Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[N:9][CH:10]=1.[CH2:23]([O:25][C:26]1[C:30]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][NH:28][N:27]=1)[CH3:24].O>CN(C)C=O>[CH2:23]([O:25][C:26]1[C:30]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][N:28]([CH2:4][C:5]2[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)=[CH:7][CH:6]=2)[N:27]=1)[CH3:24]
Reactant: ClCc1ccc(OCc2ccc3ccccc3n2)nc1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccc4ccccc4n3)nc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of 2-(5-chloromethyl-2-pyridyloxymethyl)quinoline (498 mg), ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (371 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[6-(2-quinolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionate (733 mg, yield: 91%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: C([O:3][C:4](=[O:29])[C@H:5]([CH3:28])[CH2:6][C@H:7]([N:21]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]1=[O:27])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].C1C[O:35]CC1.C(O)C>O>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:13]=[CH:14][C:9]([CH2:8][C@@H:7]([NH:21][C:25](=[O:26])[CH2:24][CH2:23][C:22]([OH:27])=[O:35])[CH2:6][C@@H:5]([CH3:28])[C:4]([OH:3])=[O:29])=[CH:10][CH:11]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)N1C(=O)CCC1=O
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)O)C(=O)O
Reaction time: 16 h

Procedure:
(2R,4S)-5-Biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (590 mg) is added to a mixture of 1 M NaOH (2.75 ml), THF (9 ml) and ethanol (9 ml). The mixture is stirred for 16 h. The mixture is diluted with water (20 ml) and extracted with isopropyl acetate. The water phase is acidified with 1 M HCl (5 ml) and extracted with isopropyl acetate. The combined organic phases are dried (MgSO4) and concentrated in vacuo to give (2R,4S)-5-Biphenyl-4-yl-4-(3-carboxypropionylamino)-2-methyl-pentanoic acid (3-a, R1=4-oxo-pentanoic acid, R2=H, R3=H). 1H NMR (DMSO): 1.05 (2H), 1.35 (1H), 1.79 (1H), 2.29 (2H), 2.39 (3H), 2.70 (2H), 3.97 (1H), 7.25 (2H), 7.34 (1H), 7.44 (2H), 7.56 (2H), 7.63 (2H), 7.74 (1H), 12.01 (2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:35][CH2:36][CH2:37][S:38]([OH:41])(=[O:40])=[O:39]>CN(C=O)C>[C:9]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@H:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:35][CH2:36][CH2:37][S:38]([OH:41])(=[O:40])=[O:39])=[CH:27][CH:28]=2)=[O:30])[C@@H:14]([CH3:31])[CH2:13]1)(=[O:11])[CH3:10]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: O=S(=O)(O)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCS(=O)(=O)O)cc2)c2ccccc21

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (207 mg, 0.481 mmol) was dissolved in DMF (5 mL) at room temperature. NaH (58 mg, 2.40 mmol) was added followed by 3-chloro-propane-1-sulfonic acid (sodium salt, 135 mg, 0.60 mmol) and the reaction was allowed to stir over night. The mixture was partitioned between methylene chloride and HCl (1.0N/water), then extracted three times with methylene chloride, dried over MgSO4, filtered and concentrated. The crude residue was purified by preparatory HPLC to afford the product.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:19][CH2:18][CH:17]([O:20][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCOc1ccc(S(=O)(=O)N2CCC(O)C2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(S(=O)(=O)N2CCC(OS(C)(=O)=O)C2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
To a solution of 1-(4-Butoxy-benzenesulfonyl)-pyrrolidin-3-ol (1.50 g, 5 mmol) in dichloromethane (8 ml) was added triethylamine (0.61 g, 6 mmol) and cooled to 0° C. A solution of methanesulfonyl chloride (0.46 ml, 6 mmol) in dichloromethane (2 ml) was then introduced slowly, and the resulting suspension was stirred at 0° C. for 15 min., and at room temperature for 2 h. The solvent was evaporated, and the residue was stirred with 10 ml of water, 5 ml of saturated sodium carbonate solution, and 20 ml of hexanes. The resulting suspension was filtered, and the precipitate was washed with water and hexanes, and dried to give 1.88 g of a white solid; m.p. 80-81° C.; MS (ES) m/z 377.9 (MH+); HRMS (El) Calcd. for C15H23NO6S2 (M+): 377.0967, Found: 377.0969.
Reaction SMILES: [C@H:1]12[NH:8][C@H:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH:2]2[NH:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]2[NH:18][N:19]=[C:20]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH3:30])[N:25]=[CH:24]4)[C:14]=2[CH2:13]1)=[O:11].[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br.C(N(C(C)C)CC)(C)C>ClCCl>[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][N:8]1[CH:5]2[CH2:6][CH2:7][CH:1]1[CH:2]([NH:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]3[NH:18][N:19]=[C:20]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[N:26]([CH3:30])[N:25]=[CH:24]5)[C:14]=3[CH2:13]1)=[O:11])[CH2:3][CH2:4]2
Reactant: Fc1ccccc1CBr
Reactant: Cn1ncc2cc(-c3n[nH]c4c3CN(C(=O)NC3CC[C@H]5CC[C@@H]3N5)CC4)ccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc2cc(-c3n[nH]c4c3CN(C(=O)NC3CCC5CCC3N5Cc3ccccc3F)CC4)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dichloromethane (1.78 mL) was added to N-((1S,5R)-8-azabicyclo[3.2.1]octan-2-yl)-3-(1-methyl-1H-indazol-5-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide (72.3 mg, 0.178 mmol) in a flask. 2-Fluorobenzylbromide (0.0214 mL, 0.178 mmol) was added to the reaction. At room temperature, diisopropylethylamine (0.0920 mL, 0.534 mmol) was added dropwise to the reaction. The reaction was allowed to stir at room temperature for 1 hr. The reaction was quenched using water, was extracted three times using dichloromethane. The dichloromethane extractions were combined, dried over sodium sulfate, filtered, and concentrated. The crude was further purified using HPLC. The endo and exo products were separated. LC-MS: 514.3 [M+H]. LC/MS RT=2.17 and 2.238 min.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18](O)=[O:19])[CH:8]=1)=[O:5].C([N:39]1[CH2:44][CH2:43][O:42][C@@H:41]([CH2:45][NH2:46])[CH2:40]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH:46][CH2:45][C@@H:41]2[O:42][CH2:43][CH2:44][NH:39][CH2:40]2)=[O:19])[CH:8]=1)=[O:5]
Reactant: NC[C@H]1CN(Cc2ccccc2)CCO1
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: O=C(NC[C@H]1CNCCO1)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The title compound was prepared according to the method described for Example 3 using 5-(2-chloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 105) and (S)-(4-benzylmorpholin-2-yl)methanamine. The residue was dissolved in DCM and treated with 1-chloroethyl chloroformate (37.2 μL, 0.192 mmol) and stirred at room temperature for 4 hours. The reaction was concentrated in vacuo, methanol (4 mL) was added, and the resulting solution stirred for 2 hours at 65° C. The reaction was concentrated in vacuo, and the residue purified by elution through an SCX cartridge followed by silica gel column chromatography eluting with 2% NH3(aq) and 8% propan-2-ol in dichloromethane.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:14]([CH:23]=C)[O:13][C:12]1([CH3:26])[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:27]1CCOCC1>O.[Os](=O)(=O)(=O)=O>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:14]([CH:23]=[O:27])[O:13][C:12]1([CH3:26])[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: C=CC1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC1CCCCC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: CC1(C)OC(C=O)[C@H](CC2CCCCC2)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
960 mg of (4S,5RS)-3-benzyloxycarbonyl-4-cyclohexylmethyl-5-ethenyl-2,2-dimethyloxazolidine was dissolved in 7 ml of dioxane, and 5 ml of dioxane solution containing 35 mg of osmium tetraoxide was added thereto, and reacted for 15 minutes at room temperture in the absence of light. The reaction mixture was diluted with 2.5 ml of water, and 8 ml of a solution containing 1.15 g of sodium periodide was dropwise added over a period of 40 minutes. After the completion of the addition, the mixture was stirred for 1.5 hours at room temperature. Insolubles were filtered off, and the filtrate was diluted with 100 ml of diethyl ether. The diluted filtrate was washed sequentially with a 5% sodium sulfide solution, water and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 992 mg of (4S,5RS)-3-benzyloxycarbonyl-4-cyclohexylmethyl-5-formyl-2,2-dimethyloxazolidine as a colorless oily substance.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([I:23])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([I:22])[CH:16]=1)[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].[Br:24][CH2:25][C:26](Br)=[O:27]>C(OCC)(=O)C>[Br:24][CH2:25][C:26]([NH:7][C@H:6]([C:8]([OH:10])=[O:9])[CH2:5][C:4]1[CH:3]=[C:2]([I:1])[C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([I:22])[CH:16]=2)=[C:12]([I:23])[CH:11]=1)=[O:27]
Reactant: N[C@@H](Cc1cc(I)c(Oc2ccc(O)c(I)c2)c(I)c1)C(=O)O
Reactant: O=C(Br)CBr
Solvent: CCOC(C)=O
Product: O=C(CBr)N[C@@H](Cc1cc(I)c(Oc2ccc(O)c(I)c2)c(I)c1)C(=O)O

Procedure:
According to the present invention a solution of 3,3',5-triiodo-L-thyronine and bromoacetyl bromide in ethyl acetate is refluxed for a period of time to produce the bromoacetylated hormone which is then fractionated by high speed countercurrent chromatography to yield highly pure N-bromoacetyl-3,3',5-triiodo-L-thyronine.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([CH3:11])[S:7]([CH3:10])(=[O:9])=[O:8])#[N:2]>[Pd].N.CO>[NH2:2][CH2:1][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([CH3:11])[S:7]([CH3:10])(=[O:9])=[O:8]
Reactant: CN(Cc1ccccc1C#N)S(C)(=O)=O
Agent: [Pd]
Agent: N
Solvent: CO
Product: CN(Cc1ccccc1CN)S(C)(=O)=O

Procedure:
156 b) To a Paar bottle (250 mL) was added 10% palladium on carbon (50% wet)(1.1 g, 0.52 mmol) followed by a solution of N-(2-cyano-benzyl)-N-methyl-methanesulfonamide (1.28 g, 5.71 mmol) in 7 M of ammonia in methanol (50 mL). The mixture was degassed and charged with Hydrogen (50 psi). The mixture was shaken on a Paar apparatus until adsorption of hydrogen ceased. The mixture was degassed and kept under an atmosphere of nitrogen. The mixture was filtered through a plug of diatomaceous earth, rinsed with dichloromethane and evaporated. N-(2-Aminomethyl-benzyl)-N-methyl-methanesulfonamide was isolated as tan viscous oil (1.28 g, 98%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.41 (d, J=7.4 Hz, 1H), 7.36-7.24 (m, 3H), 4.40 (s, 2H), 3.99 (s, 2H), 2.89 (s, 3H), 2.72 (s, 3H). MS=229 (MH)+.
Reaction SMILES: C([O:5][C:6]([N:8]([CH:17]([CH3:33])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)[O:9]C(OC(C)(C)C)=O)=O)(C)(C)C.F[C:35](F)(F)C(O)=O>C(Cl)Cl>[CH3:33][CH:17]([N:8]([C:6](=[O:5])[CH3:35])[OH:9])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1
Reactant: CC(C=Cc1cccc(Oc2ccccc2)c1)N(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N(O)C(C)/C=C/c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from step (e) (1.97 g) was taken up in methylene chloride (12 ml) and trifluoroacetic acid (3 ml) was added under N2. The mixture was stirred for 1 hour at room temperature and then stripped to give the hydroxylamine as a viscous tan/red oil which was taken up in methylene chloride (5 ml).
Reaction SMILES: [NH3:1].F[C:3]1[N:8]=[C:7]([F:9])[CH:6]=[C:5]([O:10][CH3:11])[N:4]=1>C(OC)(C)(C)C>[NH2:1][C:3]1[N:4]=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([F:9])[N:8]=1
Reactant: COc1cc(F)nc(F)n1
Reactant: N
Solvent: COC(C)(C)C
Product: COc1cc(F)nc(N)n1
Reaction time: 2 h

Procedure:
13.6 g (0.8 mol) of ammonia in 30 ml of methyl tert.-butyl ether were added at -20° to -10° C. to a stirred mixture of 52 g (0.356 mol) of 2,4-difluoro-6-methoxypyrimidine in 300 ml of methyl tert.-butyl ether within 20 minutes. After a further 2 hours at -15° C. and 3 hours at 25° C., the precipitate was filtered off with suction, washed with methyl tert.-butyl ether, stirred with water, filtered off, washed again and subsequently dried, resulting in 36.1 g (71% of theory) of the title compound of melting point 171°-173° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[N:14]1([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH2:26][NH:25][CH2:24][CH2:23]3)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][CH:29]=[C:20]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)[CH:21]=4)[CH2:26]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: c1cc2c(cc1N1CCOCC1)CCNC2
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2cc(N3CCOCC3)ccc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[H-].[Na+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Cl>C1COCC1.CN(C=O)C>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:10])[CH3:1]
Reactant: COc1ccccc1CCl
Reactant: CN(C)CCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccccc1COCCCCCCN(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 97 %

Procedure:
6-Dimethylamino-1-hexanol (8.80 g, 60.6 mmol) was dissolved in 2/1 mixture of THF/DMF (150 mL) and the solution was cooled in an ice/water bath. Sodium hydride (3.25 g, 80.8 mmol, 60% in oil) was added. After 40 min., 2-methoxybenzyl chloride (6.28 g, 40.4 mmol) was added and the solution was allowed to warm to room temperature over 1 h. After 3 h, the reaction was quenched by the addition of 1M NaHSO4. Tetrahydrofuran was removed in vacuo, and the solution was washed with EtOAc. The aqueous phase was basified with 3M NaOH and extracted with ether. The combined ether phases were dried over K2CO3, filtered, and the product was crystallized by the addition of 4M HCl/dioxane to give O-(2-methoxybenzyl)-6-dimethylaminohexanol (10.4 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:70][O:71][CH2:72][CH2:73][NH2:74]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:25](=[O:26])[NH:74][CH2:73][CH2:72][O:71][CH3:70])([CH3:28])[CH3:27])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1
Reactant: COCCN
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)CO)C12C(=O)Nc1cc(Cl)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxy-1,1-dimethyl-ethoxy)-phenyl]-2′-[5-fluoro-2-methylphenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (35 mg, 0.06 mmol), EDCl (18 mg, 0.094 mmol), HOBt (14 mg, 0.094 mmol) and DIPEA (23 mg, 0.2 mmol) in THF (2 mL) was added 2-methoxy-ethylamine (14 mg, 0.18 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (10 mg).
Reaction SMILES: FC(F)(F)C(OC[S:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:22])[CH:15]([CH3:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:10][CH:9]=1)=O>CO.CCN(CC)CC>[SH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14](=[O:22])[CH:15]([CH3:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:13]=1
Reactant: COC(=O)CC(C)C(=O)c1ccc(SCOC(=O)C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CC(C)C(=O)c1ccc(S)cc1
Yield: 97 %

Procedure:
To the neat trifluoroacetate from Step D of this Example (12.3 g) was added a mixture of 1:1 MeOH-NEt3 (600 ml) and the resulting reaction mixture was evaporated under vacuum. The procedure was repeated twice more. The residue was dissolved in CH2Cl2, washed with 1N HCl and brine and dried over Na2SO4. Evaporation of the solvent gave the title compound as an oil (7.8 g, 97%).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@H:7]([S:9][C:10]([CH2:12][C@H:13]2[N:16]([C:17](=O)[C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])[C:15](=[O:32])[C@@H:14]2[C@H:33]([O:35][C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)=[O:37])[CH3:34])=[O:11])[CH2:6][N:5]1[C:49](=[N:51][C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=1)=[O:53])[CH3:50])(=[O:3])[NH2:2].[P:65]([O:74][CH:75]([CH3:77])[CH3:76])([O:70][CH:71]([CH3:73])[CH3:72])[O:66][CH:67]([CH3:69])[CH3:68]>C1(C)C=CC=CC=1>[C:1]([C@@H:4]1[CH2:8][C@H:7]([S:9][C:10]([CH2:12][C@H:13]2[N:16]([C:17]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[P:65]([O:70][CH:71]([CH3:73])[CH3:72])([O:74][CH:75]([CH3:77])[CH3:76])[O:66][CH:67]([CH3:69])[CH3:68])[C:15](=[O:32])[C@@H:14]2[C@H:33]([O:35][C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)=[O:37])[CH3:34])=[O:11])[CH2:6][N:5]1[C:49](=[N:51][C:52]([O:54][CH2:55][C:56]1[CH:57]=[CH:58][C:59]([N+:62]([O-:64])=[O:63])=[CH:60][CH:61]=1)=[O:53])[CH3:50])(=[O:3])[NH2:2]
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(=O)C[C@@H]2[C@@H]([C@@H](C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)N2C(=O)C(=O)OCc2ccc([N+](=O)[O-])cc2)C[C@H]1C(N)=O
Reactant: CC(C)OP(OC(C)C)OC(C)C
Solvent: Cc1ccccc1
Product: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(=O)C[C@@H]2[C@@H]([C@@H](C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)N2C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(OC(C)C)(OC(C)C)OC(C)C)C[C@H]1C(N)=O
Temperature: 90 °C
Yield: 60 %

Procedure:
454 mg (0.5 mmole) of (3S,4R)-4-{[(2S,4S)-2-carbamoyl-1-[N-(p-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-4-ylthio]carbonylmethyl}-3-[1(R)-(p-nitrobenzyloxycarbonyloxy)ethyl]-1-(p-nitrobenzyloxyoxalyl)-2-azetidinone and 520 mg (2.5 mmole) of triisopropyl phosphite were dissolved in 10 ml of toluene. The solution was heated in a stream of a nitrogen gas at 90° C. for 2 hours. The solvent was then distilled off under reduced pressure. The residue was subjected to chromatography using a Lobar column eluted with a 30:10:1 by volume mixture of ethyl acetate, chloroform and methanol, to afford 330 mg (yield 60%) of the title product as an oily substance.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[CH2:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:16]2[CH2:17][CH2:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15]2)=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(OCCCBr)cc1
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCCN2CCc3ccccc3C2)cc1
Reaction time: 24 h
Yield: 73.6 %

Procedure:
A mixture of 1-(3-bromopropoxy)-4-nitrobenzene (10 g), 1,2,3,4-tetrahydroisoquinoline (5.1 g) and potassium carbonate (10.6 g) in DMF (100 ml) was stirred at 70° for 24 h. The mixture was then filtered and the filtrate evaporated. The residue was taken up with water and extracted with dichloromethane. The organic layer was washed with water, dried, evaporated and purified by column chromatography eluting with dichloromethane/methanol (96:4) to give the title compound (8.8 g) as a yellow oil. NMR includes signals at d 3.6 (2H,s,N--CH2Ar), 4.1 (2H,t,O--CH2).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[CH3:8].C([O-])([O-])=O.[K+].[K+].[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:20]=1[CH2:21]Cl>CN(C=O)C.CCOC(C)=O>[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:20]=1[CH2:21][O:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cccc(C)c1CCl
Reactant: Cc1ccc(CC#N)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(CC#N)cc1OCc1c(C)cccc1C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-(3-Hydroxy-4-methylphenyl)acetonitrile (Step A, 2.18 g, 14.8 mmol), K2CO3 (2.66 g, 19.2 mmol) in dry DMF (20 ml) was added 2,6-Dimethylbenzyl chloride (2.97 g, 19.2 mmol) at room temperature under argon. The reaction mixture was stirred for 16 hours, diluted with EtOAc (40 ml), washed with water (20 ml) and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 2:1) to give the title compound as a white solid.