Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]1)#[N:2].[BH4-].[Na+].Cl>CO>[NH2:2][CH2:1][CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][CH2:11]1
Reactant: CCOC(=O)N1CCN(CCCC#N)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCN(CCCCN)CC1
Yield: 14.7 %

Procedure:
A solution of 200 g of ethyl 4-(3-cyanopropyl)-piperazine-1-carboxylate and 20 g of cobaltous chloride hexahydrate in 2 liters of methanol was cooled in ice and 125 g of sodium borohydride were added in portions with stirring at a temperature of less than 10° C. When the addition was complete, the mixture was stirred at 20° C. for 16 hours and then ~300 ml of concentrated HCl were added thereto until the black suspension turned blue. The solvent was removed under vacuum and the residue was dissolved in 2 liters of water and filtered. The filtrate was adjusted to a pH of 8 with potassium carbonate and was washed with 200 ml of carbon tetrachloride to remove non-polar impurities. The pH of the solution was increased to 9-10 by the addition of more potassium carbonate and then was saturated with sodium chloride. The mixture was extracted 6 times with 250 ml of chloroform and the combined extracts were dried over MgSO4 and evaporated to dryness to obtain 30 g of ethyl 4-(4-aminobutyl)-piperazine-1-carboxylate in the form of a light brown oil which was distilled under reduced pressure to give a pure fraction with a boiling point of 135°-140° C. at 0.3 mm Hg.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:20][O:21][CH2:22][CH2:23][NH2:24]>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH2:16][NH:24][CH2:23][CH2:22][O:21][CH3:20])=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COCCN
Reactant: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Product: COCCNCc1ccc(C(=O)N2CCN(C(C)C)CC2)cc1

Procedure:
Prepared from the product of Example 15 and (2-methoxy-ethyl)-amine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[C:5]([OH:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[CH3:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:19]=O>>[CH2:25]([O:24][C:23]1[CH:22]=[CH:21][C:18](/[CH:19]=[CH:10]/[C:8]([C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=2[OH:11])=[O:9])=[CH:17][C:16]=1[CH3:15])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)c1cc(C)cc([N+](=O)[O-])c1O
Reactant: Cc1cc(C=O)ccc1OCc1ccccc1
Product: Cc1cc(C(=O)/C=C/c2ccc(OCc3ccccc3)c(C)c2)c(O)c([N+](=O)[O-])c1
Yield: 66.2 %

Procedure:
2-Hydroxy-5-methyl-3-nitroacetophenone (345 mg, 1.76 mmol) and 3-methyl-4-benzyloxybenzaldehyde (400 mg, 1.76 mmol) were reacted according to the same procedure as Preparation 22 to give 470 mg (Yield 66%) of the title compound.
Reaction SMILES: [C:1]([C:3]([NH:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH3:4])#[N:2]>N.[Ni]>[NH2:2][CH2:1][C:3]([NH:11][C:12](=[O:21])[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)([CH3:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: COc1ccc(C(=O)NC(C)(C#N)c2ccccn2)cc1
Agent: [Ni]
Agent: N
Product: COc1ccc(C(=O)NC(C)(CN)c2ccccn2)cc1
Temperature: 40 °C

Procedure:
N-[-1-cyano-1-(2-pyridinyl)ehtyl]-4-methoxy-benzamide (4.7 g, 0.0167 mole) was dissolved in 100 mL methanolic ammonia and treated with 1.5 g Raney nickel under 50 psi and warmed to 40° C. for 10 hours. The mixture was filtered and the supernate concentrated in vacuo to yield a pale green oil. The crude product (2.3 g) was used in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][C:6]1[O:30][C:9]2[CH2:10][N:11]([C:14](=[O:29])[C:15]3[CH:20]=[CH:19][C:18]([C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[CH2:12][CH2:13][C:8]=2[CH:7]=1)[CH3:4].[BH4-].[Na+].[OH-].[Na+]>CO>[CH3:4][N:3]([CH2:5][C:6]1[O:30][C:9]2[CH2:10][N:11]([C:14]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[OH:28])=[CH:17][CH:16]=3)=[O:29])[CH2:12][CH2:13][C:8]=2[CH:7]=1)[CH3:2]
Reactant: CN(C)Cc1cc2c(o1)CN(C(=O)c1ccc(C(=O)c3ccccc3)cc1)CC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1cc2c(o1)CN(C(=O)c1ccc(C(O)c3ccccc3)cc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.196 g (0.461 mmol) of N,N-dimethyl-[6-(4-benzoylbenzoyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-2-ylmethyl]amine hydrochloride in 10 ml of methanol, 70 mg (1.9 mmol) of sodium borohydride was added under ice-cooling, followed by overnight stirring at room temperature. Aqueous sodium hydroxide was added, followed by 3 extractions with dichloromethane. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure to yield the desired product.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:9]2[C:10](=[O:15])[O:11][C:12](=O)[NH:13][C:8]=2[CH:7]=[C:6]([C:16]([F:19])([F:18])[F:17])[CH:5]=1.C(OCC)C>CO>[NH2:13][C:8]1[CH:7]=[C:6]([C:16]([F:17])([F:18])[F:19])[CH:5]=[C:4]([Cl:3])[C:9]=1[C:10]([O:11][CH3:12])=[O:15]
Reactant: O=c1[nH]c2cc(C(F)(F)F)cc(Cl)c2c(=O)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1c(N)cc(C(F)(F)F)cc1Cl
Temperature: 60 °C
Yield: 87.3 %

Procedure:
To a stirred solution of sodium hydroxide (0.012 g, 0.31 mM) in anhydrous methanol (1.5 mL) under a nitrogen atmosphere was added 5-chloro-7-trifluoromethyl-2H-3,1-benzoxazine-2,4(1H)-dione (0.60 g, 2.3 mM). The resulting mixture was warmed to 60° C. for 0.5 hr, allowed to cool to room temperature and poured into diethyl ether. The ether was washed with water, dried (MgSO4), filtered and concentrated to leave (0.50 g, 88%) the title compound as a yellow oil; MS(CI): 254 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl-].[Li+].[F:13][C:14]([F:27])([F:26])[C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/B(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO>[F:13][C:14]([F:26])([F:27])[C:15]1[CH:16]=[CH:17][C:18]([CH:21]=[CH:22][C:2]2[CH:3]=[C:4]3[CH:10]=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)=[CH:19][CH:20]=1
Reactant: OB(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: FC(F)(F)c1ccc(C=Cc2cnc3[nH]ccc3c2)cc1
Temperature: 105 °C
Yield: 45.4 %

Procedure:
To a solution of bromide 27 (76 mg, 0.39 mmol), lithium chloride (49 mg, 1.16 mmol), trans-2[4-(trifluoromethyl)-phenyl]vinyl boronic acid (125 mg, 0.58 mmol) in a mixture of toluene (3 mL), EtOH (3 mL) and 1 M aqueous Na2CO3 solution (0.96 mL, 0.96 mmol) was added (PPh3)2PdCl2 (27 mg, 0.04 mmol) in one portion. The mixture was heated in the dark to 105° C. under a nitrogen atmosphere for 20 h, filtered through a pad of cotton wool and concentrated. The residue was purified by PTLC with CH2Cl2:MeOH=98:2 as eluent to afford styrene 28 (51 mg, 46%) as a pale yellow solid. 1H NMR (400 MHz; CDCl3) δ 6.55 (dd, J=2.0, 3.5 Hz, 1H), 7.15 (d, J=16.3 Hz, 1H), 7.31 (d, J=16.3 Hz, 1H), 7.35 (m, 1H), 7.62 (s, 4H), 8.13 (d, J=1.8 Hz, 1H), 8.50 (m, 1H), 9.17 (br s, NH).
Reaction SMILES: [O:1]=[C:2]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.[NH2:15][C:16]1[CH:32]=[CH:31][CH:30]=[CH:29][C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[O:19]>>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:18](=[O:19])[C:17]2[CH:29]=[CH:30][CH:31]=[CH:32][C:16]=2[NH:15][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:26][CH:25]=1
Reactant: O=C(O)CCCC(=O)N1CCOCC1
Reactant: COc1ccc(NC(=O)c2ccccc2N)cc1
Product: COc1ccc(NC(=O)c2ccccc2NC(=O)CCCC(=O)N2CCOCC2)cc1

Procedure:
Using the procedure described in Example 161, 5-oxo-5-morpholinopentanoic acid (166 mg, 0.826 mmol) and 2-amino-N-(4-methoxyphenyl)benzamide yielded, after recrystallization from ethyl acetate/hexanes, 220 mg (63%) of the title compound as a white amorphous solid.
Reaction SMILES: [C:1]1([Si:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:28]([CH3:31])([CH3:30])[CH3:29])[O:8][C:9]2[CH:10]=[C:11]([CH:15]([OH:27])[CH2:16][CH2:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20]([OH:22])=[O:21])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:38]([O-])([O-])=O.[K+].[K+].CI.CCOC(C)=O>CC(C)=O>[C:32]1([Si:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:28]([CH3:30])([CH3:31])[CH3:29])[O:8][C:9]2[CH:10]=[C:11]([CH:15]([OH:27])[CH2:16][CH2:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20]([O:22][CH3:38])=[O:21])[CH:12]=[CH:13][CH:14]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)[Si](Oc1cccc(C(O)CCc2ccccc2C(=O)O)c1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1ccccc1CCC(O)c1cccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To the product of Example 2, Step 1 (95 g, 0.187 mol) in acetone (1 L) was added K2CO3 (55 g, 0.374 mol) and MeI (128 mL, 1.31 mol). After refluxing for 1.5 h, the reaction mixture was cooled to r.t. EtOAc (1 L) was then added to the reaction mixture and the K2CO3 was removed by filtration. The filtrate was evaporated to dryness to provide 93 g (98%) of the title ester.
Reaction SMILES: [ClH:1].C[O:3][C:4]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][C:5]=1[CH2:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([NH2:13])[C@@H:8]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.OC1C=CC(OC(F)(F)F)=CC=1C=O>>[ClH:1].[OH:3][C:4]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:20][C:5]=1[CH2:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([NH2:13])[C@@H:8]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(OC(F)(F)F)cc1C[C@@H]1CCCN(N)[C@@H]1c1ccccc1
Agent: Cl
Agent: O=Cc1cc(OC(F)(F)F)ccc1O
Product: NN1CCC[C@@H](Cc2cc(OC(F)(F)F)ccc2O)[C@H]1c1ccccc1

Procedure:
The title compound was prepared in a manner similar to the compound of Example 4 by replacing 2-methoxy-5-trifluoromethoxybenzaldehyde with 2-hydroxy-5-trifluoromethoxybenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](/[C:15](/[CH3:33])=[CH:16]/[CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([O:30][CH2:31][CH3:32])[C:27]([O-:29])=[O:28])=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12](/[C:15](/[CH3:33])=[CH:16]/[CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([O:30][CH2:31][CH3:32])[C:27]([OH:29])=[O:28])=[CH:21][CH:20]=3)=[CH:13][CH:14]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(Cl)cc(Cl)c3)cc2)cc1)C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(Cl)cc(Cl)c3)cc2)cc1)C(=O)O
Yield: 86.9 %

Procedure:
The title compound was prepared from (E)-(S)-ethyl 3-{4-[3-(3′,5′-dichloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate (example 125) (513 mg, 1.0 mmol) and sodium hydroxide (1M, 5.0 ml, 5.0 mmol) by a procedure analogous to that described in example 51, yielding (E)-(S)-3-{4-[3-(3′,5′-dichloro-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid (422 mg, 87%) as a colourless glass.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][C:15]1[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=1)[C:5]2=[O:28].C(N(C(C)C)CC)(C)C.[F:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][C:46]#[CH:47])=[CH:41][CH:40]=1.O>CN(C=O)C.[Cu]I>[F:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][C:46]#[C:47][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])=[CH:17][CH:16]=2)[C:5]3=[O:28])=[CH:41][CH:40]=1
Reactant: C#CCc1ccc(F)cc1
Reactant: Cn1c(=O)n(Cc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)c2cc(I)ccc21
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n(Cc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)c2cc(C#CCc3ccc(F)cc3)ccc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To 1.0 g (2.0 mmol) 3-(3,4-Difluoro-benzyl)-6-iodo-1-methyl-1H-quinazoline-2,4-dione from Example 14 Step 1 and 1.0 g (8.4 mmol) di-isopropyl ethylamine in 15 ml DMF is added bis-triphenylphosphine palladium di-chloride (catalytic) followed by CuI (catalytic). 0.44 g (3.3 mmol) 1-fluoro-4-prop-2-ynyl-benzene is added and the mixture is heated to 70° C. for 6 hrs. The mixture is allowed to cool to room temperature and stir overnight. Water is added and the mixture stirred 30 minutes. Filtered and dry under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].[C:11](OC(=O)C)(=[O:13])[CH3:12].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([NH:1][C:11](=[O:13])[CH3:12])[C:3]=1[CH2:4][OH:5]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(N)c1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Nc1cccc(C)c1CO
Reaction time: 3 h
Yield: 64.6 %

Procedure:
To a suspension of 2-amino-6-methylbenzyl alcohol (30 g) in methylene chloride (300 ml) was added dropwise acetic anhydride (22.3 g) at 5° to 10° C. After being stirred for 3 hours, the mixture was neutralized with sodium bicarbonate aqueous solution to give precipitates. To said mixture was added chloroform to dissolve said precipitates and then the organic layer was washed with water and sodium chloride aqueous solution, dried over magnesium sulfate and evaporated in vacuo. The resultant residue was suspended in diethyl ether and the precipitates were collected by filtration to give 2-methyl-6-acetamidobenzyl alcohol (25.30 g).
Reaction SMILES: [CH:1]1([S:6]([C:9]2[CH:10]=[C:11]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][C@@H:30]([C:32]4[CH:43]=[CH:42][C:35]5[O:36][C:37]([CH3:41])([CH3:40])[O:38][CH2:39][C:34]=5[CH:33]=4)[O:29][C:28]3=[O:44])[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CCOC(C)=O.CCO.[Pt]=O>[CH:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][C@@H:30]([C:32]4[CH:43]=[CH:42][C:35]5[O:36][C:37]([CH3:40])([CH3:41])[O:38][CH2:39][C:34]=5[CH:33]=4)[O:29][C:28]3=[O:44])[CH:12]=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCC#Cc4cccc(S(=O)(=O)C5CCCC5)c4)C(=O)O3)ccc2O1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCCCc4cccc(S(=O)(=O)C5CCCC5)c4)C(=O)O3)ccc2O1
Yield: 92.4 %

Procedure:
A solution of (5R)-3-[6-({5-[3-(cyclopentylsulfonyl)phenyl]-4-pentyn-1-yl}oxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (215 mg) in EtOAc (10 ml) and EtOH (10 ml) was hydrogenated over platinum oxide (30 mg). When hydrogen uptake had ceased the mixture was filtered through celite and the solvent was evaporated in vacuo to give the title compound (200 mg). LCMS RT=3.83 min.
Reaction SMILES: [CH:1]12[N:8]([C:9]3[CH:32]=[CH:31][C:12]([CH2:13][NH:14][C:15]([NH:17][C:18]4[CH:26]=[CH:25][CH:24]=[C:23]5[C:19]=4[CH:20]=[N:21][N:22]5C(OC)=O)=[O:16])=[C:11]([Cl:33])[CH:10]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[OH-].[Na+]>CO>[CH:5]12[N:8]([C:9]3[CH:32]=[CH:31][C:12]([CH2:13][NH:14][C:15]([NH:17][C:18]4[CH:26]=[CH:25][CH:24]=[C:23]5[C:19]=4[CH:20]=[N:21][NH:22]5)=[O:16])=[C:11]([Cl:33])[CH:10]=3)[CH:1]([CH2:7][CH2:6]1)[CH2:2][CH2:3][CH2:4]2
Reactant: COC(=O)n1ncc2c(NC(=O)NCc3ccc(N4C5CCCC4CC5)cc3Cl)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCc1ccc(N2C3CCCC2CC3)cc1Cl)Nc1cccc2[nH]ncc12
Reaction time: 0.5 h

Procedure:
Methyl 4-[({[4-(8-azabicyclo[3.2.1]oct-8-yl)-2-chlorobenzyl]amino}carbonyl)amino]-1H-indazole-1-carboxylate (803 mg, 1.72 mmol) in methanol (40 mL) was treated with 1.2N NaOH in MeOH (20 mL). After stirring for 30 minutes, the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated NaHCO3 solution. The separated aqueous phase was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (7% to 10% MeOH/CH2Cl2) to provide the title compound as a solid. The obtained solid was treated with ethanolic HCl followed by precipitation with diethyl ether to provide the hydrochloride salt. 1H NMR (300 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.16 (s, 1H), 7.65 (d, 1H, J=7.5 Hz), 7.27 (d, 1H, J=8.5 Hz), 7.19 (t, 1H, J=8.1 Hz), 7.05 (d, 1H, J=8.5 Hz), 6.87 (m, 2H), 6.79 (m, 1H), 4.29 (m, 2H), 4.21 (m, 2H), 2.05-1.65 (m, 7H), 1.40 (m, 1H), 1.26 (m, 2H); MS (ESI) 410 (M+H)+; Anal. Calcd for C22H24ClN5O.1.6HCl: C, 56.43; H, 5.51; N, 14.96. Found: C, 56.30; H, 5.29; N, 14.81.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.CCCCCC.C([Li])CCC.[CH3:21][C:22]([CH3:24])=[O:23]>>[OH:23][C:22]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)([CH3:24])[CH3:21]
Reactant: c1ccc2occc2c1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC(C)(O)c1cc2ccccc2o1
Temperature: -50 °C
Reaction time: 0.08 h

Procedure:
1.00 g of benzofuran was dissolved in 20 ml of anhydrous tetrahdyrofuran. Thereto was dropwise added 6.2 ml of 1.5 M n-butyllithium hexane solution, in 5 minutes with stirring at -50° C. The mixture was stirred at 0° C. for 30 minutes and then cooled to -50° C. Thereto was added 0.94 ml of acetone. The resulting mixture was stirred at room temperature for 30 minutes. The solvent was removed by distillation under reduced pressure. The residue was mixed with 30 ml of chloroform and 10 ml of water to dissolve the residue. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 1.50 g of 2-(1-hydroxy-1-methylethyl)benzofuran as a colorless oily material.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[C:8]([O:11][C:12]3[CH:21]=[CH:20][N:19]=[C:18]4[C:13]=3[C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16](=[O:22])[NH:17]4)[CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]=[C:35]=[O:36])[CH:29]=1.CCN(C(C)C)C(C)C>O1CCOCC1.O.CCOC(C)=O>[Cl:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]([N:4]2[C:5]3[CH:10]=[CH:9][C:8]([O:11][C:12]4[CH:21]=[CH:20][N:19]=[C:18]5[C:13]=4[C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16](=[O:22])[NH:17]5)=[CH:7][C:6]=3[O:1][CH2:2][CH2:3]2)=[O:36])[CH:31]=[CH:32][CH:33]=1
Reactant: O=c1[nH]c2nccc(Oc3ccc4c(c3)OCCN4)c2c2ccccc12
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1cccc(Cl)c1)N1CCOc2cc(Oc3ccnc4[nH]c(=O)c5ccccc5c34)ccc21
Yield: 22.9 %

Procedure:
Compound 218 (25 mg, 0.07 mmol), 1-chloro-3-isocyanato-benzene (17 mg, 0.11 mmol), and DIEA (0.04 mL, 0.22 mmol) were dissolved in dioxane (2 mL) and stirred and stirred for 30 minutes at 100° C. in microwave. The reaction mixture was diluted with H2O/EtOAc, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 50 to 100% EtOAc in hexanes to provide 221 (8 mg, 22% yield) as a tan solid. LC-MS (M+H=499, obsd.=499).
Reaction SMILES: [N+](CCC(CC)C(O)=O)([O-])=O.[NH2:12][C@H:13]([C:21]([O:23]C)=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.OS([O-])(=O)=O.[Na+]>ClCCl.CN(C1C=CN=CC=1)C>[NH2:12][C@H:13]([C:21]([OH:23])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CCC(CC[N+](=O)[O-])C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
γ-Nitro-α-ethylbutyric acid 3 (97 mg, 0.6 mmol) was dissolved in dry dichloromethane (20 ml). Then L-Phe-OMe.HCl (142 mg, 0.66 mmol), EDCI.HCl (138 mg, 0.72 mmol), DIEA (128 μL, 0.72 mmol) and catalytic amount of DMAP were successively added. The mixture was stirred 24 h at room temperature, then was acidified with aqueous NaHSO4, extracted with EtOAc (3×). The organic layers were washed with saturated NaHCO3 and brine. The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified via column chromatography eluted with EtOAc/hexane to give L-phenylalanine derivative 7 as a while solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][C:10]=2[O:18][CH3:19])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[C:42]([O:43][CH3:44])=[CH:41][C:25]2[CH2:26][CH2:27][N:28]([CH2:31][C:32]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[O:33])[CH2:29][CH2:30][C:24]=2[CH:23]=1>>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][C:10]=2[O:18][CH3:19])=[N:7][C:2]([NH:21][C:22]2[C:42]([O:43][CH3:44])=[CH:41][C:25]3[CH2:26][CH2:27][N:28]([CH2:31][C:32]([N:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)=[O:33])[CH2:29][CH2:30][C:24]=3[CH:23]=2)=[N:3][CH:4]=1
Reactant: COc1cc(N(C)C)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N1CCN(C)CC1)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N(C)C)cc3OC)n1)CCN(CC(=O)N1CCN(C)CC1)CC2
Yield: 43 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from N(1)-(2,5-Dichloro-pyrimidin-4-yl)-2-methoxy-N(4),N(4)-dimethyl-benzene-1,4-diamine and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1-(4-methyl-piperazin-1-yl)-ethanone. Product isolated as a grey foam (50 mg, 43%). mp: 145° C. (glass @ 83), MS (ESI+): 609.5 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.13 (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 7.40 (s, 1H), 7.28 (s, 1H), 6.64 (s, 1H), 6.37 (s, 1H), 6.34 (s, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 3.74 (m, 2H), 3.67 (m, 2H), 3.28 (s, 2H), 2.99 (s, 6H), 2.87 (m, 2H), 2.81 (m, 2H), 2.66 (m, 4H), 2.46 (m, 2H), 2.41 (m, 2H), 2.34 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:15][C:16]([OH:20])([C:18]#[CH:19])[CH3:17].C(OCC)(=O)C>COCCOC.[Cu]I>[CH3:15][C:16]([OH:20])([C:18]#[C:19][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH3:17]
Reactant: C#CC(C)(C)O
Reactant: Brc1cccnc1
Agent: [Cu]I
Solvent: COCCOC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(O)C#Cc1cccnc1
Temperature: 0 °C
Yield: 40 %

Procedure:
3-Bromopyridine (3.0 mL, 31 mmol), triethylamine (22 mL, 160 mmol), CuI (1.2 g, 6.2 mmol), and PdC2(PPh3)2 (1.1 g, 1.5 mmol) were combined in DME (92 mL) and cooled to 0° C. 2-Methyl-3-butyne-2-ol (9.0 mL, 93 mmol) was then added and the reaction was allowed to slowly warm to ambient temperature. The mixture was then heated to 55-60° C. for 16 h. The mixture was filtered through Celite™, and the pad was washed thoroughly with ethyl acetate. The combined filtrates were washed with brine (3×100 mL), dried over MgSO4, and filtered. The solution was concentrated in vacuo, and the residue was purified by column chromatography eluting with 90:10 hexane:ethyl acetate then ethyl acetate to afford 2-methyl-4-(3-pyridinyl)-3-butyn-2-ol (2.0 g; 40% yield) as a brown oil 1H NMR (CDCl3, 300 MHz) δ 8.76 (br s, 1H), 8.52 (br s, 1H), 7.74-7.70 (m, 1H), 4.08 (br s, 1H), 1.63 (s, 3H). MS (EI ionization) 161 (M+).