Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:17][OH:18])[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]=[CH:6][C:5]1=[O:16].[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[Si:19]([O:18][CH2:17][CH:2]([OH:1])[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]=[CH:6][C:5]1=[O:16])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: COc1ccc2ncc(=O)n(CC(O)CO)c2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2ncc(=O)n(CC(O)CO[Si](C)(C)C(C)(C)C)c2c1
Reaction time: 12 h

Procedure:
1-(2,3-Dihydroxypropyl)-7-methoxyquinoxalin-2(1H)-one (3.06 g, 12.22 mmol) was dissolved in dichloromethane (75 ml). To the solution, tert-butyldimethylsilyl chloride (2.03 g, 13.44 mmol), triethylamine (2.21 ml, 15.89 mmol) and 4-dimethylamino pyridine (299 mg, 2.44 mmol) were added under cooling on ice, and the reaction mixture was stirred for 12 hours while the temperature was rising to room temperature. The reaction solution was diluted with dichloromethane, washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to yield 5.29 g (quantitative) of the title compound in the form of a dark orange oily product.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/C)\[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9].C(O)(=[O:16])C#CC.[Li]N1C(C)(C)CCCC1(C)C.BrCC=C(C)C>>[CH3:9][C:8]([CH3:10])=[CH:7][CH2:6][CH2:5][C:4]#[C:3][C:2]([OH:1])=[O:16]
Reactant: CC#CC(=O)O
Reactant: CC(C)=CCC/C(C)=C\CO
Agent: CC(C)=CCBr
Agent: [Li]N1C(C)(C)CCCC1(C)C
Product: CC(C)=CCCC#CC(=O)O

Procedure:
The overall process can be illustrated by the manufacture of nerol, ((Z)-3,7-dimethylocta-2,6-dien-1-ol), which begins with the treatment of 2-butynoic acid with lithium 2,2,6,6-tetramethylpiperidide, followed by alkylation with 1-bromo-3-methyl-2-butene to yield 7-methyloct-6-en-2-ynoic acid as the major product. 2-Ethenylidene-5-methyl-4-hexenoic acid is produced as a minor product in the course of the alkylation. The acids are esterified conveniently with methyl iodide, and treated with morpholine, followed by acid workup, to give a mixture of a major amount of methyl 7-methyloct-6-en-2-ynoate and a minor amount of methyl 2-acetyl-5-methyl-4-hexenoate. The latter compounds are separated by chromatography on a silica gel column using ethyl acetate-n-hexane as eluant. Contacting of the isolated methyl 7-methyloct-6-en-2-ynoate with a mixture of lithium dimethyl cuprate and methyl copper at low temperatures gives methyl (Z)-3,7-dimethylocta-2,6-dienoate, which is reduced to nerol, (Z)-3,7-dimethylocta-2,6-dien-1-ol, for example, with aluminium hydride.
Reaction SMILES: [ClH:1].CCOC(C)=O.[C:8]1([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)[CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1>CCOC(C)=O>[ClH:1].[ClH:1].[NH:30]1[CH2:31][CH2:32][CH:27]([CH2:26][CH2:25][CH2:24][N:21]2[CH2:20][CH2:19][N:18]([C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:11]=[CH:10][N:9]=3)[CH2:23][CH2:22]2)[CH2:28][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN2CCN(c3nccc4ccccc34)CC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc2c(N3CCN(CCCC4CCNCC4)CC3)nccc2c1
Reaction time: 8 h

Procedure:
4 M hydrogen chloride/EtOAc solution (5.0 ml) was dropwise added to an EtOAc (15 ml) solution of tert-butyl 4-[3-(4-isoquinolin-1-ylpiperazin-1-yl)propyl]piperidine-1-carboxylate (1.44 g), followed by stirring overnight. The solvent was evaporated, the solid was washed with EtOAc and collected by filtration to obtain 1-[4-(3-piperidin-4-ylpropyl)piperazin-1-yl]isoquinoline dihydrochloride (1.32 g) as a white solid.
Reaction SMILES: [NH3:1].[C:2]1([CH3:27])[CH:7]=[CH:6][C:5]([C:8](=[O:26])/[CH:9]=[C:10](/[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:14][CH:13]=2)\[CH3:11])=[CH:4][CH:3]=1>CCO.CS(C)=O.CCOC(C)=O>[NH2:1][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][C:22]([F:24])([F:25])[F:23])=[CH:14][CH:13]=1)([CH3:11])[CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:27])=[CH:3][CH:4]=1)=[O:26]
Reactant: N
Reactant: C/C(=C\C(=O)c1ccc(C)cc1)c1ccc(OCCCC(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1ccc(C(=O)CC(C)(N)c2ccc(OCCCC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
Ammonia was bubble into a solution of Intermediate 11D (1.34 mg, 0.64 mmol) in EtOH (20 mL) and DMSO (12 mL) for 10 min at 0° C. The reaction was stirred at rt overnight in a sealed pressure vessel. Analytical HPLC showed reaction to have progressed only ca. 10%. The mixture was cooled to −15° C., then ammonia was bubbled through for 7 min. The vessel was sealed and the reaction was stirred at rt overnight. Analytical HPLC showed the reaction to be ca. 25-30% complete. The mixture was diluted with EtOAc (75 mL), washed with water and sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to provide Intermediate 11E (281 mg, 20%) as a light brown oil. LCMS Anal. Calc'd for C21H24F3NO2 379.42, found [M+H] 380.3.
Reaction SMILES: [C:1](=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:31])=[C:19]([C:21]2([CH:28]3[CH2:30][CH2:29]3)[NH:26][C:25](=O)[CH2:24][O:23][CH2:22]2)[CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>O1CCCC1.C(OCC)(=O)C>[C:1](=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:31])=[C:19]([C:21]2([CH:28]3[CH2:30][CH2:29]3)[NH:26][C:25](=[S:41])[CH2:24][O:23][CH2:22]2)[CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1COCC(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)(C2CC2)N1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(N=C(c2ccccc2)c2ccccc2)cc1C1(C2CC2)COCC(=S)N1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of (RS)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-cyclopropyl-morpholin-3-one (2.10 g, 5.07 mmol) and Lawesson's reagent (0.926 mg, 2.3 mmol) in tetrahydrofuran (15 mL) was stirred at 70° C. for 3 hours. For the workup, the reaction mixture was diluted with ethyl acetate and extracted with a saturated solution of sodium hydrogen-carbonate. The organic layer was dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel using a gradient of hexane/ethyl acetate as the eluent. The (RS)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-cyclopropyl-morpholine-3-thione was obtained as a yellow foam (1.42 g, 65% of theory). Mass (calculated) C26H23FN2OS [430.545]; (found) [M+H]+=431.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:18]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:9]=3[S:8](=[O:27])[C:7]=2[CH:18]=1)#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#Cc1ccc2c(c1)Sc1ccc(O)cc1C=C2
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)S(=O)c1ccc(O)cc1C=C2
Reaction time: 0.5 h

Procedure:
Suspend 50.2 mg. of 3-cyano-8-hydroxydibenzo[b,f]thiepine in 9 ml. of methylene chloride and add 40.6 mg. of m-chloroperbenzoic acid. Allow the mixture to stand at room temperature for 30 minutes. Separate the solids by filtration to obtain the title product (m.p., 241°-243° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl.[NH2:35][OH:36]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([NH:35][OH:36])=[NH:28])=[CH:25][CH:26]=2)[CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
4-Chloro-N-(4-cyano-benzyl)-N-(2-oxo-azepan-3-yl)-benzenesulfonamide (2.09 g, 5.00 mmol), sodium bicarbonate (0.52 g, 6.15 mmol) and hydroxylamine hydrochloride (0.43 g, 6.15 mmol) in a mixture of 20 ml ethanol and 4 ml water were refluxed for 11 hours. The solvents were removed by distillation and the residue was recrystalized from water. The solid was then suspended in dichloromethane, refluxed, cooled to room temperature and filtered to yield 1.74 g (77%) 4-{[(4-chloro-benzenesulfonyl)-(2-oxo-azepan-3-yl)-amino]-methyl}-N-hydroxy-benzamidine as white solid, MS: m/e (%)=451.0 (MH+, 100).
Reaction SMILES: B(O)(O)O.S(=O)(=O)(O)O.[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.[C:20]1([CH:27]=[CH:26][C:24](O)=[CH:23][CH:22]=1)[OH:21].B(O)(O)O.S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1.O.C1(C)C=CC=CC=1>[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:17][C:24]2[CH:26]=[CH:27][C:20]([OH:21])=[CH:22][CH:23]=2)=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: Oc1ccc(O)cc1
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: Cc1ccccc1
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C(Oc1ccc(O)cc1)c1ccc(O)cc1
Reaction time: 3.75 h
Yield: 98.5 %

Procedure:
To carry out the process according to a preferred embodiment the catalysts e.g. 0.01 to 3, preferably 0.1 to 1.5% by weight of boric acid and 0.01 to 3, preferably 0.1 to 1.5% by weight of concentrated sulphuric acid are added to the starting components 4-hydroxybenzoic acid and hydroquinone in an inert solvent, preferably an aromatic hydrocarbon, for example toluene or xylene, and the mixture is esterified under reflux and with removal of the water of condensation, for example through a water separator). Preferably used is a boric acid/sulphuric acid mixture containing 25 to 70 parts by weight of boric acid and 75 to 30 parts by weight of sulphuric acid, in particular about 40 to 60 parts by weight of boric acid and 60 to 40 parts by weight of concentrated sulphuric acid. The esterification reaction in the heterogeneous mixture (when using xylene as solvent) is completely after 3.5 to 4 hours. In the case of lower-boiling solvents such as toluene, the esterification time is extended until virtually complete water separation has occurred. The batch is allowed to cool, and the well-crystallized crude product is rapidly filtered off under suction, and washed with an inert solvent, preferably xylene or toluene, then with dilute sodium hydrogen carbonate solution and subsequently with water. After drying, 4-hydroxyphenyl 4-hydroxy-benzoate is obtained in a yield of 98.5% of theory; melting point 242°-245° C. (when using xylene as solvent). In another preferred embodiment the combination sulforic acid/boric acid is replaced by p-toluene sulfonic acid.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[OH-].[Na+]>>[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCOc1ccc(O)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCOc1ccc(OCCCOc2ccc(C[C@H](OC)C(=O)O)cc2)cc1

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 4-Heptyloxy-phenol under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C36H36O6 [M+Na]+: 467, [M+H]+: 445.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1>C(O)(=O)C.[C].[Pd]>[O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH2:3][CH2:2]1
Reactant: c1cc2occc2cn1
Agent: [Pd]
Solvent: CC(=O)O
Product: c1cc2c(cn1)CCO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.7 %

Procedure:
To a solution of furo[3,2-c]pyridine (500 mg, 4.20 mmol) in acetic acid (8 mL) was added 5% palladium-carbon powder (manufactured by WAKO, 250 mg), and the mixture was stirred at room temperature for 24 hr under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (365 mg, yield 72%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([N:22]1[CH2:23][CH2:24][CH2:25][C:20]([OH:26])([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[CH2:21]1)=[O:5]
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3cc(F)ccc3F)C2)c1

Procedure:
The compound of Example 5 was prepared according to the general preparation protocol A from 2,5-difluorobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]2[O:8][C:9](I)=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[C:3]=1[OH:18].[CH3:19][N:20]([CH3:39])[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:19][N:20]([CH3:39])[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:9]2[O:8][C:5]3[N:6]=[CH:7][C:2]([F:1])=[C:3]([OH:18])[C:4]=3[C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:26][CH:25]=1
Reactant: Oc1c(F)cnc2oc(I)c(-c3ccccc3)c12
Reactant: CN(C)CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CN(C)CCOc1ccc(-c2oc3ncc(F)c(O)c3c2-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
The mixture of 5-fluoro-2-iodo-3-phenyl-furo[2,3-b]pyridin-4-ol (5) (90.0 mg, 0.24, mmol), dimethyl-(2-[4-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)-phenoxy]-ethyl)-amine (114.0 mg, 0.39 mmol), LiCl (33.1 mg, 0.78 mmol), Pd(dppf)2Cl2 DCM (24.5 mg, 0.03 mmol) and Na2CO3 (0.33 mL, 2.0 M in water, 0.65 mmol) was degassed and heated to 80° C. with stirring under nitrogen for 5 h. The solvent was removed. The residue was purified by preparative HPLC to give the title compound. MS (m/z), M+H+ 393.2.
Reaction SMILES: NC1C=C(C)C=CC=1S(N)(=O)=O.C(N=C=S)(C)C.[NH2:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[S:27]([NH:30][C:31]([NH:33][CH:34]([CH3:36])[CH3:35])=S)(=[O:29])=[O:28].C(Cl)(Cl)=O>>[CH:34]([NH:33][C:31]1[NH:19][C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=2[S:27](=[O:29])(=[O:28])[N:30]=1)([CH3:36])[CH3:35]
Reactant: Cc1ccc(S(=O)(=O)NC(=S)NC(C)C)c(N)c1
Agent: CC(C)N=C=S
Agent: Cc1ccc(S(N)(=O)=O)c(N)c1
Agent: O=C(Cl)Cl
Product: Cc1ccc2c(c1)NC(NC(C)C)=NS2(=O)=O

Procedure:
Starting from 2-amino-4-methylbenzenesulfonamide and isopropyl isothiocyanate, and following a procedure analogous to the one described in Example 4a, N-(2-amino-4-methylbenzenesulfonyl)-N′-isopropylthiourea was prepared, m.p. 137-139° C. Subsequent ring closure with phosgene by a procedure analogous to the one described in Example 4b gave the title compound; m.p. 309-311° C.
Reaction SMILES: C1([C:7]2[N:8]=[C:9]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)C=CC=CC=1.[CH3:31][O:32]C1C=CC=CC=1C(=O)C=O>>[CH3:31][O:32][C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:11]1[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:24])([CH3:23])[CH3:25])[C:9]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[N:8][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1c(CCC(=O)O)nc(-c2ccccc2)c1-c1ccccc1
Reactant: COc1ccccc1C(=O)C=O
Product: COc1ccccc1-c1cnc(CCC(=O)O)n1COCC[Si](C)(C)C

Procedure:
Prepared in analogy to the methods described for 3-[4,5-diphenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-propionic acid replacing benzil with (2-methoxy-phenyl)-oxo-acetaldehyde.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.CN.[Li].O>O1CCCC1.C(O)CCC>[CH2:1]1[C:10]2[CH:5]([CH2:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: c1ccc2c(c1)CCNC2
Agent: CN
Agent: [Li]
Solvent: CCCCO
Solvent: O
Solvent: C1CCOC1
Product: C1=CCC2CCNCC2=C1
Temperature: -10 °C

Procedure:
Typically, the tetrahydroisoquinoline was suspended or dissolved in a cosolvent such as tetrahydrofuran ort-butyl alcohol. This mixture was cooled to −10° C. and methylamine was added and the temperature was maintained at −10° C. The lithium metal was charged in portions and the reaction mixture was stirred at −10° C. for another 30 minutes to about 2 hours after sufficient lithium metal was charged. The reaction mixture was warmed to room temperature and then added to water to produce the product hexahydroisoquinoline as a precipitate.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:21])[C:10]=2[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])[N:5](COCC[Si](C)(C)C)[C:4]=1[C:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH:31]=1)#[N:2].Cl>O1CCCC1>[F:21][C:9]1[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[C:11]2[C:3]([C:1]#[N:2])=[C:4]([C:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH:31]=3)[NH:5][C:6]2=[N:7][CH:8]=1
Reactant: COc1ccc(F)cc1-c1c(F)cnc2c1c(C#N)c(C1=CCN(C(=O)OC(C)(C)C)CC1)n2COCC[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CCNCC3)c(C#N)c12
Temperature: 65 °C

Procedure:
To a solution of Example 263F (0.42 g, 0.7 mmol) in tetrahydrofuran (10 mL) was added 35% hydrochloric acid (6 mL) and the mixture was heated at 65° C. overnight. Concentration and purification by HPLC (Zorbax C-18, using a 0-100% gradient of water/acetonitrile, containing 0.1% trifluoroacetic acid) afforded the title compound. 1H NMR (400 MHz, Methanol-d4) δ 3.00 (tq, J=6.2, 2.3 Hz, 2H), 3.58 (td, J=6.5, 2.8 Hz, 2H), 3.77 (s, 3H), 3.77 (s, 3H), 3.98 (q, J=2.7 Hz, 2H), 6.68 (tt, J=3.5, 1.7 Hz, 1H), 7.06-7.17 (m, 2H) 7.19-7.29 (m, 1H), 8.35 (d, J=2.3 Hz, 1H). MS (ESI+) m/z 367 (M+H)+.
Reaction SMILES: [OH:1][C:2]([CH3:15])([CH3:14])[CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[S:4]([NH2:7])(=[O:6])=[O:5].[CH:16]1([N:22]=[C:23]=S)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].BrN1C(=O)CCC1=O>CN1C(=O)CCC1.C1COCC1.O>[CH:16]1([NH:22][C:23]2[O:1][C:2]([CH3:15])([CH3:14])[CH:3]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[S:4](=[O:5])(=[O:6])[N:7]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: S=C=NC1CCCCC1
Reactant: CC(C)(O)C(c1ccccc1)S(N)(=O)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CC1(C)OC(NC2CCCCC2)=NS(=O)(=O)C1c1ccccc1
Reaction time: 0.33 h
Yield: 20.9 %

Procedure:
A solution of 150 mg of 2-hydroxy-2-methyl-1-phenylpropane-1-sulfonamide and 97 mg of cyclohexyl isothiocyanate in 1.5 ml of NMP was admixed with 0.20 ml of a 2 N solution of sodium bis(trimethylsilyl)amide in THF. After stirring for 20 minutes, 71 mg of N-bromosuccinimide were added and the mixture was stirred at room temperature for a further 15 minutes. The reaction solution was admixed with 50 ml of water and extracted twice with 50 ml of ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated by rotary evaporation. The residue was purified in a purification laboratory by means of preparative HPLC, and the product-containing fractions were freed of the organic solvent under reduced pressure. The aqueous residue was extracted three times with dichloromethane, and the combined organic phases were dried using a phase separator cartridge (Chromabond® PTS) and concentrated by rotary evaporation. The residue was dissolved in a mixture of acetonitrile and water and lyophilized. This gave the product (46 mg) with a molecular weight of 336.4 g/mol (C17H24N2O3S); MS (ESI): m/e=337 (M+H+).
Reaction SMILES: [BH4-].[Na+].C([O:10][C:11]1[C:15]([C:16](=O)[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[C:14]([C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[N:13]([CH:35]([CH3:37])[CH3:36])[N:12]=1)C1C=CC=CC=1.[ClH:38]>O1CCCC1>[ClH:38].[CH3:34][N:32]([C:29]1[CH:30]=[CH:31][C:26]([C:14]2[N:13]([CH:35]([CH3:36])[CH3:37])[NH:12][C:11](=[O:10])[C:15]=2[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[CH:27][CH:28]=1)[CH3:33]
Reactant: COc1ccc(C(=O)c2c(OCc3ccccc3)nn(C(C)C)c2-c2ccc(N(C)C)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cc2c(-c3ccc(N(C)C)cc3)n(C(C)C)[nH]c2=O)cc1
Reaction time: 1 h

Procedure:
To a suspension of sodium borohydride (0.016 g) in tetrahydrofuran (4 mL) was added 3-benzyloxy-5-[4-(N,N-dimethylamino)phenyl]-1-isopropyl-4-(4-methoxybenzoyl)-1H-pyrazole (0.098 g) in tetrahydrofuran (1 mL) at 0° C., and the mixture was stirred for 1 hour. Diluted hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was dissolved in methanol (5 mL), and 10% palladium-carbon powder (10 mg) and a hydrochloric acid aqueous solution (2 mol/L, 0.1 mL) were added to the solution. The mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours. The insoluble material was removed by filtration and the solvent of the filtrate was removed under reduced pressure to give the title compound (0.051 g).
Reaction SMILES: [CH3:1][NH2:2].C(O[C:6](=[O:42])[CH2:7][CH:8]([NH:21][CH2:22][CH2:23][N:24]([CH2:32][C:33]1[CH:41]=[CH:40][C:36]2[O:37][CH2:38][O:39][C:35]=2[CH:34]=1)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[N:10]=1)C>C1COCC1>[C:28]([O:27][C:25](=[O:26])[N:24]([CH2:32][C:33]1[CH:41]=[CH:40][C:36]2[O:37][CH2:38][O:39][C:35]=2[CH:34]=1)[CH2:23][CH2:22][NH:21][CH:8]([C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[N:10]=1)[CH2:7][C:6](=[O:42])[NH:2][CH3:1])([CH3:31])([CH3:30])[CH3:29]
Reactant: CCOC(=O)CC(NCCN(Cc1ccc2c(c1)OCO2)C(=O)OC(C)(C)C)c1cc(C)nc(-n2ccnc2)n1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)CC(NCCN(Cc1ccc2c(c1)OCO2)C(=O)OC(C)(C)C)c1cc(C)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
Methylamine (800 μL, 40 wt % aqueous) was added to a solution of 3-[2-(benzo[1,3]dioxol-5-ylmethyl-tert-butoxycarbonyl-amino)-ethylamino]-3-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-propionic acid ethyl ester (15 mg, 0.027 mmol) in THF (0.8 mL). The reaction mixture stirred at room temperature for 16 h then was concentrated under reduced pressure. The residue was purified using column chromatography (DCM to 9:1 DCM/MeOH) to afford 14 mg (96%) of benzo[1,3]dioxol-5-ylmethyl-{2-[1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-2-methylcarbamoyl-ethylamino]-ethyl}-carbamic acid tert-butyl ester as a clear oil.