Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(N(C(C)C)C(C)C)C>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[N:4]=[C:10]=[S:11]
Reactant: Nc1c(F)cccc1Cl
Reactant: S=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cccc(Cl)c1N=C=S
Yield: 27.5 %

Procedure:
The title compound was prepared following the procedure described for intermediate-2 using 2-chloro-6-fluoro aniline (3.0 g, 19.35 mmol), thiophosgene (5.01 g, 43.47 mmol) and N-ethyl di-isopropyl amine (8.0 g, 64.00 mmol) to afford 1.0 g of the desired product. 1HNMR (DMSO-d6): δ 7.26 (m, 2H), 7.06 (t, J=9.6 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[F:18]>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:13][C:12]=1[F:18]
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(Cl)c(F)c1
Product: O=Cc1ccc(Oc2ccc(Cl)c(F)c2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 4-fluorobenzaldehyde and 4-chloro-3-fluorophenol.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([N:15]=[C:16]=[S:17])(=O)C1C=CC=CC=1>CC(C)=O>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][C:16]([NH2:15])=[S:17]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1nccs1
Solvent: CC(C)=O
Product: NC(=S)Nc1nccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
To a solution of 2-aminothiazole (630 mg, 6.29 mmol) in acetone (30 mL) was slowly added benzoyl isothiocyanate (845 μL, 6.29 mmol) at room temperature. The reaction mixture was heated to a gentle reflux for 6.5 h, at which time it was cooled to room temperature and concentrated in vacuo. The residue was added acetonitrile (50 mL) and the yellow precipitate was filtered. The filtrate was concentrated in vacuo and the residue was taken up in 10% aqueous sodium hydroxide (50 mL). The heterogeneous reaction mixture was heated to a gentle reflux for 1 h then cooled to room temperature and stirred for 16 h. To the reaction mixture was added 6 N hydrochloric acid until pH reached 7. To the aqueous layer was added ammonium hydroxide (50 mL) followed by ethyl acetate then separated. The organic layer was washed with brine then dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo to afford N-1,3-thiazol-2-ylthiourea (717 mg, 71%) as a pale yellow powder. The powder was then taken up in chloroform (50 mL) and to this suspension was added iodomethane (281 μL, 4.50 mmol). The reaction mixture was heated to reflux for 2 h, at which time it was cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexanes/ethyl acetate) to afford methyl N-1,3-thiazol-2-ylimidothiocarbamate (200 mg, 26%). MS (EI) for C5H7N3S2: 174 (MH+).
Reaction SMILES: Cl.[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[N:33]=[C:32]([O:38][CH3:39])[N:31]=1>>[ClH:29].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([C:30]4[N:35]=[C:34]([O:36][CH3:37])[N:33]=[C:32]([O:38][CH3:39])[N:31]=4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Reactant: COc1nc(Cl)nc(OC)n1
Agent: Cl
Product: COc1nc(OC)nc(N2CN(c3ccccc3)C3(CCN(C4CCCCCCCCC4)CC3)C2=O)n1

Procedure:
The title compound, white solid, m. p. 216° C. and MS: m/e=509.5 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and 2-chloro-4,6-dimethoxy-[1,3,5]triazine.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[CH:7][C:8](/[CH:12]=[CH:13]\[C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[C:5]([CH3:25])([CH3:24])[CH2:4][CH2:3]1.[OH-].[K+]>O>[CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[CH:7][C:8](/[CH:12]=[CH:13]\[C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=3)=[CH:9][CH:10]=2)[C:5]([CH3:25])([CH3:24])[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(/C=C\c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(/C=C\c3ccc(C(=O)O)cc3)ccc21
Temperature: 70 °C
Yield: 98.1 %

Procedure:
In a 50 mL round bottom flask was charged methyl 4-((Z)-2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-6-yl)vinyl)benzoate 11 (0.16 g, 0.46 mmol) in 15 mL and water (1.5 mL) and KOH was added (103 mg, 1.84 mmol). The suspension was heated for 6 h at 70° C. Methanol was removed in vacuo, water (20 mL) was added and the solution washed with diethyl ether (2×50 mL). The aqueous solution was carefully acidified to pH=1 using a solution of HCl 1N and extracted with diethyl ether (3×50 ml). The organic layer was dried over MgSO4, filtered and evaporated to yield to 4-((Z)-2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-6-yl)vinyl)benzoic acid 13 (0.151 g, 98% yield) as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[O:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][NH2:24])[CH2:18][CH2:17]1>CS(C)=O>[Br:8][C:6]1[N:7]=[C:2]([NH:24][CH2:23][CH2:22][CH:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)[C:3]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=1
Reactant: CCOC(=O)CNc1ncc(Br)nc1Br
Reactant: NCCC1CCOCC1
Solvent: CS(C)=O
Product: CCOC(=O)CNc1ncc(Br)nc1NCCC1CCOCC1
Temperature: 150 °C
Yield: 44.1 %

Procedure:
Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (See Example 6.B) (1.0 g, 2.95 mmol) and 2-(tetrahydro-2H-pyran-4-yl)ethanamine (0.381 g, 2.95 mmol) were placed in a microwave vial, dimethylsulfoxide (2 mL) was added and the resulting mixture was heated in a Biotage Emrys Optimizer microwave reactor at 150° C. for 3600 s. The crude reaction mixture was purified using silica gel chromatography (33% ethyl acetate in hexanes) to yield the title compound (0.5 g, 1.3 mmol, 44% yield). MS (ESI) m/z 387.1 [M]+, 389.1 [M+2]+.
Reaction SMILES: C1(O[C:8]([N:10]2[C:16]([CH3:17])=[CH:15][C:14]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:13]=3[C:12]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([CH3:32])[CH:24]=3)=[N:11]2)=[O:9])C=CC=CC=1.[CH3:33][NH2:34]>C(O)C>[CH3:33][NH:34][C:8]([N:10]1[C:16]([CH3:17])=[CH:15][C:14]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:13]=2[C:12]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([CH3:32])[CH:24]=2)=[N:11]1)=[O:9]
Reactant: CN
Reactant: CC1=Cc2ccc(Cl)cc2C(c2ccc([N+](=O)[O-])c(C)c2)=NN1C(=O)Oc1ccccc1
Solvent: CCO
Product: CNC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc(Cl)ccc2C=C1C
Yield: 87 %

Procedure:
11.86 g (26.4 mmoles) of 8-chloro-4-methyl-1-(3-methyl-4-nitrophenyl)-3H-2,3-benzodiazepine-3-carboxylic acid phenyl ester are stirred with a solution of 43 ml of methylamine (˜8M) in ethanol at room temperature for 24 hours. The separated crystals are filtered off and washed with ethanol. Thus 8.87 g (87%) of the desired compound (yellow) melting at 196-198° C. are obtained.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([OH:5])=[O:4].[CH3:12]O.Cl>>[OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH3:12])=[O:4]
Reactant: CCCCCCC(O)C(=O)O
Reactant: CO
Agent: Cl
Product: CCCCCCC(O)C(=O)OC
Reaction time: 1.5 h

Procedure:
2-Hydroxyoctanoic acid (1.0 g) was stirred in 10% hydrogen chloride methanol solution (20 ml) at room temperature. After 1.5 hours, the reaction mixture was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with aqueous NaHCO3 solution and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave methyl 2-hydroxyoctanoate (0.684 g) as a colorless oil.
Reaction SMILES: S(C)C.[NH2:4][C:5]1[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:7][CH:8]=[C:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.[CH3:23][S:24]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1)(=[O:26])=[O:25]>C(Cl)Cl.CC(O)=O>[CH2:11]([C:9]1[CH:10]=[C:5]([NH:4][CH2:31][C:30]2[CH:29]=[CH:28][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:34][CH:33]=2)[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:7][CH:8]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: CCOC(=O)c1ncc(Cc2ccccc2)cc1N
Solvent: CSC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1ncc(Cc2ccccc2)cc1NCc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1M BH3.SMe2 in CH2Cl2 (7 mL, 7 mmol) was added dropwise to a solution of ethyl 3-amino-5-benzylpyridine-2-carboxylate (600 mg, 2.34 mmol) and 4-methylsulfonyl benzaldehyde (647 mg, 3.51 mmol) in CH2Cl2 (8 mL) and HOAc (4 mL). The mixture was stirred at rt for 30 min and additional amounts of 1M BH3.SMe2 (2 mL, 2 mmol) and 4-methylsulfonyl benzaldehyde (160 mg, 3.51 mmol) were added. After stirring overnight at rt, the solution was concentrated in vacuo, dissolved in CH2Cl2 and washed with NaHCO3 solution. The organic layer was dried, concentrated and chromatographed on silica gel eluting with 0-5% MeOH/CH2Cl2. This afforded the product as an amber foam: 1H NMR (CDCl3) δ 8.31 (1H, br m), 7.97 (1H, s), 7.86 (2H, d, J=8 Hz), 7.42 (2H, d, J=8 Hz), 7.22 (3H, m), 7.02 (2H, dd, J=8, 2 Hz), 6.58 (1H, s), 4.46 (2H, br), 4.46 (2H, q, J=7 Hz), 3.87 (2H, s), 3.04 (3H, s), 1.45 (3H, t, J=7 Hz); HRMS calcd for C23H24N2O4S+H+: 425.1535. Found: 425.1524.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[N:13]=[C:12]([CH3:14])[C:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)=[O:6].CC(C)([O-])C.[K+].O>CN(C=O)C>[CH3:14][C:12]1[C:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[CH:10][CH:9]=[C:8]([N:7]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])[N:13]=1
Reactant: COC(=O)c1ccc(-c2ccc(NC(=O)CCCCl)nc2C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(N3CCCC3=O)nc2C)cc1
Reaction time: 3 h
Yield: 85.3 %

Procedure:
A stirred solution of methyl 4[6-(4-chlorobutanoylamino)-2-methylpyridin-3-yl]benzoate (D8, 0.60 g, 1.7 mmole) in DMF (7 ml) at 25° C. under argon was treated portionwise over 15 minutes with potassium t-butoxide (0.23 g, 2.0 mmole). The mixture was stirred for 3 h, then poured into water (100 ml) and extracted with ethyl acetate. The extract was washed with water, dried (Na2SO4) and concentrated in vacuo to afford the title compound as an orange solid (0.45 g, 85%).
Reaction SMILES: C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1.[NH:24]([C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[C@H:25]([C:28]([NH:30][C@H:31]([C:47](O)=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:35][CH:34]=1)=[O:29])[CH2:26][OH:27].[NH2:60][C@@H:61]([C:72]([NH:74][C@H:75]([C:80]([NH:82][C@H:83]([C:91]([N:93]1[CH2:102][CH2:101][CH2:100][C@H:94]1[C:95]([NH:97][CH2:98][CH3:99])=[O:96])=[O:92])[CH2:84][CH2:85][CH2:86][NH:87][C:88](=[NH:90])[NH2:89])=[O:81])[CH2:76][CH:77]([CH3:79])[CH3:78])=[O:73])[CH2:62][CH2:63][CH2:64][C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66].Cl.Cl.ON1C(=O)C2C=CC=CC=2N=N1>CC(N(C)C)=O>[NH:24]([C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[C@H:25]([C:28]([NH:30][C@H:31]([C:47]([NH:60][C@@H:61]([C:72]([NH:74][C@H:75]([C:80]([NH:82][C@H:83]([C:91]([N:93]1[CH2:102][CH2:101][CH2:100][C@H:94]1[C:95]([NH:97][CH2:98][CH3:99])=[O:96])=[O:92])[CH2:84][CH2:85][CH2:86][NH:87][C:88](=[NH:89])[NH2:90])=[O:81])[CH2:76][CH:77]([CH3:79])[CH3:78])=[O:73])[CH2:62][CH2:63][CH2:64][C:65]([O:67][C:68]([CH3:69])([CH3:71])[CH3:70])=[O:66])=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:35][CH:34]=1)=[O:29])[CH2:26][OH:27]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)CCCC(=O)OC(C)(C)C
Reactant: O=C(N[C@@H](CO)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCCC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.26 ml of N-ethylmorpholine and 440 mg of dicyclohexylcarbodiimide are added at 0° C. to a solution of 1 g (approx. 2 mmoles) of Z-Ser-Tyr(Bzl)-OH, 1.4 g (2 mmoles) of H-D-Aad(OBut)-Leu-Arg-Pro-NH-C2H5.2HCl and 0.326 g (2 mmoles) of 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine in 8 ml of dimethylacetamide. The mixture is stirred for two hours at 0° C. and is then left to stand overnight at room temperature. The precipitate is filtered off and the filtrate is partitioned between 50 ml of n-butanol and 50 ml of saturated NaCl solution. The n-butanol phase is extracted by shaking with two 25 ml portions of saturated NaHCO3 solution and with 25 ml of water and is concentrated. The residue is triturated with ether and the product is filtered off and dried. Yield 2.05 g (94%), amorphous. [α]D22 =-37.4° (c=1, methanol).
Reaction SMILES: C([O-])(=O)C.[Na+].[Na].C([O:10][CH2:11][CH2:12][O:13][CH2:14][N:15]1[CH:23]=[N:22][C:21]2[C:20](=[O:24])[NH:19][C:18]([NH2:25])=[N:17][C:16]1=2)(=O)C>>[OH:10][CH2:11][CH2:12][O:13][CH2:14][N:15]1[CH:23]=[N:22][C:21]2[C:20](=[O:24])[NH:19][C:18]([NH2:25])=[N:17][C:16]1=2
Reactant: CC(=O)OCCOCn1cnc2c(=O)[nH]c(N)nc21
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Na]
Product: Nc1nc2c(ncn2COCCO)c(=O)[nH]1

Procedure:
A process for the synthesis of 9-(2-hydroxyethoxy methyl) guanine, comprising reacting guanine, or a salt thereof with between 2 and 4 moles of hexamethyldisilazane, in the presence of an aprotic solvent and of a catalytic amount of ammonium sulphate; reacting the resulting guanine trimethylsilyl derivative, without being isolated, with a stoichiometric quantity of acyloxyethoxy methyl halide at a temperature of 50° to 100° C.; and hydrolyzing with a sodium acetate or sodium hydroxyde water solution the resulting 9-(2-acetoxyethoxy methyl) guanine, to provide 9-(2-hydroxyethoxy methyl) guanine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:14]1([C:11]([C:8]2[N:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[O:13])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)N2CCOCC2)nc1
Reaction time: 16 h
Yield: 87.4 %

Procedure:
5-(Methoxycarbonyl)pyridine-2-carboxylic acid (758 mg, 4.18 mmol) was dissolved in DMF (25 mL) and morpholine (603 uL, 5.23 mmol), Et3N (2.45 mL, 16.7 mmol) and HBTU (1.67 g, 4.39 mmol) were added. The reaction mixture was stirred for 16 h and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with sat aq Na2CO3 (100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (914 mg, 87.3%) as a yellow oil. LCMS (ES+): 251.2 [MH]+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:10]([Br:11])=[C:9]([Br:12])[NH:8][N:7]=1.C(OC(=O)C)(=O)C>C(O)(=O)C>[N+:1]([N:7]1[C:6]([Br:5])=[C:10]([Br:11])[C:9]([Br:12])=[N:8]1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Brc1n[nH]c(Br)c1Br
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])n1nc(Br)c(Br)c1Br
Temperature: 15 °C
Reaction time: 2 h

Procedure:
HNO3 (d=1.50 g/ml; 18 ml, 0.429 mol) was added dropwise over 10 minutes to a solution of 3,4,5-tribromopyrazole (1) (50 g, 0.164 mol) in glacial acetic acid (750 ml) while maintaining the temperature at 15° C. Acetic anhydride (250 ml) was added and the reaction mixture was stirred at room temperature for 2 hours. Once the reaction was complete, the reaction mixture was poured onto crushed ice (1 kg). After stirring for 1 hour, the crude product was filtered off and then washed with demineralized water (2×60 ml) to give crude 1-nitro-3,4,5-tribromopyrazole. The water (24.6 ml) contained in the wet product was removed by heating a solution of the product in toluene (750 ml) at reflux in Dean-Stark apparatus. The toluene solution was maintained at reflux for a further 30 minutes until a TLC (eluent:toluene) showed that the rearrangement of the 1-nitro-3,4,5-tribromopyrazole (Rf=0.77), the intermediate formed, into 3,5-dibromo-4-nitropyrazole 2 (Rf=0.05) was complete. The solution was concentrated to a residual volume of 150 ml and then cooled to 60° C., followed by addition of hexane (275 ml). The solution was cooled to 0–5° C. for 1 hour and the 3,5-dibromo-4-nitropyrazole (2) (29.1 g, 65%) was recovered, by filtration and drying under vacuum in the form of a pale yellow solid.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.CCCCCC.[Br:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[F:30].[Cl-].[NH4+].C1C[O:36][CH2:35]C1>CN(C=O)C>[Br:22][C:23]1[C:28]([F:29])=[C:27]([CH:26]=[CH:25][C:24]=1[F:30])[CH:35]=[O:36]
Reactant: C1CCOC1
Reactant: Fc1cccc(F)c1Br
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1ccc(F)c(Br)c1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 18 %

Procedure:
To a cooled (0° C.) solution of 2,2,6,6-tetramethylpiperidine (1.64 mL, 9.75 mmol) in THF (20 mL) was added 1.6 M n-butyllithium in hexane (5.54 mL, 8.86 mmol). The solution was stirred for 20 min, then brought to −78° C. 1-bromo-2,6-difluorobenzene (1.00 mL, 8.86 mmol) in THF was added slowly, and the solution was stirred at −78° C. for 30 min. DMF (1 mL) was added slowly, and the solution was stirred at −78° C. for 20 min. Saturated aqueous ammonium chloride was added and the reaction was allowed to warm to rt. The organic solvent was removed in vacuo, and the residual material was extracted with EtOAc and washed with water (2×). The organic layer was purified by column chromatography (1 to 2% EtOAc:hexanes) to afford 350 mg (18%) of the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 6.97 (td, J=9.2, 1.5 Hz, 1 H), 7.78 (ddd, J=9.0, 7.5, 5.7 Hz, 1 H), 10.34 (s, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:30][CH3:31])=[C:6]([C@H:12]2[CH2:16][CH2:15][C@H:14]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)[C:13]2=[O:29])[S:7][C:8]=1[CH2:9][CH2:10][CH3:11])[CH3:2].[BH4-].[Na+].N#N>CO>[CH2:1]([O:3][C:4]1[C:5]([O:30][CH3:31])=[C:6]([CH:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=3)[CH:13]2[OH:29])[S:7][C:8]=1[CH2:9][CH2:10][CH3:11])[CH3:2]
Reactant: CCCc1sc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)C2=O)c(OC)c1OCC
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCc1sc(C2CCC(c3cc(OC)c(OC)c(OC)c3)C2O)c(OC)c1OCC

Procedure:
To a solution of crude trans-2-(4-ethoxy-3-methoxy-5-n-propylthiophenyl)-5-(3,4,5-trimethoxyphenyl)cyclopentanone (6.87 g, 14.5 mmoles) in MeOH (230 ml) was added at room temperature NaBH4 (1.64 g, 43.4 mmoles) in several portions over 5 minutes. The solution was stirred at room temperature in a N2 atmosphere for 21 hours and most of the MeOH removed in vacuo. The residue was suspended in H2O and extracted with Et2O (4×). The combined extracts were washed with H2O (3×) and saturated NaCl solution and dried (MgSO4). The residue after evaporation of the Et2O in vacuo was filtered through a 9.5×11 cm column of silica gel (E. Merck, Kriselgel 60 ) with (1:1) EtOAc-hexane (21). Evaporation in vacuo gave 6.12 g of a crude mixture of cyclopentanols. Separation by HPLC on a Prep 500 with silica gel and 2:1 hexane-EtOAc gave 2.27 g (33 % from 1) of 1β, 2β, 5α)-2-(4-ethoxy-3-methoxy-5-n-propylthiophenyl)-5-(3,4,5-trimethoxyphenyl)cyclopentanol (5, eluted first).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH:3]1[O:5][CH2:4]1.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>>[CH2:14]([NH:15][CH2:4][CH:3]([OH:5])[C:2]([CH3:7])([CH3:6])[CH3:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][CH2:4][CH:3]([OH:5])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: NCCCCCCN
Reactant: CC(C)(C)C1CO1
Product: CC(C)(C)C(O)CNCCCCCCNCC(O)C(C)(C)C

Procedure:
Condensation of 3,3-dimethyl-1-butene oxide and hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[2-hydroxy-3,3-dimethylbutylamine] (I: R= (CH3)3C, R' = H, X= (CH2)6, Z= H).
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].CC(C)([O-])C.[K+].CS(O[CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:29][CH2:28][C:27]3[CH:30]=[CH:31][S:32][C:26]=3[C:25](=[O:33])[C:24]=2[CH:34]=1)(=O)=O>C(O)C>[O:33]=[C:25]1[C:24]2[CH:34]=[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][N:3]([OH:4])[CH3:2])[CH:21]=[CH:22][C:23]=2[O:29][CH2:28][C:27]2[CH:30]=[CH:31][S:32][C:26]1=2
Reactant: CS(=O)(=O)OCCCCc1ccc2c(c1)C(=O)c1sccc1CO2
Reactant: CNO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CN(O)CCCCc1ccc2c(c1)C(=O)c1sccc1CO2
Temperature: 25 °C
Yield: 51.1 %

Procedure:
To a stirring solution of 4.77 g of N-methylhydroxylamine hydrochloride in 100 ml of absolute ethanol was added 6.38 g of potassium tert-butoxide. To the resulting suspension was added 6.98 g of 4-(4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-yl)butanol methanesulfonate, and an additional 150 ml of absolute ethanol. The suspension was allowed to reflux for 24 hours and was then cooled to room temperature. The suspension was filtered to remove potassium chloride and the filter cake was washed with absolute ethanol. The resulting solution was concentrated in vacuo to a waxy solid. The solid was dissolved in 300 ml of methylene chloride and partitioned against 200 ml of water. The organic phase was dried with 200 ml of saturated aqueous sodium chloride, collected, dried again (Na2SO4), filtered, and concentrated in vacuo to an oil. The oil solidified upon standing, and was recrystallized from isopropanol to give 3.09 g of 4-(4,10-dihydro-10 -oxothieno[3,2-c][1]benzoxepin-8-yl)-N-hydroxy-N-methyl-1-butylamine, m.p. 107°-108° C.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[CH3:12][C@H:13]1[C:21]2[C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:19][CH:18]=[N:17][C:16]=2[CH2:15][CH2:14]1.[C:28]([O:32][C:33]([NH:35][CH2:36][CH2:37][C:38]([C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=1)([CH3:42])[C:39](O)=[O:40])=[O:34])([CH3:31])([CH3:30])[CH3:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CCOC(C)=O>[Cl:49][C:46]1[CH:47]=[CH:48][C:43]([C:38]([CH3:42])([C:39]([N:25]2[CH2:26][CH2:27][N:22]([C:20]3[C:21]4[C@H:13]([CH3:12])[CH2:14][CH2:15][C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:23][CH2:24]2)=[O:40])[CH2:37][CH2:36][NH:35][C:33](=[O:34])[O:32][C:28]([CH3:30])([CH3:31])[CH3:29])=[CH:44][CH:45]=1
Reactant: C[C@@H]1CCc2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)NCCC(C)(C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)C(C)(CCNC(=O)OC(C)(C)C)c4ccc(Cl)cc4)CC3)c21
Reaction time: 8 h
Yield: 62.4 %

Procedure:
DIPEA (35.5 mg, 0.275 mmol) was added to a suspension of (R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (20 mg, 0.69 mmol), 4-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)-2-methylbutanoic acid (27.0 mg, 0.082 mmol), and O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (31.3 mg, 0.082 mmol) in CH2Cl2 (5.0 mL) at room temperature. The resulting mixture was stirred overnight, diluted with EtOAc, washed with saturated aqueous NaHCO3 and saturated aqueous NH4Cl. The organic layer was dried (MgSO4) and concentrated. The residue was purified by a silica cartridge (5.0 g), eluted by a mixture of EtOAc and hexane (60:40) to give tert-butyl 3-(4-chlorophenyl)-3-methyl-4-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-oxobutylcarbamate as a clear oil (27 mg, 74%). LCMS (APCI+) [M+H]+ 528.1; Rt: 3.38 min.