5.26-5.21 (m, 1H), 4.68-4.60 (m, 2H), 4.58-4.39 (m, 2H), 4.01-3.85 (m, 1H), 3.81 (s, 3H), 3.74-3.72 (m, 4H), 3.25 (d, J=4.8 Hz, 1H), 2.99-2.85 (m, 2H), 2.53-2.39 (m, 4H), 1.74-1.61 (m, 8H), 1.53 (s, 3H), 1.33 (d, J=6.9 Hz, 3H), 1.28-1.20 (m, 3H). MS(EI) for C30H44N4O8, found 589.3 (MH)+.
Reaction SMILES: Cl.[CH:2]1([CH2:9][NH2:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:11]([N:18]1[CH:22]=[CH:21]N=C1)(N1C=CN=C1)=[O:12]>>[CH:2]1([CH2:9][NH:10][C:11]([NH:18][CH2:22][CH:21]2[CH2:5][CH2:4][CH2:3][CH2:2][CH2:8][CH2:7]2)=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NCC1CCCCCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Product: O=C(NCC1CCCCCC1)NCC1CCCCCC1
Yield: 24 %

Procedure:
In the manner of step (a) of Example 6, cycloheptanemethylamine hydrochloride (R. B. Turner and R. H. Garner, J. Amer. Chem. Soc. 1958, 80:1424-1430; 22.00 g, 0.135 mole) was reacted with 1,1'-carbonyldiimidazole to give 1,3-bis(cycloheptylmethyl)urea as a white powder (4.45 g, 24%), m.p. 106°-108° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [C:1]([C:3]1[S:7][CH:6]=[C:5]([N:8](C(OC(C)(C)C)=O)[NH:9]C(OC(C)(C)C)=O)[CH:4]=1)#[N:2].[ClH:24].O1CCOCC1>CC(O)C>[ClH:24].[NH:8]([C:5]1[CH:4]=[C:3]([C:1]#[N:2])[S:7][CH:6]=1)[NH2:9]
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1csc(C#N)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: N#Cc1cc(NN)cs1
Yield: 97 %

Procedure:
To a stirring solution of compound 12 (1.38 g, 4.07 mmol) in 2-propanol (10 mL) was added 4M HCl in dioxane (10 mL, 40.0 mmol). The reaction heated to 80 degrees for 1 hour turning into a dark brown solution. The mixture was evaporated to dryness and the resulting the brown solid suspended and sonicated in diethyl ether. The suspension was filtered to afford compound 13 (0.701 g, 97%) as a brown solid. LRMS (ESI): calc. 139.0; found 140.1 (MH)+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([NH:19][C:20]([CH2:26]C)([CH2:24]C)[C:21](O)=O)=[O:18])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH2:3][CH2:2]1.C(N)(C)(C)C>>[C:20]([NH:19][C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:3][CH2:2]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:8]=1)=[O:18])([CH3:26])([CH3:21])[CH3:24]
Reactant: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CCCO2)n1)C(=O)O
Solvent: CC(C)(C)N
Product: CC(C)(C)NC(=O)c1ccc(C2CC2)c(OCC2CCCO2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 2-(5-cyclopropyl-6-((tetrahydrofuran-2-yl)methoxy)picolinamido)-2-ethylbutanoic acid (Example 166 b) and tert-butylamine (CAN 75-64-9) as starting materials. MS (EI): m/e=319.4 [M+H]+.