Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br[CH2:44][C:45]1C=C[CH:48]=[C:47]([Cl:51])[CH:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:44]=[CH:45][CH:46]=[C:47]([Cl:51])[CH:48]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Clc1cccc(CBr)c1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cccc(Cl)c3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-3-chlorobenzene and isolated as light-yellow gum (7.0 mg, 42%). MS(m/e): 407.4 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]1[OH:15])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1O.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[O:15][C@@H:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][CH2:14][C@H:5]1[CH2:4][N:2]([CH3:1])[CH3:3]
Reactant: CN(C)C[C@@H]1CCc2ccccc2[C@H]1O
Reactant: COc1ccccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COc1ccccc1O[C@@H]1c2ccccc2CC[C@H]1CN(C)C
Reaction time: 2 h

Procedure:
A mixture of 8.21 g (0.04 M) of TRANS-1,2,3,4-tetrahydro-2-(N,N-dimethylaminomethyl)naphthalen-1-ol, 11.54 triphenyl phosphine, 5.46 g (0.044 M) of triphenyl phosphine, 5.46 g (0.044 M) of 2-methoxyphenol and 100 ml of benzene was stirred and a solution of 7.83 g (0.004 M) of 95% diethyl azodicarbox-ylate in 25 ml of benzene was added dropwise over 45 minutes. After 2 hours, the mixture was filtered and extracted with cold 3% hydrochloric acid. The acid extracts were made basic with dilute sodium hydroxide and the oil which separated was extracted into ether. The solvent was removed and the residual oil chromatographed on silica gel.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C@H:10]([OH:15])[CH2:11][N:12]=[N+:13]=[N-:14])=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][C@@H:9]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C@H:10]([OH:15])[CH2:11][N:12]=[N+:13]=[N-:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](O)CN=[N+]=[N-]
Agent: Cl
Solvent: C1COCCO1
Product: [N-]=[N+]=NC[C@@H](O)[C@@H](N)CC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2R,3S)-3-(t-Butoxycarbonylamino)-1-azido-4-cyclohexylbutan-2-ol (94 mg, (0.30 mmol) was dissolved in dioxane (1 mL) and treated with 4M HCl in dioxane (1 mL). The reaction was allowed to stir for 2 h at rt. The solvent was evaporated and the hydrochloric acid salt of (3R)-3-(1-hydroxy-5-methoxy-1-(2-phenoxyphenyl)pentyl)-N-(piperidin-3-yl)piperidine-1-carboxamide (˜74 mg) was used directly.
Reaction SMILES: [NH3:1].[CH3:2][O:3][C:4]1[C:11]([F:12])=[C:10](F)[C:7]([C:8]#[N:9])=[C:6]([F:14])[C:5]=1[F:15]>>[NH2:1][C:10]1[C:11]([F:12])=[C:4]([O:3][CH3:2])[C:5]([F:15])=[C:6]([F:14])[C:7]=1[C:8]#[N:9]
Reactant: COc1c(F)c(F)c(C#N)c(F)c1F
Reactant: N
Product: COc1c(F)c(N)c(C#N)c(F)c1F
Reaction time: 8 h

Procedure:
150 ml of liquid ammonia and 100.0 g (0.49 mole) of 4-methoxy-2,3,5,6-tetrafluorobenzonitrile (XIX) [prepared as described in Step (E1) above] were placed in an autoclave, and the mixture was allowed to stand at room temperature overnight. The ammonia was then evaporated off, and the solid obtained was washed with water to afford 84.4 g of 2-amino-4-methoxy-3,5,6-trifluorobenzonitrile (XX) as a colorless powder.
Reaction SMILES: Cl.C[C:3](C)([O:5][C:6](=[O:33])[CH2:7][NH:8][CH2:9][CH:10]([NH:15][C:16]([CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])C>CO>[CH3:3][O:5][C:6](=[O:33])[CH2:7][NH:8][CH2:9][CH:10]([NH:15][C:16]([CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)CC(CNCC(=O)OC(C)(C)C)NC(=O)C1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CO
Product: COC(=O)CNCC(CC(C)C)NC(=O)C1CCCN1C(=O)OCc1ccccc1
Reaction time: 4 h

Procedure:
To 50 ml of methanol, saturated with hydrogen chloride gas is added 1.77 g of [S-(R*,R*)]-2-[[[1-[[[-2-(1,1-dimethylethoxy)-2-oxoethyl]amino]methyl]-3-methylbutyl]amino]carbonyl]-1-pyrrolidinecarboxylic acid, phenylmethyl ester in 10 ml of methanol. After standing at room temperature for four hours, the solution is kept at 0° overnight. The solvent is then removed under reduced pressure and the residue taken up in ethyl acetate. The ethyl acetate solution is washed two times with saturated sodium bicarbonate solution, once with saturated sodium chloride solution, and then dried over magnesium sulfate. Removal of the solvent under reduced pressure gives 1.14 g of [S-(R*,R*)]-2-[[[1-[[(2-methoxy-2-oxoethyl)amino]methyl]-3-methylbutyl]amino]carbonyl]-1-pyrrolidinecarboxylic acid, phenylmethyl ester.
Reaction SMILES: [I-].[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Zn+])=[CH:9][CH:8]=1)=[O:6])[CH3:3].[C:14](Cl)(=[O:18])[CH:15]([CH3:17])[CH3:16]>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.C1COCC1>[C:14]([C:10]1[CH:11]=[CH:12][C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])=[CH:8][CH:9]=1)(=[O:18])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)c1ccc([Zn+])cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(=O)C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.4 %

Procedure:
To a 100-mL round-bottom flask was added THF (25 mL). The solvent was bubbled with nitrogen for a few minutes then cooled to 0° C. and added bis(triphenylphosphine)palladium(II) chloride (0.44 g, 0.63 mmol) followed by 4-(ethoxycarbonyl)phenylzinciodide (25.0 mL, 12.5 mmol; 0.50 M in THF). After stirred at at 0° C. for 15 min, isobutyryl chloride (1.32 mL, 12.5 mmol) was added and the resulting mixture was stirred at 0° C. for 2 h. The reaction was quenched with slow addition of 1 N HCl and extracted with EtOAc (3×100 mL). After separation, combined organic extracts were washed with sat. NaHCO3, water, brine, dried (MgSO4), and concentrated. Flash column chromatography (EtOAc:hexanes, 0:1 to 1:9) afforded ethyl 4-isobutyrylbenzoate (2.49 g, 90%) as a slight-brown oil. LC-MS: (FA) ES+ 221; 1H NMR (CDCl3, 400 MHz) δ8.13 (d, J=8.5 Hz, 2H), 7.99 (d, J=8.5 Hz, 2H), 4.40 (q, J=7.2 Hz, 2H), 3.56 (m, 1H), 1.42 (t, J=7.2 Hz, 3H), 1.23 (d, J=7.2 Hz, 6H).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:15]([CH3:21])([CH3:20])[C:16]([O:18]C)=[O:17])(=[O:13])=[O:12])=[CH:7][CH:6]=1>O.CO>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH:14]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:15]([CH3:21])([CH3:20])[C:16]([OH:18])=[O:17])(=[O:13])=[O:12])=[CH:9][CH:10]=1
Reactant: COC(=O)C(C)(C)C(CCCCc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(S(=O)(=O)C(CCCCc2ccccc2)C(C)(C)C(=O)O)cc1
Yield: 65.9 %

Procedure:
A solution of sodium hydroxide (0.40 g, 10 mmol) in water (6 mL) is added to a solution of methyl 3-(4-methoxybenzenesulfonyl)-2,2-dimethyl-7-phenylheptanoate (1.00 g, 2.4 mmol) in MeOH (8 mL). The reaction is heated at reflux 24 hours. The solvent is then removed in vacuo, CH2Cl2 (50 mL) added and the solution washed with 1 N HCl (2×40 mL). The organic layer is dried over MgSO4 and the solvent removed in vacuo to yield 3-(4-methoxybenzenesulfonyl)-2,2-dimethyl-7-phenylheptanoic acid (0.64 g, 66%): 1H NMR (300 MHz, CDCl3) δ 7.90-7.80 (m, 2H), 7.26-7.16 (m, 3H), 7.00-6.92 (m, 4H), 4.05-3.92 (m, 1H), 3.78 (s, 3H), 2.40-2.30 (m, 2H), 2.00-1.85 (m, 1H), 1.70-1.55 (m, 1H), 1.44 (s, 3H), 1.40-1.25 (m, 3H), 1.21 (s, 3H), 1.12-0.95 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][O:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][C@H:18]([CH2:22][CH:23]=[C:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])[CH2:17]1>C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][O:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][C@H:18]([CH2:22][CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])[CH2:17]1
Reactant: Cc1cccc(-c2nc(CO[C@@H]3CCC[C@H](CC=C4SC(=O)NC4=O)C3)c(C)o2)c1
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2nc(CO[C@@H]3CCC[C@H](CCC4SC(=O)NC4=O)C3)c(C)o2)c1
Reaction time: 9 h

Procedure:
81 mg of 5-{2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]-ethylidene}thiazolidine-2,4-dione are dissolved in 10 ml of ethyl acetate, and 10 mg of paladium (10% on activated carbon) are added. The mixture is stirred under an atmosphere of hydrogen (5 bar) for 9 hours. The catalyst is then filtered off through Celite and the filtrate is concentrated under reduced pressure. The residue is purified by RP-HPLC. This gives 60 mg of 5-{2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]-ethyl}thiazolidine-2,4-dione as a lyophilisate.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[N:14]=[C:13]([C:15](=O)[CH2:16]Br)[CH:12]=[CH:11][CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH3:33])[C:25]([NH2:27])=[S:26])[CH3:20]>>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([C:25]2[S:26][CH:16]=[C:15]([C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[OH:8])[N:14]=3)[N:27]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH3:33])[CH3:20]
Reactant: O=C(CBr)c1cccc(C(O)c2ccccc2)n1
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Product: CCOc1ccc(-c2nc(-c3cccc(C(O)c4ccccc4)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 6-(1-phenyl-1-hydroxymethyl)-2-(α-bromoacetyl)pyridine and 3,4-diethoxythiobenzamide, to obtain 2-(3,4-diethoxyphenyl)-4-[6-(1-phenyl-1-hydroxymethyl)-2-pyridyl]thiazole.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.C(O)C.Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>O>[OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](=[N:21][OH:22])[C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 75 °C

Procedure:
4,4'-dihydroxybenzophenone (100.0 grams, 0.467 mole) is added to ethanol (300 milliliters) in a 1 liter Erlenmeyer flask and stirred. After dissolution of the 4,4'-dihydroxybenzophenone, a solution of hydroxylamine hydrochloride (48.6 grams, 0.699 mole) and sodium acetate (57.4 grams, 0.700 mole) in deionized water (70 milliliters) is added followed by an additional 100 milliliters of ethanol. This mixture is stirred and heated on a hot plate to a gentle reflux (75° C.). After heating for 4 hours, the solution is allowed to cool to room temperature (25° C.) with stirring and then filtered. The filter cake is washed with ethanol (100 milliliters); then the total filtrant obtained (600.4 grams) is concentrated to a weight of 219.2 grams by evaporation of the ethanol and water. The concentrated solution is placed into a 1 liter Erlenmeyer flask then stirred as 600 milliliters of deionized water is added. The addition of the deionized water induced formation of a white precipitate. After thirty minutes of stirring, the mixture is filtered. The solid 4,4'-dihydroxybenzophenone oxime thus obtained weighed 98.22 grams after drying. 4,4'-Dihydroxybenzophenone oxime (66.0 grams, 0.288 mole) and glacial acetic acid (330 milliliters) are added to a 500 milliliter round bottom flask equipped with a stirrer, water cooled condensor, nitrogen purge and heating mantle. A catalytic amount of p-toluenesulfonic acid (1.85 grams, 0.027 mole) is added and the reaction mixture then heated to 83° C. After heating for approximately two hours, a precipitate formed and the mixture is stirred for an additional two hours at 87° C. After this time, 25 milliliters of deionized water is added to the reactor and after thirty minutes, the contents of the reactor is transferred to a 1 liter Erlenmeyer flask and maintained therein with stirring. Immediately following the transfer, 400 milliliters of deionized water is added to the flask. The mixture is stirred for forty five minutes and then filtered. The filter cake thus obtained is washed with 800 milliliters of deionized water and then dried. The resultant light beige colored solid weighed 54.82 grams. Fourier transform infrared spectrophotometric analysis of a portion of the product confirmed the product structure as that of 4,4'-dihydroxybenzanilide. Differential scanning calorimetry demonstrated a sharp melting point endotherm at 273° C. for the 4,4'-dihydroxybenzanilide product.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:41][CH:42]3[CH2:45][CH2:44][CH2:43]3)=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=4[F:40])[CH2:27][CH2:26]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[CH:42]1([NH:41][C:19]2[N:18]=[C:17]3[CH2:16][NH:15][CH2:24][CH2:23][C:22]3=[N:21][C:20]=2[N:25]2[CH2:30][CH2:29][CH:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[F:40])[CH2:27][CH2:26]2)[CH2:43][CH2:44][CH2:45]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC3CCC3)CN(Cc3ccccc3)CC4)CC2)c(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC3CCC3)CNCC4)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 6-benzyl-N-cyclobutyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (103.4 mg, 0.164 mmol) and Pd(OH)2 on carbon (10 mg, 0.014 mmol) in THF (818 μL) was stirred at rt under an atmosphere of hydrogen gas (balloon) for 4 h. The mixture was filtered through a pad of Celite™, washing with MeOH, and concentrated to afford the title compound as its TFA salt (89 mg, 100%) as a yellow solid. ESI-MS m/z [M+H]+ 428.4.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[N:15]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH:20]([C:16]1[N:15]=[C:14]([CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:19]=[CH:18][N:17]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1nccc(C2CN(C(=O)OC(C)(C)C)CCO2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1nccc(C2CNCCO2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.4 %

Procedure:
2-(2-Isopropylpyrimidin-4-yl)-morpholine-4-carboxylic acid tert-butyl ester (256 mg, 833 μmol) was dissolved in 5 mL of dichloromethane and TFA (2 mL) was added. The solution was stirred at room temperature for 2 h. The solvents were evaporated. The residue was extracted with dichloromethane and 1N NaOH solution. The organic layer was dried over Na2SO4 and concentrated. The residue was dried under vacuum to afford 2-(2-isopropylpyrimidin-4-yl)-morpholine (175 mg) as a colorless oil. (M+H)+=208 m/e.
Reaction SMILES: Cl[C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[CH2:10][CH2:9][CH:8]2[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:4][CH:3]=1>CO.[Ni]>[NH2:18][CH2:17][C:14]1[CH:15]=[C:16]2[C:11]([CH2:10][CH2:9][CH:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH:7]2[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:28][CH:27]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(C#N)cc2C1Cc1ccc(Cl)cc1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCc2ccc(CN)cc2C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tert-butyl [1-(4-chlorobenzyl)-7-cyano-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (52 mg, 0.131 mmol, cf. example 30d) were dissolved in methanol (5 mL). Raney nickel (about 30 mg) was added and the reaction mixture was stirred at room temperature for 4 h under an atmosphere of hydrogen. The catalyst was removed by filtration. The solvent was evaporated in vacuo. The crude product was used without further purification for the next step. Yield: 32 mg (0.087 mmol, 67%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:24])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:26])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:25])[CH:6]=[CH:5]1.[CH3:27][O:28][CH2:29][CH2:30][C:31](Cl)=[O:32]>>[OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:24])[C:17](=[O:20])[CH2:18][O:19][C:31](=[O:32])[CH2:30][CH2:29][O:28][CH3:27])[C@H:12]2[C@H:3]1[C@:4]1([CH3:26])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:25])[CH:6]=[CH:5]1
Reactant: COCCC(=O)Cl
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Product: COCCC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
Under the conditions of Example 3(a), 10.0 g of 11β,17,21-trihydroxy-1,4-pregnadiene-3,20-dione is reacted with 3-methoxypropionic acid chloride, worked up, and purified, thus isolating 7.3 g of 11β,17-dihydroxy-21-(3-methoxypropionyloxy)-1,4-pregnadiene-3,20-dione.
Reaction SMILES: [H-].[Na+].[C:3]1([C@H:9]2[NH:19][C:18](=[O:20])[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[NH:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C1COCC1>[O:20]=[C:18]1[C:13]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[NH:12][CH2:11][CH2:10][C@@H:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:19]1[CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]
Reactant: O=C1N[C@H](c2ccccc2)CCNC12CCCC2
Reactant: O=C(CBr)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CN1C(=O)C2(CCCC2)NCC[C@H]1c1ccccc1)OCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (0.147 g, 6.14 mmol) in THF (10 mL) was added (9S)-9-phenyl-6,10-diazaspiro[4.6]undecan-11-one (0.300 g, 1.23 mmol) at ambient temperature. The reaction was warmed to 60° C. for 2 h, then cooled to ambient temperature. Benzyl bromoacetate (0.309 g, 1.35 mmol) was added dropwise to the reaction. After 1 h, the mixture was quenched with a saturated aqueous ammonium chloride solution. The mixture was concentrated in vacuo then partitioned between H2O and CH2Cl2. The aqueous phase was then extracted several times with CH2Cl2. The combined organic extracts were washed with saturated brine, then dried over MgSO4, filtered and concentrated in vacuo The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc:hexane—0:100 to 100:0, to yield the title compound. MS: m/z=393 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:9][CH:8]=1.CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[OH:36])O1>>[OH:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:2]1[CH:21]=[CH:20][CH:19]=[C:4]([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=2)[CH:3]=1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Reactant: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Product: O=C(O)CCc1ccc(OCc2cccc(-c3ccccc3O)c2)cc1

Procedure:
The title compound was synthesized in the same manner as in Example 272 from methyl 3-[4-[(3-bromobenzyl)oxy]phenyl]propanoate and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol. colorless crystals (yield 33%). MS (APCI−): 347 (M−H).
Reaction SMILES: COC1C=CC(C[NH:8][CH:9]2[C:15]3=[N:16][C:17]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)=[CH:18][C:19](=[O:20])[N:14]3[CH2:13][CH2:12][O:11][CH2:10]2)=CC=1.[N+]([O-])([O-])=O.[Ce].[NH4+]>C(#N)C.O>[NH2:8][CH:9]1[C:15]2=[N:16][C:17]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:18][C:19](=[O:20])[N:14]2[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: COc1ccc(CNC2COCCn3c2nc(-c2ccncc2)cc3=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: NC1COCCn2c1nc(-c1ccncc1)cc2=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2.00 g (1.32 mmol) of 9-(4-methoxy-benzylamino)-2-pyridin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4a-diaza-benzocyclohepten-4-one in acetonitrile/water (20/10 mL) was added 2.17 g (3.96 mmol) of ammonium cerium nitrate. The reaction was stirred at room temperature for 15 hours. After an acido-basic work-up and extraction with dichloromethane, the organic phase was washed with a saturated solution of sodium chloride, dried over sodium sulphate and concentrated. The crude product was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 98/2/0.2 to give 0.226 g (5%, 3 steps) of product as a white powder.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]3)[N:11]=2)=[CH:2]1.[C:23](OC(=O)C)(=[O:25])[CH3:24].N1C=CC=CC=1.C1COCC1>O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[CH2:17][CH2:18][CH:19]([NH:22][C:23](=[O:25])[CH3:24])[CH2:20][CH2:21]3)[N:11]=2)=[CH:2]1
Reactant: NC1CCN(c2nccc(-c3c[nH]c4ncccc34)n2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)NC1CCN(c2nccc(-c3c[nH]c4ncccc34)n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 661.6 %

Procedure:
To a flask was added compound 62 (10.2 mg), acetic anhydride (0.5 mg), pyridine (0.1 mL) and THF (1 mL) at 0° C. The mixture was warmed to rt slowly and stirred for 1 hr, then poured into water and extracted with EtOAc. The organic layer was separated, dried with MgSO4, then concentrated to provide 10.9 mg (94%) of the desired product as a white solid. 1H NMR (400 MHz, DMSO) δ 12.30 (s, 1 H), 8.70 (d, 1 H), 8.40 (s, 1 H), 8.25 (m, 1 H), 8.20 (d, 1 H), 7.80 (d, 1 H), 7.25 (m, 1 H), 7.10 (d, 1 H), 4.60 (d, 2 H), 3.90 (m, 1 H), 3.15 (m, 2 H), 1.85 (m, 2 H), 1:80 (s, 3 H), 1.40 (m, 2 H). MS (ESI) m/z: 337 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][SH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]>>[CH2:8]([S:9][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: SCCc1ccccc1
Reactant: OCCCCCCCBr
Product: OCCCCCCCSCCc1ccccc1

Procedure:
2-Phenylethanethiol was alkylated with 7-bromo-1-heptanol in analogy with example 18, step 1, affording 7-phenethylsulfanyl-heptan-1-ol.
Reaction SMILES: [CH:1]([C:13]([O:15]CC)=[O:14])([C:8]([O:10]CC)=[O:9])[CH2:2][C:3]([O:5]CC)=[O:4].[OH-].[Na+]>O>[CH:1]([C:13]([OH:15])=[O:14])([C:8]([OH:10])=[O:9])[CH2:2][C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CC(C(=O)O)C(=O)O
Yield: 38.6 %

Procedure:
A reaction mixture comprising 49.2 g of triethyl 1,1,2-ethanetricarboxylate, 135 ml of 5N sodium hydroxide and 65 ml of water was stirred at 100° C. for 3 hours, then cooled and concentrated to about 150 ml. A 50 ml portion of cold concentrated hydrochloric acid was added and the mixture was extracted three times with ether. The ether extracts were combined, dried and evaporated, giving 12.5 g of 1,1,2-ethanetricarboxylic acid, mp 169°-170° C.