Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[H-].[Na+].Cl[CH:22]([C:28](=[O:31])[CH2:29][CH3:30])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1(C)C=CC=CC=1.O.C(O)(=O)C>[CH2:1]([C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][CH:22]([C:28](=[O:31])[CH2:29][CH3:30])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCc1cccc(O)c1
Reactant: CCOC(=O)C(Cl)C(=O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCc1cccc(OC(C(=O)CC)C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.4 %

Procedure:
A mixture of 7.0 grams (0.028 mole) of 3-undecylphenol (prepared in Steps A-C of this Example) and 1.1 grams (0.028 mole) of 60% sodium hydride (in mineral oil) in 100 mL of toluene was stirred for about 20 minutes, and 4.2 grams (0.028 mole) of ethyl 2-chloro-3-oxopentanoate (prepared in Step D of this example) was added dropwise during about a 12 minute period. Upon completion of addition, the reaction mixture was heated to reflux, where it was stirred for about 6.5 hours. After this time, the reaction mixture was allowed to cool to ambient temperature, where it stood for about 16 hours. The reaction mixture was then taken up in 50 mL of water and 5 mL of acetic acid. The mixture was washed with an additional 50 mL of water and then with 25 mL of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 8.9 grams of ethyl 2-(3-undecylphenoxy)-3-oxopentanoate. The NMR spectrum was consistent with the proposed structure.
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]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[NH2:26][CH2:27][CH2:28][CH2:29][OH:30]>>[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]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[NH:26][CH2:27][CH2:28][CH2:29][OH:30])=[O:13])[CH2:8]2
Reactant: NCCCO
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1NCCCO

Procedure:
5-(3-Hydroxy-propylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and 3-amino-1-propanol. Mass spectrum (ES) MH+=395.
Reaction SMILES: [C:1]1([C:7]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:24]1([CH2:30][CH2:31]O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[C:1]1([C:7]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:31][CH2:30][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:21][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCN1CCCCC1
Reactant: Oc1ccc(C2=C(c3ccccc3)Sc3ccccc3O2)cc1
Product: c1ccc(C2=C(c3ccc(OCCN4CCCCC4)cc3)Oc3ccccc3S2)cc1

Procedure:
The entitled compound was obtained according to the method of Example 3 but using 4-(3-phenyl-1,4-benzoxathiin-2-yl)phenol synthesized in Reference Example 1-1 and 2-piperidin-1-ylethanol as the starting material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:5][C:4]=1[CH2:21][CH2:22][C:23]([O:25]C)=[O:24].[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:20])[C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[CH:5][C:4]=1[CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: COC(=O)CCc1cc(C(=O)c2ccc(OC)cc2)c(OC)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C(=O)c2cc(CCC(=O)O)c(OC)cc2OC)cc1
Reaction time: 8 h

Procedure:
60.9 g of methyl 3-[2,4-dimethoxy-5-(4-methoxybenzoyl)phenyl]propionate are mixed with 300 ml of 2N sodium hydroxide solution and 300 ml of dioxane and stirred overnight. The dioxane is then removed in vacuo, and the alkaline aqueous solution is extracted once with 100 ml of ethyl acetate. The aqueous phase is adjusted to pH 2 with concentrated hydrochloric acid, when part of the product separates out. The mixture is extracted three times with 200 ml of ethyl acetate each time, and the organic phase is washed with water, dried over sodium sulfate and concentrated. The residue is recrystallized from ethyl acetate/acetone/hexane.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:38][C:39]([F:49])([F:48])[C:40]1[CH:47]=[CH:46][C:43]([CH2:44]Cl)=[CH:42][CH:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:44][C:43]2[CH:42]=[CH:41][C:40]([C:39]([F:38])([F:48])[F:49])=[CH:47][CH:46]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccc(C(F)(F)F)cc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 87.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 4-(trifluoromethyl)benzyl chloride (0.48 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-trifluoromethylphenyl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.84 g) was obtained.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH2:4][CH2:3]1.Cl[C:13]1[N:18]=[CH:17][C:16]([B:19]([OH:21])[OH:20])=[CH:15][N:14]=1>>[S:8]([CH:5]1[CH2:6][CH2:7][N:2]([C:13]2[N:18]=[CH:17][C:16]([B:19]([OH:21])[OH:20])=[CH:15][N:14]=2)[CH2:3][CH2:4]1)(=[O:10])(=[O:9])[NH2:11]
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: NS(=O)(=O)C1CCNCC1
Agent: Cl
Product: NS(=O)(=O)C1CCN(c2ncc(B(O)O)cn2)CC1

Procedure:
Prepared from piperidine-4-sulfonamide hydrochloride (1.27 g, 6.315 mmol) and (2-chloropyrimidin-5-yl)boronic acid (1 g, 6.32 mmol) in accordance with General Method C to give the title compound as an off-white semi-solid. HPLC-MS: m/z (M−H)+ 285.1, RT 0.14 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:13])[CH2:8][S:9][CH2:10]2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:24][C:25]([F:34])([F:33])[C:26](C1NC=CN=1)=[O:27].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:13])[CH:8]([C:26](=[O:27])[C:25]([F:34])([F:33])[F:24])[S:9][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(c1ncc[nH]1)C(F)(F)F
Reactant: COc1ccc2c(c1)CSCC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CSC(C(=O)C(F)(F)F)C2=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
7-Methoxyisothiochroman-4-one from Step 3 (0.58 g, 3.0 mmol) was dissolved in tetrahydrofuran (30 mL) and cooled to -78° C. A solution of sodium bistrimethylsilylamide (3.0 mL of a 1.0M tetrahydrofuran solution) was added and the reaction stirred for 0.5 hours at -78° C. Trifluoroacetyl imidazole (0.41 mL, 3.6 mmol) was added and the reaction was warmed to room temperature and stirred under a nitrogen atmosphere for 16 hours. At this time, 1N hydrochloric acid (200 mL) was added to the reaction followed by extraction with ether (250 mL). The organics were washed with brine (150 mL), dried over MgSO4 and concentrated in vacuo. The resulting yellow oil (0.42 g, 48%) was used without further purification.
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[F:8][C:9]([F:21])([F:20])[C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][CH2:15][C:16]2=O)=[CH:12][CH:11]=1>C1COCC1.C(O[Ti](OCC)(OCC)OCC)C>[CH3:1][C:2]([S@:5]([N:7]=[C:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([C:9]([F:8])([F:20])[F:21])[CH:18]=2)[CH2:14][CH2:15]1)=[O:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=C1CCc2ccc(C(F)(F)F)cc21
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N=C1CCc2ccc(C(F)(F)F)cc21
Temperature: 75 °C

Procedure:
To a stirred solution of (R)-2-methylpropane-2-sulfinamide (578 mg, 4.77 mmol) and 6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one (1000 mg, 5.00 mmol) in THF (4 mL) at rt was added tetraethoxytitanium (1.88 mL, 9.08 mmol). The reaction mixture was heated at 75° C. overnight. The reaction mixture was allowed to cool and used directly in the next step. LC-MS (ESI) 304.0 (M+H), RT=2.20 min (Method B).
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[C:11]1(=[O:18])[O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C1C=CC=CC=1)([O-])=O>[CH3:4][O:3][C:2]1[CH:5]=[C:6]([C:11](=[O:18])[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:7]=[CH:8][C:1]=1[O:9][CH3:10]
Reactant: COc1ccccc1OC
Reactant: O=C1CCCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)CCCC(=O)O)cc1OC
Reaction time: 18 h

Procedure:
A solution containing 36 g of veratrole and 30 g glutaric anhydride in 120 ml of nitrobenzene was gradually added while stirring and cooling at 0° C. to a mixture of 72 g of anhydrous aluminium chloride and 240 ml of nitrobenzene. The mixture was stirred for 1 h at 0° C. and then for 18 h at 20° C. Ice and hydrochloric acid were added to thereaction mixture. Nitrobenzene layer was separated and to this ethyl acetate was added whereupon the product crystallized. After filtering the crystals were washed with ethyl acetate. Yield 42.3 g (64%).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([CH:5]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][CH2:6]1)=[O:4].CO.[H][H]>[Pd]>[CH3:1][N:2]([CH3:21])[C:3]([CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)=[O:4]
Reactant: [H][H]
Reactant: CN(C)C(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)C1CCNCC1

Procedure:
Palladium (10.0 mg, 9.40 E-6 mol) was added to a solution of benzyl 4-[(dimethylamino)carbonyl]piperidine-1-carboxylate (190.0 mg, 0.0006544 mol) in methanol (5.0 mL, 0.12 mol) under nitrogen. The mixture was hydrogenised with a balloon filled with hydrogen for 3 h. The mixture was filtered and the filtrate was concentrated to give the desired product.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([O:30][CH3:31])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[C-:32]#[N:33].[Na+]>CS(C)=O>[CH3:31][O:30][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[C:15]2[O:14][CH:13]([CH2:12][C:32]#[N:33])[CH2:17][C:16]=2[CH:18]=1
Reactant: COc1cc2c(c(-c3ccccc3OC)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc2c(c(-c3ccccc3OC)c1)OC(CC#N)C2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of (±)-[5-methoxy-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.25 g, 0.57 mmol) in dimethylsulfoxide (20 mL) was added sodium cyanide (0.07 g, 1.43 mmol) and the reaction mixture was allowed to stir at 50° C. for 1 h. The reaction was quenched by the addition of water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organics were washed with water (3×20 mL), saturated aqueous sodium chloride (20 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:8) gave (±)-[5-methoxy-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]acetonitrile as a colorless oil. The oil was dissolved in ethanol (30 mL), 28% aqueous ammonium hydroxide (20 mL), and treated with rhodium on alumina (0.1 g, 5 wt. %) generally according to procedure described for Example 1 to afford 0.025 g (13%) of (±)-{2-[5-methoxy-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]ethyl}amine as a yellow solid, hydrochloride salt. mp 240-242° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([CH3:16])[CH:3]=1.O.[CH:18]1(B(O)O)[CH2:20][CH2:19]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH:18]1([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([CH3:16])[CH:3]=2)[CH2:20][CH2:19]1
Reactant: OB(O)C1CC1
Reactant: Cc1cc(I)ccc1NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C2CC2)ccc1NC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 15 h
Yield: 86.5 %

Procedure:
A mixture of tert-butyl (4-iodo-2-methylphenyl)carbamate (1.04 g), cyclopropylboronic acid monohydrate (422 mg), palladium(II) acetate (35.1 mg), tricyclohexylphosphine (87.5 mg), tripotassium phosphate monohydrate (2.52 g), toluene (8.7 mL), and water (0.87 mL) was stirred at 100° C. for 15 hours. The reaction mixture was left to cool and then diluted with ethyl acetate and filtered through Celite (registered trademark). The filtrate was washed with brine and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (668 mg). 1H-NMR (CDCl3) δ ppm: 0.55-0.70 (2H, m), 0.80-1.00 (2H, m), 1.51 (9H, s), 1.75-1.90 (1H, m), 2.21 (3H, s), 5.85-6.45 (1H, br), 6.75-7.00 (2H, m), 7.45-7.75 (1H, m).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:32]5[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]5)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: C1CNCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN5CCNCC5)c4)cc23)CC1
Yield: 19.6 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (15.0 mg, 0.034 mmol), piperazine (3.5 mg, 0.04 mmol) and NaBH(OAc)3 (23.0 mg, 0.102 mmol) were reacted to give the title compound (3.4 mg, 19.7%).
Reaction SMILES: C([S:8][CH2:9][CH2:10][CH2:11][C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])C1C=CC=CC=1>O.N>[SH:8][CH2:9][CH2:10][CH2:11][C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CCCSCc1ccccc1
Agent: N
Solvent: O
Product: O=C(O)[C@@H]1CCCN1C(=O)CCCS
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-Benzylthiobutanoyl)-L-proline (1.08 g.) is dissolved in a mixture of water (4 ml.) and concentrated ammonia (2.7 ml.). After one hour stirring at room temperature, the mixture is diluted with water, filtered, extracted with ethyl acetate, and the aqueous phase is concentrated in vacuo. This ammonium salt of 1-(4-mercaptobutanoyl)-L-proline is purified by ion exchange chromatography on a column of diethylaminoethyl-Sephadex(cross linked dextran) with a gradient of ammonium bicarbonate, yield 0.7 g. The ammonium salt is dissolved in water (2 ml.) and applied to a column of Dowex 50 sulfonic acid resin analytical grade in the hydrogen form, and the free acid is eluted with water. The fractions containing the desired material (sulfhydryl reagent and carboxyl reagent positive) are pooled and freeze dried to obtain 1-(4-mercaptobutanoyl)-L-proline. The dicyclohexyl ammonium salt is produced by the procedure of Example 44, m.p. 157°-158°.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:25](ON1C(=O)CCC1=O)=[O:26])[CH2:16][CH2:17][C:18](=[O:24])[O:19]C(C)(C)C)=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6]C(C)(C)C.[NH2:42][C@H:43]([C:51]([OH:53])=[O:52])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[NH2:1][C@H:2]([C:12]([NH:14][C@H:15]([C:25]([NH:42][C@H:43]([C:51]([OH:53])=[O:52])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:26])[CH2:16][CH2:17][C:18](=[O:19])[OH:24])=[O:13])[CH2:3][CH2:4][C:5](=[O:6])[OH:11]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
Glu-Glu-Phe-Amp was synthesized by a similar method except the amino acid starting material was Boc-Glu(OtBu)-Glu(OtBu)-OSu and the starting drug conjugate was Phe-Amp (see Phe-Amp synthesis).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:36])(=[N:29][CH2:30][C:31](OCC)=[O:32])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.[BH4-].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:36])(=[N:29][CH2:30][CH2:31][OH:32])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: CCOC(=O)CN=S(C)(=O)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=NCCO)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reaction time: 5 h
Yield: 33.3 %

Procedure:
To a stirring solution of S-[4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-chlorophenyl}carbamoyl)phenyl]-S-methyl-N-(ethoxycarbonyl methyl)sulfoximide (1.3 g, 0.00237 mol) in DMSO (4 mL) was added Sodium borohydride (360 mg, 0.00948 mol) at 60° C. in several lots. Reaction mixture was stirred at same temperature for 5 hr. Subsequent work up and column purification (100-200 mesh silica gel, 2% methanol in chloroform) gave 400 mg of titled product in 80% yield.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:13]([O:16][CH:17]2[CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]([CH2:28][N:29](CC3C=CC=CC=3)CC3C=CC=CC=3)[CH2:19][O:18]2)[CH2:14][OH:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C([O-])=O.[NH4+]>CO>[NH2:29][CH2:28][CH:20]1[CH2:19][O:18][CH:17]([O:16][CH:13]([C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:6]=2)[CH2:14][OH:15])[CH:21]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: OCC(OC1OCC(CN(Cc2ccccc2)Cc2ccccc2)C1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: NCC1COC(OC(CO)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Yield: 53.5 %

Procedure:
(2SR, 3SR, 4SR, 2[(1′)]SR) 2-(3,5-Bis(trifluoromethyl)phenyl)-2-{4-[(N,N-dibenzylamino)methyl]-3-phenyl-tetrahydrofuran-2-yloxy}-ethanol (Description 9(a); 53 mg, 0.084 mmol) was dissolved in methanol (5 ml) and paladium on carbon (10 mg) and ammonium formate (37.1 mg) were added and the mixture refluxed for 1 hour. Further ammonium formate (20 mg) was added and the mixture refluxed for another hour. The catalyst was filtered off, the solvent was removed in vacuo and the residue purified using preparative TLC plates in 6% methanol in dichloromethane and 0.2% ammonia. The product was removed from the silica by washing with methanol (2×20 ml) and the solvent removed in vacuo. The residue was dissolved in dichloromethane (10 ml) and dried over MgSO4 to give the title compound (20.2 mg, 54%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[C:10]2[C:15]([C:16]=1[N:17]=[C:18]=[O:19])=[C:14]([CH3:20])[C:13]([C:21]([F:24])([F:23])[F:22])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][O:31][C:32]([C:34]1[C:38]([NH2:39])=[CH:37][S:36][CH:35]=1)=[O:33].C(OCC)(=O)C>FC(C1C=CC=CC=1)(F)F>[C:1]([O:5][C:6]([C:8]1[N:9]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[C:10]2[C:15]([C:16]=1[NH:17][C:18]([NH:39][C:38]1[C:34]([C:32]([O:31][CH3:30])=[O:33])=[CH:35][S:36][CH:37]=1)=[O:19])=[C:14]([CH3:20])[C:13]([C:21]([F:23])([F:22])[F:24])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cscc1N
Reactant: Cc1c(C(F)(F)F)ccc2c1c(N=C=O)c(C(=O)OC(C)(C)C)n2-c1ccsc1
Solvent: FC(F)(F)c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cscc1NC(=O)Nc1c(C(=O)OC(C)(C)C)n(-c2ccsc2)c2ccc(C(F)(F)F)c(C)c12
Temperature: 150 °C
Yield: 59 %

Procedure:
To a solution of 3-isocyanato-1-thiophen-3-yl-methyl-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 1F (˜4.39 mmol) in trifluoromethylbenzene (10 mL) was added 4-aminothiophene-3-carboxylic acid methyl ester 1G (1.38 g, 8.79 mmol). The reaction mixture was heated in a microwave reactor at 150° C. for 20 minutes. Ethyl acetate (100 mL) was added and the organic layer was washed with 1 N hydrochloric acid and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to provide 3-[3-(4-methoxycarbonyl-thiophen-3-yl)-ureido]-1-thiophen-3-yl-methyl-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 1H (1.50 g, 2.59 mmol).
Reaction SMILES: [OH:1][C@:2]12[CH2:19][CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=O)[C@@H:11]1[CH2:10][CH:9]=[C:8]1[C@:3]2([CH3:23])[CH2:4][CH2:5][C:6]([O:21][CH3:22])=[CH:7]1.[N+:24]([CH:26](P(=O)(OCC)OCC)[CH3:27])#[C-:25]>>[N+:24]([C:26](=[C:15]1[C@:16]2([CH3:17])[C@H:12]([C@H:11]3[C@:2]([OH:1])([CH2:19][CH2:18]2)[C@:3]2([CH3:23])[C:8]([CH:7]=[C:6]([O:21][CH3:22])[CH2:5][CH2:4]2)=[CH:9][CH2:10]3)[CH2:13][CH2:14]1)[CH3:27])#[C-:25]
Reactant: [C-]#[N+]C(C)P(=O)(OCC)OCC
Reactant: COC1=CC2=CC[C@H]3[C@@H]4CCC(=O)[C@@]4(C)CC[C@]3(O)[C@@]2(C)CC1
Product: [C-]#[N+]C(C)=C1CC[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@@]3(O)CC[C@]12C
Yield: 69 %

Procedure:
Using the procedure of Example 27, 3.10 g of 9α-hydroxy-3-methoxyandrosta-3,5-dien-17-one and 8.02 g of diethyl α-isocyanoethylphosphonate were reacted for 5 hours to produce 2.39 g of the title compound as a mixture of 2 diastereomers. Chromatography was performed on silica gel with toluene/acetone 9/1 containing 0,1% triethylamine as eluent.