Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][O:18][C:19](=[O:25])[C@H:20]([C@@H:22]([CH3:24])[OH:23])[NH2:21]>>[CH3:17][O:18][C:19](=[O:25])[C@H:20]([C@@H:22]([CH3:24])[OH:23])[NH:21][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Agent: Cl
Product: COC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc1ccccc1)[C@@H](C)O

Procedure:
Following General Procedure U and using N-(phenylacetyl)-L-alanine (from Example B1 above) and L-threonine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.[C:27]([C:31]1[N:36]=[C:35]([N:37]2[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])[CH2:39][CH2:38]2)[CH:34]=[C:33]([CH:48]2[CH2:51][CH2:50][CH2:49]2)[N:32]=1)([CH3:30])([CH3:29])[CH3:28].[ClH:52].C(N=C=NCCCN(C)C)C>CN(C)C=O>[ClH:52].[C:27]([C:31]1[N:36]=[C:35]([N:37]2[CH2:38][CH2:39][N:40]([CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:1](=[O:9])[C:2]3[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=3)[CH2:41][CH2:42]2)[CH:34]=[C:33]([CH:48]2[CH2:51][CH2:50][CH2:49]2)[N:32]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C(O)c1ccncc1
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3ccncc3)CC2)n1
Reaction time: 16 h
Yield: 72.3 %

Procedure:
0.35 g of isonicotinic acid (2.84 mmol) and 0.87 g of triethylamine (8.62 mmol) were dissolved in 30 ml of dimethylformamide. 0.45 g of hydroxybenzotriazole (HOBt, 3.33 mmol), 1.1 g of 4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (3.18 mmol), and 0.6 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCl, 3.13 mmol) were added at room temperature, and the reaction mixture was stirred for 16 h. The reaction mixture was then partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (2-10%). The oily residue was re-dissolved in isopropanol, and 1 N hydrochloric acid in diisopropyl ether was added. The mixture was slowly evaporated to yield 1.0 g of the title compound as a yellowish foam.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH:9]=[N:10][O:11][CH3:12])=[O:7])=[C:4]([CH3:15])[CH:3]=1.[CH:16]([O-])=[O:17].[Na+]>CN(C)C=O.O>[CH:16]([C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH:9]=[N:10][O:11][CH3:12])=[O:7])=[C:4]([CH3:15])[CH:3]=1)=[O:17]
Reactant: CON=CNC(=O)c1ccc(Br)cc1C
Reactant: O=C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON=CNC(=O)c1ccc(C=O)cc1C
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 43.7 %

Procedure:
In a solution of 0.20 g of 4-bromo-N-(methoxyiminomethyl)-2-methyl benzoic acid amide in 5 ml of N,N-dimethylformamide, 0.065 g of sodium formate and 0.026 g of dichlorobis(triphenylphosphine) palladium (II) were added, and stirred under carbon monoxide atmosphere at 120° C. for 1.5 hour. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, and poured in 30 mL of water, and extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with water, and dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that were eluated with ethyl acetate-hexane (gradient of 1:3 to 1:1) to obtain 0.071 g of the aimed product as colorless oily substance.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[SH:34].CCN(C(C)C)C(C)C>CN(C=O)C>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[S:34][CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1
Reactant: Fc1ccc(S)c(F)c1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2c(ccn2CCSc2ccc(F)cc2F)c2nc(-c3ccco3)nn12
Temperature: 10 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), 2,4-difluorobenzenethiol (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 10° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give 7-(2-(2,4-difluorophenylthio)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=412.91). 1H NMR (DMSO-d6, 400 MHz) δ 3.40 (m, 2H), 4.32 (m, 2H), 6.56 (m, 1H), 6.72 (m, 1H), 7.05 (m, 1H), 7.12 (m, 1H), 7.22 (m, 2H), 7.53 (m, 3H), 7.92 (s, 1H). Anal. calculated for (C19H14F2N6OS): C, 55.33; H, 3.42; F, 9.21; N, 20 38; 0, 3.88; S, 7.77. Found C, 55.01; H, 3 75; N, 21.95; S, 6.89.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([F:24])[C:21]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]#[N:19])[CH:8]=1)=[O:5].C([O-])([O-])=[O:33].[K+].[K+].OO>CS(C)=O>[Cl:1][C:2]1[CH:23]=[C:22]([F:24])[C:21]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[C:9]([C:18]([NH2:19])=[O:33])[CH:8]=1)=[O:5]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(NC(=O)c2cc(-c3ncccc3F)c(F)cc2Cl)n(-c2ccccc2)n1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)c(F)cc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
To a solution of 2-chloro-N-(3-cyano-1-phenyl-1H-pyrazol-5-yl)-4-fluoro-5-(3-fluoropyridin-2-yl)benzamide (Example 98, 89 mg, 0.20 mmol) in DMSO (5 mL) was added K2CO3 (56 mg, 0.41 mmol) followed by H2O2 (30% aqueous solution, 926 mg, 8.17 mmol). The reaction was stirred at room temperature for 3 hours. The reaction was quenched by the addition of water (20 mL) and extracted into EtOAc (2×20 mL). The combined organic layers were washed with water (2×40 mL), brine (40 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting from 5-45% MeCN (with 0.1% HCO2H) in water (with 0.1% HCO2H) to afford the title compound as a white solid (70 mg, 75%).
Reaction SMILES: I[CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH:13]1([NH:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[NH3:18].[CH:2]1([N:18]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: IC1CCCC1
Reactant: CC(C)(C)OC(=O)NCCNC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)NCCN(C1CCCC1)C1CCCC1
Product: N
Temperature: 60 °C
Reaction time: 72 h
Yield: 6.5 %

Procedure:
Iodocyclopentane (1.68 g, 8.6 mmol) was added to a suspension of potassium carbonate (1.8 g, 13.2 mmol) and tert-butyl 2-[cyclopentylamino]ethylcarbamate (1.5 g, 6.6 mmol) (Preparation 53) in N′,N′-dimethylformamide (10 ml). The reaction mixture was stirred at 60° C. for 72 hours. The reaction mixture was allowed to cool and was then partitioned between ethyl acetate (50 ml) and water (50 ml). The ethyl acetate layer was washed with brine (30 ml) and dried over anhydrous magnesium sulphate. The solvent was removed to give a residue that was purified by chromatography on silica gel eluting with dichloromethane:methanol (98:2 by volume) increasing in polarity to dichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:1 by volume) to give the title compound (64 mg) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:16])=[C:4]([C:13](Cl)=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](Cl)=[O:8].[CH2:17]([NH2:20])[CH:18]=[CH2:19]>ClCCl>[CH2:17]([NH:20][C:13](=[O:14])[C:4]1[C:3]([I:16])=[C:2]([NH2:1])[C:10]([I:11])=[C:6]([C:7]([NH:1][CH2:2][CH:10]=[CH2:6])=[O:8])[C:5]=1[I:12])[CH:18]=[CH2:19]
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reactant: C=CCN
Solvent: ClCCl
Product: C=CCNC(=O)c1c(I)c(N)c(I)c(C(=O)NCC=C)c1I
Reaction time: 18 h

Procedure:
To a solution of 5-Amino-2,4,6-triiodo-isophthaloyl dichloride in dichloromethane was added allylamine (4 equivalents) under a nitrogen atmosphere at ambient temperature. The reaction was stirred for 18 hours. This yielded a precipitate which was found to be the desired product. 1H NMR (DMSOd6) 8.62 (2H, t, j 4.5 Hz), 5.90 (2H, m), 5.46 (2H, br s), 5.37 (2H, d, j 9 Hz), 5.14 (2H, d, 6 Hz), 3.84 (4H, t, 3 Hz). 13C (DMSOd6) 169.6, 149.0, 147.4, 116.0, 79.7, 41.5.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:14][CH2:15][CH3:16])[C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1)[CH3:2].[CH3:17]C(C)[O-].[Na+]>C(O)(C)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:14][CH:15]([CH3:17])[CH3:16])[C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1)[CH3:2]
Reactant: CCOc1cc(OCC)c2nnc(N)n2n1
Reactant: CC(C)[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CCOc1cc(OC(C)C)c2nnc(N)n2n1
Temperature: 85 °C

Procedure:
6,8-Diethoxy-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W1.126; 80 mg, 0.358 mmol) was dissolved in isopropanol (10 ml), and sodium isopropoxide (297 mg) was added. The mixture was heated to 85° C. for 1 h and concentrated, the residue was dissolved in water and a pH of 6 was established by adding aqueous hydrochloric acid. The mixture was extracted with ethyl acetate and the combined organic phases were dried and concentrated. The remaining residue was purified by flash chromatography (dichloromethane:MeOH). Yield: 58 mg.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3=[N:20][C:21]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:22][CH:23]=[C:18]3[CH2:17][N:16]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[C:15]2=[O:39])[CH2:10][CH2:9]1)=O)(C)(C)C.O>FC(F)(F)C(O)=O.ClCCl>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([N:16]2[CH2:17][C:18]3[C:19](=[N:20][C:21]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:22][CH:23]=3)[N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:15]2=[O:39])=[CH:36][CH:35]=1
Reactant: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N(C3CCNCC3)C2=O)cc1
Reaction time: 1.5 h

Procedure:
4-[3-(4-Methoxy-phenyl)-2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (70 mg, 0.13 mmol) (from Example 2a supra) was dissolved at 0° C. in a 50% solution of trifluoroacetic acid in dichloromethane (6 mL) that contained 100 μL of water. After stirring for 1.5 hours the mixture was partitioned between ethyl acetate and 1 N aqueous sodium hydroxide and the pH of the aqueous layer was adjusted to 12 by the addition of solid sodium hydroxide. The organic layer was then washed with water, dried over sodium sulfate, filtered and concentrated. The crude material was purified by precipitation out of tetrahydrofuran with excess of pentane to give 3-(4-methoxy-phenyl)-7-phenylamino-1-piperidin-4-yl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as an off white solid. (Yield 42 mg, 75%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@@H:5]1[N:10]([C:11](=[O:33])[C@@H:12]([NH:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:9][CH2:8][N:7]([CH2:34][C:35]([OH:37])=[O:36])[C:6]1=[O:38].C([O-])(O)=O.[Na+].[CH:44]1[CH:49]=[CH:48][C:47]([CH2:50][O:51][C:52](Cl)=[O:53])=[CH:46][CH:45]=1>O1CCOCC1>[CH2:26]([O:25][C:23]([NH:22][C@@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:11]([N:10]1[CH2:9][CH2:8][N:7]([CH2:34][C:35]([OH:37])=[O:36])[C:6](=[O:38])[C@@H:5]1[CH2:4][CH2:3][CH2:2][NH:1][C:52]([O:51][CH2:50][C:47]1[CH:48]=[CH:49][CH:44]=[CH:45][CH:46]=1)=[O:53])=[O:33])=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N2CCN(CC(=O)O)C(=O)[C@@H]2CCCN)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N2CCN(CC(=O)O)C(=O)[C@@H]2CCCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In 100 ml of a 50% aqueous solution of dioxane was dissolved 3.8 g of (S,S)-3-(3-aminopropyl)-4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl]-2-oxopiperazine-1-acetic acid produced in Reference Example 33. To the solution was added 1.52 g of NaHCO3, to which was added dropwise, under ice-cooling, 1.24 ml of Z-chloride. The mixture was stirred for 1.5 hour at room temperature. Dioxane was distilled off. To the residue was added a 3% aqueous solution of KHSO4 to adjust the pH to 2. The mixture was subjected to extraction with ethyl acetate. The extract solution was washed with a saturated aqueous solution of NaHCO3 and dried (Na2SO4), followed by concentration under reduced pressure. To the concentrate was added ether. The mixture was subjected to decantation twice to afford 4 g of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([C:15]([O:17]CC)=[O:16])[CH2:9][C:10]([O:12]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)(=O)C>[CH2:7]([CH:8]1[C:15](=[O:16])[O:17][C:10](=[O:12])[CH2:9]1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(Cc1ccccc1)C(=O)OCC
Solvent: CC(=O)Cl
Product: O=C1CC(Cc2ccccc2)C(=O)O1

Procedure:
The product from step (b) was suspended in acetyl chloride (24 ml) and the suspension refluxed for 3 hours, then evaporated in vacuo to give a white solid which was triturated and washed with 60-80 petrol and dried in vacuo to give the desired product (9.7 g). The 200 MHz 1H NMR was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@H:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[C@H:10]([OH:11])[CH2:9][S:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:18][CH:19]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1[C@H](O)CSCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4[C@H](O)CSCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using (S)-2-benzylsulfanyl-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([C:19]([CH3:21])=[CH2:20])[CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([CH:19]([CH3:21])[CH3:20])[CH:10]=1
Reactant: C=C(C)c1cc(OCc2ccccc2)ccc1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(O)cc1C(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 4-(benzyloxy)-2-(prop-1-en-2-yl)benzoate (i-1d) (4.6 g, 16.3 mmol) in methanol (100 ml) was added Pd/C (0.46 g). The mixture was stirred at rt under H2 atmosphere for 24 h. Then the mixture was filtered, and the filtrate was concentrated to afford the title compound. LCMS (ESI) calc'd for C11H14O3 [M+H]+: 195.1. found: 195.1.
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@H:22]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])[CH2:21][C@H:20]([C:35]([OH:37])=O)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:72][O:73][CH2:74][CH2:75][CH2:76][CH2:77][O:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][C:80]=1[CH:85]([C:88]1[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=1)[CH2:86][NH2:87]>C(Cl)Cl.CC#N>[CH3:72][O:73][CH2:74][CH2:75][CH2:76][CH2:77][O:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][C:80]=1[CH:85]([C:88]1[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=1)[CH2:86][NH:87][C:35]([C@H:20]1[CH2:21][C@@H:22]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)(=[O:26])=[O:27])[CH2:23][NH:18][CH2:19]1)=[O:37]
Reactant: COCCCCOc1ccccc1C(CN)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H]2C[C@H](C(=O)O)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)cc1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCCCCOc1ccccc1C(CNC(=O)[C@@H]1CNC[C@H](NS(=O)(=O)c2ccc(C)cc2)C1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
An ice-cooled mixture of (3S*,5R*)-5-(toluene-4-sulfonylamino)-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester (208.2 mg, 0.4 mmol), O-(1H-6-chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (182 mg, 0.44 mmol) and N-ethyldiisopropylamine (27.4 μL, 0.16 mmol) in CH2Cl2/CH3CN 1:1 (3 mL) is stirred for 10 min. After the addition of 2-[2-(4-methoxy-butoxy)-phenyl]-2-phenyl-ethylamine (119.8 mg, 0.4 mmol), the ice-bath is removed and stirring is continued for 14 h at RT. The reaction mixture is distributed between ethyl acetate and 10% K2CO3 solution. The aqueous layer is separated and extracted twice with ethyl acetate. The combined organic layers are dried over Na2SO4 and evaporated in vacuo. The residue is stirred for 1 h with a freshly prepared mixture of CH2Cl2/piperidine 4:1 (5 mL), evaporated and the residue purified by preparative HPLC (C18 column; 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA/20 min, flow 20 mL/min). The combined pure fractions are treated with Na2CO3, CH3CN is removed in vacuo, and the residual aqueous phase is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound as a slightly beige amorphous solid. MS: 580.4 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.61 min.
Reaction SMILES: C1(C(=[N:14][CH:15]([CH2:21][CH:22]=[C:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])C2C=CC=CC=2)C=CC=CC=1.O.C(O)(=O)C>C1COCC1>[NH2:14][CH:15]([CH2:21][CH:22]=[C:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(CC=C1CCOCC1)N=C(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C(N)CC=C1CCOCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.4 %

Procedure:
To a solution of ethyl 2-[(diphenylmethylidene)amino]-4-(tetrahydro-4H-pyran-4-ylidene)butanoate (162) (6.8 g, 18.0 mmol) in THF (30 mL) was added water (30 mL) and glacial acetic acid (20 mL) and the reaction stirred at room temperature for 2.5 h. The reaction was concentrated in vacuo and the residue dissolved in 0.1 N HCl. It was extracted twice with ethyl acetate and the organic layer was discarded. To the aqueous layer was added solid potassium carbonate until the solution gave blue pH paper. The aqueous layer was extracted with 15% isopropanol/dichloromethane (3×) and the organic layer dried over sodium sulfate and concentrated in vacuo to afford the title compound as a clear oil (3.05 g, 79% yield).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[Cl:12][Si](CC)(CC)CC.[Cl:20][C:21]1[CH:22]=[C:23]([N:36]2[C:41](=[O:42])[NH:40][C:39](=[O:43])[CH:38]=[N:37]2)[CH:24]=[CH:25][C:26]=1[C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31](Cl)=[CH:30][CH:29]=1.[NH4+].[Cl-]>C1COCC1>[OH2:35].[Cl:20][C:21]1[CH:22]=[C:23]([N:36]2[C:41](=[O:42])[NH:40][C:39](=[O:43])[CH:38]=[N:37]2)[CH:24]=[CH:25][C:26]=1[C:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:12])([OH:35])[C:11]1[N:7]([CH3:6])[CH:8]=[N:9][CH:10]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: Cn1ccnc1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccccc1Cl)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Product: O
Temperature: -70 °C
Reaction time: 0.67 h
Yield: 25 %

Procedure:
n-Butyllithium, 1.6M (0.0203 mol) was added dropwise at −70° C. under N2 flow to a solution of 1-methyl-1H-imidazole (0.0203 mol) in THF (60 ml). The mixture was stirred at −70° C. for 40 minutes. Chlorotriethylsilane (0.203 mol) was added quickly and the mixture was allowed to warm to 0° C. on an ice bath. The mixture was cooled to −70° C. and n-butyllithium (0.0203 mol) was added dropwise. The mixture was allowed to warm to −20° C. and cooled to −70° C. A solution of 2-[3-chloro-4-(4-chlorobenzoyl)phenyl-1,2,4-triazine-3,5(2H,4H)-dione (0.00812 mol) in THF (20 ml) was added dropwise. The mixture was allowed to warm to −5° C., then poured out into a satured NH4Cl solution and ice, and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 96/4). The pure fractions were collected and the solvent was evaporated. The residue (0.85 g) was crystallized from 2-propanone and diethyl ether. The precipitate was filtered off and dried, yielding 0.47 g (13%) of (±)-2-[3-chloro-4-[(chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione monohydrate (compound 121).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][N:10]([CH3:40])[C:11](=[O:39])[NH:12][CH:13]([CH3:38])[CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22]C=1)[N:20]([CH3:24])[CH:19]=[C:18]2[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=1[O:36][CH3:37].Cl[CH2:42][Cl:43]>>[Cl:1][C:19]1[N:20]([CH3:24])[C:21]2[C:17]([C:18]=1[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=1[O:36][CH3:37])=[CH:16][C:15]([CH2:14][CH:13]([NH:12][C:11]([N:10]([CH3:40])[CH3:9])=[O:39])[CH3:38])=[C:42]([Cl:43])[CH:22]=2
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(CC(C)NC(=O)N(C)C)cc23)c(OC)c1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ClCCl
Product: COC(=O)c1ccc(Cc2c(Cl)n(C)c3cc(Cl)c(CC(C)NC(=O)N(C)C)cc23)c(OC)c1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
N-Chlorosuccinimide (0.313 g) was added in one portion to a stirred solution of methyl 4-[5-[2-(N',N'-dimethylureido)propyl]-1-methylindol-3-ylmethyl]-3-methoxybenzoate (0.5 g) in dichloromethane (25 ml). After 30 minutes, the solvent was evaporated, and the product isolated by flash chromatography, eluting with 3:7 ethyl acetate:toluene, to give methyl 4-[2,6-dichloro-5-[2-(N',N'-dimethylureido)propyl]-1-methylindol-3-ylmethyl]-3-methoxybenzoate (60%) as a white solid; mp 175°-176° C.; NMR (300 MHz, DMSO-d6): 1.00 (d, 3H, CH3), 2.61 (s, 6H), 2.82 (d, 2H), 3.72 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 3.85-3.96 (m, 4H), 4.00 (s, 2H), 5.91 (d, 1H, NH), 6.99 (d, 1H), 7.33 (s, 1H), 7.38-7.50 (m, 2H), 7.61 (s, 1H).