Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:4][C@H:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]2)[CH2:13][CH2:12]4)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[N+:31]([O-])([O:33]C(C)C)=[O:32].CO>C(Cl)(Cl)Cl>[CH:1]1([O:4][C@H:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14](=[C:15]([N+:31]([O-:33])=[O:32])[C:16](=[O:24])[CH2:17][CH2:18]2)[CH2:13][CH2:12]4)[CH2:2][CH2:3]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Reactant: CC(C)O[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@]12CC[C@H]3[C@@H](CCC4=C([N+](=O)[O-])C(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1

Procedure:
17β-cyclopropyloxy-androst-4-en-3-one (9.70 g, 29.5 mM), potassium tert-butoxide (7.0 g, 62.4 mM), and isopropyl nitrate (2.99 ml) are reacted by the method of Example 1 to yield 17β-cyclopropyloxy-4-nitroandrost-4-en-3-one, m.p. 137°-38° C. (methanol) IR (CHCl3) , 1695, 1622(m) , 1535, 1373 cm-1MS(CI) 374(100%, M+10, 316(20%, M+1-c-C3H5 -O) 1H-NMR (CDCl3) 0.38-0.61(4H, m), 0.80(3H, s, C18 -Me), 1.29(s, C19 -Me), 3.25-3.33(1H, m, cyclopropyl-CHO), 3.44(1H, t, C17 -H) .
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([C@H:12]1[CH2:16][O:15]C(C)(C)[O:13]1)[CH2:6][CH2:5]2.O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([C@H:12]([OH:13])[CH2:16][OH:15])[CH2:6][CH2:5]2
Reactant: CC1(C)OC[C@H]([C@H]2CCc3cc(F)ccc3O2)O1
Solvent: O
Solvent: CC(=O)O
Product: OC[C@@H](O)[C@H]1CCc2cc(F)ccc2O1
Temperature: 65 °C
Yield: 26 %

Procedure:
(R)-6-fluoro-3,4-dihydro-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2H-chromene (2.92 g, 11.6 mmol) was dissolved in acetic acid (24 ml) and demi water (9 ml). The reaction mixture was stirred vigorously and heated to 65° C. After 3 h at 65° C. the reaction mixture was cooled to 25° C. The solution was then concentrated in vacuo to obtain a vetrous oil. Chromatographic separation on silica of the crude, using a mixture of heptane:ethyl acetate 1:1 as eluent, furnished 0.64 g of (R)-1-((R)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethane-1,2-diol as a white solid (26% yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:11]#[N:12])=[N:7][C:8]=1[CH2:9]Br.[CH3:13][Si:14]([CH3:30])([CH3:29])[CH2:15][CH2:16][O:17][CH2:18][N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C:20]1=[O:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[O:28]=[C:20]1[N:19]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:30])([CH3:29])[CH3:13])[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[C:21]21[CH2:9][C:8]1=[N:7][C:6]([C:11]#[N:12])=[CH:5][CH:4]=[C:3]1[CH2:2]2
Reactant: N#Cc1ccc(CBr)c(CBr)n1
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3ccc(C#N)nc3C2)c2cccnc21
Reaction time: 0.08 h

Procedure:
To a solution of 5,6-bis(bromomethyl)pyridine-2-carbonitrile from Step C (1.80 g, 6.21 mmol) and 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (1.64 g, 6.21 mmol, described in Intermediate 7) in DMF (207 mL) was added cesium carbonate (6.07 g, 18.6 mmol), portionwise, over 5 min. After 18 h, the mixture was partitioned between CH2Cl2 (100 mL), saturated aqueous NaHCO3 (100 mL) and brine (200 mL). The organic layer was removed and the aqueous layer was extracted further with CH2Cl2 (2×100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 10:90, to give the title compound. MS: m/z=393 (M+1).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:37]([O:36][C:34]([N:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:35])[CH3:38]
Reactant: O=C(N[C@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCOC(=O)N1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-pyrrolidin-3-ylamide hydrochloride (example A143) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Li]CCCC.C(NC(C)C)(C)C.[F:21][C:22]([F:40])([F:39])[C:23]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]([Cl:34])[CH:26]=[C:25]([C:35]([F:38])([F:37])[F:36])[N:24]=1.Cl[C:42]([O:44][CH2:45][CH3:46])=[O:43]>COCCOC>[F:40][C:22]([F:21])([F:39])[C:23]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]([Cl:34])[C:26]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:25]([C:35]([F:36])([F:37])[F:38])[N:24]=1
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1Cl
Reaction time: 0.08 h
Yield: 30 %

Procedure:
To a cold (-78° C.) solution of LDA, from 0.0155 mol of n-BuLi, 0.0157 mol (2.2 ml) of diisopropylamine and 30 ml of dry DME was added a solution of 3.2 g (0.01 mol) of product of Example 9 in 5 ml of DME. The resulting purple solution was stirred for 5 minutes and treated with 4 ml of ethyl chloroformate. The mixture was stirred at -78° C. for 10 minutes, the cooling bath was removed, and the reaction mixture was stirred for an additional 30 minutes, then poured into water. The mixture was extracted with ether. The ether extract was washed with 50 ml of 3N HCl, dried, and concentrated. The residue was kugelrohr distilled at 53 Pa. The low bp distillate (pot temperature 50°-60° C.) was identified as ethyl N,N-diisopropylurethane. The higher bp distillate (pot temperature 100° C.) was 1.64 g of a solid which was recrystallized from hexane at low temperature to give 1.2 g (30%) of product; mp 76°-77° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.[NH:14]1[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15]1.C(N(CC)CC)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([N:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:15]2)=[C:3]2[CH2:13][CH2:12][CH2:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (40.0 mg, 0.201 mmol), tert-butyl (3S)-piperidin-3-ylcarbamate (80.7 mg, 0.403 mmol) and triethylamine (84.2 μL, 0.604 mmol) in isopropyl alcohol (0.462 mL) was stirred at 100° C. for 30 min. The mixture was concentrated and purified by flash chromatography on a silica gel column (12 g column, 0-40% EtOAc in hexanes) to give the sub-title compound as light yellow powder (43 mg, 59%). LCMS calc. for C18H27N4O4 (M+H)+: m/z=363.3. Found: 363.2.
Reaction SMILES: [H-].[Na+].CI.[Cl:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([N:17]3[CH2:21][CH2:20][CH:19]([CH2:22][NH:23][C:24](=O)OC(C)(C)C)[CH2:18]3)=[O:16])[S:14][C:7]=12>C1COCC1>[Cl:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([N:17]3[CH2:21][CH2:20][CH:19]([CH2:22][NH:23][CH3:24])[CH2:18]3)=[O:16])[S:14][C:7]=12
Reactant: CC(C)(C)OC(=O)NCC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CNCC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Temperature: 25 °C
Yield: 134.3 %

Procedure:
NaH (0.033 g, 0.82 mmole) and CH3I (0.064 ml, 1.02 mmole) were added to a solution of tert-butyl {1-[(7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl]pyrrolidin-3-yl}methyl-carbamate 43 (0.271 g, 0.68 mmole) in THF at 0° C. The reaction mixture was stirred and warmed to room temperature overnight and partitioned between H2O (50 ml) and EtOAc (2×50 ml). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 0-2% CH3OH in CH2Cl2 to give a yellow solid (0.283 g, 82%). 1H NMR (300 MHz, CDCl3) δ8.62 (1H, d, J=5.1 Hz), 7.85 (1H, s), 7.34 (1H, d, J=5.1 Hz), 4.72 (1H, s), 3.99 (1H, m), 3.77 (2H, m), 3.50 (1H, m), 3.19 (2H, m), 2.88 (3H, d, J=12.06 Hz), 2.62 (1H, m), 2.14 (1H, m), 1.83 (1H, m); ESIMS (MH+): 310.10.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O-:10])=[O:9])[N:5]2[C:11](=[O:26])[CH:12]([NH:13][C:14](=[O:25])[C:15](=[N:22][O:23][CH3:24])[C:16]3[NH:17][C:18](=[NH:21])[S:19][CH:20]=3)[C@H:4]2[S:3]1.[Na+].[C:28]([O:34][CH2:35]I)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].C(OCC)(=O)C>CN(C)C=O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:35][O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:9])[N:5]2[C:11](=[O:26])[CH:12]([NH:13][C:14](=[O:25])[C:15](=[N:22][O:23][CH3:24])[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C@H:4]2[S:3]1
Reactant: CC(C)(C)C(=O)OCI
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CC(C)S[C@H]12)c1csc(=N)[nH]1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=CC(C)S[C@H]12)c1csc(N)n1
Temperature: 0 °C

Procedure:
To a suspension of 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (4.8 g.) in water (48 ml.) was added dropwise 1 N aqueous sodium hydroxide solution at the rate that the pH value of the mixture was not more than 7. The mixture was filtered and then lyophilized to give sodium 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), which can be represented as sodium 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), (4.8 g.), mp>250° C. This compound is suspended in dried dimethylformamide (20 ml.), and to the suspension was added iodomethyl pivalate (2.30 g.) with vigorous stirring under cooling to 3° to 5° C., and then the mixture was stirred for 20 minutes at the same temperature. The reaction mixture was poured into a mixture of ethyl acetate (60 ml.) and ice-water (10 ml.), and the mixture was well shaken. The ethyl acetate layer was separated, washed with a saturated aqueous sodium bicarbonate solution, water and a saturated aqueous sodium chloride solution in turn. After the ethyl acetate layer was dried over magnesium sulfate, ethyl acetate was distilled off under reduced pressure. The residual oil was pulverized in diethyl ether (25 ml.), collected by filtration and then dried to give pivaloyloxymethyl 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), which can be represented as pivaloyloxymethyl 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), (1.44 g.), mp 165° to 170° C. (dec.).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH3:31])[N:25]=1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2](=[O:3])[N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[N:25]=3)[CH3:31])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CNc1cccc(OC)n1
Product: COc1cccc(N(C)C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)n1

Procedure:
The crude product was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and and 2-methoxy-6-methylaminopyridine. The reaction mixture was evaporated to dryness, dissolved in dichloromethane (100 ml) and extracted with a aqueous phosphate buffer, pH 7. The aqueous phase was extracted with dichloromethane (100 ml×2) and the combined organic phases were dryed and evaporated to dryness. The product was subjected to flash chromatography, ethyl acetate/heptane (1:7) to give the titlew product (86%, white crystals). HPLC-MS m/z=420.4 (M+1), Rt: 5.23 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:6](O)=O)[CH3:2].C=O.N1CCCCC1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:22])[C:5](=[CH2:6])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[CH3:2]
Reactant: CCOC(=O)C(CCCCOCCC1CCCCC1)C(=O)O
Agent: C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: C=C(CCCCOCCC1CCCCC1)C(=O)OCC

Procedure:
11.2 g of 6-(2-cyclohexylethoxy)-2-methylenehexanoic acid ethyl ester, in the form of a nearly colourless oil, which is purified by chromatography on silica gel (migrating agent: 9:1 petroleum ether/ethyl acetate), are obtained by the procedure described in Example 1b from 16.5 g of [4-(2-cyclohexylethoxy)-butyl]-malonic acid ethyl ester, 1.97 g of paraformaldehyde, 12 ml of pyridine and 0.7 ml of piperidine.
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(OC(=O)C)(=O)C.[CH3:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[C:8]([C:7]1[C:2]([C:21]2[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)#[N:9]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1cccnc1Br
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(-c2ncccc2C#N)cc1

Procedure:
Synthetic Scheme XXV shows the 8-step preparation of the alkylating reagent 2-(4-bromomethylphenyl)-3-cyanopyridine (57) from 2-amino-3-picoline (58) (Aldrich). In step 1, the aminopicoline 58 was converted to the bromopicoline 59 by reaction with bromine, concentrated hydrobromic acid, and sodium nitrite at 0° C. In step 2, the picoline 59 was oxidized with KMNO4 to give the corresponding carboxylic acid 60. In step 3, the acid 60 was reduced to the alcohol 61 with borane/THF. In step 4, the alcohol 61 was oxidized to the aldelyde 62 under Swern conditions or by using MnO2. In step 5, the aldehyde 62 was reacted with hydroxylamine to give the oxime 63. In step 6, the oxime 63 was converted to 2-bromo-3-cyanopyridine (64) with acetic anhydride at reflux. In step 7, the nitrile 64 was coupled with 4-methylphenylboronic acid (56) (Scheme XXIV) using Snieckus conditions (Scheme XIII) to give 3-cyano-2-(4-methylphenyl)pyridine (65). In step 8, 65 was brominated with NBS/AIBN in carbon-tetrachloride at reflux to give the desired alkylating reagent 57. ##STR83##
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH2:10])[S:5][C:6]=1[CH3:7].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])[S:5][C:6]=1[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(CCN)sc1C
Product: CC(=O)NCCc1cc(C)c(C)s1
Yield: 79 %

Procedure:
In close analogy to the procedure described above, 2-(4,5-Dimethyl-thiophen-2-yl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: CO.[C:3]([NH:8][C@H:9]([C:20]([O:22]C)=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(=[O:7])/[CH:4]=[CH:5]/[CH3:6].[OH-].[Na+]>O>[C:3]([NH:8][C@H:9]([C:20]([OH:22])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(=[O:7])/[CH:4]=[CH:5]/[CH3:6]
Reactant: C/C=C/C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C/C=C/C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reaction time: 20 h
Yield: 71.7 %

Procedure:
To methanol (230 mL) solution of the compound obtained in Example 161 (4.4 g) was added 1 mol/L of an aqueous sodium hydroxide solution (23 mL), and the mixture was allowed to stir for 20 hours. Water was added to the residue obtained by distilling off the solvent under a reduced pressure, and the mixture was made acidic with a 10% aqueous citric acid solution. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with saturated sodium chloride solution, and thereafter dried over anhydrous sodium sulfate. The solvent was distilled off under a reduced pressure, to give the captioned compound (3.0 g, 71%) as an amorphous solid product.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C@@:11]1([NH:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[C:16](=[O:17])[C@@:15]2([CH2:18][OH:19])[C@H:13]([O:14]2)[C@@H:12]1[NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:44][C:45]([Si:48](Cl)([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([CH3:47])[CH3:46].[NH4+].[Cl-]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:1]([O:8][C@H:9]([C@@:11]1([NH:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[C:16](=[O:17])[C@@:15]2([CH2:18][O:19][Si:48]([C:45]([CH3:47])([CH3:46])[CH3:44])([C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C@H:13]([O:14]2)[C@@H:12]1[NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:10])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@]1(NC(=O)N(C)C)C(=O)[C@]2(CO)O[C@@H]2[C@@H]1NC(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@]1(NC(=O)N(C)C)C(=O)[C@]2(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O[C@@H]2[C@@H]1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
A flame-dried 25-mL round-bottomed flask was charged with alcohol 11 (1.0 g, 1.9 mmol, 1.0 equiv) and CH2Cl2 (9.5 mL). NEt3 (0.8 mL, 5.7 mmol, 3.0 equiv) and DMAP (0.023 g, 0.19 mmol, 0.1 equiv) were added and the solution was cooled 0° C. TBDPSCl (1.47 mL, 5.7 mmol, 3.0 equiv) was added dropwise and the reaction was warmed to rt and stirred for 8 h. Saturated NH4Cl(aq.) (10 mL) was added and the mixture was extracted with Et2O (3×15 mL). The combined organic extracts were washed with brine (10 mL), dried with magnesium sulfate, and concentrated in vacuo. The crude product was purified via flash chromatography (70:30 hexanes:EtOAc) to give the title compound as a pale yellow oil (1.1 g, 76%). Analytical data: [α]D19 −4.4 (c=0.70, CHCl3); 1H NMR (600 MHz, CDCl3): δ 7.67 (d, J=7.2 Hz, 2H), 7.62 (d, J=7.2 Hz, 2H), 7.44-7.30 (m, 11H), 5.68 (d, J=10.2 Hz, 1H), 5.23 (d, J=12.0 Hz, 1H), 4.97 (d, J=12.6 Hz, 1H), 4.74 (dd, J=3.0, 7.2 Hz, 1H), 4.70 (br s, 1H), 4.26 (d, J=12, 6 Hz, 1H), 4.11 (d, J=3.0 Hz, 1H), 4.03 (q, J=6.0 Hz, 1H), 3.92 (d, J=12.0 Hz, 1H), 2.68 (s, 6H), 1.19 (d, J=6.0 Hz, 3H), 1.01 (s, 9H), 0.92 (s, 9H), 0.13 (s, 6H); 13C NMR (150 MHz, CDCl3): δ 203.9, 156.8, 156.0, 136.7, 135.5, 135.4, 132.6, 132.3, 129.8, 129.7, 128.3, 128.1, 127.9, 127.8, 127.7, 74.1, 69.4, 66.4, 66.2, 60.8, 57.5, 52.2, 36.1, 26.6, 25.6, 19.1, 18.3, 17.8, −3.8, −4.8; LRMS (ESI+) Calcd. for C41H57N3O7Si2+H, 760.38. Found, 760.31. IR (thin film, cm−1) 3419, 2931, 2857, 2359, 1716, 1651, 1507, 1226, 1113, 828, 733; TLC (70:30 hexanes/EtOAc): Rf=0.30.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][O:13]C(Cl)Cl.Cl.O>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:12]=[O:13])=[C:7]([OH:11])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: COC(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc(C=O)c(O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
A solution of 5.69 g (30 mmol) of titan tetrachloride in 15 ml DCM were added dropwise at 0° C. under nitrogen to 3.76 g (25 mmol) of 3-tert-butylphenol dissolved in 75 ml DCM. After stirring for 30 min 3.16 g (27.5 mmol) of dichloromethyl methyl ether was added. The reaction mixture was stirred for 2 h at 0° C. Carefully 30 ml of 1N aqueous HCl solution and then 90 ml water were added. The reaction mixture was extracted twice with DCM. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (250 g silica gel, DCM) to yield 2.32 g (52%) 4-tert-butyl-2-hydroxy benzaldehyde as a light yellow oil. 1H NMR (DMSO-d6, 300 MHz): δ 10.62 (br s, 1H), 10.18 (s, 1H), 7.61 (d, 1H), 7.04 (d, 1H), 6.98 (s, 1H).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]1([CH3:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:7]1([C:13]2[C:13]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:12][CH:7]=[CH:8][CH:9]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: c1ccc(-c2ccccc2-c2ccccc2)cc1
Yield: 40 %

Procedure:
6.4 mmol of the dibromide (VI) and 6.4 mmol of the arylboronic acid derivative (V) (2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)pyridine) are dissolved in 25 ml of toluene. 0.4 mmol of Pd(PPh3)4 and 10 ml of a 4N solution of Na2CO3 are added, and the mixture is heated up to reflux under nitrogen. The reaction mixture is heated under reflux for 6 hours and cooled, the phases formed are separated, and the water phase is extracted with dichloromethane and dried. The solvent is removed under reduced pressure and the crude product is purified by means of a short silica gel column. After purification by column chromatography (dichloromethane/hexane, 2:1), the desired o-terphenyl derivative is obtained in from 40 to 50% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[CH2:13]([O:20][C:21]1[C:29]([Cl:30])=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([O:31][CH3:32])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:25](=[O:26])[C:24]2[CH:28]=[C:29]([Cl:30])[C:21]([O:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:22][C:23]=2[O:31][CH3:32])[CH2:7]1
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1cc(OCc2ccccc2)c(Cl)cc1C(=O)O
Product: COc1cc(OCc2ccccc2)c(Cl)cc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 4-benzyloxy-5-chloro-2-methoxybenzoic acid.