Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH3:9])[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]([NH2:19])=[O:18].[Cl:20][C:21]1[CH:22]=[C:23]([CH2:29][C:30](OC)=O)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].[O-]CC.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:29][C:30]1[NH:19][C:17](=[O:18])[C:3]2[C:4]([CH3:16])=[N:5][N:6]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH3:9])[C:2]=2[N:1]=1
Reactant: CCCCCCC(CC)n1nc(C)c(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc(OC)c(Cl)c1
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(CC)n1nc(C)c2c(=O)[nH]c(Cc3ccc(OC)c(Cl)c3)nc21
Yield: 46.9 %

Procedure:
13 mg (0.050 mmol) of 5-amino-3-methyl-1-(3-nonyl)-1H-pyrazole-4-carboxamide and 53 mg (0.248 mmol) of methyl 3-chloro-4-methoxyphenylacetate are refluxed for 6 hours in 0.5 ml of a 0. 5M ethanolic sodium ethoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 10.1 mg (47%) of a solid, Rf=0.63 (dichloromethane/methanol=15:1).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]([NH:13][C:14]2[C:15]([CH3:26])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[NH:13][C:11]([NH:10][S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])=[O:12])=[CH:20][CH:21]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)NS(=O)(=O)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)NS(=O)(=O)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 1-benzenesulfonyl-3-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-urea and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]#[N:13])[C:8]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:27]1([CH2:33][C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)(Cl)Cl>[CH:1]1([N:6]2[C:10]([NH:11][C:34]([CH2:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:35])=[C:9]([C:12]#[N:13])[C:8]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N#Cc1c(Cc2ccccc2)nn(C2CCCC2)c1N
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: N#Cc1c(Cc2ccccc2)nn(C2CCCC2)c1NC(=O)Cc1ccccc1
Reaction time: 3 h
Yield: 33.3 %

Procedure:
To a stirred solution of 1-cyclopentyl-3-phenylmethyl-5-amino-1H-pyrazole-4-carbonitrile (2.3 g, 8.6 mmol), CHCl3 (50 ml) and pyridine (20 ml) in an ice bath was added a solution of phenylacetyl chloride (2.3 ml, 17.2 mmol) in CHCl3 (10 ml) over a period of 20 minutes. The reaction mixture was stirred in an ice bath for 3 hours, then at room temperature for 2 hours. The solvent was removed in vacuo, the residue was partitioned between CHCl3 (100 ml) and water (50 ml) , and the organic layer was separated. Concentration of the organic layer afforded a gummy solid which was recrystallized from isopropanol to afford 1.1 g (88%) of 1-cyclopentyl-3-phenylmethyl-4-cyano-5-(phenylmethylcarbonylamino)-1H-pyrazole, as white needles, m.p. 166-168° C.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C@@:18]2([CH3:37])[C:22](=[O:23])[N:21]([C@@H:24]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:20](=[O:36])[NH:19]2)=[CH:14][CH:13]=1>CN(C=O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C@@:18]2([CH3:37])[C:22](=[O:23])[N:21]([C@@H:24]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C:20](=[O:36])[N:19]2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: CC(C)C[C@@H](C(=O)OC(C)(C)C)N1C(=O)N[C@@](C)(c2ccc(Br)cc2)C1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)OC(C)(C)C)N1C(=O)N(Cc2ccccc2)[C@@](C)(c2ccc(Br)cc2)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
540 μl (4.4 mmol) of benzyl bromide and then, at 0° C., 140 mg of a 55-65% strength sodium hydride dispersion in oil were added to a solution of 1.75 g (4 mmol) of 169.2 in 20 ml of absolute DMF and the mixture was stirred at 0° C. for 15 min and at room temperature for 3 h. After allowing to stand overnight, the solvent was removed in vacuo and the residue was chromatographed on silica gel using heptane/ethyl acetate=8/2. The product fractions were combined and the solvent was removed in vacuo. 1.97 g (93%) of 169.3 were obtained.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([OH:26])=O)=[CH:9][N:8]=1)[CH2:2]2.[OH:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([NH:34][C@H:31]3[CH2:32][CH2:33][C@H:28]([OH:27])[CH2:29][CH2:30]3)=[O:26])=[CH:9][N:8]=1)[CH2:2]2
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1Cl
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)N[C@H]2CC[C@H](O)CC2)cc1Cl
Reaction time: 8 h

Procedure:
In THF (20 mL) were dissolved 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)pyrimidine-5-carboxylic acid (180 mg, 0.48 mmol), trans-4-hydroxycyclohexylamine (66 mg, 0.58 mmol) and HATU (220 mg, 0.58 mmol). The solution was cooled in an ice bath and DIEA (0.25 mL, 1.44 mmol) was added then. The reaction was conducted at ambient temperature for 8 h, followed by concentration, addition of water and extraction with ethyl acetate. The organic phase was dried, concentrated and purified by silica gel column chromatography (DCM/methanol=20/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-(trans-4-hydroxycyclohexanyl)pyrimidine-5-formamide (141 mg, 62% yield).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:21][CH2:22][CH:23]([OH:25])[CH3:24]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:14]1([O:13][C:8]2[CH:7]=[C:6]3[C:11]([CH2:12][C:4]4[CH:3]=[CH:2][N:21]([CH2:22][CH:23]([OH:25])[CH3:24])[C:5]=43)=[CH:10][CH:9]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(O)CN
Reactant: O=CCC1Cc2ccc(OC3CCCC3)cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O)Cn1ccc2c1-c1cc(OC3CCCC3)ccc1C2
Reaction time: 0.75 h
Yield: 48.5 %

Procedure:
A solution of 2.58 g of (RS)-2-(2-oxoethyl)-6-cyclopentoxy-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 7:3). 1.44 g (48%) of (RS)-1-(7-cyclopentoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a light yellow oil.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([C@@]1(O)[C@@H](CO)O[C@@](C(=O)C)([N:19]2[C:29]3[N:28]=[C:26]([NH2:27])[NH:25][C:23](=[O:24])[C:22]=3[N:21]=[CH:20]2)[C@]1(C(=O)C)O)(=O)C.Cl>C(#N)C>[CH2:1]([N:21]1[C:22]2[C:23](=[O:24])[NH:25][C:26]([NH2:27])=[N:28][C:29]=2[N:19]=[CH:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)[C@@]1(O)[C@@](O)(C(C)=O)[C@@H](CO)O[C@@]1(C(C)=O)n1cnc2c(=O)[nH]c(N)nc21
Agent: Cl
Solvent: CC#N
Product: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Temperature: 60 °C
Reaction time: 19 h
Yield: 79.2 %

Procedure:
Benzyl bromide (0.73 ml, 2.50 equivalents) was added to 4.24 g of an acetonitrile solution containing 1.0 g (corresponding to 2.45 mmols) of triacetylguanosine obtained in Example 1, and the mixture was stirred at 60° C. for 19 hours. The temperature was returned to room temperature, and 2.1 ml (10 equivalents) of conc. hydrochloric acid were added thereto. The mixture was reacted for 2 hours. The solid was precipitated in 1.5 hours. Ten milliliters of methanol were added thereto, and the slurry was stirred for 2 hours, and then filtered. The crystals were washed twice with 5 ml of methanol, and dried at 55° C. under reduced pressure for 3 hours to give 0.61 g of 7-benzylguanine in a yield of 79.2%.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@H:15]([C:18]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:20])[CH2:14]1)=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](C(=O)N2CCCC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pyrrolidine (51 μL, 1.03 mmol) was added to a solution of (S)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (200 mg, 0.93 mmol), HATU (391 mg, 1.03 mmol) and DIPEA (410 μL, 2.35 mmol) in DMF and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give (S)-3-(pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of (S)-3-(pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a pale brown oil (110 mg, 70%). 1H NMR (CDCl3, 400 MHz) δ 4.01 (m, 3H); 3.52-3.41 (m, 3H); 3.25-3.11 (m, 2H); 3.10-2.97 (m, 2H); 2.89 (dt, J=11.4, 7.5 Hz, 1H); 2.11-1.99 (m, 1H); 2.01-1.91 (m, 2H) and 1.93-1.82 (m, 2H).
Reaction SMILES: O=[C:2]1[C:10]2(CCN(C(OC(C)(C)C)=O)C[CH2:11]2)[C:9]2[C:4](=[CH:5][C:6]([B:23]3[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]3)=[CH:7][CH:8]=2)N1.BrC1C=CC2C(C)(C)[O:40][C:39](=[O:44])[N:38](C)[C:37]=2C=1>>[CH3:37][N:38]1[C:4]2[CH:5]=[C:6]([B:23]3[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]3)[CH:7]=[CH:8][C:9]=2[C:10]([CH3:11])([CH3:2])[O:44][C:39]1=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)Nc1cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: CN1C(=O)OC(C)(C)c2ccc(Br)cc21
Product: CN1C(=O)OC(C)(C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc21

Procedure:
Following the procedure described for intermediate 7.33 (Step 2), starting from 7-bromo-1,4,4-trimethyl-1H-benzo[d][1,3]oxazin-2(4H)-one 7.38 (540 mg), 560 mg of 1,4,4-trimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,3]oxazin-2(4H)-one 7.40 was obtained. LCMS [M+H]+: 318.12.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([OH:20])[CH2:15]3)=[O:13])[C:6]=2[CH:21]=1.[C:22]1(=[O:28])[O:27][C:25](=[O:26])[CH2:24][CH2:23]1>N1C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([O:20][C:22]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:28])[CH2:15]3)=[O:13])[C:6]=2[CH:21]=1
Reactant: O=C1CCC(=O)O1
Reactant: O=C(Cn1c(=O)sc2ccc(Cl)cc21)N1CCCC(O)C1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)OC1CCCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)C1
Reaction time: 8 h
Yield: 47.8 %

Procedure:
A solution of 5-chloro-3-(3-hydroxypiperidinocarbonylmethyl)benzothiazolin-2-one (3.2 g) in dry pyridine (2.5 ml) and dry tetrahydrofuran (50 ml) was cooled. To the solution was dropwise added a solution of succinic anhydride (1.1 g) in dry tetrahydrofuran (5 ml) under stirring. The mixture was refluxed for two hours and then left overnight. The solvent was evaporated off under vacuum from the reaction mixture. The residue was dissolved in 5% aqueous sodium bicarbonate (20 ml). The resultant solution was cooled and adjusted to pH 2 with 1% hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and then recrystallized from isopropyl alcohol to yield the title compound as colorless crystals (2.0 g). m.p. 131°-133° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]([CH3:20])[CH3:19])=[C:7]([Cl:21])[C:6]=1[Cl:22])=O.[C:23]([N:26]1[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]1)(=[S:25])[NH2:24]>CN(C=O)C>[Cl:22][C:6]1[C:7]([Cl:21])=[C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]([CH3:20])[CH3:19])[CH:9]=[CH:10][C:5]=1[C:3]1[N:24]=[C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]2)[S:25][CH:2]=1
Reactant: CC(=O)N1CCN(C(N)=S)CC1
Reactant: CC(C)c1ccccc1Sc1ccc(C(=O)CBr)c(Cl)c1Cl
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2nc(-c3ccc(Sc4ccccc4C(C)C)c(Cl)c3Cl)cs2)CC1

Procedure:
A solution of compound 41 (30 mg, 0.07 mmole) and 1-thiocarbamyl-4-acetyl piperazine (20.5 mg, 0.11 mmole) in DMF (1.0 ml) was stirred at ambient temperature for two hours. The solvent was evaporated and the residue was purified on a 5-g silica gel cartridge, giving the desired product 39 as a white solid. 23 mg, 65.7%. 1H-NMR (CDCl3, 500 MHz) δ 1.19 (d, J=8.5 Hz, 6H), 2.14 (s, 3H), 3.46–3.60 (m, 7H),), 3.75–3.78 (m, 2H), 6.48 (d, J=8.4 Hz, 1H), 7.09 (s, 1H), 7.21 (m, 1H), 7.44–7.51 (m, 3H), 7.57 (d, J=8.4 Hz, 1H). MS (DCI/NH3) m/z 506 (M+H)+.
Reaction SMILES: C([O:8][N:9]1[C:13](=[O:14])[CH2:12][C@H:11]([NH:15][S:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)(=[O:18])=[O:17])[C:10]1=[O:35])C1C=CC=CC=1>CCOC(C)=O.CO.[Pd]>[OH:8][N:9]1[C:13](=[O:14])[CH2:12][C@H:11]([NH:15][S:16]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=3)[CH2:23][CH2:24]2)(=[O:17])=[O:18])[C:10]1=[O:35]
Reactant: O=C1C[C@H](NS(=O)(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)C(=O)N1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1C[C@H](NS(=O)(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)C(=O)N1O
Reaction time: 1 h

Procedure:
4-(4Trifluoromethyl-phenyl)-piperazine-1-sulfonic acid ((3S)-1-benzyloxy-2,5-dioxo-pyrrolidin-3-yl)-amid (67 mg; 0.13 mmol) was dissolved in EtOAc (4 ml) +MeOH (4 ml). A slurry of 10% Pd/C (30 mg) in MeOH (1 ml) was added under a stream of nitrogen. The mixture was hydrogenated at room temperature at 1 atm. pressure of H2 for 1 h. The reaction mixture was filtered through celite and the filtercake was washed with EtOAc and MeOH. The filtrate was evaporated and the crude product were purified twice by flash chromatography on Si-60-gel using EtOAc:Heptane (1:1) as eluent 1 to remove impurities, and EtOAc to elute the product. The fractions containing the product is evaporated and the residue is trituated with Et2O, the resulting colourless solid was dried to give the title compound. Obtained 20 mg (36% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15][CH2:16][O:17][CH3:18])[C:4]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=[C:26]([O:36][CH2:37][O:38][CH3:39])[C:25]=1[O:40][CH3:41].CN(C)CCN(C)C.C([Li])CCC.[I:55]N1C(=O)CCC1=O>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH3:41][O:40][C:25]1[C:26]([O:36][CH2:37][O:38][CH3:39])=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:30][CH2:31][O:32][CH3:33])[C:24]=1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:4]1[C:5]([O:15][CH2:16][O:17][CH3:18])=[C:6]([O:13][CH3:14])[C:7]([I:55])=[C:8]([O:9][CH2:10][O:11][CH3:12])[C:3]=1[O:2][CH3:1]
Reactant: COCOc1cc(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c1OC
Reactant: O=C1CCC(=O)N1I
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COCOc1cc(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)c(I)c(OC)c2OCOC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1.53 Grams of 2,2'-pentamethylenebis[1,4-dimethoxy-3,6-bis(methoxymethoxy)benzene] was dissolved in a mixed solvent of 40 ml of tetrahydrofuran with 4 ml of hexamethylphosphoric triamide, to this solution was added 0.79 ml of N,N,N',N'-tetramethylethylenediamine, then this mixture was cooled to -78° C. on a dry ice-acetone mixture bath. 3.49 Milliliters of n-butyllithium (1.6 M, n-hexane solution) was added dropwise to the reaction mixture and stirred for 30 minutes. Next, 15 ml of tetrahydrofuran solution containing 1.18 g of N-iodosuccinimide was added dropwise and the reaction mixture was stirred overnight. The solvent was removed under reduced pressure, and the residue obtained was extracted twice with 100 ml of diethyl ether, and the diethyl ether layer was washed twice with 100 ml of water, and washed twice with 100 ml of a saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate. The dried diethyl ether extract was concentrated under reduced pressure, the residue obtained was purified by means of a separative thin layer chromatography (thickness: 2 mm, adsorbent: Merk 5717 silica gel, developing solvent: ethyl acetate-dichloromethane (1:9). There were obtained 685 mg of 1-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]-5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)-4-iodophenyl]pentane, as well as 575 mg of 2,2'-pentamethylenebis[1,4-dimethoxy-3,6-bis(methoxymethoxy)-5-iodobenzene].
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:15]([F:18])([F:17])[F:16])[CH2:13][OH:14])=[CH:8][CH:7]=1)[CH3:4].[O:19]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[O:19]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][O:14][CH2:13][CH:12]([C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:3][CH3:4])=[CH:11][CH:10]=1)[C:15]([F:16])([F:17])[F:18])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOc1ccc(C(CO)C(F)(F)F)cc1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(COCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Reaction time: 14 h
Yield: 55.9 %

Procedure:
Under a nitrogen atmosphere, 132 mg of sodium hydride (60% oil dispersion) was added to 20 ml of dry DMF. A solution of 0.77 g of 2-(4-ethoxyphenyl)-3,3,3-triflouropropanol and 0.69 g of 3-phenoxybenzyl bromide in 5 ml of dry DMF was then added at room temperature, and the reaction solution was stirred at that temperature for 14 hours. Thereafter, the reaction mixture was poured into dilute HCl-ice water and extracted twice with diethyl ether. The ether layers were combined, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure, and the residue was subjected to column chromatography on silica gel [eluted with n-hexane/ethyl acetate (25:1 ) mixture] to obtain 0.61 g of the desired compound.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH2:8]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:40]([O:42][C:43]([CH:45]1[CH2:50][CH2:49][CH:48](O)[CH2:47][CH2:46]1)=[O:44])[CH3:41].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:40]([O:42][C:43]([CH:45]1[CH2:50][CH2:49][CH:48]([O:19][C:16]2[CH:15]=[CH:14][C:13]([C:12](=[O:20])[NH:11][CH:2]3[CH:3]4[CH2:9][CH:7]5[CH2:6][CH:5]([CH2:10][CH:1]3[CH2:8]5)[CH2:4]4)=[CH:18][CH:17]=2)[CH2:47][CH2:46]1)=[O:44])[CH3:41]
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(O)cc1
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(Oc2ccc(C(=O)NC3C4CC5CC(C4)CC3C5)cc2)CC1
Temperature: 0 °C
Reaction time: 48 h
Yield: 31.9 %

Procedure:
To a stirred solution of N-adamantan-2-yl-4-hydroxy-benzamide (6 g, 22.11 mmol) in dry THF (100 mL) was added triphenyl phosphine (8.7 g, 33.17 mmol) and 4-hydroxy cyclo-hexane carboxylic acid ethyl ester (4.57 g, 26.53 mmol). The reaction mixture was cooled to 0° C. and DEAD (5.22 mL, 33.17 mmol) was added dropwise from an addition funnel over a period of 30 min. The reaction was gradually brought to room temperature and stirring continued for 48 hrs. The solvent was removed under vacuum and ether (100 mL) was added and cooled to 0° C. The solid formed was filtered off and the clear filtrate concentrated and purified by column chromatography (Gyan-flash). Desired fractions were collected and the solvent evaporated. The residue was crystallised from diethyl ether and filtered off affording 3 g (32%) of 4-[4-(adamantan-2-ylcarbamoyl)-phenoxy]-cyclohexane carboxylic acid ethyl ester as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH3:2].I[CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:12][CH3:13])[CH3:2]
Reactant: CCOc1ccccc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccccc1OCC
Temperature: 80 °C
Reaction time: 30 h

Procedure:
15.0 g of 2-ethoxyphenol, 18.0 ml of iodoethane and 30.0 g of potassium carbonate were suspended in 150 ml dimethylformamide, and the mixture was stirred at 80° C. for 30 hours. Ethyl acetate was added thereto, and the mixture was washed with water for five times and with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound quantitatively as a red-brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]4[NH:22][N:21]=[C:20]([CH:23]5[CH2:25][CH2:24]5)[N:19]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[N:29][C:28]=1[C@:33]([OH:37])([C:35]#[CH:36])[CH3:34].C(NC(C)C)(C)C>CN(C=O)C>[CH:23]1([C:20]2[N:19]=[C:18]([C:12]3[N:8]4[CH2:9][CH2:10][O:11][C:5]5[CH:4]=[CH:3][C:2]([C:36]#[C:35][C@@:33]([OH:37])([C:28]6[N:29]=[CH:30][CH:31]=[CH:32][N:27]=6)[CH3:34])=[CH:26][C:6]=5[C:7]4=[N:14][C:13]=3[C:15]([NH2:17])=[O:16])[NH:22][N:21]=2)[CH2:25][CH2:24]1
Reactant: C#C[C@@](C)(O)c1ncccn1
Reactant: NC(=O)c1nc2n(c1-c1nc(C3CC3)n[nH]1)CCOc1ccc(Br)cc1-2
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: C[C@@](O)(C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(-c3nc(C4CC4)n[nH]3)n1CCO2)c1ncccn1
Yield: 41.6 %

Procedure:
3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-10-[(3R)-3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was prepared similarly according to General Procedure E with slight modification. 10-bromo-3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was reacted with (2R)-2-pyrimidin-2-ylbut-3-yn-2-ol in a solution of DMF (1.3 mL/mmol) and diisopropylamine (2.6 mL/mmol) to afford 36.7 mg (41.6% yield). M+1=483.2. 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J=4.8 Hz, 2H), 8.57 (d, J=2.2 Hz, 1H), 8.30 (br s, 1H), 7.72 (br s, 1H), 7.49 (t, J=4.8 Hz, 1H), 7.35 (dd, J=8.5, 2.3 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 6.14 (s, 1H), 5.00-4.77 (m, 2H), 4.58-4.50 (m, 2H), 2.13-2.03 (m, 1H), 1.88 (s, 3H), 1.03-0.96 (m, 2H), 0.94-0.86 (m, 2H).