Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)[C:11]2=[O:21])=[CH:6][CH:5]=1.C([Li])CCC.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36](Cl)(=[O:38])=[O:37]>C1COCC1>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([N:17]1[CH2:18][CH2:19][C:12]2([C:11](=[O:21])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:15][C:16]1=[O:20])(=[O:38])=[O:37]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: O=C1CC2(CCN1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1CC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CCN1S(=O)(=O)c1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 31.7 %

Procedure:
2-(4-Trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-1,7-dione (0.105 g), product of example 1 step D), was dissolved in dry THF (10 ml), cooled to −78° C. under an argon atmosphere, treated dropwise with n-butyllithium (1.6 molar solution in hexanes, 0.22 ml) and then stirred for 20 minutes at −78° C. 2-Chlorobenzenesulfonyl chloride (0.074 g) in THF (2 ml) was then added dropwise, the mixture was stirred 15 minutes at −78° C., the cooling bath was removed and stirring was continued for further 75 minutes, allowing the temperature of the reaction mixture to rise to RT. The reaction mixture was then concentrated in vacuo, the residue adsorbed on silica gel and chromatographed on silica gel (AcOEt/heptane, gradient from 0 to 30%) to give the desired product (0.051 g) as an off-white solid. MS (ESI): 503.0 (MH−).
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][CH2:14][N:15]1[C:24]2[C:19](=[CH:20][C:21]([N+:25]([O-])=O)=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1)[C:3](=[O:11])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1COCC1.C(O)C.[Pd]>[NH2:25][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[N:15]([CH2:14][CH2:13][CH2:12][N:2]([CH3:1])[C:3](=[O:11])[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:16][CH2:17][CH2:18]2
Reactant: CN(CCCN1CCCc2cc([N+](=O)[O-])ccc21)C(=O)Oc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(CCCN1CCCc2cc(N)ccc21)C(=O)Oc1ccccc1
Reaction time: 3 h
Yield: 88.6 %

Procedure:
To a stirred solution of phenyl methyl(3-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)propyl)carbamate (1.02 g, 2.76 mmol) in THF (15.00 ml) and ethanol (15 ml) was added palladium 10 wt. % on activated carbon (0.294 g, 0.276 mmol). The reaction mixture was stirred under an atmosphere of hydrogen (balloon pressure) for 3 h. The mixture was then filtered through celite and concentrated, giving a dark oil. The crude product (phenyl 3-(6-amino-3,4-dihydroquinolin-1(2H)-yl)propyl(methyl)carbamate (830 mg, 2.445 mmol, 89% yield)) was used directly in the subsequent reaction. ESI-MS (m/z, %) 340 (MH+, 100).
Reaction SMILES: Br[C:2]1[C:3]([O:14][CH2:15][C:16]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][O:19][C:20]=2[CH3:21])=[N:4][CH:5]=[C:6]([CH:13]=1)[C:7]([NH:9][CH:10]([CH3:12])[CH3:11])=[O:8].Br[C:29]1C(OCC2C(C3C=CC=CC=3)=NOC=2C)=NC=C(C=1)C(NC1CCOCC1)=O>>[CH:10]([NH:9][C:7](=[O:8])[C:6]1[CH:13]=[C:2]([CH3:29])[C:3]([O:14][CH2:15][C:16]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][O:19][C:20]=2[CH3:21])=[N:4][CH:5]=1)([CH3:12])[CH3:11]
Reactant: Cc1onc(-c2ccccc2)c1COc1ncc(C(=O)NC2CCOCC2)cc1Br
Reactant: Cc1onc(-c2ccccc2)c1COc1ncc(C(=O)NC(C)C)cc1Br
Product: Cc1cc(C(=O)NC(C)C)cnc1OCc1c(-c2ccccc2)noc1C
Yield: 52 %

Procedure:
As described for example 66, 5-bromo-N-isopropyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamide (150 mg, 0.35 mmol), instead of 5-bromo-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide was converted to the title compound (73 mg, 52%) which was obtained as an off white gum. MS: m/e=366.0 [M+H]+.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:19][CH3:20])[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:14]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[S:12][N:11]=1)#[N:2].[OH-:21].[Na+]>Cl>[C:1]([N:3]=[C:4]([NH:19][CH3:20])[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:14]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[S:12][N:11]=1)(=[O:21])[NH2:2]
Reactant: [OH-]
Reactant: CNC(=NC#N)NCCSCc1nsc(NC(=N)N)n1
Agent: Cl
Agent: [Na+]
Product: CNC(=NC(N)=O)NCCSCc1nsc(NC(=N)N)n1

Procedure:
A mixture of 3-[-2-(2-cyano-3-methylguanidino)ethylthiomethyl]-5-guanidino-1,2,4-thiadiazole (0.2 g.) and 1 N hydrochloric acid (50 ml.) was heated under reflux for 30 minutes, cooled, neutralised with 1 N sodium hydroxide and extracted with ethyl acetate (6×25 ml.). The combined extracts were dried (MgSO4) and evaporated in vacuo to a white solid which was dissolved in ethanol (3 ml.) and added to a solution of oxalic acid (0.071 g.) in ethanol (2 ml.). The precipitated solid was filtered off, washed with ethanol and dried at 50°/0.1 m.m. to give 3-[2-(2-carbamoyl-3-methylguanidino)ethylthiomethyl]-5-guanidino-1,2,4-thiadiazole. 1.75 oxalate. Found: C, 31.0; H, 4.3; N, 25.7; S, 13.5; C9H17N9OS2.1.75 C2H2O4 requires C, 30.7; H, 4.2; N, 25.8; S, 13.1%.
Reaction SMILES: O1CCOCC1.[C:7]([N:11]1[C:16](=[O:17])[C:15]([Cl:18])=[C:14](Cl)[CH:13]=[N:12]1)([CH3:10])([CH3:9])[CH3:8].[Cl:20][C:21]1[CH:40]=[CH:39][C:24]([C:25]([C:27]2[CH:38]=[CH:37][C:30]([CH2:31][NH:32][CH2:33][CH2:34][CH2:35][OH:36])=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1>O>[C:7]([N:11]1[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([N:32]([CH2:33][CH2:34][CH2:35][OH:36])[CH2:31][C:30]2[CH:29]=[CH:28][C:27]([C:25](=[O:26])[C:24]3[CH:39]=[CH:40][C:21]([Cl:20])=[CH:22][CH:23]=3)=[CH:38][CH:37]=2)[CH:13]=[N:12]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CNCCCO)cc1
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)n1ncc(N(CCCO)Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(Cl)c1=O
Temperature: 100 °C
Reaction time: 64 h
Yield: 11.5 %

Procedure:
In a solvent mixture of dioxane (5 ml) and water (5 ml) were dissolved 2-tert-butyl-4,5-dichloro-3(2H)-pyridazinone (473 mg) and 3-[4-(4-chlorobenzoyl)benzyl-amino]-1-propanol (1.30 g) and the mixture was stirred at 100° C. for 64 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=4:1-2:1) to provide the title compound as white powder (120 mg; yield 12%). 1H-NMR (CDCl3) δ: 1.63(9H,s), 1.83-1.98(3H,m), 3.51(2H,t,J=7.2Hz), 3.70(2H,m), 4.71(2H,m), 7.40(2H,d,J=8.4Hz), 7.46(2H,d,J=8.4Hz), 7.60(1H,s), 7.75(2H,d,J=8.4Hz), 7.77(2H,d,J=8.4Hz).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH2:12][CH3:13])[C:9]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO>[Cl:18][C:15]1[CH:16]=[CH:17][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH2:12][CH3:13])[C:9]=2[CH:14]=1
Reactant: CCC1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC1CNCCc2ccc(Cl)cc21
Reaction time: 3.5 h
Yield: 80.6 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine (63 mg, 0.207 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred for 3.5 hours at 60 C. The product mixture was concentrated, extracted 3 times with CH2Cl2 (5 mL), dried with Na2SO4 and concentrated to give 35 mg of a clear oil. 1H NMR (400 MHz, DMSO-d6) d 7.2 (m, 3 H), 3.3−3.0 (m, 7 H), 1.9−1.6 (m, 2 H), 0.91 (t, J=7 Hz, 3 H). MS calculated for C12H16ClN+H: 210, observed: 210.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5](OC=C)(=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C[O-].[Na+]>>[C:5]([NH:4][CH2:3][CH2:1][OH:2])(=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: NCCO
Reactant: C=COC(=O)CCCCCCCCCCCCCCC
Agent: C[O-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCCC(=O)NCCO

Procedure:
In an exemplary embodiment, 20 mmol ethanolamine was reacted with 1 mmol vinyl stearate at 80° C. for 1 hour in the presence of 1% sodium methoxide. N-stearoylethanolamine with 96% purity was obtained after the removal of excess ethanolamine without further purification. In another exemplary embodiment, 20 mmol ethanolamine was reacted with 1 mmol vinyl palmitate at 60° C. for 1.5 hours in the presence of 1% sodium methoxide. N-palmitoylethanolamine with 98% purity was obtained after the removal of excess ethanolamine without further purification. More examples of reacting the alkanolamine and the vinyl ester of the fatty acid to prepare the high-purity fatty acid N-acylalkanolamine in a high yield are described in Examples 1-8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17]2[N:21]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:20]=[C:19]([CH3:28])[CH:18]=2)[C@H:14]([C:29]([NH:31][C:32]2([C:35]#[N:36])[CH2:34][CH2:33]2)=[O:30])[CH2:13]1)(=[O:11])=[O:10].[NH:37]1[CH:41]=[CH:40][CH:39]=[N:38]1>>[C:35]([C:32]1([NH:31][C:29]([CH:14]2[CH2:13][CH:12]([S:9]([C:3]3[CH:4]=[CH:5][C:6]([N:37]4[CH:41]=[CH:40][CH:39]=[N:38]4)=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:10])[CH2:16][N:15]2[C:17]2[N:21]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:20]=[C:19]([CH3:28])[CH:18]=2)=[O:30])[CH2:34][CH2:33]1)#[N:36]
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1
Reactant: c1cn[nH]c1
Product: Cc1cc(N2CC(S(=O)(=O)c3ccc(-n4cccn4)cc3Cl)CC2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1

Procedure:
In analogy to the procedure described in example 416, (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolidine-2-carboxamide (example 464d) was reacted with pyrazole (CAS Reg. No. 288-11-9) to give the title compound as colorless oil. MS (ESI): m/z=584.2 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][CH2:12][C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:14])=[CH:5][CH:4]=1.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([CH2:27][C:28](O)=[O:29])[N:26]=1.Cl.Cl.CN(C)CCCN=C=NCC.[OH-].[Na+]>O>[NH2:21][C:22]1[S:23][CH:24]=[C:25]([CH2:27][C:28]([NH:2][C:3]2[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][NH:11][CH2:12][C@H:13]([OH:14])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:7][CH:8]=2)=[O:29])[N:26]=1
Reactant: Nc1ccc(CCNC[C@H](O)c2ccccc2)cc1
Reactant: Nc1nc(CC(=O)O)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1nc(CC(=O)Nc2ccc(CCNC[C@H](O)c3ccccc3)cc2)cs1
Reaction time: 1 h

Procedure:
To a mixed solution of 13.50 kg of (R)-2-[[2-(4-aminophenyl) ethyl]amino]-1-phenylethanol monohydrochloride, 7.29 kg of 2-aminothiazol-4-yl-acetic acid, 4.46 kg of concentrated hydrochloric acid and 270 L of water, 9.73 kg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (EDC) was added at 15° C., and the mixture was stirred for one hour. A mixed solution of 4.10 kg of sodium hydroxide and 110 L of water was dropped in the reaction solution, thereby undergoing crystallization. A generated crystal was collected by filtration and washed with water to obtain 26.2 kg of a wet cake of the β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide. This crystal was used for recrystallization as it was in the wet state.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[OH:5]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O

Procedure:
In most cases the Z-Asp dialkali metal salt was prepared in a 1 liter multi-necked flask equipped with a reflux condenser, two dropping funnels, a thermometer, a pH probe and a mechanical stirrer. L-Aspartic acid and water were charged into the flask and a 25% NaOH solution was added with stirring until the L-aspartic acid was fully dissolved. Benzyl chloroformate was added to the reaction mixture with sufficient sodium hydroxide solution to maintain the reaction mixture within the desired pH range. After the reaction was completed, each reaction mixture was separated into two equal portions and the Z-Asp was isolated under the conditions set forth in TABLE I. The temperatures of the crystallizations were controlled as shown in TABLE I. The product analyses are also set forth.
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:26])[N:13](CC(OC(C)(C)C)=O)[CH:14]=[N:15]2)=[CH:10][C:9]=1[O:27][CH3:28]>CO>[OH:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:26])[NH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:27][CH3:28]
Reactant: COc1cc2c(=O)n(CC(=O)OC(C)(C)C)cnc2cc1OCCCO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCO
Yield: 111.7 %

Procedure:
Aqueous sodium hydroxide solution (100 ml, 0.2 mol) was added to a solution of tert-butyl 2-[7-(3-hydroxypropoxy)-6-methoxy-4-oxo-3(4H)-quinazolinyl]acetate (33.8 g, 93 mmol) in methanol (300 ml) and the solution heated to reflux for 1 hour. The methanol was evaporated in vacuo and the aqueous residue acidified with aqueous hydrochloric acid then sodium bicarbonate was added. Collection of the solid by suction filtration, washing with water and drying yielded 7-(3-hydroxypropoxy)-6-methoxy-4-quinazolone (26 g, 95% yield):
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.CC(C)([O-])C.[K+].CN(P(N(C)C)(N(C)C)=O)C.O>O1CCCC1.C(OCC)C>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH:6]2[CH2:2][CH2:3][CH2:4][S:5]2)[CH:8]=1
Reactant: ClCCCSCc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: c1cncc(C2CCCS2)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
A solution of pyrid-3-yl-methyl 3-chloropropyl sulphide (59 g) in anhydrous tetrahydrofuran (75 cc) is added dropwise, in the course of 15 minutes and whilst keeping the temperature below 32° C. to a solution of potassium tert.-butoxide (50.8 g) in a mixture of anhydrous hexamethylphosphorotriamide (77 cc) and anhydrous tetrahydrofuran (410 cc). After stirring for 1 hour at a temperature of about 20° C. the reaction mixture is added to a mixture of distilled water (750 cc) and diethyl ether (420 cc). After decantation, the aqueous phase is re-extracted with diethyl ether (200 cc). The combined ether phases are washed three times with distilled water (2100 cc in total), dried over anhydrous magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 45° C. 2-(Pyrid-3-yl)-tetrahydrothiophen (30 g) is thus obtained in the form of a brown oil.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][S:5][CH2:4]1.S(Cl)(Cl)(=O)=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][S:5][CH:4]=1
Reactant: COC1CSC=C1C(N)=O
Solvent: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cscc1C(N)=O
Yield: 75 %

Procedure:
1.59 Parts of 3-methoxy-dihydrothiophene-4-carboxylic acid amide are reacted with 0.88 part by volume of sulfuryl chloride in 25 parts by volume of carbon tetrachloride in the course of 2 hours at 0° C. The end product is isolated from the reaction mixture by the method described in Example 1c. 1.17 parts (75% of theory) of 3-methoxythiophene-4-carboxylic acid amide are obtained.
Reaction SMILES: [CH:1]([O:4][C:5]1[NH:9][N:8]=[C:7]([NH2:10])[CH:6]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([Br:28])=[CH:23][N:22]=1>C1COCC1>[Br:28][C:24]1[C:23]([NH:10][C:7]2[CH:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[NH:9][N:8]=2)=[N:22][C:21]([Cl:20])=[N:26][CH:25]=1
Reactant: CC(C)Oc1cc(N)n[nH]1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Nc2nc(Cl)ncc2Br)n[nH]1
Reaction time: 16 h

Procedure:
To a solution of 5-isopropoxy-1H-pyrazol-3-amine (11.6 g, 82.1 mmol) in THF (85 ml) was added DIPEA (16 ml) and 2,4-dichloro-5-bromopyrimidine (17 g, 74.6 mmol) and the resulting solution was aged at 40° C. for 16 hours. The mixture was partitioned between EtOAc and H2O, the organic layer was washed with brine and dried. The solvents were removed under reduced pressure and column chromatography gave the title compound as a solid. m/z: 332.
Reaction SMILES: O[C:2]1([CH:7]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1>S(Cl)(Cl)=O>[C:2]1(=[C:7]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1ccc(C(c2ncc[nH]2)C2(O)CCCC2)cc1
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(C(=C2CCCC2)c2ncc[nH]2)cc1
Yield: 48.2 %

Procedure:
6.9 g of crude 4-[1-hydroxycyclopent-1-yl-1-(imidazolyl)methyl]benzonitrile is refluxed in 82 ml of thionyl chloride to 0.5 hour. Then the mixture is concentrated to dryness under vacuum, combined with 2N sodium hydroxide solution, extracted with dichloromethane, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, thus producing 3.1 g of 4-[1-cyclopentylidene-1(imidazolyl)methyl]benzonitrile as the free base, mp 108°-110°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([OH:21])=O)[C@@H:10]([CH3:18])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[F:37][C@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[O:5]([C:6]([NH:8][C@@H:9]([C@H:10]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[CH3:18])[C:19]([N:40]1[CH2:41][CH2:42][C@H:38]([F:37])[CH2:39]1)=[O:21])=[O:7])[C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: F[C@H]1CCNC1
Reactant: C[C@@H](c1ccc(F)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(F)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of (βS)-N-(tert-butoxycarbonyl)4-fluoro-β-methyl-L-phenylalanine Example 1, Step E, 0.15 g, 0.51 mmol) in anhydrous DMF (2 mL) was added EDC (0.25 g, 1.33 mmol), HOBT (0.18 g, 1.33 mmol), (3S)-3-fluoropyrrolidine hydrochloride (0.18 g, 1.45 mmol) and N,N′-diisopropylethylamine (0.23 mL, 1.31 mmol). After stirring at room temperature for 12 h, the reaction was diluted with ethyl acetate. The organic phase was washed sequentially with brine, 1N hydrochloric acid and 1N aqueous sodium hydroxide solution, dried over sodium sulfate, and evaporated in vacuo to yield the crude coupled product, which was used directly for the next step.
Reaction SMILES: [C:1]1(=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>CC(C)=O>[C:1]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:18][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Yield: 45 %

Procedure:
The O-alkylation procedure described for 190 was used. To a suspension of 4,4′-(cycloheptylidenemethanediyl)diphenol (189) (0.510 g, 1.74 mmol), K2CO3 (0.300 g, 2.17 mmol), and acetone (75 mL) was added ethyl 2-bromo-2-methylpropanoate (0.0.382 mL, 2.6 mmol) at RT. The reaction mixture was refluxed for 48 h and filtered. The filtrate was concentrated and purified to afford 0.320 g (45%) of the title compound 225 as a white foam. In addition, 0.210 g of unreacted starting material was recovered. 1H NMR (300 MHz, CD3OD): δ 7.02 (d, J=1.8 Hz, 2H), 6.99 (d, J=2.1 Hz, 2H), 6.76 (d, J=1.5 Hz, 2H), 6.73 (d, J=1.5 Hz, 2H), 4.71 (br s, 1H), 4.24 (q, J=7.2 Hz, 2H), 2.30 (br d, J=3.3 Hz, 4H), 1.59 (s, 6H), 1.58 (br s, 8H), 1.24 (t, J=6.9 Hz, 3H). LCMS (ESI): m/z 407 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[CH:7][C:6]=2[CH:12]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH3:18].O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][O:11][CH2:16][CH2:17][CH3:18])=[CH:7][C:6]=2[CH:12]=1
Reactant: CCCBr
Reactant: OCc1cc2cc(Br)ccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCOCc1cc2cc(Br)ccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In THF (57 ml) was dissolved 5-bromo-2-(hydroxymethyl)-1-benzofuran (5.7 g), and to the solution was added at 0° C. 60% sodium hydride (1.4 g). The mixture was stirred at room temperature for 1 hour, and to the mixture was added at 0° C. 1-bromopropane (3.1 ml). The mixture was stirred at 65° C. for 16 hours and cooled to room temperature. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=8/1) to give 5-bromo-2-(propoxymethyl)-1-benzofuran (5.0 g).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[CH3:13].C[N:15](C=O)C>>[F:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([NH2:15])[CH:10]=[C:9]2[CH3:13]
Reactant: CN(C)C=O
Reactant: Cc1c[nH]c2c(F)cccc12
Agent: [H-]
Agent: [Na+]
Product: Cc1cn(N)c2c(F)cccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of NaH (805 mg, 20.1 mmol, 60% in mineral oil) in DMF (5 mL) at 0° C. is treated with 7-fluoro-3-methylindole (200 mg, 1.34 mmol) and stirred at 0° C. for 1 h. The mixture is treated with HOSA (757 mg, 6.7 mmol) portion wise and warmed to rt over 2 h. The mixture is then poured over ice, and extracted with EtOAc (3×100 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo to afford 7-fluoro-3-methyl-indol-1-ylamine, which is used in the next step without further purification.
Reaction SMILES: [I:1]I.Br[C:4]1[CH:5]=[C:6]2[C:19]3[C:9]([CH2:10][C@@H:11]4[C@@H:16]([C:17]=3[CH:18]=1)[CH2:15][C@H:14]([NH:20][C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:13][N:12]4[CH2:28]CC)=[CH:8][N:7]2[Si](C(C)(C)C)(C)C>>[I:1][C:18]1[C:17]2=[C:19]3[C:6]([NH:7][CH:8]=[C:9]3[CH2:10][C@@H:11]3[C:16]2=[CH:15][C@H:14]([NH:20][C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:13][N:12]3[CH3:28])=[CH:5][CH:4]=1
Reactant: II
Reactant: CCCN1C[C@@H](NC(=O)N(CC)CC)C[C@@H]2c3cc(Br)cc4c3c(cn4[Si](C)(C)C(C)(C)C)C[C@H]21
Product: CCN(CC)C(=O)N[C@H]1C=C2c3c(I)ccc4[nH]cc(c34)C[C@H]2N(C)C1

Procedure:
With iodine and 3-(13-bromo-1-tert-butyldimethylsilyl-6-n-propyl-8α-ergolinyl)-1,1-diethylurea:
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.O.O.[Sn](Cl)Cl.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][C:16]([CH2:20][OH:21])=[CH:15][N:14]=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][C:16]([CH2:20][O:21][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)=[CH:15][N:14]=1
Reactant: OCc1cnc(Cl)c(Cl)c1
Reactant: C1=COCCC1
Agent: Cl[Sn]Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: Clc1cc(COC2CCCCO2)cnc1Cl
Temperature: 25 °C
Reaction time: 63 h

Procedure:
3,4-Dihydro-2H-pyran (1.1 mL) and tin (II) chloride dihydrate (0.38 g) were added to a chloroform solution of 2,3-dichloro-5-hydroxymethylpyridine (1.5 g), and the reaction mixture was stirred at room temperature for 63 hours. The reaction mixture was filtered, and the solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 90:10). The title compound (1.7 g) was obtained as colorless oil.