Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13](O)=[CH:14][CH:15]=1.C1CCCCC1.[CH2:23]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:24]1[O:26][CH2:25]1.C(OCC1OC1)C1[O:46]C1>O>[CH2:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[O:46][CH2:25][CH:24]([OH:26])[CH2:23][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: CCCCCCCCCc1ccccc1OCC1CO1
Reactant: C(OCC1CO1)C1CO1
Solvent: C1CCCCC1
Solvent: O
Product: CCCCCCCCCc1ccccc1OCC(O)COc1ccccc1CCCCCCCCC

Procedure:
To a five neck, two liter round bottom flask equipped with an addition funnel, thermometer, nitrogen dispersant tube, mechanical stirrer, and a decanting head with a water-cooled condenser were added 220 grams (1.00 mole) of nonylphenol and 250 milliliters of cyclohexane. The solution was then heated to reflux and 2.8 grams (1.3 wt. % based on nonylphenol) of potassium hydroxide in 10 milliliters of water was slowly added to the flask. After essentially all the water was recovered in the decanting head (10 milliliters+1 milliliter formed), 250.7 grams (0.91 mole) of nonylphenyl glycidyl ether as added dropwise. During the addition of the glycidyl ether, the reaction temperature was maintained between 60° and 80° C. After the addition was complete, the solution was refluxed for four hours. The contents of the flask were then washed with a five percent aqueous solution of phosphoric acid, and the organic layer was separated from the water layer and washed twice with deionized water. The reaction mixture was then placed in a one liter round bottom flask, and the remaining cyclohexane and unreacted nonylphenol were recovered by distillation, first at atmospheric pressure, then under vacuum at 0.2 mm Hg. The kettle temperature was not allowed to exceed 180° C. during the distillation to prevent discoloration of the product. The concentrated solution was then refiltered to give 425 grams of a pale-yellow liquid. End-group MW analysis gave a molecular weight of 506.8 (theoretical MW=496.8). Ir and nmr spectra were identical to previously recorded spectra for the compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24](O)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([NH:34][CH3:35])[CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:34]([CH3:35])[CH:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: CNC1CCN(C)CC1
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(N(C)C(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.6 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (60 mg, 0.16 mmol) in DMF (1 mL) were added 1-methyl-4-(methylamino)piperidine (23 mg, 0.18 mmol), diisopropylethylamine (DIPEA) (63 μL, 0.36 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (75 mg, 0.20 mmol). The solution obtained was stirred at room temperature for 1 hr then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified using chromatography (silica gel, gradient 1% Et3N in 10-20% MeOH/ethyl acetate) yielding Compound 51 as a solid (2 mg).
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]([OH:21])=[O:20])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:29][C@H:30]([C:35]([CH2:37][Cl:38])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33].Cl.O1CCCC1>CC(C)=O.CCOCC>[NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]([NH:29][C@H:30]([C:35]([CH2:37][Cl:38])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:20])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[NH:1]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]([OH:21])=[O:20])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)C[C@H](N)C(=O)CCl
Agent: C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)CCl

Procedure:
Boc-Phe-Gly-Ala-LeuCH2Cl was prepared by coupling Boc-Phe-Gly-Ala-OH (11.8 g, 30 mmol) to H-LeuCH2Cl.HCl (6.06 g, 30 mmol) using a mixed anhydride procedure. A mixed anhydride of Boc-Phe-Gly-Ala-OH was prepared in a solution of 300 mL of tetrahydrofuran and 25 mL of acetone, and then H-LeuCH2Cl HCl was added in acetone. The resulting crude product, 17.6 g, was dissolved in ether, treated with carbon, and filtered. Product Boc-Phe-Gly-Ala-LeuCH2Cl crystallized from ether (10.0 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].Br[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.[Cu]=O>[CH:20]([C:17]1[CH:18]=[CH:19][C:14]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[C:2]2[C:10]([OH:12])=[O:11])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1ccc(Br)cc1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccc(-n2c(C(=O)O)cc3ccccc32)cc1

Procedure:
A suspension of 128.8 g (0.8 mol) of 1H-indole-2-carboxylic acid, of 159.2 g (0.8 mol) of 4-bromocumene, of 111.6 g (0.808 mol) of potassium carbonate and of 8 g (0.1 mol) of copper oxide in 200 ml of dimethylformamide is stirred at reflux for 24 hours. After cooling, 6 l of water are added to the beige suspension obtained. The suspension is filtered and then the insoluble material is taken up in 1 l of a 5N hydrochloric acid solution. This mixture is extracted with 500 ml of dichloromethane. The organic phase is washed with water, dried over sodium sulfate and then concentrated under reduced pressure. After drying under reduced pressure, 204.4 g of a white solid are obtained, which solid is used as is in the following stage.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:2][CH2:3][CH2:4][S:5][S:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)SCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)SCCCN2CCN(C)CC2)cc1

Procedure:
Toluene-4-thiosulfonic acid S-(3-chloro-propyl) ester (4.9 g, 18.4 mol, 1.00 eq.), N-methylpiperazine (1.9 g, 19.3 mmol) 1.05 eq.) and potassium carbonate (2.7 g, 19.4 mmol, 1.05 eq.) were stirred together in acetonitrile (100 mL) at room temperature for 64 hours. The mixture was concentrated and the residue was partitioned between ethyl acetate (500 ml) and water (250 ml). The organic solution was washed with water (2×200 mL), dried using MgSO4, concentrated and purified by MPLC to give a light yellow oil weighing 2.1 g (36%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]1([C:26]([OH:28])=O)[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([OH:25])=O)[CH:18]=1>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:23](=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:26]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:28])[CH:18]=1)=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: O=C(O)c1cccc(C(=O)O)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)c1cccc(C(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)c1
Yield: 72.1 %

Procedure:
Using General Procedure A with 5.8 g (24.0 mmol) D-Proline benzyl ester hydrochloride and 2.0 g (12.0 mmol) benzene-1,3-dioic acid afforded, after flash chromatography (EtOAc), 4.68 g (72%) of the title compound as a yellow oil.
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]([C:8]1[CH:9]=[C:10]([C:19]2[O:20][CH:21]=[C:22]([CH2:24][CH2:25]I)[N:23]=2)[CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])([CH3:7])([CH3:6])[CH3:5].C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCCCCC>[C:4]([C:8]1[CH:9]=[C:10]([C:19]2[O:20][CH:21]=[C:22]([CH2:24][CH2:25][C:1]#[N:2])[N:23]=2)[CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)c1cc(-c2nc(CCI)co2)cc(C(C)(C)C)c1O
Reactant: [C-]#N
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)c1cc(-c2nc(CCC#N)co2)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
To a solution of sodium cyanide (84.5 mmole, 5.50 g) in dimethylsulfoxide (120 ml) at 92° C. was added 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-(2-iodoethyl)oxazole (70.4 mmole, 30.08 g) via a powder addition funnel over an eightyfive minute period. Approximately 1.5 hours later, the reaction was cooled to room temperature and treated with 1:1 ethyl acetate:hexane (250 ml) and 10% aqueous potassium carbonate (250 ml). Three distinct phases result. The lowest phase was separated and discarded. The remaining phases were separated. The aqueous phase was extracted with 1:1 ethyl acetate:hexane (2×200 ml). Combined organic phases were dried over sodium chloride, filtered, reduced in volume and subjected to preparatory chromotography. The material was eluted with 10 to 30% ethyl acetate:hexane. Fractions containing the desired product were combined, dried over MgSO4, filtered and concentrated in vacuo to afford 18.25 g (79%).
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[CH3:11])=[O:2].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:11][C:4]1[CH:5]=[C:6]([C:8]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)=[O:10])[NH:7][C:3]=1[CH:1]=[O:2]
Reactant: Cc1cc(C(=O)O)[nH]c1C=O
Reactant: CN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2CCN(C)CC2)[nH]c1C=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 68 %

Procedure:
To a suspension of 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (1.53 g, 10 mmol) in DMF (20 mL) was added 1-methylpiperazine (1.2 g, 12 mmol), followed by 1-ethyl-3-(3-dimethylaminopropyl)carboiimide hydrochloride (EDAC, 2.3 g, 12 mmol), 1-hydroxybenzotriazole (HOBt, 1.6 g, 12 mmol) and triethylamine (3.2 mL, 24 mmol). The reaction mixture was stirred at room temperature for 2 days. The reaction was concentrated, diluted with water and extracted with ethyl acetate (5×). The combined ethyl acetate was concentrated to a volume of 20 mL and triturated with hexane (10 mL). The resulting solid was collected by vacuum filtration to give 1.6 g (68%) of 3-methyl-5-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde as a yellow solid. 1N NMR (300 MHz, DMSO-d6) δ 12.21 (s, 1H, NH), 9.7 (s, 1H, CHO), 6.35 (s, 1H), 3.58 (m, 4H 2×CH2), 2.30 (m, 7H, 2×CH2 & CH3), 2.18 (s, 3H, CH3). MS 236 [M+1].
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3][CH:2]=1.[C:10]([C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:22][CH2:21]2)[CH:17]=[C:16]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[N:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:10]([C:14]1[N:19]=[C:18]([N:20]2[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:7]([C:5]3[CH:4]=[N:3][CH:2]=[N:1][CH:6]=3)=[O:9])[CH2:24][CH2:25]2)[CH:17]=[C:16]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[N:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Reactant: O=C(O)c1cncnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3cncnc3)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
0.1 g of pyrimidine-5-carboxylic acid (0.805 mmol) and 0.28 g of 4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (0.805 mmol) were dissolved in 10 ml of dichloromethane. 0.46 g of diisopropylethylamine (3.17 mmol), 0.054 g of hydroxybenzotriazole (HOBt, 0.4 mmol), and 0.17 g of N-ethyl-N′-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDCl, 0.88 mmol) were added at 0° C. The reaction mixture was stirred for 16 h at room temperature. Then, 0.085 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added and the reaction mixture was stirred for 4 h. The solvent was evaporated and the residue partitioned between and ethyl acetate and saturated aqueous sodium chloride. 4 ml of acetone were added to improve phase separation. The organic phase was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using ethyl acetate and ethyl acetate-methanol (5-10%). Evaporation of the solvent yielded 0.16 g of the title compound as a white solid.
Reaction SMILES: N.[Na].[C:3]1([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)=[O:9])[S:7][CH:6]=[CH:5][CH:4]=1.[CH3:20]I>C(OCC)C>[C:3]1([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:20])[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)=[O:9])[S:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1ccc(C(=O)c2cccs2)cc1
Reactant: CI
Agent: N
Agent: [Na]
Solvent: CCOCC
Product: CC(C(=O)O)c1ccc(C(=O)c2cccs2)cc1
Reaction time: 0.5 h

Procedure:
To 400 parts of liquid ammonia are added a trace of ferric chloride and 3 parts of sodium. The mixture is stirred for 30 minutes, after which 14.8 parts of 2-[p-(2-thenoyl)phenyl]acetic acid are added slowly during 30 minutes, and the mixture is further stirred for 45 minutes. 13.6 Parts of methyl iodide are added dropwise and the reaction mixture is stirred for 2h. 30 400 parts of diethyl ether are then added and the mixture is stirred overnight. The ammonia is evaporated and the resulting solution is acidified with diluted hydrochloric acid. The ethereal layer is separated and extracted with 10% sodium hydroxide solution. The extract is washed with ether, acidified and extracted with ether. The ethereal solution is dried on sodium sulfate and the ether is evaporated in vacuo. The residue is triturated in petroleumether, filtered off and crystallized twice from acetonitrile, first at -20° C, yielding p-(2-thenoyl)hydratropic acid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.C([O:35][C@@H:36]([CH3:40])[C:37](Cl)=[O:38])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][N:29]([C:37](=[O:38])[C@@H:36]([OH:35])[CH3:40])[CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC1
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCN(C(=O)[C@H](C)O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f15) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH:13]1([C:19](Cl)=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.O>[CH:13]1([C:19]2[O:12][C:11]3[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=3)[N:2]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1c(O)cccc1C(=O)O
Agent: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1cccc2oc(C3CCCCC3)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.2 %

Procedure:
To a mixture of 2-amino-3-hydroxybenzoic acid hydrobromide (500 mg, 2.13 mmol) and cyclohexane carbonyl chloride (0.29 mL, 2.13 mmol) in dichloromethane (20 mL) was added triethylamine (0.90 mL, 6.41 mmol) dropwise, then the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with dichloromethane, and then washed with 2 N HCl. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in toluene (8 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (485 mg, 2.55 mmol). The reaction mixture was then heated to reflux for 5 h. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was separated, then washed with water (7×100 mL), brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by re-crystallization from ethyl acetate and hexanes to afford 2-cyclohexylbenzoxazole-4-carboxylic acid (346 mg, 66%) as a brown solid: 1H NMR (500 MHz, DMSO-d6) δ 13.01 (br s, 1H), 7.92 (dd, J=8.0, 0.9 Hz, 1H), 7.84 (dd, J=7.8, 0.9 Hz 1H), 7.44 (t, J=7.8 Hz, 1H), 3.08-3.02 (m, 1H), 2.14-2.05 (m, 2H), 1.82-1.75 (m, 2H), 1.72-1.60 (m, 3H), 1.47-1.38 (m, 2H), 1.35-1.25 (m, 1H); MS (ESI+) m/z 246 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[Br:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14](=[O:16])[NH:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([O:18][CH3:17])=[O:28])=[C:21]([Br:27])[CH:22]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(N)cc1Br
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@@H]2C[C@@H](F)CN2C(=O)OC(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of (2S,4R)-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (355 mg, 1.52 mmol), and 4-amino-2-bromo-benzoic acid methyl ester (prepared as described in Part C) (350 mg, 1.52 mmol), HBTU (865 mg, 2.282 mmol) and DIPEA (0.531 mL, 3.04 mmol) in CH2Cl2 (15 mL) was stirred at RT for 60 h. Additional aliquots of (2S,4R)-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (180 mg), HBTU (580 mg) and DIPEA (0.265 mL) were added to the mixture, and stirring was continued at RT for 20 h and subsequently at 40° C. for 24 h. The reaction mixture was diluted with CH2Cl2 and the organic layer was washed with water, 1N aqueous HCl (3×), aqueous NaHCO3 solution (2×) and brine, dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: EtOAc/c-hexane gradient 1:3 to 1:2) to afford the title compound as a white foam. TLC Rf (EtOAc/c-hexane 1:2)=0.24; MS (LC/MS): 468 [M+Na]+, 388/390 [MH−tBu]+, 345/347 [MH−Boc]+; tR (HPLC conditions b): 4.36 min.
Reaction SMILES: S([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]1[CH2:30][C:29]2[CH:28]=[C:27]([OH:31])[CH:26]=[CH:25][C:24]=2[C@@H:23]2[C@@H:14]1[C@H:15]1[C@@:19]([CH2:21][CH2:22]2)([CH3:20])[C@@H:18]([OH:32])[CH2:17][CH2:16]1)(C)(=O)=O.[Br-].C[Si](C)(C(C)(C)C)OCCCCCC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:67]([S:72][CH2:73][CH2:74]O)[CH2:68][CH2:69][CH2:70][CH3:71]>>[CH2:67]([S:72][CH2:73][CH2:74][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]1[CH2:30][C:29]2[CH:28]=[C:27]([OH:31])[CH:26]=[CH:25][C:24]=2[C@@H:23]2[C@@H:14]1[C@H:15]1[C@@:19]([CH2:21][CH2:22]2)([CH3:20])[C@@H:18]([OH:32])[CH2:17][CH2:16]1)[CH2:68][CH2:69][CH2:70][CH3:71]
Reactant: CCCCCSCCO
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCOS(C)(=O)=O)[C@H]3[C@@H]1CC[C@@H]2O
Agent: CC(C)(C)[Si](C)(C)OCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCCCCSCCOCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12

Procedure:
The process described in Example 32 was repeated using 7α-(7-mesyloxyheptyl)oestra-1,3,5(10)-triene-3,17β-diol (obtained as described in Example 41 using initially 6-(dimethyl-t-butylsilyloxy)hexyltriphenylphosphonium bromide) and 2-n-pentylthio-ethanol (obtained from pentanethiol and 2-bromoethanol) as starting materials. There was thus obtained as an oil 7α-[7-(2-n-pentylthioethoxy)heptyl]oestra-1,3,5(10)-triene-3,17β-diol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:7][NH:6][C:5]2=[O:15])[CH2:3][CH2:2]1.Cl[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][N:6]1[CH:7]=[C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]1=[O:15])[CH3:22]
Reactant: O=c1[nH]cc(-c2ccccc2)n1C1CC1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cn1cc(-c2ccccc2)n(C2CC2)c1=O

Procedure:
270 mg (1.35 mmol) of 1-cyclopropyl-5-phenyl-1,3-dihydro-2H-imidazol-2-one from Example 119A are dissolved in 5 ml acetonitrile and treated with 165 mg (1.35 mmol) of ethyl chloroacetate and 373 mg (2.70 mmol) of potassium carbonate. The mixture is stirred under reflux for 4 hrs, then a further 165 mg (1.35 mmol) of ethyl chloroacetate are added. After stirring overnight under reflux the reaction mixture is evaporated, the residue is partitioned between dichloromethane and water, the organic phase is separated, and this is dried over sodium sulphate and again concentrated. The crude product is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol firstly 200:1, then 100:1) and thus yields 353 mg (91% of theory) of the target compound.