Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][CH:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[C:3]=1[C:19]([OH:21])=O.[F:22][C:23]1[CH:24]=[C:25]([NH:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([NH2:40])[CH:38]=3)[NH:33][N:32]=2)[CH:26]=[C:27]([F:29])[CH:28]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:22][C:23]1[CH:24]=[C:25]([NH:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([NH:40][C:19]([C:3]4[CH:4]([C:9]5[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][CH:10]=5)[NH:5][C:6](=[O:8])[NH:7][C:2]=4[CH3:1])=[O:21])[CH:38]=3)[NH:33][N:32]=2)[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2)NC(=O)N1
Reactant: Nc1ccc2[nH]nc(Nc3cc(F)cc(F)c3)c2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4cc(F)cc(F)c4)c3c2)C(c2ccc(C(F)(F)F)cc2)NC(=O)N1

Procedure:
The titled compound was prepared following the procedure of Example 175 using 6-Methyl-2-oxo-4-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, N3-(3,5-difluoro-phenyl)-1H-indazole-3,5-diamine, PyBroP and diisopropylethylamine in methylene chloride. MS (ESI) m/z=543 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]([NH2:20])=O)=[N:4][C:5]([S:8][CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[CH:6][CH:7]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:18]#[N:20])=[N:4][C:5]([S:8][CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[CH:6][CH:7]=1
Reactant: NC(=O)c1nc(SCc2cc(F)cc(F)c2)ccc1N
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1nc(SCc2cc(F)cc(F)c2)ccc1N
Temperature: 140 °C
Yield: 106.5 %

Procedure:
A mixture of 3-amino-6-(3,5-difluorobenzylthio)picolinamide (2.37 mmol, 0.7 g) and P2Cl5 (9.48 mmol, 1.346 g), 20 ml of toluene and 1 ml of ionic solvent (1-butyl-3-methylimidazolium tetrafluoroborate) are placed in a microwave reactor and then heated at 140° C. for 30 minutes. The crude reaction product is then concentrated under reduced pressure and the orange crystals thus obtained are redissolved in ethyl acetate and washed using saturated aqueous NaHCO3 solution. The organic phase is dried on magnesium sulfate and then concentrated to yield 0.7 g of a brown oil. This crude reaction product is purified by silica gel chromatography (AcOEt/heptane+0.1% of NEt3) to yield, after concentration, 0.15 g (23%) of orange crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9]2)[CH:7]=1.[NH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([F:29])[CH:28]=1>>[F:15][C:14]1([F:16])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9][C@@:8]1([C:6]1[CH:7]=[C:2]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[C:27]([F:29])[CH:28]=2)[CH:3]=[CH:4][C:5]=1[F:21])[CH3:20]
Reactant: Nc1cncc(F)c1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(Br)ccc2F)C1(F)F
Product: CC1(C)OCC(=O)N[C@](C)(c2cc(Nc3cncc(F)c3)ccc2F)C1(F)F
Yield: 26 %

Procedure:
Prepared in an analogous manner as described for intermediate A9A or A13A from (R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (intermediate A16B) (200 mg, 546 μmol) and commercially available 3-amino-5-fluoropyridine [CAS no 210169-05-4] (122 mg, 1.09 mmol). The (R)-6,6-difluoro-5-(2-fluoro-5-(5-fluoropyridin-3-ylamino)phenyl)-5,7,7-trimethyl-1,4-oxazepan-3-one (56 mg, 26%) was obtained as an off-white foam. MS (ISP): m/z=398.2 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([OH:25])=O)=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:64][CH2:65][C:66]1[CH:67]=[CH:68][C:69]2[C:73]([CH2:76][F:77])([CH2:74][F:75])[O:72][B:71]([OH:78])[C:70]=2[CH:79]=1>CN(C=O)C>[F:77][CH2:76][C:73]1([CH2:74][F:75])[O:72][B:71]([OH:78])[C:70]2[CH:79]=[C:66]([CH2:65][NH:64][C:23]([C:20]3[C:19]4[N:15]([CH:16]=[CH:17][CH:18]=4)[C:14]([C:11]4[CH2:10][C:9]([C:4]5[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=5)([C:26]([F:29])([F:27])[F:28])[O:13][N:12]=4)=[CH:22][CH:21]=3)=[O:25])[CH:67]=[CH:68][C:69]1=2
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reactant: NCc1ccc2c(c1)B(O)OC2(CF)CF
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc2c(c1)B(O)OC2(CF)CF)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reaction time: 0.17 h

Procedure:
A solution of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.24 mmol) and DIPEA (124 mg, 0.88 mmol) in DMF (5 mL) can be stirred at rt for 5 min and then HATU (183 mg, 0.48 mmol) can be added. The mixture can be stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-bis(fluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (126 mg, 0.44 mmol). And the resulting mixture can be stirred at rt overnight. It can be then concentrated under vacuum, and the residue can be partitioned between 1N HCl and ethyl acetate. The organic layer separated can be concentrated under vacuum, and the residue can be purified by prep-TLC to provide the final title product.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16]Br)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:4]2[C:5](=[O:7])[CH2:6][N:2]([CH3:1])[C:3]2=[O:8])=[CH:12][CH:11]=1
Reactant: CN1CC(=O)NC1=O
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CC(=O)N(Cc2ccc(Br)cc2)C1=O

Procedure:
1-Methylimidazolidine-2,4-dione (0.876 mmol, 100 mg), 1-bromo-4-(bromomethyl)benzene (0.964 mmol, 241 mg) and potassium carbonate (1.75 mmol, 242 mg) in acetonitrile (3 ml) were heated in the microwave at 120° C. for 1 h. The mixture was partitioned between water and DCM and the organic phase separated using a hydrophobic frit and concentrated to afford 3-(4-bromobenzyl)-1-methylimidazolidine-2,4-dione (3D3); 1H NMR (400 MHz, CDCl3) δ 7.44 (d, 2H) 7.29 (d, 2H) 4.59 (s, 2H) 3.85 (s, 2H) 2.98 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([C:9]2[CH:10]=[CH:11][C:12]([S:19][CH3:20])=[C:13]([S:15]([NH2:18])(=[O:17])=[O:16])[CH:14]=2)=[O:8])=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:28]>C(Cl)Cl>[CH3:20][S:19]([C:12]1[CH:11]=[CH:10][C:9]([C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=2)=[CH:14][C:13]=1[S:15]([NH2:18])(=[O:17])=[O:16])=[O:28]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(C(=O)c2ccc(SC)c(S(N)(=O)=O)c2)cc1
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(S(C)=O)c(S(N)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
To a solution of 5-(4-methoxy-benzoyl)-2-methylsulfanyl-benzenesulfonamide (0.06 g, 0.18 mmol) dissolved in methylene chloride (3 mL) at 0° C. is added m-chloroperoxybenzoic acid (0.061 g, 0.36 mmol). The reaction mixture is stirred at room temperature for 30 minutes. Then, the reaction is quenched with saturated sodium sulfite and sodium bicarbonate solution. The aqueous layer is extracted with methylene chloride three times. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (75% ethyl acetate-hexane) followed by recrystallization (methylene chloride-hexane) provides 0.022 g (35%) of the title compound as a pale yellow solid. 1H NMR (CDCl3): δ 8.35 (d, J=8 Hz, 1H), 8.10 (dd, J=8, 1 Hz, 1H), 7.80 (d, J=9 Hz, 2H), 7.00 (d, J=9 Hz, 2H), 5.60 (s, 2H), 3.95 (s, 3H), 3.00 (s, 3H). Analytics calculated for C15H15NO5S2: C, 50.98; H, 4.28; N, 3.96. Found: C, 50.17; H, 4.46; N, 3.40. MS (m/z): 352 (M−1).
Reaction SMILES: Br[C:2]12[CH2:11][C:6]3([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:7][CH:8]([CH2:10][C:4]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:5]3)[CH2:3]1)[CH2:9]2.[NH2:20]C(N)=O.[ClH:24]>O>[ClH:24].[NH2:20][C:2]12[CH2:11][C:6]3([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:7][CH:8]([CH2:10][C:4]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: CCCCC12CC3CC(Br)(C1)CC(CCCC)(C3)C2
Reactant: NC(N)=O
Agent: Cl
Solvent: O
Product: CCCCC12CC3CC(N)(C1)CC(CCCC)(C3)C2
Reaction time: 0.17 h

Procedure:
3.27 grams of 1-bromo-3,5-di-n-butyl-adamantane were warmed with 1.2 grams of urea for 160 minutes at 165° C. The heating was performed in a closed vessel in a thermostatically controlled oil bath. After cooling, the reaction product was suspended in 50 ml. water. The water phase was brought to a pH of about 4 through dropwise addition of concentrated hydrochloric acid. The water phase was then extracted with two 10-ml. portions of ether, and brought to a pH of about 13 by dropwise addition of sodium hydroxide. The alkaline solution was stirred for about 10 minutes, after which the aqueous alkaline phase was extracted with four 10-ml. portions of benzene. The combined benzene extracts were dried over fused potassium sulfate. 1-amino-3,5-di-n-butyl-adamantane hydrochloride was precipitated by exposure to dried hydrogen chloride gas. Yield: 1.86 grams (62% of the theoretical yeild).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1>CN(C=O)C>[N:1]1([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
9.5 g of imidazole were dissolved in 100 ml of DMF, and the resultant solution was further added with 6.1 g of 60% NaH while cooling it with ice. The solution was then stirred for 30 min. and further for 1 hour at room temperature. Then, the solution was added with 20.0 g of 4-chloronitrobenzene and then stirred for 2 hours at a temperature of from 80 to 85° C. The solution reacted was poured into ice water, and the crystals precipitated was filtered and then dried to obtain 22.5 g of 4-(imidazole-1-yl)nitrobenzene.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)([O-:7])=[O:6].[C:17]1([O:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[N+](C1C=CC=CC=1)([O-])=O>[CH3:24][O:23][C:17]1[CH:22]=[CH:21][C:20]([C:12]([C:11]2[CH:15]=[CH:16][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=2)=[O:13])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
150 ml of nitrobenzene were cooled in an ice-bath and treated portionwise with 41 g of aluminium chloride. In so doing, the temperature was held at below 5°. Subsequently, a solution of 50 g of 4-nitrobenzoyl chloride in 50 ml of nitrobenzene was added dropwise in such a manner that the temperature remains at below 5°. At the same temperature there were added dropwise 27.8 g of anisole. Subsequently, the mixture was stirred at 20° overnight. The solution was poured on to 1 liter of ice-water, extracted with methylene chloride, dried over magnesium sulphate and concentrated. The nitrobenzene was distilled off in a high vacuum and the yellowish crystals which remained were recrystallized from cyclohexane. There were obtained 36.5 g (52%) of 4-methoxy-4'-nitrobenzophenone as a yellow solid; m.p. 124°.
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](S(C)(=O)=O)[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].[NH2:32][C:33]([CH3:38])([CH2:36][OH:37])[CH2:34][OH:35]>C1COCC1>[OH:35][CH2:34][C:33]([NH:32][C:16]1[N:17]=[C:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[CH3:26])[C:13]2[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1)([CH3:38])[CH2:36][OH:37]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CC(N)(CO)CO
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NC(C)(CO)CO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 72 h

Procedure:
The product of Example 48 (300 mg, 0.67 mmol) and 2-amino-2-methyl-1,3-propanediol (158 mg, 1.5 mmol) were combined in THF (10 mL) and stirred under Ar at 50° for 3 days. The solvents were removed in vacuo, and the residue was flash chromatographed with 0-25% EtOAc/CH12Cl2. Recrystallization from CH2Cl2/hexane gave the title compound as a white crystalline solid. mp 158-160°, LC MS m/z=471 (MH+) Retention time=1.75 min.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[S:23][C:13]=2[N:14]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: Fc1ccc(CNc2nc(-c3cnccn3)nc3sc(C(F)(F)F)cc23)cc1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2(pyrazin-2-yl)-4-(4-fluorobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:23]1[CH2:28][CH2:27][CH:26]([CH2:29][C:30](O)=[O:31])[CH2:25][CH2:24]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[C:30](=[O:31])[CH2:29][CH:26]2[CH2:27][CH2:28][O:23][CH2:24][CH2:25]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(CNC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: O=C(O)CC1CCOCC1
Product: Cc1cccc(CN(C(=O)CC2CCOCC2)C2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 42 %

Procedure:
Using general procedure E, 4-(3-methylbenzylamino)-piperidine-1-carboxylic acid tert-butyl ester (365 mg, 1.2 mmol) and (tetrahydropyran-4-yl)-acetic acid (173 mg, 1.2 mmol) afforded 4-[(3-methylbenzyl)-(2-tetrahydropyran-4-yl-acetyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (217 mg, 42%).
Reaction SMILES: [Li+].[OH-].[NH2:3][C:4]1[C:5]([C:11]([O:13]CC)=[O:12])=[N:6][C:7]([Cl:10])=[N:8][CH:9]=1.Cl>O.C1COCC1>[NH2:3][C:4]1[C:5]([C:11]([OH:13])=[O:12])=[N:6][C:7]([Cl:10])=[N:8][CH:9]=1
Reactant: CCOC(=O)c1nc(Cl)ncc1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cnc(Cl)nc1C(=O)O
Temperature: 25 °C

Procedure:
A 0.5 M aqueous solution of LiOH (1.5 eq) was added to a stirring mixture of ethyl 5-amino-2-chloropyrimidine-4-carboxylate (1 eq) in H2O (0.1 M) and THF (0.1M). The reaction was maintained for 2 h at rt. 1.0 N HCl was added and the crude mixture was concentrated in vacuo to remove residual THF. The resulting solids were collected on a paper lined Buchner funnel and dried for 16 h under vacuum to give 5-amino-2-chloropyrimidine-4-carboxylic acid. LC/MS (m/z): 174.0 (MH+). HPLC: Rt: 1.148 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH:10]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH:10]=1
Reactant: Cc1ccc2scnc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2scnc2c1

Procedure:
A mixture of 5-methylbenzothiazole (5.0 g), N-bromosuccinimide (6.0 g) and carbon tetrachloride (500 ml) was refluxed for 4 hours. Upon cooling, the mixture was evaporated to dryness and the residue chromatographed over silica gel. On elution with a mixture of methylene chloride and hexane (9:1), the title product was obtained as a white solid [0.56 g; NMR(CDCl3,60 MHz): 4.6 (s, 2H), 7.4 (dd, J=7 Hz, 2 Hz, 1H). 7.9 (d, J=7 Hz, 1H), 8.15 (d, J=2 Hz, 1H), 9.0 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:5]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1N1CCCCC1
Yield: 44.9 %

Procedure:
A suspension of methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.081 g; 0.25 mmol), piperidine (0.122 mL; 1.228 mmol) and potassium carbonate (0.102 mg; 0.737 mmol) in acetonitrile (1 mL) was irradiated at 130° C. for 2 h in a microwave oven. The mixture was partitioned between brine and ethyl acetate, the phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-10%) in heptane furnished 0.042 g (46%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]1([C@H:7]2[NH:12][CH2:11][C:10](=[O:13])[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:14]1[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[C:1]1([C@@H:7]2[CH2:8][O:9][C:10](=[O:13])[C@H:11]3[C@H:20]([C:17]4[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=4)[O:21][C@H:20]([C:17]4[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=4)[N:12]23)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CN[C@H](c2ccccc2)CO1
Reactant: O=Cc1ccncc1
Solvent: Cc1ccccc1
Product: O=C1OC[C@@H](c2ccccc2)N2[C@@H](c3ccncc3)O[C@@H](c3ccncc3)[C@H]12
Yield: 26.9 %

Procedure:
A solution of (R)-5-phenylmorpholinon-2-one EBE 06134 (3.0 g, 16.9 mmol) and pyridine-4-carboxaldehyde (5.43 g, 50.7 mmol) in toluene (75 mL) was refluxed in a soxhlet extractor filled with molecular sieves 4A (25 g) for 16 hours. All the volatiles were evaporated and the desired product was purified by column chromatography (SiO2) using a gradient of 80% to 100% [v/v] EtOAc in cyclohexane to give after evaporation (1S,3R,5R,8aR)-tetrahydro-5-phenyl-1,3-di(pyridin-4-yl)oxazolo[4,3-c][1,4]oxazin-8(311)-one EBE 06136 (1.7 g, 46% yield) as a pale yellow solid.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH:42]([NH2:52])[CH2:43][CH2:44][CH2:45][C:46]2[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=2)[CH:34]=1>O1CCCC1>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:52][CH:42]([CH2:41][CH2:40][CH2:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)[CH2:43][CH2:44][CH2:45][C:46]2[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=2)=[O:10])=[CH:25][CH:26]=1
Reactant: NC(CCCc1cccnc1)CCCc1cccnc1
Reactant: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=C/C=C/C(=O)NC(CCCc2cccnc2)CCCc2cccnc2)c2ccc(OC)cc2)cc1
Yield: 77.3 %

Procedure:
As before in Example 134, a solution of (E)-5,5-bis(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (1.94 g) and alpha-[3-(3-pyridinyl)propyl]-3-pyridinebutanamine (1.21 g) in tetrahydrofuran (25 mL) was stirred for 20 hours at 50° C. and then was worked up in the normal manner. The crude was purified by HPLC (ethyl acetate-triethylamine; 19:1) and was then lyophilized from benzene to give 1.95 g of (E)-5,5-bis(4-methoxyphenyl)-N-[1-[3-(3-pyridinyl)propyl]-4-(3-pyridinyl)butyl]-2,4-pentadienamide as a glass.
Reaction SMILES: C(OC([NH:8][CH:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:34].O1CCOCC1>CO>[ClH:34].[NH2:8][CH:9]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(COc2cccc(C(NC(=O)OC(C)(C)C)c3ccccc3)c2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1ccc(COc2cccc(C(N)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of methyl 4-((3-(((tert-butoxycarbonyl)amino)(phenyl)methyl)-phenoxy)methyl)benzoate (3.21 g, 7.20 mmol) in methanol (36 mL), was added hydrogen chloride in dioxan (4 M, 9.0 mL, 36 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed at reduced pressure to afford the title compound (2.65 g, >95%).
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]2[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=2[C:6]2[C@H:7]([CH2:13][Cl:14])[CH2:8][N:9](N)[C:10]=2[CH:11]=1.[CH3:19][S:20][S:21][CH2:22][CH2:23][C:24]([NH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([C:36](O)=[O:37])=[CH:30]2)=[O:25].C(Cl)CCl>CC(N(C)C)=O>[Cl:14][CH2:13][C@H:7]1[C:6]2[C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[C:3]([OH:2])=[CH:11][C:10]=2[N:9]([C:36]([C:31]2[NH:32][C:33]3[C:29]([CH:30]=2)=[CH:28][C:27]([NH:26][C:24](=[O:25])[CH2:23][CH2:22][S:21][S:20][CH3:19])=[CH:35][CH:34]=3)=[O:37])[CH2:8]1
Reactant: NN1C[C@@H](CCl)c2c1cc(O)c1ccccc21
Reactant: CSSCCC(=O)Nc1ccc2[nH]c(C(=O)O)cc2c1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: ClCCCl
Product: CSSCCC(=O)Nc1ccc2[nH]c(C(=O)N3C[C@@H](CCl)c4c3cc(O)c3ccccc43)cc2c1

Procedure:
To a solution of 5-hydroxy-3-amino-1-[S]-(chloromethyl)-1,2-dihydro-3H-benz(e)indole, hydrochloride salt (155 mg, 0.57 mmol) and 5-(3-(methyl-disulfanyl)propanamido)-1H-indole-2-carboxylic acid (170 mg, 0.55 mmol) in 7.0 ml of DMA was added EDC (300 mg, 1.56 mmol) under Ar. After stirred over night, the mixture was evaporated to dryness, purified by SiO2 chromatography (20% to 40% THF in toluene) and crystallized with THF/Toluene/Hexane to afford 218 mg (76%) of DC101SMe. 1H NMR (DMF-d7) 11.63 (s, 1H), 10.56 (s, 1H), 9.95 (s, 1H), 8.23 (s, 2H), 7.93 (d, 1H, J=8.3 Hz), 7.56 (dd, 1H, J=2.0, 8.1 Hz), 7.52 (s, 1H), 7.47 (dd, 1H, J=1.9, 8.9 Hz), 7.41 (d, 1H, J=1.7 Hz), 7.25 (d, 1H, J=1.7 Hz), 4.88 (dd, 1H, J=8.7, 11.0 Hz), 4.73 (dd, 1H, J=2.3, 10.9 Hz), 4.31 (m, 1H), 4.12 (dd, 1H, J=3.1, 11.0 Hz), 3.95 (dd, 1H, J=8.4, 11.2 Hz), 3.21 (t, 2H, J=7.1 Hz), 2.71 (t, 2H, J=7.1 Hz), 2.45 (s, 3H); 13C NMR 169.54, 161.06, 155.36, 134.21, 133.39, 132.54, 131.05, 128.39, 127.99, 123.98, 123.74, 123.46, 123.31, 118.88, 115.99, 112.87, 112.31, 106.40, 101.33, 55.93, 48.10, 42.61, 36.92, 30.81, 25.34. MS m/z+548.2 (M+Na), 550.2 (M+2+Na).