Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][OH:23])[S:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[NH:10][C:9]=1[C:18]([NH2:20])=[O:19])(=[O:7])=[O:6].[CH3:24][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[Br:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][OH:23])[S:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:24])[CH:15]=2)[NH:10][C:9]=1[C:18]([NH2:20])=[O:19])(=[O:6])=[O:7]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: NC(=O)c1[nH]c2ccc(O)cc2c1S(=O)(=O)N(CCO)CCBr
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N(CCO)CCBr)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-{[(2-bromoethyl)(2-hydroxyethyl)amino]sulfonyl}-5-hydroxy-1H-indole-2-carboxamide, described in Step B of Example 51, in 2:1 dichloromethane/MeOH was added excess trimethylsilyldiazomethane (solution in hexane). After stirring at room temperature for 16 hours, the mixture was concentrated in vacuo. Purification by preparative reversed phase HPLC afforded the titled product. HRMS (ES) exact mass calculated for C14H18BrN3O5S (M+H+): 420.0224. Found 420.0221.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH2:17][C:16](=[O:18])[NH:15][C:14]3[CH:19]=[C:20]([Cl:26])[C:21]([N:23]([CH3:25])[CH3:24])=[CH:22][C:13]=3[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=O.[NH2:27][C:28]([NH2:30])=[S:29]>C1COCC1.CCOC(C)=O>[NH2:30][C:28]1[S:29][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([C:11]3[CH2:17][C:16](=[O:18])[NH:15][C:14]4[CH:19]=[C:20]([Cl:26])[C:21]([N:23]([CH3:25])[CH3:24])=[CH:22][C:13]=4[N:12]=3)[CH:8]=[CH:9][CH:10]=2)[N:27]=1
Reactant: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(C(=O)CBr)c1)=N2
Reactant: NC(N)=S
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3csc(N)n3)c1)=N2
Temperature: 60 °C
Yield: 20.2 %

Procedure:
A mixture of 4-(3-bromoacetyl-phenyl)-8-chloro-7-dimethylamino-1,3-dihydro-benzo[b][1,4]diazepin-2-one (0.73 g) (Example 193a) and thiourea (0.13 g) in THF (10 mL) was heated to 60° C. for 15 min. The mixture was diluted with AcOEt and washed with sat. NaHCO3 solution and with brine. The organic layer was dried and evaporated and the residue was stirred with CH2Cl2 to give the title compound (0.14 g) as yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](O)[CH:13]([CH3:15])[CH3:14].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:5]
Reactant: O=C(O)c1cc(I)ccc1O
Reactant: CC(C)CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)COC(=O)c1cc(I)ccc1O

Procedure:
2-hydroxy-5-iodobenzoic acid (477 g, 1.8 mol), isobutanol (225 g), conc sulfuric acid (20 ml) in toluene (2 l) was refluxed for 6 h using a water separator. The solution was cooled and washed with water. The solution was treated with decolorizing carbon and the toluene was evaporated. The residue was recrystallized from methanol. Yield 376 g.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10](=[O:24])[NH:11][C:12]2[S:13][C:14]3[CH:20]=[C:19]([S:21]C#N)[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.SCC(C(CS)O)O>P([O-])(O)(O)=O.[K+]>[N:1]1([CH2:7][CH2:8][O:9][C:10](=[O:24])[NH:11][C:12]2[S:13][C:14]3[CH:20]=[C:19]([SH:21])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#CSc1ccc2nc(NC(=O)OCCN3CCOCC3)sc2c1
Agent: O=P([O-])(O)O
Agent: OC(CS)C(O)CS
Agent: [K+]
Product: O=C(Nc1nc2ccc(S)cc2s1)OCCN1CCOCC1
Yield: 173.7 %

Procedure:
The 2-morpholin-4-ylethyl(6-sulphanyl-1,3-benzothiazol-2-yl)carbamate was prepared according to the method described in Example 1b, but using 547 mg of 2-morpholin-4-ylethyl(6-thiocyanato-1,3-benzothiazol-2-yl)carbamate, 12 mg of potassium dihydrogen phosphate and 1.16 g of DL-dithiothreitol. 885 mg of 2-morpholin-4-ylethyl(6-sulphanyl-1,3-benzothiazol-2-yl)carbamate are thus obtained in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[OH-].[Na+].Cl.Cl[CH:11]([CH3:14])[CH2:12][NH2:13].O>CN(C=O)C>[CH3:1][C:2]1[N:3]([CH2:14][CH2:11][CH2:12][NH2:13])[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: CC(Cl)CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nccn1CCCN
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
A solution of 2-methylimidazole (0.820 g, 10.0 mmol) in DMF (10 mL) was cooled in an ice/water bath and sodium hydroxide (1.00 g, 25.0 mmol) added. The resulting mixture was stirred for 30 min, then 2-chloropropylamine hydrochloride (1.30 g, 10.0 mmol) added in one portion. The resulting suspension was then stirred for 16 h during which time the reaction slowly warmed to room temperature. After this time the mixture was poured into water (500 mL) and the mixture extracted with ether (3×100 mL). The combined ether extracts were dried over sodium bicarbonate, filtered and concentrated under reduced pressure to afford 0.726 g (52% yield) of 3-(2-methylimidazol-1-yl)propylamine as a yellow oil. 1H NMR (300 MHz, CD3OD) δ 7.00 (d, J=1.4 Hz, 1H), 6.79 (d, J=1.4 Hz, 1H), 3.97 (t, J=7.3 Hz, 2H), 2.63 (t, J=7.1 Hz, 2H), 2.35 (s, 3H), 1.87 (m, 2H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C@H:12]1([CH2:20][OH:21])[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]1.CCN(CC)CC>C(Cl)Cl>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:19][CH2:18][C@H:15]2[CH2:16][CH2:17][C@H:12]([CH2:20][OH:21])[CH2:13][CH2:14]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1CC[C@H](CO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](CO)CC2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
4-Toluenesulfonyl chloride (742.5 g, 3.75 mol) was added to a solution of trans-cyclohexane-1,4-diyldimethanol (500 g, 4.17 mol) and Et3N (695 g, 5 mol) in DCM (6000 mL) at −20° C. The mixture was stirred at room temperature for 10 h and then quenched with water (10 L). The organic layer was separated, the aqueous layer was extracted with DCM (2×3 L), and the combined organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give trans-4-(hydroxymethyl)cyclohexylmethyl 4-methylbenzenesulfonate as a yellow oil.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C@@H:10]([C:19]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23](=[O:37])[NH:24]2)[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.O=[CH:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][N:52]1[CH2:57][CH2:56][CH:55]([O:58][C:59](=[O:73])[NH:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=2[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[CH2:54][CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([N:8]([CH2:9][C@@H:10]([C:19]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23](=[O:37])[NH:24]2)[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][N:52]1[CH2:53][CH2:54][CH:55]([O:58][C:59](=[O:73])[NH:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=2[C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)[CH2:56][CH2:57]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: O=CCCCCCCCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN(CCCCCCCCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)Cc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 0 °C
Yield: 93.4 %

Procedure:
To a 300 mL round-bottomed flask was added 5-[(R)-2-benzylamino-1-(tert-butyldimethylsilanyloxy)ethyl]-8-benzyloxy-1H-quinolin-2-one (5 g, 9.73 mmol), dichloromethane (100 mL) and glacial acetic acid (0.6 mL, 10 mmol). This mixture was cooled to 0° C. using an ice bath and biphenyl-2-ylcarbamic acid 1-(9-oxononyl)piperidin-4-yl ester (4.6 g, 9.73 mmol) was added with stirring. This mixture was stirred at 0° C. for 30 minutes and then sodium triacetoxyborohydride (6.15 g, 29 mmol) was added in portions over 15 minutes. The reaction mixture was stirred at 0° to 10° C. for 2 hours and then aqueous saturated sodium bicarbonate solution (50 mL) was added and this mixture was stirred for 15 minutes. The layers were then separated and the organic layer was washed with 5% aqueous sodium chloride solution (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure to afford the title intermediate (8.5 g, 80% purity by HPLC), which was used without further purification.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.C(N(CC)C(C)C)(C)C.[N:44]1[CH:49]=[CH:48][N:47]=[CH:46][C:45]=1[C:50](Cl)=[O:51]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:50]([C:45]4[CH:46]=[N:47][CH:48]=[CH:49][N:44]=4)=[O:51])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: O=C(Cl)c1cnccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)c2cnccn2)C3)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.085 g, 0.00021 mol) in dry N,N-Dimethylformamide (1.00 mL, 0.0129 mol) was added N,N-Diisopropylethylamine (0.1120 mL, 0.0006430 mol) cooled at 0° C., added Pyrazine-2-carbonyl chloride (0.0508 g, 0.000356 mol) stirred at 0° C. for 30 minutes. The reaction mixture was filtered and purified by HPLC. 1H NMR (500 MHz, DMSO) δ 8.95 (dd, J=8.4, 1.3, 1H), 8.81 (dd, J=7.1, 2.5, 1H), 8.75 (d, J=3.9, 1H), 8.68 (d, J=15.6, 1H), 8.17 (dd, J=43.7, 8.7, 2H), 7.48 (dd, J=25.1, 8.8, 2H), 6.18 (dt, J=11.1, 5.6, 1H), 4.85 (d, J=18.5, 1H), 4.72 (d, J=7.4, 1H), 4.11 (d, J=5.5, 1H), 3.88 (d, J=9.3, 1H), 3.78-3.54 (m, 6H), 3.43 (t, J=12.3, 1H), 3.11 (dq, J=14.5, 7.2, 2H), 2.76 (s, 2H), 1.26 (d, J=6.6, 3H), 1.06 (q, J=7.3, 3H). LC/MS-m/z+503.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[CH3:15][S:16][C:17]1[C:28]2[O:27][C:26]([CH3:30])([CH3:29])[O:25][C:24]=2[C:23]([C:31]([C:33]2[C:43]3[O:44][C:45]([CH3:48])([CH3:47])[O:46][C:42]=3[C:41]([S:49][CH3:50])=[C:35]3[O:36][C:37]([CH3:40])([CH3:39])[O:38][C:34]=23)=[O:32])=[C:22]2[C:18]=1[O:19][C:20]([CH3:52])([CH3:51])[O:21]2>C1COCC1.C(OCC)C>[CH3:50][S:49][C:41]1[C:35]2[O:36][C:37]([CH3:39])([CH3:40])[O:38][C:34]=2[C:33]([C:31]([C:23]2[C:22]3[O:21][C:20]([CH3:52])([CH3:51])[O:19][C:18]=3[C:17]([S:16][CH3:15])=[C:28]3[O:27][C:26]([CH3:30])([CH3:29])[O:25][C:24]=23)([C:2]2[CH:3]=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=2)[OH:32])=[C:43]2[C:42]=1[O:46][C:45]([CH3:48])([CH3:47])[O:44]2
Reactant: CSc1ncc(Br)cn1
Reactant: CSc1c2c(c(C(=O)c3c4c(c(SC)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c1OC(C)(C)O3)OC(C)(C)O2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CSc1ncc(C(O)(c2c3c(c(SC)c4c2OC(C)(C)O4)OC(C)(C)O3)c2c3c(c(SC)c4c2OC(C)(C)O4)OC(C)(C)O3)cn1
Temperature: -75 °C
Reaction time: 8 h

Procedure:
5-Bromo-2-methylthio-pyrimidine (0.250 g, 1.2195 mmol) was dissolved in THF (50 mL, sodium benzophenone ketyl) and cooled to -105° C. n-Butyl lithium (0.455 ml in toluene, 1.2195 ml) was added and the temperature was increased to -75° C. for 15 minutes and thereafter reduced to -105° C. Bis(8-methylthio-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-bis(1,3)dioxole-4-yl)ketone (0.63146 g, 1.1236 mmol, Example 59) was added in solid form and the temperature was gradually increased to room temperature (removal of cooling bath). The mixture was stirred overnight, NaCl (15 mL, sat.) and diethyl ether (40 mL) were added and the phases separated after 5 minutes stirring. The organic phase was dried (MgSO4) and evaporated yielding 0.59 crude product. Pure product was obtained by crystallization in diethyl ether followed by a second crystallization in diisopropyl ether. Yield 0.115 g (0.1669 mmol, 14.9%).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH:25](=O)[CH2:26][CH2:27][CH2:28][CH3:29]>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: CCCCC=O
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: CCCCC=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Yield: 69.7 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with pentanal (0.5 g, 5.0 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 130° C. for 40 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.081 g, 70%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].C1C(=O)N([Cl:25])C(=O)C1>CC#N>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:25])[NH:10][C:9]=2[C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CC)c(=O)c2[nH]cnc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CCCCn1c(=O)n(CC)c(=O)c2[nH]c(Cl)nc21
Temperature: 120 °C

Procedure:
3-Butyl-1-ethyl-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.42 mmol) and NCS (56 mg, 0.42 mmol) were suspended in MeCN (5 mL) and heated at 120° C. under microwave irradiation. The reaction mixture was concentrated under reduced pressure and the title compound isolated using HPLC. [HPLC conditions used for the purification: 23 minute run time. Solvents: 0.1% TFA in MeCN and 0.1% TFA in water. MeCN increased from 5% to 95% linearly over 15 minutes. Held at 95% for 2 min. Then decreased to 5% linearly over 1 min., equilibrated at 5% for 5 minutes before next injection.]; 1H NMR (400 MHz; CDCl3) δ: 0.97 (3H, t), 1.31 (3H, t), 1.38-1.45 (2H, m), 1.72-1.80 (2H, m), 4.09-4.20 (4H, m), 13.40 (1H, br.s); m/z 271 [MH+].
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(=CC=3)C(=O)N([C@@H](C(C)C)C(OC)=O)C4)=CC=2)=CC=1.[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:44]=[C:45]3[C:49](=[CH:50][CH:51]=2)[C:48](=[O:52])[N:47]([C@@H:53]([CH:58]([CH3:60])[CH3:59])[C:54]([O:56][CH3:57])=[O:55])[CH2:46]3)=[CH:39][CH:38]=1.[F:61][C:62]([F:73])([F:72])[C:63]1[CH:64]=[C:65]([N:69]=[C:70]=[O:71])[CH:66]=[CH:67][CH:68]=1>>[CH3:59][CH:58]([CH3:60])[C@H:53]([N:47]1[CH2:46][C:45]2[C:49](=[CH:50][CH:51]=[C:43]([C:40]3[CH:41]=[CH:42][C:37]([NH:36][C:70]([NH:69][C:65]4[CH:66]=[CH:67][CH:68]=[C:63]([C:62]([F:61])([F:72])[F:73])[CH:64]=4)=[O:71])=[CH:38][CH:39]=3)[CH:44]=2)[C:48]1=[O:52])[C:54]([O:56][CH3:57])=[O:55]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O

Procedure:
The compound of example 246 was prepared analogous to compound of example 224 by reaction of compound of example 223 with 3-trifluoromethyl phenyl isocyanate. The compound of example 246 was used directly without isolation for the preparation of compound of example 247.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(C(N)=O)[CH2:11][C:10]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1.O.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.C([O-])(O)=O.[Na+].CC#[N:48]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH2:48])[CH2:11][C:10]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: NC(=O)C1(c2ccc(Br)cc2)CC2(C1)OCCO2
Reactant: CC#N
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NC1(c2ccc(Br)cc2)CC2(C1)OCCO2
Temperature: 25 °C

Procedure:
To a solution of Compound [XXXIV] (8.40 g, 26.9 mmol, 1.0 eq.) in CH3CN (26 mL) and water (26 mL) was added [bis(trifluoroacetoxy)iodo]benzene (17.4 g, 40.4 mmol, 1.5 eq.) and the resulting mixture stirred at room temperature. After 16 hours the reaction was slowly poured into NaHCO3 (aq sat) and extracted with ethyl acetate (×3). The combined organic layers were dried, concentrated, and the residue purified by silica gel chromatography by eluting with CHCl3 to CHCl3/MeOH/NH4OH (95:5:1) to give Compound [XXXV]: 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 2.40-2.50 (m, 2H) 2.73-2.82 (m, 2H) 3.77-3.85 (m, 2H) 3.85-3.93 (m, 2H) 7.37-7.44 (m, 2H) 7.45-7.52 (m, 2H).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:17]=[C:16]2[N:7]([C:8](=[O:19])[N:9]([CH3:18])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)[N:6]=1.[CH3:20]I>C(COC)OC.CN(C)P(=O)(N(C)C)N(C)C>[CH3:20][O:3][CH2:4][C:5]1[CH:17]=[C:16]2[N:7]([C:8](=[O:19])[N:9]([CH3:18])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)[N:6]=1
Reactant: Cn1c(=O)n2nc(CO)cc2c2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: COCCOC
Product: COCc1cc2c3ccccc3n(C)c(=O)n2n1
Reaction time: 0.25 h

Procedure:
To a suspension of 32 mg (0.0013 mole) of oil-free sodium hydride in 25 ml of glyme is added 227 mg (0.001 mole) of 2-(hydroxymethyl)-6-methylpyrazolo[1,5-c]quinazolin-5(6H)-one. The suspension is stirred for 15 minutes and then a solution of 0.66 ml (0.0107 mole) of methyl iodide in 2 ml of hexamethylphosphoric triamide added. The reaction mixture is stirred for 18 hours at room temperature. The solution is filtered and the filtrate stripped to an oil which is partitioned between dichloromethane and aqueous sodium thiosulfate. The organic phase is washed with water and stripped to an oil which is dissolved in acetone and applied to a Merck silica gel plate (20 cm × 20 cm × 2 mm thick). The chromatogram is developed with chloroform-methanol (9:1) and the product is eluted off with acetone. Evaporation of the acetone gives an oil that solidifies on standing under pentane at 5°. The yield of title compound is 100 mg (41%), m.p. 98°-100°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10])=[C:4]([F:17])[CH:3]=1.N1C=CC=CC=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>CC(C)=O>[F:17][C:4]1[CH:3]=[C:2]([NH:1][C:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])[CH:7]=[CH:6][C:5]=1[CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COC(=O)C(C(=O)OC)c1ccc(N)cc1F
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: COC(=O)C(C(=O)OC)c1ccc(NC(=O)Oc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a stirred solution of dimethyl 2-(4-amino-2-fluorophenyl)malonate (3.0 g, 12.448 mmol, 1.0 eq) in acetone (30 mL) was added pyridine (3.0 mL, 37.344 mmol, 3.0 eq) and phenyl chloroformate (1.89 mL, 14.937 mmol, 1.2 eq) at 0° C. and the mixture was stirred at RT for 1 h. The solvent was evaporated, the residue diluted with EtOAc (50 mL), washed with water (100 mL), brine (20 mL) and the solvent evaporated. The resulting residue was purified by CC using EtOAc/PE (1:4) as eluent to get dimethyl 2-(2-fluoro-4-(phenoxycarbonylamino)phenyl)malonate (3.5 g, 78%, white solid; TLC system: EtOAc/PE (3:7), Rf: 0.5).
Reaction SMILES: C(NCCO)C1C=CC=CC=1.Cl.ClCCNCC1C=CC=CC=1.S(Cl)(Cl)=O.Cl.[CH2:29]([NH:36][CH2:37][CH2:38][NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.NC1C(C)=CC=CC=1.Br[CH:56]([CH2:60]Br)[C:57]([NH2:59])=[O:58]>>[CH2:29]([N:36]1[CH2:37][CH2:38][N:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[CH3:46])[CH2:60][CH:56]1[C:57]([NH2:59])=[O:58])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1ccccc1NCCNCc1ccccc1
Reactant: NC(=O)C(Br)CBr
Agent: Cl
Agent: ClCCNCc1ccccc1
Agent: OCCNCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1N
Product: Cc1ccccc1N1CCN(Cc2ccccc2)C(C(N)=O)C1

Procedure:
2-Benzylaminoethanol (18.8 ml, 20 g, 0.13 mol) was converted to N-(2-chloroethyl)-N-benzylamine hydrochloride with thionyl chloride (19 ml, 31 g, 0.26 mol) according to the procedure described in J. Chem. Soc. 1955, 896. N-(2-chloroethyl)-N-benzylamine hydrochloride (4.0 g, 19 mmol) was converted to N-benzyl-N'-(2-methylphenyl)-1,2-diaminoethane hydrochloride by the procedure of Syn. Comm. 18, 45-50 (1988), using o-toluidine (6.1 ml, 6.1 g, 57 mmol) in place of aniline. 1-benzyl-4-(2-methylphenyl)piperazine-2-carboxamide was prepared from 2,3-dibromopropionamide (7.9 g, 34 mmol) by the procedure of J. Med. Chem. 35, 743-750 (1992) using N-benzyl-N'-(2-methylphenyl)-1,2-diaminoethane hydrochloride (4.95 g, 18 mmol) in place of N-benzyl-N'-phenyl-1,2-diaminoethane hydrochloride.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([C:15]([F:18])([F:17])[F:16])[NH:11][C:10]=2[C:9](=[O:19])[NH:8]/[C:7]/1=[N:20]\[NH2:21])[CH2:2][CH2:3][CH2:4][CH3:5].[CH:22](OCC)(OCC)OCC>>[CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([C:15]([F:16])([F:18])[F:17])[NH:11][C:10]=2[C:9](=[O:19])[N:8]2[CH:22]=[N:21][N:20]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]c(C(F)(F)F)nc21
Reactant: CCOC(OCC)OCC
Product: CCCCCn1c2nc(C(F)(F)F)[nH]c2c(=O)n2cnnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 227.3 %

Procedure:
A mixture of (2E)-3-pentyl-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-dione-2-hydrazone (0.020 g, 0.14 mmol) and triethyl orthoformate (2 mL, 0.01 mol) was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum and the residue was purified by preparative LCMS. The product fractions were collected and lyophilized to yield pure product as white powder (0.1 g, 48%). LCMS calculated for C12H13F3N6O: (M+H) 315.1; found: 315.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7]([OH:9])=[O:8].[N+:18]([C:21]1[C:22]([S:27]Cl)=[N:23][CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].C(N(CC)CC)C>ClCCl>[C:14]([O:13][C:11]([NH:10][C@@H:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:27][C:22]1[C:21]([N+:18]([O-:20])=[O:19])=[CH:26][CH:25]=[CH:24][N:23]=1)[C:7]([OH:9])=[O:8])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)O
Reactant: O=[N+]([O-])c1cccnc1SCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNSc1ncccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.1 %

Procedure:
(S)-6-Amino-2-((tert-butoxycarbonyl)amino)hexanoic acid (Compound tk86) (270 mg, 1.096 mmol) was added to a solution of nitro-2-pyridinesulfenyl chloride (313 mg, 1.644 mmol) in dichloromethane (30 ml), and triethylamine (1.53 ml, 10.96 mmol) was added dropwise to the suspension over 3 minutes. The reaction solution was stirred at room temperature for 3 hours and then concentrated under reduced pressure using an evaporator, and the resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (S)-2-((tert-butoxycarbonyl)amino)-6-(((3-nitropyridin-2-yl)thio)amino)hexanoic acid (Compound tk87) (62 mg, 14%).