Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:27])[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20](=O)[CH2:19]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[I:16][C:13]1[CH:14]=[CH:15][C:10]([C:8](=[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[CH2:23][C:18]([CH3:27])([CH3:17])[CH2:19]2)[C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:11][CH:12]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(I)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(I)cc2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 54.9 %

Procedure:
To a stirred suspension of zinc powder (2.20 g, 33.6 mmol) in THF (75 mL) was slowly added TiCl4 (1.85 mL, 16.8 mmol) via syringe at room temperature under a nitrogen atmosphere. The mixture was heated at reflux for 2 h. A solution of (4-hydroxyphenyl) (4-iodophenyl)methanone (143) (1.36 g, 4.20 mmol) and 3,3,5,5-tetramethylcyclohexanone (1.98 g, 12.6 mmol) in THF (20 mL) was added to the mixture. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 25 minutes. The reaction mixture was allowed to cool to room temperature. To the reaction mixture was slowly added 10% aqueous K2CO3 (75 mL). The reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc (200 mL). The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was further extracted with EtOAc (50 mL). The combined organic phase washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as yellow oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 15% EtOAc:hexanes to give a solid residue, which was triturated with hot hexanes to afford 1.03 g (55%) compound 144 as white solid. mp 148-149° C. 1H NMR (400 MHz, DMSO-d6): δ 0.86 (s, 6H), 0.87 (s, 6H), 1.23 (s, 2H), 1.85 (s, 2H), 1.89 (s, 2H), 6.65 (d, J=8.4 Hz, 2H), 6.85-6.95 (m, 4H), 7.61 (d, J=8.3 Hz, 2H), 9.29 (s, 1H). LCMS (ESI): m/z 445 (M−H)−.
Reaction SMILES: [CH3:1][Si:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O:5][CH3:6])[O:3][CH3:4].[H][H]>CCCCCC.[Pd]>[CH:7]1([Si:2]([CH:1]2[CH2:11][CH2:12][CH2:7][CH2:8][CH2:9]2)([O:3][CH3:4])[O:5][CH3:6])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CO[Si](C)(OC)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCCCCC
Product: CO[Si](OC)(C1CCCCC1)C1CCCCC1

Procedure:
An amount, as set forth in Table 1, of a catalyst constituted by palladium supported on active carbon, sold by DUTRAL Company under the trade name MPT/5, containing 5% by weight of palladium, was loaded, in the form of a suspension in n-hexane at 30% by weight, into an autoclave having a volume of 500 cm3. Then methyl-phenyl-dimethoxy-silane and the solvent were added in the amount, as set forth in the Table, till the volume reached 200 cm3. The mixture was then heated gradually over one hour, under strong stirring, at the temperature and the hydrogen pressure, as set forth in Table 1. After the reaction times indicated hereinbefore, the hydrogenation was practically over. The final mass was cooled, the catalyst was separated by decantation and filtration then the solvent was evaporated. Di-cyclohexyl-dimethoxy-silane was obtained, having a purity of 99.6% and in the amount and with yields as set forth in Table 1.
Reaction SMILES: [N+:1]([NH:4][C:5]([NH2:7])=[NH:6])([O-:3])=[O:2].C[O-].[Na+].[CH3:11][C:12]1[CH:13]=[C:14]([CH2:19][CH:20]([CH:26]=O)[C:21](OCC)=[O:22])[CH:15]=[N:16][C:17]=1[CH3:18]>CO>[CH3:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20]2[C:21](=[O:22])[NH:6][C:5]([NH:4][N+:1]([O-:3])=[O:2])=[N:7][CH:26]=2)[CH:15]=[N:16][C:17]=1[CH3:18]
Reactant: N=C(N)N[N+](=O)[O-]
Reactant: CCOC(=O)C(C=O)Cc1cnc(C)c(C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cnc1C

Procedure:
Nitroguanidine (6.05 g) was added to a solution of sodium methoxide (prepared from 1.45 g sodium) in dry methanol (65 ml) and the mixture was heated under reflux for 0.75 hours. Ethyl 3-(5,6-dimethyl-3-pyridyl)-2-formylpropionate (14.3 g) was added and the mixture was heated under reflux for 40 hours and evaporated to dryness. Water (40 ml) was added to the residue and the mixture was extracted with chloroform. The aqueous phase was adjusted to pH 6 with hydrochloric acid and the solid which separated was filtered off and recrystallised from dimethylformamideethanol to give 5-(5,6-dimethyl-3-pyridylmethyl)-2-nitroamino-4-pyrimidone, m.p. 212°-3°.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:19]=[C:9]2[N:10]=[C:11]([C:15]([O:17]C)=[O:16])[CH:12]=[C:13](Cl)[N:8]2[N:7]=1)(=O)C.NC(N)=[S:22]>C(O)C>[C:15]([C:11]1[CH:12]=[C:13]([SH:22])[N:8]2[N:7]=[C:6]([CH2:5][OH:4])[N:19]=[C:9]2[N:10]=1)([OH:17])=[O:16]
Reactant: NC(N)=S
Reactant: COC(=O)c1cc(Cl)n2nc(COC(C)=O)nc2n1
Solvent: CCO
Product: O=C(O)c1cc(S)n2nc(CO)nc2n1
Yield: 85.3 %

Procedure:
In 200 ml of ethanol was dissolved 12 g of 2-acetoxymethyl7-chloro-5-methoxycarbonyl-s-triazolo[1,5-a]pyrimidine under heating, and 8.36 g of thiourea was added to the solution and the mixture was stirred under reflux for 10 minutes. After cooling by allowed to stand, precipitates were collected by filteration, washed with ethanol and then dissolved in 100 ml of a 10% KOH, and the solution was stirred at room temperature for one hour. This solution was adjusted to pH 1 with 2N HCl under ice-cooling and stirring, and precipitates were collected by filtration, washed with water and then dried to obtain 8.13 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[NH2:14][CH2:15][C:16]([OH:18])=[O:17].[OH-].[Na+]>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:7]
Reactant: NCC(=O)O
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 70 °C

Procedure:
5.5 of 3-trifluoromethylbenzoyl chloride were dropped slowly onto 15 ml of an aqueous solution containing 2.0 g of glycine and 2.1 g of sodium hydroxide, and then, after the dropwise addition was complete, the reaction solution was heated at 70° C. for 2 hours, with stirring. The mixture was allowed to stand to cool, and then the reaction solution was washed with ethyl acetate, the aqueous layer was neutralized with 8N hydrochloric acid, and the crystals which separated out were filtered to afford 4.6 g of the title compound, after drying.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]([F:21])([F:20])[C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][N:14]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([C:12]([F:21])([F:11])[F:20])[CH:18]=1)[CH:5]=[O:6]
Reactant: Oc1ccnc(C(F)(F)F)c1
Reactant: O=Cc1ccc(F)c(F)c1
Product: O=Cc1ccc(Oc2ccnc(C(F)(F)F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 2-(trifluoromethyl)pyridin-4-ol.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][CH3:16])[CH:8]=2)[C:3]=1[OH:17].[CH3:18][O:19][CH2:20]Cl.C(N(C(C)C)CC)(C)C>C1COCC1>[Br:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][CH3:16])[CH:8]=2)[C:3]=1[O:17][CH2:18][O:19][CH3:20]
Reactant: CCCc1cc2cc(OC)ccc2c(O)c1Br
Reactant: COCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc2cc(OC)ccc2c(OCOC)c1Br
Yield: 92 %

Procedure:
2-Bromo-6-(methyloxy)-3-propyl-1-naphthalenol (94) (0.62 g, 2.10 mmol) was treated with chloromethyl methyl ether in the presence of diisopropylethylamine in THF to give 0.66 g (92%) of the title compound (95) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.02 (t, J=7.3 Hz, 3H), 1.65-1.75 (m, 2H), 2.84 (t, J=7.7 Hz, 2H), 3.72 (s, 3H), 3.90 (s, 3H), 5.23 (s, 2H), 7.04 (d, J=2.6 Hz, 1H), 7.12 (dd, J1=9.3 Hz, J2=2.5 Hz, 1H), 7.38 (s, 1H), 8.03 (d, J=9.1 Hz, 1H). LCMS (ESI): m/z 361 (M+Na)+, m/z 337 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][C:6]([CH:15]=[O:16])=[CH:5][C:4]=1[CH3:17].[OH-:18].[Na+]>[Ag-]=O>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][C:6]([C:15]([OH:18])=[O:16])=[CH:5][C:4]=1[CH3:17]
Reactant: [OH-]
Reactant: COc1c(C)cc(C=O)cc1-c1ccccc1
Agent: O=[Ag-]
Agent: [Na+]
Product: COc1c(C)cc(C(=O)O)cc1-c1ccccc1
Yield: 89 %

Procedure:
The tide compound was prepared according to the procedure in Example 6, step 3 using 6-methoxy-5-methyl-biphenyl-3-carbaldehyde (1.53 g, 6.77 mmol), silver (I) oxide (1.56 g, 6.77 mmol) and NaOH (2.71 g, 67.7 mmol) to give 1.46 g (89%) of the title compound as a white solid, mp 165-168° C. 1H NMR (DMSO-d6) δ2.34 (s, 3 H), 3.36 (s, 3 H), 7.38-7.55 (m, 5 H), 7.71 (d, 1 H), 7.81 (dd, 1 H). IR (KBr) 3400, 2950, 1700, 1600 and 1410 cm−1. mass spectrum (EI), m/z 242 (M+). Anal. Calcd. for C15H14O30.2 H2O: C, 73.27; H, 5.91; N, 0.00. Found: C, 73.21; H, 5.93; N, 0.17.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][N:12]([S:14](=[O:19])(=[O:18])[N:15]([CH3:17])[CH3:16])[CH:13]=1.C([Li])CCC.CN(C)[CH:27]=[O:28].Cl>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH:27]=[O:28])[N:12]([S:14](=[O:18])(=[O:19])[N:15]([CH3:16])[CH3:17])[CH:13]=1
Reactant: CN(C)S(=O)(=O)n1cnc(-c2ccc(Cl)cc2Cl)c1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)S(=O)(=O)n1cc(-c2ccc(Cl)cc2Cl)nc1C=O
Temperature: 25 °C

Procedure:
To 4-(2,4-Dichlorophenyl)-1-(dimethylsulphamoyl)imidazole, (8.0 g) in tetrahydrofuran (125ml), maintained under a dry nitrogen atmosphere at -60° was added 2.6M butyllithium in hexane (10.57 ml). The solution was stirred and after a short time dimethylformamide (2.9 ml) was added. The mixture was warmed slowly to room temperature and then added to dilute hydrochloric acid. The product was extracted with ethyl acetate and the extract washed with water, dried the solvent evaporated and the solid residue recrystallised from toluene to give 4-(2,4-dichlorophenyl)-1-(dimethylsulphamoyl)-2-formylimidazole, m.p. 148°-157° (dec.).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.Cl[CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.[Ag]=O>[N+:8]([C:7]1[C:2]([O:1][CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)=[N:3][CH:4]=[C:5]([C:11]([F:12])([F:14])[F:13])[CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1O
Reactant: COC(=O)c1ccc(CCl)cc1
Agent: O=[Ag]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(COc2ncc(C(F)(F)F)cc2[N+](=O)[O-])cc1
Yield: 57.4 %

Procedure:
To a solution of 2-hydroxy-3-nitro-5-trifluoromethylpyridine (1.0 g) in toluene (10 ml), methyl 4-chloromethylbenzoate (1.32 g) and silver oxide (1.23 g) were added in a stream of argon. The mixture was refluxed for 18 hours with heating. The reaction mixture was filtered. The filtrate was concentrated. The residue was recrystallized from ethyl acetate to give the title compound (982 mg) having the following physical data.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[N:27][OH:28])[NH2:26].[C:29](OC(=O)C)(=O)[CH3:30]>O>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25]1[N:26]=[C:29]([CH3:30])[O:28][N:27]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=NO)OCO3
Solvent: O
Product: Cc1nc(N2N=C(c3ccc([N+](=O)[O-])cc3)c3cc4c(cc3CC2C)OCO4)no1
Temperature: 110 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A mixture of 3.0 g (7.82 mmol) of the starting material XXIV and 15 ml of acetic anhydride was stirred at 110° C. for 1 h, then after cooling it was diluted with water and extracted with dichloromethane. The organic layer was concentrated and the residue was purified by column chromatography using silica gel (MN Kieselgel 60) as adsorbent and a mire of n-hexane-ethyl acetate (2:1) as eluent to yield 1.58 g (50%) of the title compound; Mp.: 191-200° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:16](=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:19]1[CH:20]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:23][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:16](=[O:17])[CH2:15][CH2:14][N:13]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[CH2:12][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCNCCN1CCCN1CCCCC1
Reactant: FC(F)(F)c1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C1CCN(c2cccc(C(F)(F)F)c2)CCN1CCCN1CCCCC1
Temperature: 110 °C
Yield: 260.8 %

Procedure:
A suspension of 0.02 g (0.10 mmol) of 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one, 3-iodobenzotrifluoride 0.03 g (0.12 mmol), Pd(OAc)2 0.01 g (0.05 mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl 0.03 g (0.05 mmol), cesium carbonate 0.16 g (0.5 mmol) in toluene (1 ml) was heated at 110° C. for 24 h. The reaction was then filtered, concentrated and the residue purified by preparative HPLC affording the title compound 0.1 g (26%) as a gum. MS: 384.2 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31](=[O:51])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[C:42]([CH2:43][O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)=[CH:41][N:40]=[N:39]2)[CH:33]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31](=[O:51])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[C:42]([CH2:43][O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)=[CH:41][N:40]=[N:39]2)[CH:33]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C#N)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C#N)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1

Procedure:
The title compound was prepared from (2-amino-4-cyano-5-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester (Example J12) (318 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (402 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (370 mg, 57%).
Reaction SMILES: C[O:2][C:3]1[CH:16]=[C:15]2[C:6]([CH:7]([CH3:28])[N:8]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=32)=[CH:5][CH:4]=1.B(Cl)(Cl)Cl.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([N:8]2[CH:7]([CH3:28])[C:6]3[C:15](=[CH:16][C:3]([OH:2])=[CH:4][CH:5]=3)[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)(=[O:19])=[O:18])=[CH:21][CH:22]=1
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3cc(OC)ccc3C2C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: CC1c2ccc(O)cc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Yield: 55 %

Procedure:
The title compound was prepared from 9-methoxy-5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.35 g, 0.89 mmol), tetrabutylammonium iodide (0.82 g, 2.2 mmol), and 1 M boron trichloride in dichloromethane (4.44 mL, 4.44 mmol) according to the procedure and in the same manner as described in Example 35, Step b. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (3:7 to 1:1 gradient), to yield 5-[(4-hydroxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridin-9-ol as a solid (0.18 g, 56%), m.p. 212° C.;
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:22][CH:23]([CH2:26][OH:27])[CH2:24][OH:25]>>[OH:25][CH2:24][CH:23]([NH:22][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4])[CH2:26][OH:27]
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)[nH]n1
Reactant: NC(CO)CO
Product: CCCCc1noc(C)c1COc1cc(C(=O)NC(CO)CO)[nH]n1
Yield: 10 %

Procedure:
As described for example 27, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.34 mmol) was converted, using 2-amino-1,3-propandiol instead of L-alaninol, to the title compound (12 mg, 10%) which was obtained as a white solid. MS: m/e=353.3 [M+H]+.
Reaction SMILES: [C:1]([C:3]([CH3:39])([CH3:38])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:19]([CH:26]3[CH2:28][CH2:27]3)[CH2:20][C:21]([O:23]CC)=[O:22])[CH:16]=[CH:17][CH:18]=2)[CH:8]=[CH:7][C:6]=1[C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1[F:37])#[N:2].[OH-].[Na+].Cl>C(O)C>[C:1]([C:3]([CH3:39])([CH3:38])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:19]([CH:26]3[CH2:27][CH2:28]3)[CH2:20][C:21]([OH:23])=[O:22])[CH:16]=[CH:17][CH:18]=2)[CH:8]=[CH:7][C:6]=1[C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1[F:37])#[N:2]
Reactant: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C#N)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(C(CC(=O)O)C4CC4)c3)cc2CC(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.6 %

Procedure:
To a solution of ethyl 3-(3-(((2-(2-cyano-2-methylpropyl)-2′-fluoro-5′-methoxybiphenyl-4-yl)oxy)methyl)phenyl)-3-cyclopropylpropanoate (200 mg) in ethanol (3.0 mL) was added 2N aqueous sodium hydroxide solution (0.38 mL), and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (164 mg) as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.O[C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][N:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:11]([O:10][C:8]([C@@H:5]1[CH2:4][CH2:3][C@H:2]([O:1][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][N:17]=2)[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@H](O)CC1
Reactant: CCOC(=O)c1ccc(O)nc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(O[C@H]2CC[C@@H](C(=O)OC(C)(C)C)CC2)nc1
Reaction time: 1 h
Yield: 45.7 %

Procedure:
1.63 g of tert-butyl trans-4-hydroxycyclohexanecarboxylate (8.14 mmol, 1 eq.) and 1.62 g of ethyl 6-hydroxynicotinate (10.58 mmol, 1.3 eq.) are placed in 24 mL of tetrahydrofuran at room temperature. 3.20 g of triphenylphosphine (12.21 mmol, 1.5 eq.) are added, followed by dropwise addition of 2.37 mL of diisopropyl azodicarboxylate (12.21 mmol, 1.5 eq.) to the reaction medium with stirring. After 1 hour at room temperature, the medium is concentrated to dryness and taken up in diethyl ether. The triphenylphosphine oxide is filtered off. The organic phase is washed successively with sodium hydroxide solution and than with water, dried over magnesium sulfate, filtered and evaporated to give a residue. This residue is chromatographed on silica gel, eluting with a gradient of ethyl acetate in heptane ranging from 3% to 30%. 1.3 g of ethyl cis-6-(4-tert-butoxycarbonylcyclohexyloxy)-nicotinate are obtained.
Reaction SMILES: C([O:8][P:9]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[C:22]([O:28][P:29]([O:39]CC2C=CC=CC=2)([O:31]CC2C=CC=CC=2)=[O:30])[CH:21]=1)([O:11]CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1>[C].[Pd].C(O)C>[P:9]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[C:22]([O:28][P:29]([OH:31])([OH:39])=[O:30])[CH:21]=1)([OH:11])([OH:10])=[O:8]
Reactant: CCc1ccc(OP(=O)(OCc2ccccc2)OCc2ccccc2)cc1OP(=O)(OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(OP(=O)(O)O)cc1OP(=O)(O)O
Temperature: 25 °C
Reaction time: 7 h
Yield: 93.8 %

Procedure:
To an ethanol solution (10 ml) of 1,3-bis(dibenzylphosphonooxy)-4-ethylbenzene (1.09 g), 5% palladium-carbon (50% water-containing product) (97.3 mg) was added and stirred under a hydrogen atmosphere at room temperature for 7 hours. After the removal of the catalyst by filtration, the filtrate was concentrated, to give the title compound (463 mg, yield: 93%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].C([Li])CCC.Cl[C:21]([O:23][CH3:24])=[O:22]>C1COCC1.C(OCC)(=O)C>[CH3:4][C:2]([NH:5][S:6]([C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][C:13]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: Cn1cccc1S(=O)(=O)NC(C)(C)C
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccn(C)c1S(=O)(=O)NC(C)(C)C
Reaction time: 0.5 h
Yield: 14.3 %

Procedure:
To a solution of 2.5 g (11.5 mmol) of N-(1,1-dimethylethyl)-1-methyl-1H-pyrrole-2-sulfonamide in 50 mL THF under nitrogen atmosphere cooled to below -70° C. was added dropwise 13 mL (32.5 mmol) of 2.5M n-butyllithium at such a rate as to keep the temperature below -58° C. After stirring at -20° C. to -10° C. for 30 min then 1 h at 0° C., the mixture was recooled to -70° C. and treated with a solution of 1.63 g (17.3 mmol) of methyl chloroformate in 6 mL THF causing an exotherm to -57° C. The reaction mixture was stirred overnight at ambient temperature then diluted with 200 mL of ethyl acetate. This solution was washed successively with two 60 mL portions of 1N HCl, brine, then dried (Na2SO4) and evaporated to a dark oil. The crude product was purified by chromatography on silica gel (30% ethyl acetate/70% hexanes) then collected from hexanes to afford 0.45 g of the title compound, m.p. 105°-108° C.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][NH2:15])[CH:10]=[CH:11][CH:12]=1.CCN(CC)CC>C(Cl)Cl>[CH3:5][O:4][C:2](=[O:3])[NH:15][CH2:14][CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=1
Reactant: COC(=O)Cl
Reactant: NCCc1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0, methyl chloroformate (4.6 g, 48 mmol) was added dropwise to a solution of 2-(3-chloro-phenyl)-ethylamine (5.0 g, 32 mmol) and Et3N (6.4 g, 64 mmol) in DCM (100 mL). After the addition, the mixture was stirred at room temperature for 0.5 hour. The organic layer was washed with water (3×30 mL), 1N HCl (20 mL) and brine (30 mL), dried over anhy. Na2SO4, filtered and concentrated in vacuo. After vacuum drying, the title compound was obtained (6.49 g, 95%) as a white solid. MS: 214.1 (M+H+).