Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[CH:24][CH:23]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44][C@H:45]1[CH2:47][O:46]1.CCN(C(C)C)C(C)C>C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:29][CH2:30][N:31]([CH2:44][C@@H:45]([OH:46])[CH3:47])[CH2:32][CH2:33]5)=[CH:26][CH:27]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=3)(=[O:35])=[O:36])[CH:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Yield: 62.1 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-benzyl-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (175 mg. 0.249 mmol) was alkylated using (S)-2-methyloxirane (27 mg, 0.498 mmol), DIPEA (129 mg, 0.996 mmol) and ethanol (5 mL) to get 100 mg (62.1% yield) of the titled compound. MS: m/z=647.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:19])[C:5]2[CH:11]=[C:10](Br)[C:9](=[O:13])[N:8]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][N:31](C(OC(C)(C)C)=O)[CH:32]=2)O1.O>CC(N(C)C)=O>[NH2:1][C:2]1[N:3]=[C:4]([CH3:19])[C:5]2[CH:11]=[C:10]([C:28]3[CH:29]=[N:30][NH:31][CH:32]=3)[C:9](=[O:13])[N:8]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nc(N)nc2c1cc(Br)c(=O)n2N1CCCC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nc(N)nc2c1cc(-c1cn[nH]c1)c(=O)n2N1CCCC1
Temperature: 100 °C

Procedure:
To a flask was added a 2-amino-6-bromo-4-methyl-8-(pyrrolidin-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (21.0 mg, 0.06 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (20.9 mg, 0.07 mmol) potassium carbonate (25.6 mg, 0.19 mmol) in DMAC (1.20 ml):H2O (0.1 ml). The reaction mixture was degassed by alternating between N2 and vacuum. To the reaction mixture was added PdCl2(PPh3)2 (4.3 mg). After heating in microwave for 60 min at 100° C., the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by reversed phase column eluted with acetonitrile: 0.1% acetic acid in water to give the titled compound weighted 2.5 mg
Reaction SMILES: [C:1]([C:3]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:4]=1[O:5][C:6]1[CH:7]=[CH:8][C:9](SC)=[C:10](O)[CH:11]=1)#[N:2].Br[CH:21]([CH3:25])[C:22]([NH2:24])=[O:23].C[S:27]([CH3:29])=O.O>CCCCCC.C(OCC)(=O)C>[C:1]([C:3]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:8])=[C:29]([CH:7]=1)[S:27][CH:21]([CH3:25])[C:22]([NH2:24])=[O:23])#[N:2]
Reactant: CC(Br)C(N)=O
Reactant: CS(C)=O
Reactant: CSc1ccc(Oc2ccc(F)cc2C#N)cc1O
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc(F)cc2C#N)cc1SC(C)C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(2-Cyano-4-fluorophenoxy)-2-(methylthio)phenol (0.05 mole) potassium carbonate (0.2 mole), 2-bromopropionamide (0.08 mole) and dimethylsulfoxide (200 ml) are charged into a 500 ml glass reaction flask equipped with a mechanical stirrer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into 500 ml of water. The resulting mixture is extracted three times with 100 ml portions of methylene chloride. The extracts are then combined, washed with water and thereafter dried. The dried solution is then stripped of solvent under reduced pressure to leave a residue. The residue is subjected to chromatography using a clay column and hexane/ethyl acetate mixtures as the eluant. The fractions containing the product are combined and stripped of solvent to yield the desired product 2-[5-(2-cyano-4-fluorophenoxy)-2-methylthiophenoxy]propionamide as the residue.
Reaction SMILES: Br[C:2]1[N:3]([CH2:7][C:8]2[CH:9]=[C:10]([C:14]3[CH:18]=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:16][C:15]=3[S:23]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])=[O:24])[CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][N:6]=1.C(O)C.[S:34]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35]1.[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:34]1[CH:38]=[CH:37][C:36]([C:2]2[N:3]([CH2:7][C:8]3[CH:9]=[C:10]([C:14]4[CH:18]=[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:16][C:15]=4[S:23]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])=[O:24])[CH:11]=[CH:12][CH:13]=3)[CH:4]=[CH:5][N:6]=2)=[CH:35]1
Reactant: OB(O)c1ccsc1
Reactant: CC(C)Cc1cc(-c2cccc(Cn3ccnc3Br)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)Cc1cc(-c2cccc(Cn3ccnc3-c3ccsc3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 90 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
To a solution of 3-[3-(2-bromoimidazol-1-ylmethyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (61.7 mg, 0.121 mmol; see Example 11((b)) in toluene (5 mL) and ethanol (0.5 mL) was added 3-thienyl boronic acid (77.3 mg, 0.604 mmol), Pd(PPh3)4 (8.4 mg, 7.25 μmol) and NaOH (0.48 mL, 0.725 mmol, 1.5 M aq), and the reaction mixture stirred for 4 h at 90° C. Another portion of 3-thienyl boronic acid (60.0 mg, 0.469 mmol) and Pd(PPh3)4 (5.0 mg, 4.3 μmol) was added and the reaction was stirred overnight at 90° C. The reaction mixture was diluted with EtOAc (30 mL) and washed with water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using EtOAc:hexane (8:2 to 9:1) as eluent to give the sub-title compound in 71% yield (44.3 mg, 0.0862 mmol).
Reaction SMILES: [C:1](Cl)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[CH2:9]([O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([NH:18][NH2:19])=[O:17])=[CH:14][CH:13]=1)[CH3:10].C(N(CC)CC)C>O1CCOCC1>[C:1]([NH:19][NH:18][C:16](=[O:17])[C:15]1[CH:20]=[CH:21][C:12]([O:11][CH2:9][CH3:10])=[CH:13][CH:14]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOc1ccc(C(=O)NN)cc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)NNC(=O)c1ccc(OCC)cc1
Yield: 90.7 %

Procedure:
29 g of ethoxalyl chloride are added, in the course of 30 minutes, to 36 g of 4-ethoxybenzhydrazide and 21.3 g of triethylamine in 360 ml of anhydrous dioxane, whilst keeping the temperature of the reaction medium at about 10° C. The stirring is continued (sic) for about two hours, whilst allowing the temperature to return to the ambient value. The reaction mixture is filtered, the filtrate is concentrated under reduced pressure (20 mm Hg, 50° C.) and the residue is stirred in the presence of 200 ml of isopropyl ether and then filtered off. After drying (20° C., 1 mm Hg), 50.8 g of 1-ethoxalyl-2-(4-ethoxybenzoyl)-hydrazine, which melts at 126° C. after a first melting at 120° C., are obtained. Yield: 90.7%.
Reaction SMILES: [CH3:1][N:2]([CH3:40])[C:3]([C@H:5]1[N:10]([C:11](=[O:25])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][C:8]2[N:26]=[CH:27][N:28]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[C:32]([CH3:39])[CH:31]=3)[C:7]=2[CH2:6]1)=[O:4].O.O.[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.CO>[NH2:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][N:28]2[C:7]3[CH2:6][C@@H:5]([C:3]([N:2]([CH3:40])[CH3:1])=[O:4])[N:10]([C:11](=[O:25])[CH:12]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:9][C:8]=3[N:26]=[CH:27]2)=[CH:31][C:32]=1[CH3:39]
Reactant: Cc1cc(Cn2cnc3c2C[C@@H](C(=O)N(C)C)N(C(=O)C(c2ccccc2)c2ccccc2)C3)ccc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(Cn2cnc3c2C[C@@H](C(=O)N(C)C)N(C(=O)C(c2ccccc2)c2ccccc2)C3)ccc1N
Yield: 100.1 %

Procedure:
(S)-N,N-dimethyl-5-diphenylacetyl-1-(3-methyl-4-nitrophenyl)methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxamide (III-2) (2.3636 g, 0.00440 mol) was dissolved in a mixture of 28 ml of ethyl acetate and 5 ml of methanol, followed by addition of tin chloride dihydrate (4.9580 g, 0.0220 mol) and agitation of the solution on an 80° C. oil bath in a stream of nitrogen for 30 minutes. The reaction mixture was cooled, neutralized by adding a 5% sodium carbonate solution, and concentrated. The residue was extracted with chloroform. The chloroform layer was washed with water, dried over sodium sulfate, and then concentrated to obtain a light-yellow foamy material (2.2368 g). This material was purified by silica gel column chromatography (Kieselgel 60, 120 g, chloroform methanol=50/1) to obtain the objective compound (II-2) (2.0077 g; yield: 90.0%) as a white foamy material. MS (EI): 508 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.[C:15]([O:19][C:20]([NH:22][O:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C.CN(C)C1C=CN=CC=1>[C:15]([O:19][C:20]([N:22]([O:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:12](=[O:14])[CH2:11][CH2:10][S:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1ccc(SCCC(=O)O)cc1
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(SCCC(=O)N(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
To a solution of the compound prepared in Example 8(11) (106 mg) in DMF (5 ml), N-t-butoxycarbonyl-N-t-butoxycarbonyloxyamine (120 mg), EDC hydrochloride (106 mg) and 4-(dimethylamino)pyridine (6 mg) were added at 0° C. The mixture was stirred for 16 hours at room temperature. To the reaction solution, water was added and it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the title compound (211 mg) having the following physical data.
Reaction SMILES: [CH:1]1N=CN(C(N2C=NC=C2)=O)C=1.[OH-].[K+].C([C:17]([CH2:22][OH:23])(CO)[CH2:18][CH3:19])O.[C:24]1([CH3:30])[CH:29]=CC=C[CH:25]=1>>[CH3:25][CH:24]([CH2:30][CH:22]([OH:23])[CH2:17][CH:18]([CH3:19])[CH3:1])[CH3:29]
Reactant: CCC(CO)(CO)CO
Reactant: Cc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Agent: [OH-]
Product: CC(C)CC(O)CC(C)C
Temperature: 55 °C
Reaction time: 3 h

Procedure:
CDI (0.55 g, 3.4 mmol) and KOH (0.1 g, 1.8 mmol) were added to a solution of CIH-HEAP-HEAP-OH (4 g, 3.33 mmol) (as prepared in Example 2(b)) in toluene 50 ml. The reaction mixture was heated to 50-60° C. under nitrogen or 5 hours. Trimethylolpropane (0.15 g, 1.11 mmol) was added and the mixture was stirred for a further 3 hours. The reaction mixture was allowed to cool overnight. The crystallised solid was removed by filtration and the filtrate concentrated in vacuo. The residue was dissolved in dichloromethane, washed with water, dried (MgSO4), filtered and concentrated in vacuo to give the dendrimer product (CIH-HEAP-HEAP-TMP) shown below as a clear viscous liquid (3.96 g, 92%) ##STR54##
Reaction SMILES: C([Li])CCC.[CH:6]([C:9]1[C:10]([CH:17]([CH3:19])[CH3:18])=[C:11]([CH:14]([CH3:16])[CH3:15])[CH2:12][CH:13]=1)([CH3:8])[CH3:7].S(C1C=CC(C)=CC=1)(O[CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])(=O)=O.O>O1CCCC1>[CH3:27][N:26]([CH2:25][CH2:24][C:13]1[CH2:12][C:11]([CH:14]([CH3:16])[CH3:15])=[C:10]([CH:17]([CH3:19])[CH3:18])[C:9]=1[CH:6]([CH3:8])[CH3:7])[CH3:28]
Reactant: CC(C)C1=CCC(C(C)C)=C1C(C)C
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)C)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C1=C(C(C)C)C(C(C)C)=C(CCN(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a dry 500 mL three-necked flask with a magnetic stirrer, a solution of 62.5 mL of n-butyllithium (1.6 M in n-hexane; 100 mmol) was added under a dry nitrogen atmosphere to a solution of 19.2 g (100 mmol) of triisopropyl-cyclopentadiene in 250 mL of tetrahydrofuran at -60° C. After heating to room temperature (in approximately one hour) stirring continued for a further two hours. After cooling to -60° C., a solution of dimethylaminoethyl tosylate (105 mmol) prepared in situ was added over a period of 5 minutes. The reaction mixture was heated to room temperature, followed by overnight stirring. After addition of water, the product was extracted with petroleum ether (40-60° C.). The combined organic layer was dried with sodium sulphate, and evaporated under reduced pressure. The conversion was greater than 95%. The yield of product after distillation (based on triisopropyl-cyclopentadiene) was approximately 55%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:9])[C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=1[F:19]
Reactant: COc1ccc(F)c(F)c1C(=O)c1ccc(Cl)nc1N
Reactant: CC(=O)N1CCC(N)CC1
Product: COc1ccc(F)c(F)c1C(=O)c1ccc(NC2CCN(C(C)=O)CC2)nc1N

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 39) and 1-(4-amino-piperidin-1-yl)-ethanone (prepared as described in Manetti et al, Biorg. Med. Chem. Lett., 13 (2003), 2303-2306) using the procedure described in Step B. Example 6. HRMS, observed: 405.1734, Calcd for (M+H)+: 405.1733.
Reaction SMILES: [NH:1]([C:3]1[C:8]([CH:9]([CH3:12])[CH2:10][CH3:11])=[N:7][C:6]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:5][N:4]=1)[NH2:2].[NH:19]1[CH:23]=[C:22]([CH2:24][CH:25]([C:31](OCC)=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:21]=[CH:20]1>>[CH3:12][CH:9]([C:8]1[C:3]2[N:4]([C:31]([CH:25]([CH2:24][C:22]3[N:21]=[CH:20][NH:19][CH:23]=3)[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:2][N:1]=2)[CH:5]=[C:6]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:7]=1)[CH2:10][CH3:11]
Reactant: CCC(C)c1nc(-c2cccnc2)cnc1NN
Reactant: CCOC(=O)C(Cc1c[nH]cn1)C(=O)OCC
Product: CCOC(=O)C(Cc1c[nH]cn1)c1nnc2c(C(C)CC)nc(-c3cccnc3)cn12

Procedure:
In a manner analogous to Example 1, by condensing rac-2-hydrazino-3-(1-methylpropyl)-5-(3-pyridyl)pyrazine with diethyl (imidazol-4-ylmethyl)malonate there is obtained ethyl (RS)-8-[(RS)-1-methylpropyl]-α-(imidazol-4-ylmethyl)-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetate, MS: 419 (M)+, which is converted into the above acid by alkaline saponification.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.C(N(CC)CC)C.[C:18](Cl)(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>ClCCl>[C:18]([CH:6]1[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:5])(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Meldrum's acid (7.20 g, 50 mmol) and triethyl amine (5.56 g, 55 mmol) were dissolved in dichloromethane (50 mL), and decanoic acid chloride (10.48 g, 55 mmol) was added to the resulting mixture dropwise while cooling with ice. The reaction mixture was stirred at room temperature for about 12 hours, and then concentrated under reduced pressure. The ethyl acetate layer thus obtained was washed with diluted hydrochloric acid and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified using silica gel chromatography (developing solvent: n-hexane/ethyl acetate=3/7) to obtain 5-decanoyl-2,2-dimethyl-1,3-dioxane-4,6-dione.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]=1[OH:13].Br[CH:15]([C:17](=[O:20])[CH2:18][CH3:19])[CH3:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]=1[O:13][CH:15]([CH3:16])[C:17](=[O:20])[CH2:18][CH3:19]
Reactant: CCC(=O)C(C)Br
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)C(C)Oc1cc(C(=O)OC)ccc1OC
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 3-hydroxy-4-methoxy benzoate (19.3 g), 2-bromo-3-pentanone (19.2 ml), potassium carbonate (29.3 g), and DMF (193 ml) was stirred at 90° C. for 2 hours. After being allowed to stand for cooling, water was added to the mixture followed by extraction with toluene. The organic layer was washed with a saturated saline and dried over sodium sulfate, and the solvent was distilled off. The residue was purified by column chromatography (silica gel, hexane:ethyl acetate=3:1) to give Compound IIk-a (25.8 g, 91.5%) as a colorless oily substance.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][NH2:13]>O>[NH:12]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1)[NH2:13]
Reactant: NN
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Solvent: O
Product: NNc1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A stirred solution of 4-chlorobenzenesulfonamide (38.33 g, 200 mmol) and anhydrous hydrazine (31.4 mL, 1.0 mol) was heated at reflux for 30 hours. After cooling to room temperature, the mixture was poured into water (500 mL) with swirling. The resulting precipitate was collected by filtration, washed thoroughly with water several times, air-dried, and dried under vacuum to give the title compound (35.5 g, 95% yield) as a white solid. Mp 169–171° C. 1H NMR (300 MHz, THF-d8) δ 7.59 (d, J=8.8 Hz, 2H), 6.77 (d, J=8.8 Hz, 2H), 6.62 (br, 1H), 5.99 (br, 2H), 3.87 (br, 2H). Mass spectrum (API-TIS) m/z 188 (MH+).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[O:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[N:12][N:13]=1.[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:38])[CH3:37])[C:31]=1[N:39]=[C:40]=[O:41])([CH3:29])[CH3:28]>C(#N)C>[CH3:29][CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:37])[CH3:38])[C:31]=1[NH:39][C:40]([NH:8][C:9]1[O:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[N:12][N:13]=1)=[O:41])[CH3:28]
Reactant: CCCCCCCCCCCCCc1nnc(N)o1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCc1nnc(NC(=O)Nc2c(C(C)C)cccc2C(C)C)o1
Reaction time: 18 h

Procedure:
Triethylamine (1.67 g, 0.017 mol) was added to a solution of the compound prepared in Step 2 above (4.0 g, 0.015 mol) in acetonitrile (200 mL) and the mixture refluxed for 30 minutes or until solution becomes homogeneous. 2,6-Diisopropylphenyl isocyanate (3.71 g, 0.018 mol) was then added and reflux continued for 18 hours. The mixture was allowed to cool, concentrated, diluted with water (20 mL), filtered, and the solid columned on silica gel, eluting with 20% ethyl acetate in hexanes (loaded in chloroform) to give 0.54 g of a solid; m.p 114°-116.5° C.
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:15](=[O:18])([O-])[O-].[Na+].[Na+].[CH3:21][OH:22]>C(O)CO>[OH:22][CH2:21][CH2:14][O:13][C:1](=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH2:9][CH2:15][OH:18])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CO
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: [Na+]
Solvent: OCCO
Product: O=C(OCCO)c1ccc(C(=O)OCCO)cc1
Yield: 81.9 %

Procedure:
This example was carried out as described in Example 1, the reaction vessel being charged with the above analysed ethylene glycol (496 parts) and dimethyl terephthalate. Instead of adding solid sodium carbonate directly, a solution was made containing 0.1 part in ethylene glycol (25 parts by volume). This solution was placed in a burette which was fitted into a suitable vacuum-tight inlet in the reaction vessel. The mixture in the reaction vessel was heated to approximately 70°-75° C and the solution of sodium carbonate in ethylene glycol was added dropwise until 13.5 parts by volume had been added, when methanol began to distil. The theoretical volume of sodium carbonate required to neutralise the free acidity of the DMT was 13.6 parts by volume agreeing well, within the experimental limits, with that actually used before reaction began. The reaction continued normally and a yield of 208 parts (81.9%) of bis-(2-hydroxyethyl)-terephthalate was obtained m.pt. 108.4 - 109.8° C. The oligomer residue weighed 14.5 parts.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)[C@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(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:57][C:58]1[N:59]=[N:60][C:61]([NH:64][NH2:65])=[CH:62][CH:63]=1>CN(C=O)C.O>[Cl:57][C:58]1[N:59]=[N:60][C:61]([NH:64][NH:65][C:12](=[O:13])[C:11]2[CH:10]=[CH:9][C:8]([N:4]3[C@@H:3]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:2]([CH3:23])([CH3:1])[O:6][C:5]3=[O:7])=[CH:16][CH:15]=2)=[CH:62][CH:63]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: CC1(C)OC(=O)N(c2ccc(C(=O)O)cc2)[C@H]1c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)N(c2ccc(C(=O)NNc3ccc(Cl)nn3)cc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-4-(5,5-Dimethyl-2-oxo-4-phenyloxazolidin-3-yl)benzoic acid (400 mg, 1.285 mmol) was dissolved in DMF (2.57 mL) at room temperature. To the reaction mixture, was successively added N-ethyl-N-isopropylpropan-2-amine (670 μL, 3.85 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (489 mg, 1.285 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) and 3-chloro-6-hydrazinylpyridazine (186 mg, 1.285 mmol). The vial was sealed and immersed in a 55° C. oil bath. After stirring overnight, LC-MS indicated complete conversion to the product. After cooling to room temperature, the reaction mixture was transferred to water in a flask in an ice/water bath. The solution was extracted w with DCM (3×50 mL). The combined organic layers were then washed with water (2×50 mL) and brine (50 mL). The organic layer was dried over Na2SO4. The solution was then filtered and concentrated under reduced pressure to give the product as a yellow solid. The product thus obtained was was used in the next step without further purification. m/z (ESI) 438.0 (M+H)+.