Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([C:7]1([O:17][CH2:18][C:19]#[CH:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH2:8]1)=O)C#C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[O:28]1CCC[CH2:29]1>>[CH2:18]([O:17][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[CH2:29][OH:28])[C:19]#[CH:20]
Reactant: C1CCOC1
Reactant: C#CCOC(=O)C1(OCC#C)CC=Cc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: C#CCOc1c(CO)ccc2ccccc12

Procedure:
14.55 g of 1-(2-propynyloxy)-naphthoic acid 2-propynyl ester dissolved in 50 ml of absolute tetrahydrofuran are cautiously added at -10° C. under a nitrogen atmosphere to a suspension of 2.09 g of lithium aluminum hydride in 200 ml of absolute tetrahydrofuran. After completion of the addition is complete, the mixture is left to react at about 0° C. for a further 1 hour. To hydrolyze, water is cautiously added dropwise at -10° C. with stirring while the temperature is maintained at 0° C. or below. The mixture is filtered using a filter aid (Celite) and the filtrate is concentrated. The residue is dissolved in ethyl acetate and washed, in sequence, with 2 N hydrochloric acid solution, 10% potassium bicarbonate solution, semi-saturated and saturated sodium chloride solution. The residue is dried over sodium sulfate and evaporated. Pure [1-(2-propynyloxy)-2-naphthyl]methanol, m.p. 65°-68° C. (from hexane/ethyl acetate), is obtained by recrystallization. This material is reacted with cyclopropane carboxylic acid chloride in the procedure described in Example 2 to yield cyclopropane carboxylic acid [1-(2-propynyloxy)-2-naphthyl]methyl ester; nD20 =1.5902.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH:7]=1)=[O:5].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Mg]Br)=[CH:30][CH:29]=1>C1COCC1>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:31]2[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)=[CH:7]1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Cl)c3)c3ccccc3c2=O)cc1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 300 mg (0.84 mmol) of 1-(3-chloro-benzyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 3 mL THF and 3.7 mL 0.5M 4-methoxyphenylmagnesium bromide. Yield: 168 mg of a white solid. LC-MSD, m/z for C24H18ClNO3 [M+H]+=404.1, 406.0; HPLC retention time: 2.4 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[CH:15][C:16](=[O:32])[NH:17][C:18]2[CH:19]=[C:20]3[C:30](=[O:31])[NH:29][N:28]=[CH:27][C:22]4=[CH:23][NH:24][C:25]([CH:26]=2)=[C:21]34)[CH2:10][CH2:9]1)=O)(C)(C)C.[O:33]1CCOCC1>C(Cl)Cl.Cl>[C:30]([OH:31])(=[O:33])[CH3:20].[O:31]=[C:30]1[C:20]2[C:21]3[C:22](=[CH:23][NH:24][C:25]=3[CH:26]=[C:18]([NH:17][C:16](=[O:32])[CH:15]=[CH:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=2)[CH:27]=[N:28][NH:29]1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CCC(C=CC(=O)Nc2cc3c4c(c[nH]c4c2)C=NNC3=O)CC1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)O
Product: O=C(C=CC1CCNCC1)Nc1cc2c3c(c[nH]c3c1)C=NNC2=O

Procedure:
Preparation of the title compound from Intermediate 146(a) (58 mg, 0.13 mmol) in CH2Cl2 (2 mL) and 4M HCl in dioxane (2 mL) was carried out analogously to Example 91. After concentration, the residue was purified by preparative HPLC (Peeke Scientific, HI-Q C18 reverse phase 5u, 100A, 250×21.2 mm column) eluting with CH3CN and 0.1% acetic acid in water at a flow rate of 20 mL/min using a gradient of 5-95% CH3CN over 40 min to give the title compound (16 mg, 0.04 mmol) as a pale yellow powder in 31% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.[NH2:31][CH2:32][C:33]([N:35]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([CH2:44][O:45][C:46]2[C:54]3[N:53]=[C:52]([O:55][CH3:56])[N:51]([CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=4)[C:50]=3[CH:49]=[CH:48][CH:47]=2)[C:38]=1[Cl:64])[CH3:36])=[O:34].O>CN(C=O)C>[Cl:64][C:38]1[C:39]([CH2:44][O:45][C:46]2[C:54]3[N:53]=[C:52]([O:55][CH3:56])[N:51]([CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=4)[C:50]=3[CH:49]=[CH:48][CH:47]=2)=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=1[N:35]([CH3:36])[C:33](=[O:34])[CH2:32][NH:31][C:18]([CH:15]1[CH2:16][CH2:17][N:13]([CH:10]2[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)[CH2:14]1)=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC(C(=O)O)C2)C1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C4CCN(C5CCN(C(=O)OC(C)(C)C)C5)C4)c3Cl)cccc2n1Cc1ccccn1

Procedure:
A solution of 1′-(tert-butoxycarbonyl)-[1,3′-bipyrrolidine]-3-carboxylic acid (0.5 g, 1.0 mmol) in anhydrous DMF (20 ml) was treated with HOBT (Hydroxybenzotriazole) (0.21 g, 1.52 mmol), EDCI (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide), hydrochloride (0.24 g, 1.27 mmol) then 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide (0.50 g, 1.0 mmol) and the mixture was stirred at room temperature overnight. The reaction was treated with water (100 mL) and the resulting precipitate was filtered. The aqueous mixture was treated with aqueous saturated sodium bicarbonate (100 mL), extracted with ethyl acetate (200 mL×2). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give a white solid, 0.62 g that was purified by chromatography (silica gel, dichloromethane and methanol gradient) to afford tert-butyl 3-((2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)carbamoyl)-[1,3′-bipyrrolidine]-1′-carboxylate as a white solid, 0.41 g (53%), that was pure by LC/MS (+ESI) m/z 766 (M+).
Reaction SMILES: [C:1]1([OH:9])[C:2]([CH3:8])=[CH:3][CH:4]=[C:5]([CH3:7])[CH:6]=1.S(Cl)([Cl:13])(=O)=O.S(=O)(O)[O-].[Na+]>ClCCl.C1(SC2C=CC=CC=2)C=CC=CC=1>[Cl:13][C:4]1[CH:3]=[C:2]([CH3:8])[C:1]([OH:9])=[CH:6][C:5]=1[CH3:7]
Reactant: Cc1ccc(C)c(O)c1
Reactant: O=S(=O)(Cl)Cl
Agent: O=S([O-])O
Agent: [Na+]
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(Cl)c(C)cc1O
Temperature: 10 °C
Yield: 97.8 %

Procedure:
To a solution of 100 g (0.82 mol) of 2,5-xylenol and 0.9 g of diphenyl sulfide in 700 mL of dichloromethane was added a solution of 106 g (0.79 mol) of sulfuryl chloride in 100 mL of dichloromethane, maintaining the temperature at 5-15° C. The mixture was stirred for an additional hour and then poured onto 400 g of ice-water containing 5 g of sodium bisulfite. The layers were separated, and the organic phase was washed with water, dried (MgSO4), and concentrated to dryness. The crude solids were slurried with a minimum amount of hexanes, filtered, and suction-dried to give 121 g (94%) of product, homogeneous by Thin Layer Chromatography (TLC), GC, and 1H-NMR analysis. 1H-NMR (CDCl3) δ 2.18 (s, 3H), 2.27 (s, 3H), 4.61 (s, 1H), 6.63 (s, 1H), 7.07 (s, 1H). Lit (Blackstock, Aust. J. Chem. 1973, 26, 775): mp 74-75° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([S:12](Cl)(=[O:14])=[O:13])=[C:9]([CH3:16])[C:8]=2[CH:17]=1)([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([S:12]([NH:18][C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([OH:24])=[O:23])(=[O:14])=[O:13])=[C:9]([CH3:16])[C:8]=2[CH:17]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(S(=O)(=O)Cl)oc2ccc(C(C)C)cc12
Reactant: Nc1cccc(C(=O)O)c1
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)oc2ccc(C(C)C)cc12
Yield: 18.7 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 5-isopropyl-3-methylbenzofuran-2-sulfonyl chloride (Intermediate 16) (24 mg, 0.09 mmol) and 3-aminobenzoic acid (24 mg, 0.18 mmol) giving 6.3 mg (19%) of the title compound. MS (ESI+) calcd for C19H19NO5S 373.098393, found 373.098603.
Reaction SMILES: C(O[C:9](=O)[N:10]([CH:12]([C:14](=[O:48])[NH:15][CH:16]([CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[C:17]([N:19]1[CH2:23][CH2:22][CH:21]2[N:24]([S:38]([CH3:41])(=[O:40])=[O:39])[CH2:25][CH:26]([C:27](=[O:37])[NH:28][CH:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:30])[CH:20]12)=[O:18])[CH3:13])C)C1C=CC=CC=1>CO.C(#N)C.O.[Pd]>[C:31]1([CH:29]([NH:28][C:27]([CH:26]2[CH2:25][N:24]([S:38]([CH3:41])(=[O:40])=[O:39])[CH:21]3[CH2:22][CH2:23][N:19]([C:17](=[O:18])[CH:16]([CH:42]4[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]4)[NH:15][C:14](=[O:48])[CH:12]([NH:10][CH3:9])[CH3:13])[CH:20]23)=[O:37])[CH3:30])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(NC(=O)C1CN(S(C)(=O)=O)C2CCN(C(=O)C(NC(=O)C(C)N(C)C(=O)OCc3ccccc3)C3CCCCC3)C12)c1ccccc1
Agent: [Pd]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: CNC(C)C(=O)NC(C(=O)N1CCC2C1C(C(=O)NC(C)c1ccccc1)CN2S(C)(=O)=O)C1CCCCC1
Reaction time: 2.5 h

Procedure:
A solution of 32 (113 mg, 0.16 mmol) in MeOH (15 mL) was treated with 10% Pd/C (wet, 151 mg) and pressurized under H2 atmosphere (50 psi) using a Parr apparatus. After 2.5 h, the reaction mixture was filtered through a filter disc (Acrodisc-PSF-0.45 μM) and rinsed with MeOH. The filtrate was concentrated to afford the crude amine 33 which was diluted with ACN/H2O containing 0.1% HOAc and purified by reverse phase HPLC (2″ Dynamax® C18, 10% ACN/H2O to 100% ACN over 30 min). The product-containing fractions were combined, frozen, and lyophilized to afford 33 as a white solid.
Reaction SMILES: O[CH:2]1[CH2:6][CH:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:4]([CH3:12])[CH2:3]1.N1C=CC=CC=1.CS(Cl)(=O)=O.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH3:12][C@@H:4]1[CH2:3][C@@H:2]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:6][C@@H:5]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:12][C@H:4]1[CH2:3][C@H:2]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:6][C@H:5]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)C1CC(O)CC1C
Agent: CS(=O)(=O)Cl
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)[C@@H]1C[C@@H](Nc2ccccc2)C[C@@H]1C
Product: CCOC(=O)[C@H]1C[C@H](Nc2ccccc2)C[C@H]1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ethyl 4-hydroxy-2-methylcyclopentanecarboxylate (1.81 g, 10.5 mmol, prepared using P from Example #7, step G and NaBH4) and pyridine (1.28 mL, 15.8 mmol) in THF (52.5 mL) was cooled to about 0° C. Methanesulfonyl chloride (0.90 mL, 12 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for about 16 h then partitioned between water (50 mL) and DCM (30 mL). The layers were separated and the aqueous layer was extracted with DCM (2×30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concd under reduced pressure to give a white solid. The resulting solid was mixed with aniline (78.0 g, 841 mmol) and heated at about 90° C. for about 16 h. The reaction mixture was concd under reduced pressure and purified by silica gel chromatography eluting with a gradient of 20-100% EtOAc in DCM to yield (1S,2R,4R)-ethyl 2-methyl-4-(phenylamino)cyclopentanecarboxylate and (1R,2S,4S)-ethyl 2-methyl-4-(phenylamino)cyclo-pentanecarboxylate with 29 mol % aniline as an excipient (2.73 g, 75%) as a dark oil: LC/MS (Table 1, Method b) Rt=2.67 min; MS m/z: 248 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[CH:5][N:4]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1>>[CH3:28][N:25]1[C:26]2[CH:27]=[C:19]([N:12]3[CH:13]=[CH:14][C:9]([C:6]4[CH:5]=[N:4][C:3]([C:2]([F:1])([F:16])[F:17])=[N:8][CH:7]=4)=[CH:10][C:11]3=[O:15])[CH:20]=[CH:21][C:22]=2[C:23]2[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:24]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(-c2cnc(C(F)(F)F)nc2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(-c5cnc(C(F)(F)F)nc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 24.4 %

Procedure:
4-(2-(Trifluoromethyl)pyrimidin-5-yl)pyridin-2(1H)-one (100 mg, 0.42 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (116 mg, 0.32 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (41 mg, 24%) as a yellow oil: ESI MS m/z 526 [M+H]+.
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl.[O:20]1[C:25]2([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)[CH2:24][NH:23][CH2:22][CH2:21]1.[CH3:38][C:39]1[S:40][CH:41]=[C:42]([C:44](O)=[O:45])[N:43]=1.C(N(CC)CC)C>CN(C=O)C.O>[CH3:38][C:39]1[S:40][CH:41]=[C:42]([C:44]([N:23]2[CH2:24][C:25]3([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)[O:20][CH2:21][CH2:22]2)=[O:45])[N:43]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Reactant: Cc1nc(C(=O)O)cs1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cs1
Reaction time: 16 h

Procedure:
1-Propanephosphonic acid cyclic anhydride (1.57M solution in THF, 4.18 mL) was added to a solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (1.92 g), 2-methylthiazole-4-carboxylic acid (0.94 g) and triethylamine (5.48 mL) in DMF (70 mL) and the resulting mixture stirred for 16 h. The reaction mixture was poured into water (500 mL) and extracted with ethyl acetate (3×200 mL). The combined organic solutions were washed with water (2×100 mL) and brine (100 mL), dried over magnesium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with ethyl acetate to give the subtitled compound as a clear oil. Yield 2.30 g.
Reaction SMILES: Br.Br.[CH3:3][N:4]([CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1)[CH3:5].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27](O)=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[CH3:5][N:4]([CH2:6][C:7]1([C:27](=[O:28])[CH2:26][C:21]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=2)[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1)[CH3:3]
Reactant: CN(C)CC1NCCc2c(O)cccc21
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C)CC1(C(=O)Cc2ccc(Cl)c(Cl)c2)NCCc2c(O)cccc21

Procedure:
Prepared as Ex. No. 5, from 4.5 g (12.2 mmoles) of 1-dimethylaminomethyl-5-hydroxy-1,2,3,4-tetrahydroisoquinoline dihydrobromide, 3.3 g (16.10 mmoles) of 3,4-dichlorophenylacetic acid, 4.3 ml (30.60 mmoles) of triethylamine and 5.1 g (24.75 mmoles) of dicyclohexylcarbodiimide in 120 ml of dry chloroform.
Reaction SMILES: C[N:2]1CCOCC1.ClC(OCC(C)C)=O.[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[C:28]([OH:30])=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].[OH-].[NH4+]>C1COCC1>[C:16]([O:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[C:28](=[O:30])[NH2:2])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
N-Methylmorpholine (9.85 g, 97.5 mmol) and isobutyl chloroformate (13.33 g, 97.5 mmol) was added to (R)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (20.0 g, 92.9 mmol) in THF (200 mL) at −78° C. and stirred for 1 h. Ammonium hydroxide (58 mL) was added slowly as the reaction warmed up to RT and stirred for a further 2 h. The reaction mixture was partitioned between DCM and water. The organic extracts were washed with 1 M HCl, dried over sodium sulphate, filtered and concentrated to afford the title product (10.8 g, 54%) as a colourless semisolid.
Reaction SMILES: [O-]Cl=O.[Na+].[OH2:5].[CH2:6]([C:13]1([CH2:19][CH:20]=[O:21])[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CS(C)=O.CCOCC>[CH2:6]([C:13]1([CH2:19][C:20]([OH:5])=[O:21])[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=CCC1(Cc2ccccc2)C=CCCC1
Reactant: O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CS(C)=O
Solvent: CCOCC
Product: O=C(O)CC1(Cc2ccccc2)C=CCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of NaH2PO4 (55.3 g), NaClO2 (36.3 g), DMSO (200 mL) and water (375 mL) was added a solution of 3-benzyl-3-formylmethylcyclohexene (57 g) in DMSO (150 mL) during a 3 hour period. After addition, the mixture was stirred overnight and diluted with ether (200 mL). This was extracted with saturated NaHCO3 (3×100 mL). The combined aqueous layer was cooled to 0° C. and acidified to PH=1 with conc. HCl. This was extracted with CH2Cl2 (3×300 mL). The combined organic layer was dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel to give the title compound as thick oil (50 g). MS (MH+=231).
Reaction SMILES: C[C:2](=[N:5]O)[CH2:3][CH3:4].[C:7]1(=[O:14])[NH:13][CH2:12][CH2:11][CH2:10]CC1.C([O-])(=O)C[C:17](C)=[O:18].C([O-])(=O)CC([O-])=O.C(OCC)(=O)CC(OCC)=O>C(OCC)(=O)C>[CH2:4]([CH2:3][CH2:2][N:5]=[C:17]=[O:18])[CH2:10][CH2:11][CH2:12][N:13]=[C:7]=[O:14]
Reactant: O=C1CCCCCN1
Reactant: CCC(C)=NO
Reactant: CC(=O)CC(=O)[O-]
Agent: O=C([O-])CC(=O)[O-]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CCOC(C)=O
Product: O=C=NCCCCCCN=C=O

Procedure:
Suitable blocking agents or example, an oxime (preferably butanone oxime), a lactam (preferably ε caprolactam), an acetoacetate (preferably ethyl acetate), a malonate (preferably diethyl malonate), or a substituted phenol. Within the substitued phenols, p-hydroxybenzoic acid esters (e.g. p-hydroxybenzoic acid ethyl ester) are particularly preferred. They have low cleavage temperatures (less than 150° C.), and the ester eliminated has a low volatility and no unpleasant odor. In one preferred embodiment of the invention, component III may be obtained by reaction of the trimer (i.e. isocyanurate) of 1,6-hexamethylene diisocyanate with a hydroxyfunctional polyester, especially a polyadipate having a melting range of no more than 100° C. In another embodiment of the invention, 1,3-bis-(isocyanato-organo)-2,4-dioxo-1,3-diazetidines or 3,5-bis-(isocyanato-organo)-2,4,6-trioxotetrahydro-1,3,5-oxadiazines, such as, e.g., the adduct of 2 moles 1,6-hexamethylene diisocyanate and 1 mole carbon dioxide, may also be used as blocked polyisocyanates.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:49][CH:50]([CH3:52])[CH3:51])[CH2:14][C@@H:15]([OH:48])[C@@H:16]([NH:36][C:37](=[O:47])[O:38][C@@H:39]3[C@H:46]4[C@H:42]([O:43][CH2:44][CH2:45]4)[O:41][CH2:40]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][O:28][Si](C(C)(C)C)(C)C)=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.C(O)(=O)C>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:49][CH:50]([CH3:52])[CH3:51])[CH2:14][C@@H:15]([OH:48])[C@@H:16]([NH:36][C:37](=[O:47])[O:38][C@@H:39]3[C@H:46]4[C@H:42]([O:43][CH2:44][CH2:45]4)[O:41][CH2:40]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][OH:28])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCO[Si](C)(C)C(C)(C)C)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCO)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2

Procedure:
(3R,3aS,6aR)-Hexahydro-furo[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-1-[4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)benzyl]-2-hydroxypropylcarbamate was treated with 1M tetra-n-butyl ammonium fluoride/tetrahydrofuran/acetic acid as described in step b (Example 213) to afford the title compound as a white solid. 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d), 1.2 (1H, dd), 1.38 (1H, quintuplet), 1.8 (2H, quintuplet), 1.9-2.0 (1H, m), 2.38 (1H, t), 2.6-2.8 (3H, m), 2.9 (1H, d), 2.96 (1H, dd), 3.3 (1H, br s) 3.4-3.6 (6H, m), 3.7 (1H, t), 3.8 (1H, dd), 3.9 (2H, t), 4.5 (1H, t), 4.8 (1H, dt), 5.0 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 6.78 (2H, d), 7.0-7.1 (3H, m), 7.2 (1H, d), 7.25 (1H, s), 7.3 (1H, d); MS: 651 (MH+)
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([CH2:12][C:13](=[O:21])C[CH2:15]1)[CH2:10][CH2:9]3.C(N(CC)[CH:26]([CH3:28])[CH3:27])(C)C.CI.[CH2:33](OCC)C>CN(C=O)C.[Ag]=O>[CH3:33][O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([CH2:12][C:13](=[O:21])[C:26]([CH3:27])([CH3:28])[CH2:15]1)[CH2:10][CH2:9]3
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reactant: CCOCC
Reactant: CCN(C(C)C)C(C)C
Agent: O=[Ag]
Solvent: CI
Solvent: CN(C)C=O
Product: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)C(C)(C)C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
17β-Hydroxy-5α-androstan-3-one (50 g.) in DMF (500 ml.) is cooled to 5° in an ice bath and silver oxide (58 g.) and N,N-diisopropylethylamine is added (85 ml.). The mixture is stirred and methyl iodide (142 g.) is slowly added keeping the temperature at about 5°. The stirring is continued and the mixture is allowed to come to 20°-25°. After 17 hours diethyl ether (2 l.) is added and the mixture filtered thru a bed of Celite to remove the inorganic solids. The filtrate is washed with water, dilute hydrochloric acid, water again, and dried over sodium sulfate, then filtered, and concentrated. The concentrate is column chromatographed over silica gel. The appropriate fractions (TLC) are pooled and concentrated to give the title compound, m.p. 116°-120°, IR (mull) 1700 cm-1 ; NMR (CDCl3) 0.77, 1.01, 1.08, 1.18, 3.24, and 3.37 δ.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:5][CH:4]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C1COCC1>[Br-:14].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]2[CH:13]=[CH:12][N:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCCCCCCBr
Reactant: COc1ccc(-n2ccnc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCn1cc[n+](-c2ccc(OC)cc2)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure 5.7 mmol (1.00 g) 1-(4-methoxyphenyl)imidazole and 6.9 mmol (1.23 g, 1.1 ml) 1-bromoheptane are dissolved in 5 ml THF and heated for 18 h to 90° C.