Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[N:13][N:14]=[C:7]1[CH2:6][CH2:5]2.[CH3:15][C:16]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[N:28][CH:29]=1)([CH3:23])[CH2:17][O:18][C:19]([F:22])([F:21])[F:20].[C:33](=O)([O-:35])[O-:34].[K+].[K+].C(O)(C)(C)C>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O>[F:22][C:19]([F:20])([F:21])[C:33]([OH:35])=[O:34].[CH3:23][C:16]([C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]2[CH:12]=[N:13][N:14]=[C:7]2[CH2:6][CH2:5]3)[CH:27]=[N:28][CH:29]=1)([CH3:15])[CH2:17][O:18][C:19]([F:20])([F:21])[F:22]
Reactant: CC(C)(COC(F)(F)F)c1cncc(B(O)O)c1
Reactant: O=C([O-])[O-]
Reactant: Brc1ccc2c(c1)CCc1nncn1-2
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(COC(F)(F)F)c1cncc(-c2ccc3c(c2)CCc2nncn2-3)c1
Product: O=C(O)C(F)(F)F
Temperature: 80 °C

Procedure:
To a vial containing the title compound from Example 22 Step B (50 mg, 0.200 mmol), the title compound from Example 64 Step C (63.1 mg, 0.240 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (28.3 mg, 0.040 mmol) and potassium carbonate (83 mg, 0.600 mmol) were added tert-butanol (2.2 mL) and water (0.28 mL). The vial was capped tightly and heated to 80° C. overnight. The reaction was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with acetonitrile and then purified by HPLC (C18 column, 10 to 100% acetonitrile/water, both 0.1% v/v trifluoroacetic acid) to provide the title compound: LCMS m/z 389.00 [M+H]+; NMR (500 MHz, CD3OD) δ 9.99 (s, 1H), 9.19 (s, 1H), 9.02 (s, 1H), 8.94 (s, 1H), 8.09-8.00 (m, 3H), 4.33 (s, 2H), 3.48-3.45 (m, 2H), 3.39-3.36 (m, 2H), 1.60 (s, 6H).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3](=[O:12])[CH2:4][C:5]([CH3:11])([CH3:10])[CH2:6][C:7]([OH:9])=O.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH2:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH:30]=[CH:31][CH:32]=1>O1CCCC1>[CH3:13][N:2]([CH3:1])[C:3](=[O:12])[CH2:4][C:5]([CH3:11])([CH3:10])[CH2:6][C:7]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH:28]=1)=[O:9]
Reactant: CN(C)C(=O)CC(C)(C)CC(=O)O
Reactant: CN(C)C(=O)Nc1cccc(N)c1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CC(C)(C)CC(=O)Nc1cccc(NC(=O)N(C)C)c1
Temperature: -5 °C
Yield: 22.7 %

Procedure:
N,N-Dimethyl-3,3-dimethyl glutaramic acid (2.6 grams) and 1.5 gram triethyl amine were mixed in 150 ml tetrahydrofuran. The mixture was stirred magnetically and cooled to -5° C. Methane sulfonyl chloride (1.7 gram) was added dropwise and stirred at -5° C. for one hour. 1-(3-amino phenyl)-3,3-dimethyl urea (2.49 grams) was dissolved in 35 ml tetrahydrofuran. This solution was added dropwise and stirred for one hour at -5° C. The cooling bath was then removed. When the reaction mixture reached room temperature it was concentrated by rotary evaporation. Methylene chloride (175 ml) was added and the mixture washed once with 10 percent w/w NaOH, twice with water and dried over sodium sulfate. Rotary evaporation yields 1.1 grams of the title compound. This compound will be referred to as compound No. 3.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:26]([N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34])(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:33][CH2:32][N:31]([C:2]2[N:7]=[N:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH:23]5[CH2:25][CH2:24]5)=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[C:30]1=[O:34])(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)nn2)CC1
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C)CC3)nn2)C1=O

Procedure:
Using (6-chloropyridazin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (179 mg) described in Preparation Example 233 and 1-acetylimidazolidin-2-one (64 mg) and by the reaction and treatment in the same manner as in Example 511, 1-acetyl-3-{6-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]pyridazin-3-yl}imidazolidin-2-one was obtained as a crude product (170 mg). Methanol (1.2 mL) and 1N aqueous sodium hydroxide solution (0.57 mL) were added to the obtained crude product (170 mg) of 1-acetyl-3-{6-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]pyridazin-3-yl}imidazolidin-2-one, and the mixture was stirred at 40° C. for 1 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was evaporated, and the residue was purified by column chromatography (ethyl acetate:methanol) to give the title compound (48 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:26])=[C:7]([NH:9][C:10]2[C:19]3[CH:18]=[CH:17][NH:16][C:15](=[O:20])[C:14]=3[C:13]3[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:12]=3[N:11]=2)[CH:8]=1.C(N(CC)CC)C.[F:34][C:35]([F:41])([F:40])[S:36](Cl)(=[O:38])=[O:37]>C1COCC1>[F:34][C:35]([F:41])([F:40])[S:36]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:26])=[C:7]([NH:9][C:10]2[C:19]3[CH:18]=[CH:17][NH:16][C:15](=[O:20])[C:14]=3[C:13]3[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:12]=3[N:11]=2)[CH:8]=1)(=[O:38])=[O:37]
Reactant: Cc1ccc(CN)cc1Nc1nc2ccc(F)cc2c2c(=O)[nH]ccc12
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(CNS(=O)(=O)C(F)(F)F)cc1Nc1nc2ccc(F)cc2c2c(=O)[nH]ccc12
Reaction time: 1 h

Procedure:
To a solution of 5-{[5-(aminomethyl)-2-methylphenyl]amino}-9-fluorobenzo[c]-2,6-naphthyridin-1(2H)-one (35 mg, 0.10 mmol) in THF (1.0 mL) at 0° C. was added triethylamine (0.03 mL, 0.20 mmol) and trifluoromethanesufonyl chloride (0.01 mL, 0.11 mmol). The reaction was stirred for one hour and then quenched by the addition of citric acid. The mixture was extracted with EtOAc/water and the extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by silica gel column chromatographpy (0-10% MeOH/CH2Cl2) afforded the title compound. 1H NMR (600 MHz, CD6SO) δ 12.21 (d, 1H), 9.92 (s, 1H), 9.45 (dd, 1H), 8.85 (s, 1H), 7.68 (m, 1H), 7.45 (m, 1H), 7.34-7.38 (m, 2H), 7.26 (d, 1H), 7.22 (d, 1H), 7.09 (d, 1H), 4.32 (s, 2H), 2.12 (s, 3H). LRMS (ESI) calc'd for C21H16F4N4O3 [M+H]+, 481.1; found 481.0.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].[C:8]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]2[C:27]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])=[C:26](Cl)[N:25]=[C:24]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[N:23]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C(OCC)(=O)C>CS(C)=O>[C:8]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:21][C:22]2[C:27]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])=[C:26]([O:4][CH2:3][CH2:2][CH2:1][OH:5])[N:25]=[C:24]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[N:23]=2)(=[O:20])=[O:19])=[CH:16][CH:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: OCCCO
Reactant: COc1ccccc1Oc1c(Cl)nc(N2CCOCC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCCO
Yield: 67.9 %

Procedure:
1,3-Propanediol (580 mg) was dissolved in dimethyl sulfoxide (15 ml). Sodium hydride (297 mg) and 4-t-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinyl]benzenesulfonamide (1.1 g) were added to the solution. The resultant mixture was stirred for 4 hours at 120° C. Ethyl acetate was added to the reaction mixture, followed by successive washing with 0.5N-HCl, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1), to thereby obtain 802 mg (yield: 68%) of the title compound as a white powder.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:16][C:15]2[C:6](=[C:7]([NH2:18])[C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([Cl:17])=[CH:10][CH:9]=3)[CH2:5][CH2:4]1.[S:19]1[CH2:23][CH2:22][CH:21]([CH2:24][C:25](O)=[O:26])[S:20]1.C1[C@@H](CC(O)=O)SSC1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[NH2:18][C:7]1[C:8]2[C:13]([N:14]=[C:15]3[C:6]=1[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:25](=[O:26])[CH2:24][CH:21]1[CH2:22][CH2:23][S:19][S:20]1)[CH2:16]3)=[CH:12][C:11]([Cl:17])=[CH:10][CH:9]=2
Reactant: NCC1CCc2c(nc3cc(Cl)ccc3c2N)C1
Reactant: O=C(O)CC1CCSS1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)C[C@@H]1CCSS1
Solvent: CN(C)C=O
Product: Nc1c2c(nc3cc(Cl)ccc13)CC(CNC(=O)CC1CCSS1)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
A solution of 16 (140 mg, 0.53 mmol) and [1,2]dithiolan-3-yl-acetic acid (Chen, Yaun-Shek and Lawton, Richard G. An efficient synthetic route to 2-(1,2-dithiolan-3-yl)acetic acid. Trisnorlipoic acid and amide derivatives. Tetrahedron Letters 1997, 38, 5785-5788) (90 mg, 0.55 mmol) in anhydrous DMF (5 mL), under N2, was cooled to 0° C. and then additioned with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (113 mg, 0.59 mmol); the reaction mixture was stirred at 0° C. for 15 min and then at room temperature for 2 h in the dark. Solvent was then evaporated, accurately avoiding heating up the mixture. An oily residue was obtained which was purified by gravity column. Elution with petroleum ether/CH2Cl2/MeOH/aqueous 30% ammonia solution (5:4:1:0.1) afforded 17 as a waxy solid: 40% yield; 1H NMR (200 MHz, CD3OD) δ 8.03 (d, J=9.2 Hz, 1H), 7.67 (d, J=2.2 Hz, 1H), 7.30 (dd, J=8.8, 2.2 Hz, 1H), 4.05 (m, 1H), 2.95-3.34 (m, 5H), 2.46-2.59 (m, 6H), 1.99-2.20 (m, 3H), 1.48-1.52 (m, 1H). Anal. Calculated for C19H22ClN3OS2: C, 55.93; H, 5.44; N, 10.30. Found: C, 56.01; H, 5.45; N, 10.11.
Reaction SMILES: Cl[C:2]1[C:3]2[S:23](=[O:24])[CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[NH2:25][C@@H:26]([CH2:31][OH:32])[CH2:27][CH:28]([CH3:30])[CH3:29].C(N(C(C)C)CC)(C)C.O>O1CCOCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[N:7]=[C:2]([NH:25][C@H:26]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:31][OH:32])[C:3]4[S:23](=[O:24])[CH2:22][CH2:21][C:4]=4[N:5]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(Cl)c21
Reactant: CC(C)C[C@@H](N)CO
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](CO)Nc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2
Temperature: 120 °C

Procedure:
220 mg 4-chloro-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidine 5-oxide (cf Example 124), 134.53 mg D-leucinol and 197.52 μl diisopropylethylamine are placed in 4 ml dioxane, heated to 120° C. in the microwave for 0.3 hours. Then the reaction mixture is mixed with water, the precipitate formed is suction filtered, washed and dried. The diastereomers are separated by preparative HPLC (method B). 43.9 mg of Diastereomer 1 (Example 53) and 46.9 mg of Diastereomer 2 (Example 69) are obtained as an oil. Analytical HPLC-MS (method B): Diastereomer 1, RT=1.86 min, Diastereomer 2, RT=1.90 min.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[C:5](=[O:8])([O-:7])[NH2:6].[NH4+:9].C(=O)=O>>[C:5](=[O:8])([O-:3])[O-:7].[NH4+:1].[NH4+:6].[NH2:1][C:2]([NH2:4])=[O:3].[NH3:9]
Reactant: NC(=O)[O-]
Agent: NC(N)=O
Agent: O=C=O
Agent: [NH4+]
Product: N
Product: O=C([O-])[O-]

Procedure:
In a method for the concurrent production of ammonia and urea comprising the steps of producing ammonia in an ammonia-synthesis apparatus, absorbing ammonia at the exit of the ammonia-synthesis reactor with water, thus obtaining a concentrated aqueous solution of ammonia, utilizing the concentrated solution of ammonia for the absorption of the CO2 contained in the raw gases for the synthesis of ammonia, obtaining ammonium carbamate, converting the ammonium carbamate partially into urea in a urea-synthesis reactor, thermally decomposing the carbamate which has not been converted into urea and stripping the decomposition products with a gas selected from the group consisting of ammonia, CO2 and inerts, discharging from the stripping zone a solution of urea which still contains carbamate, recycling the products of decomposition of the carbamate to the urea-synthesis reactor, distilling under a pressure of from 3 to 30 atm, in at least one stage, the solution of urea to obtain liquid ammonia and one or more ammoniacal solutions of ammonium carbonate, and an aqueous solution of urea deprived of ammonium carbamate the improvement which comprises introducing the CO2 -containing gas at the bottom, or near the bottom, of an absorber which is split into two sections, the lower section being a film-absorber and the upper section being a plate-absorber, the absorbing solution in the upper section being the concentrated aqueous solution of ammonia aforesaid, the absorbing solution in the lower section being one or more of the aqueous ammoniacal solutions of ammonium carbonate as obtained by distillation of the solution of urea under a pressure of from 3 to 30 atm. with addition of liquid ammonia.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[N:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:25]=[N:26][CH:27]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:22]4[CH:27]=[N:26][CH:25]=[C:24]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)[CH:23]=4)[N:19]=[C:15]3[CH:14]=[N:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(c2cncc(Br)c2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cncc3nc(N)nn23)cc1
Product: CN1CCN(c2cncc(Nc3nc4cncc(-c5ccc(S(C)(=O)=O)cc5)n4n3)c2)CC1
Yield: 4 %

Procedure:
1-(5-Bromo-pyridin-3-yl)-4-methyl-piperazine was prepared from 3,5-dibromo-pyridine (1.00 g, 4.22 mmol) and piperazine, 1-methyl-(0.936 mL, 8.44 mmol) which were combined and heated in a microwave vial to 180° C. for 2 hours. The reaction mixture was taken up in dichloromethane and purified by silica gel chromatography 0-10% methanol in dichloromethane to afford a clear oil (37%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.20 (s, 1H), 8.11 (s, 1H), 7.29 (m, 1H), 3.25 (bm, 4H), 2.58 (bm, 4H), 2.35 (s, 3H). 108b) [5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl]-[5-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine and 1-(5-bromo-pyridin-3-yl)-4-methyl-piperazine in a manner analogous to Step 2d and was isolated as an off-white lyophilate (4% yield). 1H NMR (400 MHz, CDCl3, δ, ppm): 10.5 (bs, 1H), 9.86 (bs, 1H), 9.22 (s, 1H), 8.49 (s, 1H), 8.40 (d, J=7.9 Hz, 2H), 8.35 (s, 1H), 8.19 (d, J=7.6 Hz, 2H), 8.05 (d, J=16.5 Hz, 2H), 3.84 (bm, 2H), 3.55 (bm, 2H), 3.38 (s, 3H), 3.20 (bm, 2H), 3.09 (bm, 2H), 2.88 (s, 3H). MS=465.1 (MH)+.
Reaction SMILES: I[CH2:2][O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][C:16]([NH:29][C:30]([O:32][CH2:33][C:34]2[O:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[CH:38]=2)=[O:31])([C:18](=[O:28])[NH:19][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[CH3:17])=[CH:7]1)=[O:5].[C:43]([C:46]1[CH:53]=[CH:52][C:49]([CH:50]=[O:51])=[CH:48][CH:47]=1)([OH:45])=[O:44]>C1(C)C=CC=CC=1.[Ag]>[CH:50]([C:49]1[CH:52]=[CH:53][C:46]([C:43]([O:45][CH2:2][O:3][C:4]([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]([CH2:15][C:16]([NH:29][C:30]([O:32][CH2:33][C:34]3[O:35][C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=4[CH:38]=3)=[O:31])([C:18](=[O:28])[NH:19][CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[CH3:17])=[CH:7]2)=[O:5])=[O:44])=[CH:47][CH:48]=1)=[O:51]
Reactant: CC(NC(=O)C(C)(Cc1cn(C(=O)OCI)c2ccccc12)NC(=O)OCc1cc2ccccc2o1)c1ccccc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [Ag]
Solvent: Cc1ccccc1
Product: CC(NC(=O)C(C)(Cc1cn(C(=O)OCOC(=O)c2ccc(C=O)cc2)c2ccccc12)NC(=O)OCc1cc2ccccc2o1)c1ccccc1
Yield: 80.4 %

Procedure:
Compound 7 (1.7 g, 2.5 mmol) and the silver salt of 4-carboxybenzaldehyde (1.29 g, 5.0 mmol) in dry toluene (50 mL) was refluxed for 30 minutes to give a yellow suspension. The solid was removed by filtration through celite, and the solid cake was washed with toluene. The filtrate was concentrated to give a syrup, which was purified by silica gel column eluting with CHCl3 to give compound 19 as a white foam (1.41 g, 80%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]([CH2:14][CH:15]([O:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:16])[CH2:12][OH:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C.Cl>ClCCl>[C:1]([O:9][CH2:10][CH:11]([CH2:14][CH:15]([O:17][C:18](=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:16])[CH2:12][O:13][S:27]([CH3:26])(=[O:29])=[O:28])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(CC(CO)COC(=O)c1ccccc1)OC(=O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CC(COC(=O)c1ccccc1)COS(C)(=O)=O)OC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice cooled solution of 1.85 g (5.60 mM) of 2-(2-benzoyloxypropan-1-yl)-3-hydroxy-propyl benzoate m5 in 40 ml of dichloromethane are added 0.607 ml (7.84 mM) of methanesulfonyl chloride and 1.34 ml (9.52 mM) of triethylamine. After stirring at 0° C. for 30 minutes, the mixture is poured into an ice cooled 2N aqueous hydrochloric acid and the product is isolated by dichloromethane extraction. The dichloromethane layer is washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate. Evaporation of the solvent gives the crude product of the titled compound m11'.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([C@H:13]([OH:17])[CH2:14][CH2:15][CH3:16])[C:9]([O:11]C)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>C1COCC1.CO.O>[CH:1]1([CH2:7][C@H:8]([C@H:13]([OH:17])[CH2:14][CH2:15][CH3:16])[C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC[C@@H](O)[C@@H](CC1CCCCC1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCC[C@@H](O)[C@@H](CC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.1 %

Procedure:
Methyl (2R,3R)-2-cyclohexylmethyl-3-hydroxyhexanoate (3.44 g, 14.2 mmol) is dissolved in 3:1:1 THF-MeOH-H2O (35 mL). To this is added lithium hydroxide monohydrate (1.79 g, 42.6 mmol). The reaction mixture is stirred for 18 h at 25° C. and the mixture is then extracted with ether. The aqueous layer is acidified with solid sodium bisulfate and then extracted with two 250-mL portions of ether. The combined organics are washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure to afford (2R,3R)-2-cyclohexylmethyl-3-hydroxyhexanoic acid as a solid (3.05 g, 96% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)[CH3:2].C(N(CC)CC)C.C(O)=O>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(C#N)cc1
Agent: [Pd]
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(C#N)cc1
Yield: 98.4 %

Procedure:
Pd/C (5 g, 10%) was added to a solution of 3-(4-cyanophenyl)acrylic acid ethyl ester (50 g, 0.25 mol; see step (i) above) in dry ethyl acetate (500 mL) under a nitrogen atmosphere, followed by triethylamine (50.3 g, 0.5 mol) and formic acid (57.2 g, 1.24 mol). The mixture was refluxed overnight under a nitrogen atmosphere. After the completion of the reaction (monitored by TLC), the mixture was filtered and the filtrate then washed with water, 5% NaHCO3 solution and brine, before being dried over sodium sulfate. Solvent evaporation under reduced pressure yielded 50 g (99%) of the sub-title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH:9]=O)[CH:6]=[CH:5][CH:4]=1.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][CH2:9][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)[CH2:13][CH2:12]1
Reactant: NC1CC1
Reactant: COc1cccc(C=O)n1
Product: COc1cccc(CNC2CC2)n1

Procedure:
prepared by reaction of 6-methoxypyridine-2-carbaldehyde with cyclopropylamine
Reaction SMILES: [CH:1](=[CH:10][C:11]([OH:13])=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(Cl)([Cl:16])=O>CCCCCC>[CH:1](=[CH:10][C:11]([Cl:16])=[O:13])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=CC=Cc1ccccc1
Solvent: CCCCCC
Product: O=C(Cl)C=CC=Cc1ccccc1
Yield: 77.9 %

Procedure:
Preparation of C6H5—CH═CH—CH═CH—CO2PEG—OCH2CH(OC2H5)2: A solution of cinnamylideneacetic acid (1.7 g, 0.01 moles) and thionyl chloride (3 ml, 0.04 moles) in 50ml of hexane were refluxed under N2 for 4 h, then filtered to remove a small amount of dark solid and the filtrate evaporated under vacuum. The residue was dried under vacuum overnight at room temperature to obtain 1.5 g of cinnamylideneacetyl chloride as a yellow solid, m.p. 51-52° C.)
Reaction SMILES: CCN(CC)CC.Cl.[CH3:9][O:10][C:11](=[O:16])[C@H:12]([CH2:14][OH:15])[NH2:13].[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH3:9][O:10][C:11](=[O:16])[CH:12]([NH:13][C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:14][OH:15]
Reactant: COC(=O)[C@@H](N)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
A solution of Et3N (13.4 mL, 96.78 mmol) in CH2Cl2 (40 mL) was added to a solution of L-serine methyl ester hydrochloride (5.0 g, 32.26 mmol) and Ph3CCl (13.5 g, 48.39 mmol) in CH2Cl2 (129 mL) at 0° C. under N2 atmosphere. The reaction was then allowed to warm to room temperature and was stirred overnight. The reaction was quenched with saturated NaHCO3, the aqueous layer was extracted with CH2Cl2, and the combined organic layers were washed with brine, dried and concentrated, the residue was purified by silica gel column chromatography which gave the title compound as a colourless solid (11.41 g, 98%).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:7][SiH:8]([CH3:10])[Cl:9]>>[CH2:1]([Si:8]([CH3:10])([CH3:7])[Cl:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C[SiH](C)Cl
Reactant: C=CCCC=C
Product: C=CCCCC[Si](C)(C)Cl
Reaction time: 48 h
Yield: 68 %

Procedure:
5-Hexenyldimethylchlorosilane was prepared by combining 1,5-hexadiene (164 g) and 0.05 g of platinum complex ##STR3## in a flask equipped with a condenser, addition-funnel and a thermometer. Dimethylchlorosilane (92 g) was added at such a rate that the pot temperature did not rise above 40° C. The mixture was allowed to stand at room temperature for 48 hours. The product was isolated in 68% yield by distillation under reduced pressure (bp 39°-40° C./2.2 mm Hg).