Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][O:26][C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.[C:47](=O)([O:55]C1C=CC([N+]([O-])=O)=CC=1)[O:48][CH2:49][CH2:50][CH2:51][N:52]([CH3:54])[CH3:53].C(N(CC)CC)C>C(Cl)(Cl)Cl>[O:19]=[C:1]([O:20][CH2:21][CH2:22][N:23]([CH2:24][CH2:25][O:26][C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:47](=[O:55])[O:48][CH2:49][CH2:50][CH2:51][N:52]([CH3:54])[CH3:53])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCCNCCOC(=O)CCCCCCC/C=C\CCCCCCCC
Reactant: CN(C)CCCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)OCCCN(C)C
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
Compound 73 (160 mg, 0.252 mmol) obtained in Example 73 was dissolved in chloroform (2.5 mL), and heat-stirred at 110° C. for 30 minutes with a microwave reactor after adding 3-(dimethylamino)propyl 4-nitrophenyl carbonate hydrochloride (115 mg, 0.379 mmol) synthesized according to the method described in Journal of American Chemical Society (J. Am. Chem. Soc.), 1981, Vol. 103, p. 4194-4199, and triethylamine (0.141 mL, 1.01 mmol). 3-(Dimethylamino)propyl 4-nitrophenyl carbonate hydrochloride (38.4 mg, 0.126 mmol) was added to the reaction mixture, and heat-stirred at 110° C. for 30 minutes with a microwave reactor. After being diluted with chloroform, the reaction mixture was washed with a 1 mol/L sodium hydroxide aqueous solution three times and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/5) to give compound 116 (42.6 mg, 22.1%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]#[C:10][C:11]#[N:12].[CH2:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)[CH2:14][CH3:15].N1C=CC=CC=1.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:20]([C:19]2[CH:23]=[CH:24][C:16]([CH2:13][CH2:14][CH3:15])=[CH:17][CH:18]=2)=[O:21])[CH:5]=[CH:4][C:3]=1[C:9]#[C:10][C:11]#[N:12]
Reactant: CCCc1ccc(C(=O)Cl)cc1
Reactant: N#CC#Cc1ccc(O)cc1F
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1ccc(C(=O)Oc2ccc(C#CC#N)c(F)c2)cc1
Yield: 40 %

Procedure:
To a solution of 20 mmol of 2-fluoro-4-hydroxyphenylpropiolonitrile and 21 mmol of 4-propylbenzoyl chloride in 50 ml of methylene chloride were added dropwise 25 mmol of pyridine, while stirring under ice-cooling and the solution was stirred for a further 3 hours. Water was added to the reaction solution which was extracted with toluene. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a brown oily product. Purification of the product by a silica gel column chromatography and recrystallization from ethanol gave 8 mmol of the title compound.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)([CH3:29])[CH3:28]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:30]([CH:27]([CH3:28])[CH3:29])=[CH:31][CH:32]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CC(C)c1ccc(C(=O)O)cc1
Agent: Cl
Product: CC(C)c1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)cc1

Procedure:
The title compound, light yellow solid (42 mg, 36%), MS (ISP) m/z=473.4 [(M+H)+], mp 188° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-isopropyl-benzoic acid.
Reaction SMILES: N1C=CC=CC=1C.[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH2:15]([O:17][C:18]([C:20]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][C:25](Cl)=[C:26]([F:31])[CH:27]=2)[N:22]([CH2:33][CH3:34])[CH:21]=1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][C:25]([N:12]3[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]3)=[C:26]([F:31])[CH:27]=2)[N:22]([CH2:33][CH3:34])[CH:21]=1)=[O:19])[CH3:16]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1cn(CC)c2cc(Cl)c(F)cc2c1=O
Solvent: Cc1ccccn1
Product: CCOC(=O)c1cn(CC)c2cc(N3CCN(C)CC3)c(F)cc2c1=O
Yield: 64.1 %

Procedure:
A mixture of 8 ml of α-picoline, 4.8 g of 1-methylpiperazine, and 3.6 g of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester was refluxed for 5 hrs. The reaction mixture was treated by operating as in Example 6 to give 2.8 g (64.8% yield) of 1-ethyl-6-fluoro-7-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester. mp: 176°-177° C. The above ethyl ester was hydrolyzed by the same way in Example 1 to obtain the corresponding acid.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:51])[CH2:7][N:8]([CH2:45][C:46]([O:48]CC)=[O:47])[C:9](=[O:44])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[CH:13]=[CH:12][C:11]=1[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)C>>[C:27]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:24]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][O:16][C:14]2[CH:13]=[CH:12][C:11]([O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[C:10]([CH:15]=2)[C:9]([N:8]([CH2:7][C:6]([OH:51])=[O:5])[CH2:45][C:46]([OH:48])=[O:47])=[O:44])=[CH:29][CH:28]=1
Reactant: CCOC(=O)CN(CC(=O)OCC)C(=O)c1cc(OCCCCCCOc2ccc(-c3ccccc3)cc2)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN(CC(=O)O)C(=O)c1cc(OCCCCCCOc2ccc(-c3ccccc3)cc2)ccc1OCc1ccccc1
Yield: 82 %

Procedure:
Sodium hydroxide hydrolysis of N-(2-ethoxy-2-oxoethyl)-N-[5-[[6-([1,1'-biphenyl]-4-yloxy)hexyl]oxy]-2-(phenylmethoxy)benzoyl]glycine ethyl ester under conditions described in Example 81 gave N-[5-[[6-([1,1'-biphenyl]-4-yloxy)hexyl]oxy]-2(phenylmethoxy)benzoyl]-N-(carboxymethyl)glycine (82% yield, mp 98°-100° ).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:29])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[C:30]([O:34][C:35]([NH:37][C:38]1[C:39]([C:53](O)=[O:54])=[N:40][C:41]([C:45]2[C:50]([F:51])=[CH:49][CH:48]=[CH:47][C:46]=2[F:52])=[C:42]([F:44])[CH:43]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:53]([C:39]3[C:38]([NH:37][C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:36])=[CH:43][C:42]([F:44])=[C:41]([C:45]4[C:50]([F:51])=[CH:49][CH:48]=[CH:47][C:46]=4[F:52])[N:40]=3)=[O:54])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1nc(-c3c(F)cccc3F)c(F)cc1NC(=O)OC(C)(C)C)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.8 %

Procedure:
A mixture of 3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (13.0 mg, 0.032 mmol), 3-[(tert-butoxycarbonyl)amino]-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (14.2 mg, 0.039 mmol), HATU (30.5 mg, 0.080 mmol) in DMF (0.09 mL) and DIPEA (0.019 mL, 0.096 mmol) was stirred at room temperature for 16 h. The reaction mixture was diluted with MeOH and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a white powder (14.2 mg, 59%). LCMS calc. for C38H46F3N6O7 (M+H)+: m/z=755.3. Found: 755.1.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([S:1]([OH:3])(=[O:5])=[O:2])=[CH:10][CH:9]=1
Reactant: COc1ccccc1
Reactant: O=S(=O)(O)O
Solvent: O
Product: COc1ccc(S(=O)(=O)O)cc1
Temperature: 82.5 °C
Reaction time: 3 h

Procedure:
560 g of 98% sulfuric acid was dropped into 600 g of methoxybenzene. Then, while the stirring was continued, the temperature was raised into 80 to 85° C., reacting for 3 hours. After the reaction, distillation water was added, adjusting the concentration into 55%. Then, the temperature at about 40° C. was gradually cooled. Upon the temperature reached at 20° C., a small amount of a crystalline of p-methoxybenzenesulfonic acid (4-methoxybenzenesulfonic acid), which was provided in advance, was added, generating crystalline deposition of p-methoxybenzenesulfonic acid in the system. The crystalline as obtained was collected by filtering, into which water was added and the liquid temperature was again raised at 40° C. to dissolve. The concentration was adjusted to have 55%. Then, the temperature at about 40° C. was gradually cooled. Upon the temperature reached at 20° C., a small amount of a crystalline of p-methoxybenzenesulfonic acid, which was provided in advance, was added again, generating crystalline deposition of p-methoxybenzenesulfonic acid. The crystalline was collected by filtration so as to obtain methoxybenzenesulfonic acid in which the para compound was included at 98 mole % in the whole of methoxybenzenesulfonic acid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[Cl:23]>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)/C=C/c1ccccc1CBr
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: CCOC(=O)/C=C/c1ccccc1Cc1ccc(Cl)c(Cl)c1

Procedure:
The benzyl bromide (500 mg) of example 1, step 2 was treated with 3,4-dichlorobenzeneboronic acid according to the same procedure described in step 3 of example 1 to yield 410 mg of the title compound.
Reaction SMILES: [C:1]1([C@@H:7]([NH2:10])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O-])(O)=[O:12].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[N:10]([C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH3:9])=[C:11]=[O:12]
Reactant: CC[C@H](N)c1ccccc1
Reactant: O=C([O-])O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@H](N=C=O)c1ccccc1
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a solution of (S)-1-phenylpropan-1-amine (3.00 g, 14 mmol) in the mixture of methylene chloride (50 mL) and saturated NaHCO3 (50 mL) was added triphosgene (1.40 g, 4.60 mmol) at 0° C. The mixture was stirred for 15 minutes. The organic phase was separated, dried and concentrated to give (S)-(1-isocyanatopropyl)benzene (3.0 g, 88%). 1H NMR (CDCl3): δ=0.93 (q, 3H), 1.81 (m, 2H), 4.50 (m, 1H), 7.13 (m, 2H), 7.22 (m, 1H), 7.50 (m, 2H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][C:14]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:23][CH:22]=1.C(N(CC)CC)C>ClCCl>[CH2:28]([O:27][C:24]1[CH:23]=[CH:22][C:21]([C:14]2[CH:15]=[C:16]([CH:19]=[O:20])[CH:17]=[CH:18][C:13]=2[CH:12]=[O:11])=[CH:26][CH:25]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCOc1ccc(-c2cc(CO)ccc2CO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCCCCOc1ccc(-c2cc(C=O)ccc2C=O)cc1
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
70 ml of dichloromethane were placed in a reaction vessel, admixed with oxalyl chloride (8.4 g, 5.7 ml, 66 mmol) and cooled to −60° C. A solution of DMSO (10.2 g, 9.3 ml, 131 mmol) in 30 ml of dichloromethane was added dropwise to this mixture over a period of 10 minutes. The mixture was stirred for another 5 minutes. A solution of 2,5-bis(hydroxymethyl)-4′-hexyloxybiphenyl (10 g, 32 mmol) (cf. D1) in 70 ml of dichloromethane was then added dropwise over a period of 15 minutes (the reaction solution became turbid). It was stirred for another 10 minutes and triethylamine (15.9g, 21.8 ml, 157 mmol) was subsequently added dropwise. The reaction solution became yellow during this procedure and a precipitate was formed. The acetone/dry ice bath was removed and the mixture was stirred for 2 hours at RT. A light-colored solid was then floating on the yellow liquid phase. The mixture was admixed with 150 ml of water, stirred for another 10 minutes (solid entered solution), the organic phase was separated off, the aqueous phase was extracted twice with dichloromethane, the combined organic phases were subsequently washed three times with water, dried over Na2SO4, filtered and subsequently evaporated to dryness on a rotary evaporator. The yellow oil crystallized after some time at RT and was subsequently recrystallized from hexane. It took a relatively long time for the product to become solid: pale beige, microcrystalline powder, 5.67 g (57%), purity about 98%.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]([O:14]CC)=O)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.O.[NH2:18][NH2:19]>C(O)C.ClCCl>[CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]([NH:18][NH2:19])=[O:14])[CH2:7]2)=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Reactant: NN
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: NNC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Temperature: 80 °C
Yield: 100 %

Procedure:
In a round bottom flask equipped with reflux condenser, an orange solution of ethyl [(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetate (56.1 g, 249 mmol) in ethanol (356 mL) was treated with hydrazine monohydrate (242 mL, 4.98 mol). The resultant yellow solution was stirred at 80° C. (reflux) for 15 h. The reaction was cooled to room temperature and concentrated in vacuo. Ethanol (100 mL) was added and the reaction was concentrated (2×) to give a pale yellow clear oil. The oil was dissolved in dichloromethane (white solution observed), dried over MgSO4, concentrated in vacuo, and pumped under high vacuum overnight (16 h) to give the title compound as a clear pale yellow oil (249 mmol, quantitative). MS(ES)+ m/e 212.0 [M+H]+, 423.2 [2M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C[Si]([CH2:17][C:18]([O:20][CH3:21])=[O:19])(C)C.[Si]([O:29][C@H:30]1[C:35](=[CH2:36])[C@H:34]([O:37][Si:38]([C:51]([CH3:54])([CH3:53])[CH3:52])([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:33][C:32](=O)[CH2:31]1)(C(C)(C)C)(C)C>O1CCCC1>[Si:38]([O:37][C@H:34]1[C:35](=[CH2:36])[C@H:30]([OH:29])[CH2:31]/[C:32](=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])/[CH2:33]1)([C:51]([CH3:54])([CH3:53])[CH3:52])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: COC(=O)C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=C1[C@H](O)C/C(=C/C(=O)OC)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of diisopropylamine (1.2 mL, 9.4 mmol) in 10 mL of tetrahydrofuran was cooled to −78° C.; n-butyllithium (2.5 M in hexanes, 3.6 mL) was added, followed after 5 minutes by methyl trimethylsilylacetate (1.7 mL). The resultant solution was stirred at −78° C. for 30 minutes, and then a solution of the compound of Example 13E (2.0 g, 4 mmol) in 10 mL of tetrahydrofuran was added over 5 minutes. Stirring was continued for 4 hours. The reaction was quenched by addition of saturated aqueous NH4Cl; the mixture was warmed to ambient temperature, and partitioned between ethyl acetate and water. The organic phase was washed with 1 N aqueous HCl and brine, and dried over Na2SO4. The solvents were removed in vacuo; the residue was purified by chromatography on an Analogix Intelliflash 280™, eluting with a gradient of 5% to 10% ethyl acetate in hexanes. The product (1.9 g) was dissolved in 17 mL of ethanol; 1.3 mL of concentrated HCl was added, and the resultant solution was stirred overnight at ambient temperature. The solvents were removed in vacuo, the residue was taken up in saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was concentrated in vacuo and purified by chromatography on an Analogix Intelliflash 280™, eluting with a gradient of 2% to 3% dichloromethane in acetonitrile to afford the titled compound (0.76 g).
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[O:18])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.Cl>C(#N)C>[O:2]=[C:3]1[C:8]([CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[O:18])[CH2:14][CH2:15]2)=[CH:7][CH:6]=[CH:5][NH:4]1
Reactant: COc1ncccc1CN1CCC(CC(=O)c2ccccc2NS(C)(=O)=O)CC1
Agent: Cl
Solvent: CC#N
Product: CS(=O)(=O)Nc1ccccc1C(=O)CC1CCN(Cc2ccc[nH]c2=O)CC1
Yield: 51.7 %

Procedure:
In acetonitrile (4 ml) were dissolved 90 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(2-methanesulfonylaminophenyl)-2-oxoethyl]piperidine obtained in Example 65 and 0.30 ml of concentrated hydrochloric acid, followed by heating under reflux for 5 hours. The solvent was evaporated, and then the residue was dissolved in ethyl acetate and an aqueous 1N sodium hydroxide. The organic layer was separated, washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was recrystallized from ethanol, to give 45 mg of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[NH:4][C@H:5]([C:10]([NH:12][NH:13][CH2:14][CH2:15][C@:16]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([OH:33])[C:17]([N:19]1[C@H:23]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[CH2:30][C@H:22]2[O:21]C1(C)C)=[O:18])=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].C([O-])([O-])=O.[K+].[K+].[Br:48][C:49]1[CH:56]=[CH:55][C:52]([CH2:53]Br)=[CH:51][CH:50]=1>CC(=O)CC>[CH3:1][O:2][C:3](=[O:41])[NH:4][C@@H:5]([C:10]([NH:12][N:13]([CH2:53][C:52]1[CH:55]=[CH:56][C:49]([Br:48])=[CH:50][CH:51]=1)[CH2:14][CH2:15][C@@:16]([OH:33])([C:17](=[O:18])[NH:19][C@H:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][C@H:22]1[OH:21])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:11])[C:6]([CH3:7])([CH3:9])[CH3:8]
Reactant: BrCc1ccc(Br)cc1
Reactant: COC(=O)N[C@H](C(=O)NNCC[C@@](O)(Cc1ccccc1)C(=O)N1[C@H]2c3ccccc3C[C@H]2OC1(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)N[C@@H](C(=O)NN(CC[C@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)Cc1ccc(Br)cc1)C(C)(C)C
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Compound 21i (0.105 g) was dissolved in 2-butanone (10 mL) and added K2CO3 (0.045 g, 0.32 mmol), and 4-bromobenzyl bromide (0.054 g, 0.21 mmol) and stirred at 80° C. for 3 h. Solvent was evaporated and the residue was dissolved in dichloromethane (15 mL), washed with water, brine and cooled to 0° C. TFA (1.0 mL) was added slowly and stirred for 30 min then evaporated. Residue dissolved in dichloromethane (10 mL) and washed with NaHCO3 solution, water, brine and dried. Residue was purified by analytical preparative LCMS to yield 0.023 g (15% overall yield) of the title compound.
Reaction SMILES: C([O:3][C:4]([CH:6]1[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][CH:16]([N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH3:20])[CH3:17])=[CH:14][C:8]=2[O:7]1)=[O:5])C.O.[OH-].[Li+]>CO.O>[C:24]([O:23][C:21]([N:18]([CH2:19][CH3:20])[CH:16]([CH3:17])[CH2:15][C:13]1[CH:12]=[CH:11][C:9]2[O:10][CH:6]([C:4]([OH:5])=[O:3])[O:7][C:8]=2[CH:14]=1)=[O:22])([CH3:26])([CH3:27])[CH3:25]
Reactant: CCOC(=O)C1Oc2ccc(CC(C)N(CC)C(=O)OC(C)(C)C)cc2O1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN(C(=O)OC(C)(C)C)C(C)Cc1ccc2c(c1)OC(C(=O)O)O2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 50 mg (0.13 mmol) of 2D in 2 mL of 50% methanol in water was added 50 mg (1.19 mmol) of lithium hydroxide monohydrate. The mixture was allowed to stir at room temperature 18 hours and was concentrated under reduced pressure. To the residue was added 10 mL of water, and the pH was adjusted to 6 using phosphoric acid. The resulting aqueous solution was extracted with 2×25 mL of chloroform. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give 41 mg (0.12 mmol, 82%) of 2M as a thick colorless gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([O:17][CH3:18])[CH:8]=[CH:7][C:4]=1[CH:5]=O.ClC1C(OC)=C(C=[CH:29][C:30]([OH:32])=[O:31])C=CC=1OC>>[CH3:1][O:2][C:3]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([O:17][CH3:18])[CH:8]=[CH:7][C:4]=1/[CH:5]=[CH:29]/[C:30]([OH:32])=[O:31]
Reactant: COc1ccc(C=O)c(OC)c1-c1ccccc1
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1Cl
Product: COc1ccc(/C=C/C(=O)O)c(OC)c1-c1ccccc1
Yield: 96 %

Procedure:
Compound 3c was synthesized from 2c in 96% yield using the procedure described for 3a. 1H NMR (DMSO-d6): δ 7.81 (d, J=8.8 Hz, 1H), 7.74 (d, J=16.0 Hz, 1H), 7.28-7.42 (m, 5H), 6.97 (d, J=8.8 Hz, 1H), 6.47 (d, J=16.0 Hz, 1H), 3.73 (s, 3H), 3.25 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:28](CO)[CH2:27][CH2:26][C@@:9]32[O:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=2[O:22][CH:23]([CH3:25])[CH3:24])[CH2:10]3)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][S:39]([O:42]S(C)(=O)=O)(=[O:41])=[O:40]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:28]([O:42][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:27][CH2:26][C@@:9]32[O:13][CH2:12][C@H:11]([C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=2[O:22][CH:23]([CH3:24])[CH3:25])[CH2:10]3)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CC(C)Oc1ccc(C#N)cc1C1CO[C@]2(CC[C@H](CO)[C@H]2c2ccc(F)cc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(C#N)cc1[C@H]1CO[C@]2(CC[C@H](OS(C)(=O)=O)[C@@H]2c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5R,6S,7S)-6-(4-fluorophenyl)-3-(5-cyano-2-isopropoxy-phenyl)-1-oxaspiro[4.4]nonane-7-methanol (35 mg, 0.085 mmol) in methylene chloride (1 mL) were added triethylamine (24 μL, 0.172 mmol) and methanesulfonic anhydride (22 mg, 0.126 mmol). The reaction mixture was stirred for 2 hours at room temperature, diluted with methylene chloride, washed with water, 2N hydrochloric acid, saturated sodium hydrogencarbonate solution, saturated brine solution, dried (Na2SO4), and evaporated. The product was used without further purification in Step C.