Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5](C)[CH:4]=1.[NH2:9][CH2:10][CH2:11][OH:12].[C:13](#N)C>>[CH3:13][N:6]1[CH2:5][CH:4]=[C:3]([CH2:2][NH:9][CH2:10][CH2:11][OH:12])[O:7]1
Reactant: NCCO
Reactant: CC#N
Reactant: Cc1cc(CBr)on1
Product: CN1CC=C(CNCCO)O1
Temperature: 25 °C

Procedure:
A solution of 7 g of 5-bromomethyl-3-methylisoxazole in 20 ml of acetonitrile was added dropwise to a solution of 12.2 g of 2-aminoethanol in 100 ml of acetonitrile below 10° C. After stirring for a while at room temperature, the acetonitrile and excess-2-aminoethanol were removed under reduced pressure. Chloroform was added to the residue, and it was washed with a small quantity of water. The treatment of the chloroform solution the usual way gave the desired 2-(2-methyl-5-isoxazolylmethylamino)ethanol. The yield was 4.4 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([N:23]([CH3:39])[C:24]([NH:26][C:27]2[C:32]([Cl:33])=[C:31]([O:34][CH3:35])[CH:30]=[C:29]([O:36][CH3:37])[C:28]=2[Cl:38])=[O:25])[CH:18]=1.[C:40](Cl)(=[O:43])[CH:41]=[CH2:42].C1COCC1>CO>[Cl:38][C:28]1[C:29]([O:36][CH3:37])=[CH:30][C:31]([O:34][CH3:35])=[C:32]([Cl:33])[C:27]=1[NH:26][C:24](=[O:25])[N:23]([C:19]1[N:20]=[CH:21][N:22]=[C:17]([NH:16][C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH2:13]3)=[CH:7][C:2]=2[NH:1][C:40](=[O:43])[CH:41]=[CH2:42])[CH:18]=1)[CH3:39]
Reactant: C=CC(=O)Cl
Reactant: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4c(Cl)c(OC)cc(OC)c4Cl)ncn3)c(N)c2)CC1
Solvent: C1CCOC1
Solvent: CO
Product: C=CC(=O)Nc1cc(N2CCN(CC)CC2)ccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Reaction time: 1 h
Yield: 7 %

Procedure:
To a solution of 1-(6-(2-amino-4-(4-ethylpiperazin-1-yl)phenylamino)pyrimidin-4-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylurea (280 mg, purity: 90%, 0.44 mmol) in THE (30 mL) was added a solution of acryloyl chloride in THF (20 mg/mL, 2 mL, 0.44 mmol) at −10° C., and the resulting mixture was stirred for 1 hour at this temperature. MeOH (1 mL) was added to quench the reaction. The mixture was concentrated and the residue was purified by prep-HPLC and prep-TLC to obtain the title compound (20 mg, yield: 7%). 1H NMR (400 MHz, CDCl3) δ 1.31 (t, 3H), 2.65 (q, 2H), 2.62-2.68 (m, 4H), 3.27 (s, 3H), 3.36-3.38 (m, 4H), 3.91 (s, 6H), 5.76 (d, 1H), 5.90 (s, 1H), 6.24 (dd, 1H), 6.41 (d, 1H), 6.52 (s, 1H), 6.74 (dd, 1H), 7.07 (br s, 1H), 7.23 (d, 1H), 7.72 (br s, 1H), 7.98 (br s, 1H), 8.37 (s, 1H), 12.52 (s, 1H); MS (ESI): 629 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[CH3:30][O:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>CCCCCC.C(OCC)(=O)C>[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([CH:7]2[C:6]3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:3]([CH3:29])=[C:2]([C:35]4[CH:36]=[N:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=4)[C:10]=3[O:9][CH2:8]2)=[CH:16][CH:15]=1)([CH3:18])[CH3:19]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: COc1ccc(B(O)O)cn1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)cn1
Yield: 48 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (6-methoxypyridin-3-yl)boronic acid, the title compound was synthesized in the same manner as in Example 101. Yield: 48%. Melting point: 120-123° C. (hexane-ethyl acetate).
Reaction SMILES: C1C2C(=CC=CC=2)CC1C(O)=O.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]C[CH:14]1[C:23]([Cl:25])=[O:24]>>[CH2:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH:14]1[C:23]([Cl:25])=[O:24]
Reactant: O=C(Cl)C1CCc2ccccc2C1
Agent: O=C(O)C1Cc2ccccc2C1
Product: O=C(Cl)C1Cc2ccccc2C1

Procedure:
Indan-2-carbonyl chloride (26A) is prepared from indan-2-carboxylic acid as described for 23A.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)[CH2:11][CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[N:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1)[CH2:11][CH3:12]
Reactant: CCCc1ccc(C=O)cc1
Reactant: N#Cc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCc1ccc(C=Nc2ccc(C#N)cc2)cc1

Procedure:
A mixture of 5.9 g. of p-aminobenzonitrile and 7.4 g. of p-n-propylbenzaldehyde in 100 ml. of benzene is treated with 150 mg. of p-toluenesulfonic acid and reacted as described in Example 1. After evaporation, there remain 12.5 g. of a yellowish oil which crystallizes with cooling. Purification is carried out by several recrystallizations from isopropanol as described in Example 1. The p-[(p-n-propylbenzyliden)amino]-benzonitrile which is obtained has a melting point of 64.8°-65.5° C. and a clearing point of 77.6° C. UV (ethanol): ε280 = 24300 (shoulder at 310 nm). The nuclear magnetic resonance, mass spectrum, infrared and microanalysis data confirm the structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][CH:27]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])[NH:28][CH:27]=1)=[O:25])[CH3:35]
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Reactant: CCN(CC)CCNC(=O)c1c[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 85.6 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (98.6 mg, 86%).
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13]([CH:15]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:18])=[O:17])=[CH:12][C:11]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+].[O:29]([C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39]Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CCOCC>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13]([CH:15]([CH:19]([CH3:20])[CH3:21])[C:16]([O:18][CH2:39][C:38]3[CH:41]=[CH:42][CH:43]=[C:36]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:37]=3)=[O:17])=[CH:12][C:11]=2[CH:22]=1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C(=O)O)c1cc2cc(Cl)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)C(C(=O)OCc1cccc(Oc2ccccc2)c1)c1cc2cc(Cl)ccc2s1
Reaction time: 15 h

Procedure:
A mixture of 20 ml DMF, 2-(5-chloro-2-benzothienyl)-3-methylbutanoic acid (0.5 g), K2CO3 (0.51 g) and 3-phenoxybenzyl bromide (0.44 g) is stirred, under nitrogen, for about 15 hours. The mixture is then taken up in ether, washed with water and brine, dried over Na2SO4 and solvent removed. The crude product is plated developing with 10% ether/hexane to give 3-phenoxybenzyl 2-(5-chloro-2-benzothienyl)-3-methylbutanoate.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][C@H:23]([CH2:26][C:27]1[N:28]=[CH:29][NH:30][CH:31]=1)[CH2:24][OH:25]>>[OH:25][CH2:24][C@H:23]([NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[CH2:26][C:27]1[N:28]=[CH:29][NH:30][CH:31]=1
Reactant: N[C@@H](CO)Cc1c[nH]cn1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N[C@@H](CO)Cc3c[nH]cn3)cc2c1=O
Yield: 43 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with (R)-2-amino-3-(1H-imidazol-4-yl)-propan-1-ol according to the GPA affording 22.7 mg (43%) of a red powder. Rt=1.73 min.
Reaction SMILES: [I:1][C:2]1[C:3](O)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:3]1[C:2]([I:1])=[CH:7][N:6]=[C:5]2[CH:8]=[CH:9][S:10][C:4]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1c(I)cnc2ccsc12
Product: Clc1c(I)cnc2ccsc12
Temperature: 120 °C
Yield: 44 %

Procedure:
A mixture of the crude 6-iodothieno[3,2-b]pyridin-7-ol (0.99 g, 3.6 mmol) in phosphoryl chloride (20 mL) was heated at 120° C. for 2 h. The reaction was cooled to room temperature, concentrated under reduced pressure. The residue was co-evaporated with toluene, then diluted with dichloromethane and neutralized carefully with sat. NaHCO3 solution. The black tar was filtered off and the filtrate was transferred to a separation funnel. The organic layer was concentrated and purified on silica gel (eluting with 0-35% EtOAc/hexanes) to give the desired product (44% in 2 steps). LCMS calculated for C7H4ClINS (M+H)+: m/z=295.9. Found: 295.8.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][OH:13].B.[K].O>C(O)(=O)C>[O:13]=[C:12]1[C:6]2[C:5](=[CH:4][CH:3]=[CH:2][CH:7]=2)[CH2:8][N:1]1[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CO
Agent: B
Agent: [K]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1ccc(N2Cc3ccccc3C2=O)cc1

Procedure:
1.64 g of o-phthalaldehydic acid methyl ester and 1.5 g of p-aminophenylacetic acid were added to 30 ml of methanol to form a mixture which was agitated at room temperature for one hour and incorporated with 0.54 g of potassium boron hydride in several portions. The whole was reacted at room temperature for 15 hours and freed from the solvent by distillation at a reduced pressure to obtain a residue. The thus obtained residue was incorporated with 50 ml of water and then with a small amount of acetic acid to form an acidic solution, after which crystals precipitated from said solution were filtered off, dried and recrystallized from ethanol thereby to obtain 2.4 g of 1-oxo-2-{p-(carboxymethyl)-phenyl}-isoindoline having the following properties:
Reaction SMILES: IN1C(=O)CCC1=O.[CH3:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:15](=O)[CH2:16][C:17]([O:19][CH3:20])=[O:18].[NH2:22][C:23]([NH2:25])=[S:24]>CCOC(C)=O.CO>[NH2:25][C:23]1[S:24][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([C:11]2[N:10]([CH3:9])[CH:14]=[CH:13][N:12]=2)[N:22]=1
Reactant: COC(=O)CC(=O)c1nccn1C
Reactant: NC(N)=S
Agent: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1sc(N)nc1-c1nccn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
N-Iodosuccinimide (9.3 g, 41 mmol) was added to a mixture of 7.52 g (41 mmol) methyl 3-(1-methyl-1H-imidazol-2-yl)-3-oxopropanoate (Intermediate 63) and 7.5 g Amberlyst-15 resin in 400 ml EtOAc followed by stirring for 1 hour at room temperature. The resin was filtered off and rinsed with EtOAc. Solvent was removed from the filtrate and the residue was taken up in diethyl ether. Insoluble material was filtered off and rinsed with additional ether. Solvent was removed from the filtrate and the residue was dissolved in 200 ml MeOH before addition of 4.7 g (62 mmol) thiourea. The mixture was heated at reflux for 1 hour, then the solvent was removed and the residue was taken up in aqueous Na2CO3. Insoluble material was collected by filtration and rinsed well with water. The solids were dried in vacuo affording 4.51 g of the title compound: MS (ES) (M+H)+: 239 for C9H10N4O2S; NMR: 3.48 (s, 3H), 3.57 (s, 3H), 6.90 (s, 1H), 7.12 (s, 1H), 7.98 (s, 2H).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]1([N:19]2[C:27]3[CH2:26][CH2:25][CH2:24][CH:23]([CH2:28][C:29]([OH:31])=O)[C:22]=3[CH:21]=[N:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH:32]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[C:13]1([N:19]2[C:27]3[CH2:26][CH2:25][CH2:24][CH:23]([CH2:28][C:29]([N:32]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:31])[C:22]=3[CH:21]=[N:20]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C1CCCNCC1
Reactant: O=C(O)CC1CCCc2c1cnn2-c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(CC1CCCc2c1cnn2-c1ccccc1)N1CCCCCC1
Temperature: 45 °C
Yield: 33.3 %

Procedure:
CDI (63.2 mg, 0.39 mmol) is added to a solution of 2-(4,5,6,7-tetrahydro-1-phenyl-1H-indazol-4-yl)acetic acid (100 mg, 0.39 mmol) in CH2Cl2 (20 mL) cooled in an ice bath, and is heated to 45° C. for 2.5 hours. Then it is cooled to 0° C. and azacycloheptane (38.7 mg, 0.39 mmol) is added and is heated at 45° C. for 1 hour. The solvent is evaporated under reduced pressure, diluted in AcOEt and washed with diluted HCl. The organic phase is dried and evaporated under reduced pressure. The resulting crude product is purified by means of silica gel chromatography, giving 1-(2-(4,5,6,7-tetrahydro-1-phenyl-1H-indazol-4-yl)acetyl)azepane (45 mg, 0.13 mmol, 33%, oil).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([N+:38]([O-])=O)=[C:13]([NH:15][C:16]3[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[C:18]([O:25][C@@H:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:36])[F:35])[CH3:27])[CH:17]=3)[CH:14]=2)[CH2:4][CH2:3]1.Cl.COC(OC)OC>C1(C)C=CC=CC=1.[Pd]>[NH2:38][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:14][C:13]=1[NH:15][C:16]1[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[C:18]([O:25][C@@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:35])([F:37])[F:36])[CH3:27])[CH:17]=1
Reactant: COC(=O)c1sc(Nc2cc(CN3CCN(C)CC3)ccc2[N+](=O)[O-])cc1O[C@H](C)c1ccccc1C(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: COC(OC)OC
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(Nc2cc(CN3CCN(C)CC3)ccc2N)cc1O[C@H](C)c1ccccc1C(F)(F)F

Procedure:
A mixture of methyl 5-({5-[(4-methyl-1-piperazinyl)methyl]-2-nitrophenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate (0.24 g, 0.415 mmol), 5% Pd/C (0.144 g), HCl (1.25 M in MeOH, 0.034 mL, 0.043 mmol), trimethylorthoformate (1.66 mL, 15.2 mmol) in toluene (0.58 mL) was hydrogenated under a H2 atmosphere at 1.1 bar pressure overnight. The vessel was purged with N2 and the reaction mixture was analysed by HPLC to confirm presence of the title compound which was not purified, but used crude in the next step. LRMS found m/z [ES+] 549.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[C:19]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[O:10])[S:6][CH:7]=1.[CH3:26][N:27]([CH3:32])[S:28](Cl)(=[O:30])=[O:29]>>[CH:21]1([C:19]([C:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=2[NH:11][C:9](=[O:10])[NH:8][C:5]2[S:6][CH:7]=[C:3]([CH2:2][NH:1][S:28]([N:27]([CH3:32])[CH3:26])(=[O:30])=[O:29])[N:4]=2)=[O:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1ccc(NC(=O)Nc2nc(CN)cs2)c(C(=O)C2CCCC2)c1
Reactant: CN(C)S(=O)(=O)Cl
Product: Cc1ccc(NC(=O)Nc2nc(CNS(=O)(=O)N(C)C)cs2)c(C(=O)C2CCCC2)c1
Yield: 89.3 %

Procedure:
N-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl}-N′,N′-dimethylsulfamide (104 mg, 89%) was prepared from 1-(4-aminomethyl-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (90 mg, 0.25 mmol) and dimethylsulfamoyl chloride (0.06 mL, 0.5 mmol) following the general procedure T.
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9][C:10]1[C:11]2[NH:27][CH:26]=[CH:25][C:12]=2[N:13]=[C:14]([NH:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[N:15]=1.C1C(=O)N([Br:36])C(=O)C1>C(Cl)Cl>[Br:36][C:25]1[C:12]2[N:13]=[C:14]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[N:15]=[C:10]([S:9][C:2]3[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=3[CH3:28])[C:11]=2[NH:27][CH:26]=1
Reactant: Cc1cc(C)c(Sc2nc(Nc3ccc(C#N)cc3)nc3cc[nH]c23)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cc1cc(C)c(Sc2nc(Nc3ccc(C#N)cc3)nc3c(Br)c[nH]c23)c(C)c1
Yield: 23 %

Procedure:
To a solution of 4-(4-(mesitylthio)-5H-pyrrolo[3,2-d]pyrimidin-2-ylamino)benzonitrile (22.7 mg, 0.06 mmol) in CH2Cl2 (10 mL) was added NBS (10.5 mg, 0.06 mmol) and the resultant mixture was refluxed for 16 h. After completion of the reaction, the solvent was concentrated and purified by reversed phase HPLC to give the product as a white solid (6.4 mg, 23%).
Reaction SMILES: CI.[CH3:3][C:4]([CH3:48])=[CH:5][CH2:6][CH2:7][C@@:8]1([CH3:47])[O:17][C:16]2[C:15]([CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[C:14]3[O:23][C@@:24]45[C@@:34]6([CH2:39]/[CH:40]=[C:41](\[C:43]([OH:45])=[O:44])/[CH3:42])[O:35][C:36]([CH3:38])([CH3:37])[C@@H:25]4[CH2:26][C@H:27]([C:32]6=[O:33])[CH:28]=[C:29]5[C:30](=[O:31])[C:13]3=[C:12]([OH:46])[C:11]=2[CH:10]=[CH:9]1.N12CCCN=C1CCCC[CH2:50]2>CN(C)C=O.[Cl-].[Na+].O>[CH3:3][C:4]([CH3:48])=[CH:5][CH2:6][CH2:7][C@@:8]1([CH3:47])[O:17][C:16]2[C:11](=[C:12]([OH:46])[C:13]3[C:30](=[O:31])[C:29]4[C@@:24]5([C@@:34]6([CH2:39]/[CH:40]=[C:41](\[C:43]([O:45][CH3:50])=[O:44])/[CH3:42])[O:35][C:36]([CH3:37])([CH3:38])[C@@H:25]5[CH2:26][C@H:27]([C:32]6=[O:33])[CH:28]=4)[O:23][C:14]=3[C:15]=2[CH2:18][CH:19]=[C:20]([CH3:21])[CH3:22])[CH:10]=[CH:9]1
Reactant: CC(C)=CCC[C@]1(C)C=Cc2c(O)c3c(c(CC=C(C)C)c2O1)O[C@]12C(=C[C@@H]4C[C@H]1C(C)(C)O[C@@]2(C/C=C(/C)C(=O)O)C4=O)C3=O
Reactant: C1CCC2=NCCCN2CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)/C(C)=C\C[C@@]12OC(C)(C)[C@@H]3C[C@@H](C=C4C(=O)c5c(O)c6c(c(CC=C(C)C)c5O[C@]431)O[C@](C)(CCC=C(C)C)C=C6)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
A solution of methyl iodide (29 μL, 0.477 mmol) in 1.0 mL of N,N-dimethylformamide was added to a solution of gambogic acid (0.200 g, 0.318 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (47.6 μL, 0.318 mmol) in 0.2 mL of N,N-dimethylformamide and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into brine (30 mL) and was extracted with methylene chloride. The organic layer was wash with brine (2×30 mL) and the combined organic extracts were dried over MgSO4 and concentrated in vacuo to give the crude product. It was purified by column chromatography (18×2 cm column, SiO2, EtOAc/Hexane 1:5) to afford the methyl gambogate as an orange solid (0.14 g, 69 %). 1H NMR (CDCl3): 12.85 (s, 1H), 7.54 (d, J=6.9 Hz, 1H), 6.67 (d, J=10.5 Hz, 1H), 5.94 (t, J=6 Hz, 1H), 5.43 (d, J=10.2 Hz, 1H), 5.05 (m, 2H), 3.49 (m, 1H), 3.43 (s, 3H), 3.35-3.10 (s, 2H), 3.00 (t, J=7.2 Hz, 1H), 2.52 (d, J=10.2 Hz, 1H), 2.32 (quar, J=4.8 Hz, 1H), 2.02 (m, 1H), 1.74 (s, 3H), 1.69 (s, 3H), 1.67-1.64 (m, 9H), 1.55 (s, 3H), 1.44 (s, 3H), 1.29 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]([C:23]2[S:27][C:26]([C:28]3([O:32][CH2:33][O:34][CH3:35])[CH2:31][CH2:30][CH2:29]3)=[N:25][CH:24]=2)=[C:4]2[CH:10]=[C:9]([C:11]#[N:12])[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.C(O)C.[ClH:39].[NH2:40][OH:41].C(N(CC)CC)C>O>[Cl:39][C:2]1[C:3]([C:23]2[S:27][C:26]([C:28]3([O:32][CH2:33][O:34][CH3:35])[CH2:31][CH2:30][CH2:29]3)=[N:25][CH:24]=2)=[C:4]2[CH:10]=[C:9](/[C:11](=[N:40]/[OH:41])/[NH2:12])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(C#N)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Reactant: Cl
Reactant: NO
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(/C(N)=N/O)cc34)s2)CCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A suspension of Example 22A (0.118 g, 0.223 mmol), ethanol (3 mL), water (0.25 mL), hydroxylamine hydrochloride (0.039 g, 0.558 mmol), and triethylamine (0.140 mL, 1.0 mmol) was heated at 80° C. for 30 minutes. The reaction was cooled to ambient temperature, diluted with water (13 mL) and stirred 5 minutes. The suspension was filtered. The solid collected was washed with water and dried in a vacuum oven at 50° C. to provide the title compound. MS ESI(+) m/z 408.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.O=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:9]([CH2:13][CH2:14][CH3:15])[C:10]([O-])=[O:11]>C(N(CCCC)CCCC)CCC>[OH:11][C:10]1[N:3]2[N:4]=[CH:5][N:6]=[C:2]2[N:1]=[C:8]([C:16]([F:17])([F:18])[F:19])[C:9]=1[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(C(=O)[O-])C(=O)C(F)(F)F
Reactant: Nc1nc[nH]n1
Solvent: CCCCN(CCCC)CCCC
Product: CCCc1c(C(F)(F)F)nc2ncnn2c1O
Temperature: 180 °C
Reaction time: 6 h
Yield: 76.5 %

Procedure:
A mixture of 14 g (0.17 mol) 3-amino-1,2,4-triazole, 38.4 g (0.17 mol) of 3-oxo-2-propyl-4,4,4-trifluorobutanoate and 50 ml of tributylamine were stirred at 180° C. for 6 h. Work-up was carried out analogously to Ex. 1. Drying gave 33 g (0.13 mol) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:40])[CH:3]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:32](=[O:33])[CH2:31][O:30][C:29]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:28]2)=[CH:22][CH:21]=1)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1)=[O:5]>C(O)C.[Pd]>[CH3:40][CH:2]([CH3:1])[CH:3]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:32](=[O:33])[CH2:31][O:30][C:29]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:28]2)=[CH:22][CH:21]=1)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1)=[O:5]
Reactant: CCOC(=O)/C=C/c1ccc(NC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C(C)C)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(NC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C(C)C)cc1
Reaction time: 2 h

Procedure:
41 mg (0.076 mmol) of ethyl (2E)-3-{4-[(3-methyl-2-{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}butanoyl)amino]phenyl}prop-2-enoate (Example 176A) were dissolved in 17 ml of ethanol, and 75 mg of palladium on carbon (10%) were added. Under an atmosphere of hydrogen, the mixture was hydrogenated at atmospheric pressure for 2 h. The reaction mixture was then filtered through Celite, and the filtrate was concentrated under reduced pressure. This gave 39 mg (95% of theory) of the title compound.