Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:29]=[CH:30][C:31]=2[O:32][CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:9]([NH:11][CH:12]2[CH2:17][CH:16]([OH:18])[CH2:15][CH2:14][CH:13]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)=[O:10])[CH2:3][CH2:2]1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:9]([NH:11][CH:12]3[CH:13]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=4)[CH2:14][CH2:15][CH:16]([O:18][C:37](=[O:39])[CH3:38])[CH2:17]3)=[O:10])[CH:29]=[CH:30][C:31]=2[O:32][CH2:33][CH:34]2[CH2:35][CH2:36]2)[CH2:2][CH2:3]1
Reactant: COc1ccc(C2CCC(O)CC2NC(=O)c2ccc(OCC3CC3)c(OCC3CC3)c2)cc1OC
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(C2CCC(OC(C)=O)CC2NC(=O)c2ccc(OCC3CC3)c(OCC3CC3)c2)cc1OC
Temperature: 100 °C

Procedure:
3.65 g of (±)-3,4-bis-cyclopropylmethoxy-N-[(1RS,2RS,5SR)-2-(3,4-dimethoxyphenyl)-5-hydroxycyclohexyl]benzamide (compound B2) are dissolved in 50 ml of acetic anhydride and the solution is heated to 100° C. for 3 h. The solution is concentrated and the residue is chromatographed on silica gel using a mixture of petroleum ether/ethyl acetate/triethylamine in the ratio 6/3/1. 1.8 g of the title compound of m.p. 90-95° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[OH-].[K+].[C:12](OC(=O)C)(=[O:14])[CH3:13]>O>[C:12]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH2:5][OH:6])[CH:3]=1)(=[O:14])[CH3:13]
Reactant: OCc1cccc(O)c1
Reactant: CC(=O)OC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Oc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.7 %

Procedure:
To a stirred solution of 3-hydroxybenzylalcohol (1.0 g, 8 mmol, 1 equiv.) in 6.4N KOH solution (1.86 ml, 12 mmol, 1.5 equiv.) at r.t., ice (4 g) was added followed by acetic anhydride (0.95 ml, 10 mmol, 1.25 equiv.). The reaction mixture was stirred at r.t. for 3 h. Water (50 ml) was added and the mixture was stirred for 30 min, before extracting with CH2Cl2 (2×50 ml). The combined organic extracts were washed with brine (50 ml), dried (Na2SO4) and evaporated to dryness, under reduced pressure. The clear oil residue was purified by column chromatography on silica, eluted with EtOAc/hexane (1:2), to give the desired product as a clear oil (714 mg, 54% yield). HPLC-MS (method 1): m/z 165 [M−H]−. Rt=2.52 min.
Reaction SMILES: Br[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[C:15](B(O)O)=[CH:14][CH:13]=[N:12]1.C([O-])(O)=O.[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:9]1[C:2]([C:13]2[NH:12][N:11]=[CH:15][CH:14]=2)=[C:3]([CH:6]=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: OB(O)c1ccn[nH]1
Reactant: N#Cc1cccc(F)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1cccc(F)c1-c1ccn[nH]1
Temperature: 23 °C
Yield: 20.7 %

Procedure:
2-Bromo-3-fluorobenzonitrile (1.0 g, 5.0 mmol) and (1H-pyrazol-5-yl)boronic acid (647 mg, 4.6 mmol) were combined and dissolved in degassed DME (15 mL) then treated with NaHCO3 (1260 mg, 8.4 mmol) in water and the reaction purged with bubbling N2 for 5 minutes. The reaction was treated with Pd(PPh3)4 (288 mg, 0.2 mmol) and then purged with bubbling for 5 minutes in a sealed vessel and then heated to reflux for 2 h. Cooled to 23° C. filtered and solid rinsed with EtOAc and the layers separated. The organic layers were combined, dried and concentrated under reduced pressure. Chromatography (0-30% ethyl acatate/hexanes) afforded 3-fluoro-2-(1H-pyrazol-5-yl)benzonitrile (178 mg, 19%).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[Na+].[CH3:6][O:7][C:8]1[CH:12]=[CH:11][NH:10][C:9]=1/[CH:13]=[C:14]1\[C:15](=[O:30])[NH:16][C:17]2[C:22]\1=[C:21](C#CCCC([O-])=O)[CH:20]=[CH:19][CH:18]=2>CN(C=O)C.CCN(CC)CC>[OH:4][CH2:1][C:2]#[C:3][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]=1/[C:14](=[CH:13]/[C:9]1[NH:10][CH:11]=[CH:12][C:8]=1[O:7][CH3:6])/[C:15](=[O:30])[NH:16]2
Reactant: C#CCO
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCC(=O)[O-])c21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCO)c21

Procedure:
Using Method D above, propargyl alcohol (43.9 mg, 0.78 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.31 mmol) (Starting Material I supra) using DPPFPdCl2 (12.8 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 85° C. for 18 h to yield (Z)-1,3-dihydro-4-(3-hydroxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 42 mg, 46%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:8][CH:5]1[CH2:6][CH2:7][C:2](=[O:1])[CH2:3][CH2:4]1
Reactant: O=C1CCC(O)CC1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: O=C1CCC(OC2CCCCO2)CC1
Reaction time: 2.5 h

Procedure:
A solution comprising 10 g. of 4-hydroxycyclohexanone, 10 g. of dihydropyran and 0.5 g. of p-toluenesulfonic acid in 100 ml. of ether is allowed to stand at room temperature for about 2.5 hours. The solution is then washed with saturated aqueous sodium bicarbonate solution and brine, 50 ml. of dry benzene added and the solution then evaporated to dryness to give 4-[(tetrahydropyran-2-yl)oxy]cyclohexanone as an oil.
Reaction SMILES: C(O)(=O)C.CO[CH:7]1[CH2:11][CH2:10][CH:9](OC)O1.[NH2:14][C:15]1[CH:39]=[CH:38][C:18]([C:19]([NH:21][C:22]2[CH:30]=[C:29]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:28]=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[O:31]([C:29]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[C:22]([NH:21][C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([N:14]3[CH:7]=[CH:11][CH:10]=[CH:9]3)=[CH:39][CH:38]=2)[CH:30]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccc(C(=O)Nc2cc(Oc3ccccc3)ccc2C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(Oc2ccccc2)ccc1C(=O)O)c1ccc(-n2cccc2)cc1
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
0.25 mL of acetic acid and 4.1 μL of 2,5-dimethoxytetrahydrofuran were added sequentially to 10 mg of 2-(4-aminobenzamido)-4-phenoxybenzoic acid at room temperature and stirred at 90° C. for 5 minutes. After the reaction mixture was cooled so room temperature, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified wish silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; ethyl acetate] to obtain 3.8 mg of 4-phenoxy-2-(4-(1H-pyrrol-1-yl)benzamido)benzoic acid a brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[N:3]=1.[Cl:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.C(N(CCC)CCC)CC>C(O)CC(C)C>[ClH:22].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[CH2:18][CH2:17]2)[N:3]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: Clc1ccc2ccccc2n1
Agent: CCCN(CCC)CCC
Solvent: CC(C)CCO
Product: COc1cc2nc(N3CCN(c4ccc5ccccc5n4)CC3)nc(N)c2cc1OC
Product: Cl
Yield: 79.5 %

Procedure:
Mixed were 0.72 g (2.5 mmol) of 4-amino-6,7-dimethoxy-2-piperazinoquinazoline, 0.63 g (3.9 mmol) of 2-chloroquinoline, 0.43 g (3 mmol) of tri-n-propylamine and 15 ml of isoamyl alcohol. The mixture was refluxed for 16 hours. After cooling the reaction mixture, the resultant crystals were collected by filtration, followed by their dissolution in a mixed solvent of 10 ml of dichloromethane and 10 ml of methanol. To the solution, 2 ml of a 20% ethanol solution of hydrochloric acid was added. The solvents were distilled off to obtain 0.90 g of the above-identified compound (yield: 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[C:13](=[CH:14][N:15]([CH3:18])[N:16]=2)[CH:12]=[CH:11][CH:10]=1.[Br:19]Br>C(O)(=O)C>[Br:19][C:14]1[N:15]([CH3:18])[N:16]=[C:17]2[C:13]=1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Cn1cc2cccc(-c3ccc(Cl)cc3Cl)c2n1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cn1nc2c(-c3ccc(Cl)cc3Cl)cccc2c1Br

Procedure:
To a solution of 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole (0.659 g, 2.38 mmol) in 2 mL of acetic acid was added bromine (0.122 mL, 2.38 mmol) dropwise. The yellow-orange solution was stirred for 15 m, in which time an orange solid precipitated. The mixture was concentrated to a yellow solid, which was partitioned between 20 mL of a 10% aqueous NaOH solution and 20 mL of diethyl ether. The organic layer was washed with 20 mL of a saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated to a yellow-stained white solid. Column chromatography (0→10% EtOAc/hexanes) afforded 3-bromo-7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole as a white solid (24: Ar=2,4-dichlorophenyl; 0.525 g; 62%; m.p. 137-139).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[C:9]([O:13][C:14]([NH:16][C@H:17]([C:22](O)=[O:23])[C@H:18]([CH2:20][CH3:21])[CH3:19])=[O:15])([CH3:12])([CH3:11])[CH3:10].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:10][C:9]([O:13][C:14](=[O:15])[NH:16][CH:17]([C:22]([NH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)=[O:23])[CH:18]([CH3:19])[CH2:20][CH3:21])([CH3:12])[CH3:11]
Reactant: NCc1cccnc1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(C)C(NC(=O)OC(C)(C)C)C(=O)NCc1cccnc1
Yield: 70.7 %

Procedure:
The title compound is prepared by the procedure of Example 1, using 1.0 g of 3-(aminomethyl)pyridine, 2.33 g of N-(tert-butoxycarbonyl)-L-isoleucine, 6.95 g of BOP, 11.95 g of Hunig's base and 15 ml of methylene chloride to give 2.1 g of the desired product after chromatography.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[F:5][C:6]1[CH:7]=[C:8]([CH:38]=[CH:39][C:40]=1[F:41])[O:9][C:10]1([C:33](OCC)=[O:34])[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[O:29][C:28]([CH3:30])=[N:27][CH:26]=4)=[C:21]([O:31][CH3:32])[CH:20]=3)=[N:17][N:18]=[C:11]12.[Cl-].[NH4+].[CH2:44]1COC[CH2:45]1>>[F:5][C:6]1[CH:7]=[C:8]([CH:38]=[CH:39][C:40]=1[F:41])[O:9][C:10]1([C:33]([OH:34])([CH2:1][CH3:2])[CH2:44][CH3:45])[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[O:29][C:28]([CH3:30])=[N:27][CH:26]=4)=[C:21]([O:31][CH3:32])[CH:20]=3)=[N:17][N:18]=[C:11]12
Reactant: CC[Mg]Br
Reactant: CCOC(=O)C1(Oc2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: CCC(O)(CC)C1(Oc2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21

Procedure:
Under an argon atmosphere, ethylmagnesium bromide (1M THF solution, 11.8 mL) was added to a suspension of ethyl 8-(3,4-difluorophenoxy)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (1200 mg) in THF (12 mL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hr, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (230 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24].[F:27][C:28]([F:41])([F:40])[O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([Cl:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[ClH:39].[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:36]([C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]([F:27])([F:40])[F:41])=[CH:35][CH:34]=3)(=[O:38])=[O:37])=[C:3]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(C)(=O)=O)c2)CC1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Product: CS(=O)(=O)Nc1cc(N2CCCNCC2)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1
Product: Cl

Procedure:
The compound was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}methanesulfonamide and 4-trifluoromethoxybenzenesulfonylchloride (119 mg, 0.455 mmol) give 140 mg as a purple solid. M+1 509.1 Calcd 509.11.
Reaction SMILES: CO[C:3](=O)[C:4]1[CH:9]=C(O)C=[C:6](OCC=C)[CH:5]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:24]=[C:25]([OH:27])[CH:26]=1)[C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+].BrCC=C(C)C>>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:18]=[C:17]([O:16][CH2:6][CH:5]=[C:4]([CH3:9])[CH3:3])[CH:26]=[C:25]([OH:27])[CH:24]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: C=CCOc1cc(O)cc(C(=O)OC)c1
Agent: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc(O)cc(OCC=C(C)C)c1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1a, from methyl 3,5-dihydroxybenzoate (11.3 g, 67 mmol), potassium carbonate (18.5 g, 134 mmol), and 1-bromo-3-methyl-but-2-ene (10 g, 67 mmol). Purification by column chromatography eluting with 20% EtOAc in hexane gave a pale yellow solid (3.41 g, 20% yield). 1H NMR (400 MHz, CDCl3) δ 7.17-7.20 (m, 1 H) 7.12-7.17 (m, 1 H) 6.63 (t, J=2.27 Hz, 1 H) 5.41-5.51 (m, 1 H) 5.50 (s, 1 H) 4.53 (d, J=6.57 Hz, 2 H) 3.91 (m, 3 H) 1.80 (s, 3 H) 1.69 (s, 3 H); LCMS for C13H16O4 m/z 237.10 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:6]=1[S:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16].O1CCCC1.[OH-].[Li+]>CO.O>[CH3:14][O:13][C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:5]([CH2:4][C:3]([OH:34])=[O:2])=[C:6]([S:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)(=[O:16])=[O:17])[CH:7]=1
Reactant: COC(=O)Cc1cc(OC)c(OC)cc1S(=O)(=O)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CC(=O)O)c(S(=O)(=O)N2CCN(c3ccc(C(F)(F)F)cn3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
{4,5-Dimethoxy-2-[4-(5-trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]phenyl}acetic acid methyl ester (0.3 g) was taken up in methanol (10 ml), tetrahydrofuran (10 ml) and water (10 ml). Lithium hydroxide (125 mg) was added and the reaction stirred at RT for 16 hrs. The reaction was diluted with water (10 ml), its volume reduced to one third in vacuo, and the reaction extracted with diethyl ether (3×15 ml). The aqueous layer was acidified to pH 4 with 2M hydrochloric acid and extracted with ethyl acetate (4×25 ml). The combined ethyl acetate extracts were washed with water (25 ml) and brine (25 ml) and dried over sodium sulphate. The solvent was removed in vacuo to yield the title compound as a white solid (291 mg, 100%).
Reaction SMILES: [N+]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=1)([O-])=O.[OH-].[K+].ClC[C:17](=O)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>CCO>[S:10]1[C:6]2[CH:5]=[CH:4][CH:12]=[CH:11][C:7]=2[NH:8]/[C:17](=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])/[CH2:9]1
Reactant: O=[N+]([O-])c1ccc2ncsc2c1
Reactant: CCOC(=O)CC(=O)CCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)/C=C1\CSc2ccccc2N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 4.5 %

Procedure:
steps 1 and 2—To a solution of 6-nitrobenzothiazole (10, 10.2 g, 57 mmol) in EtOH (500 mL) was added KOH (7.0 g, 125 mmol). The reaction was heated at reflux for 15 min then cooled to 0° C. Ethyl chloroacetoacetate (9.3 g, 57 mmol) was added and the mixture stirred at RT for 1 h. The reaction mixture was poured into 1N HCl (500 mL) and the resulting solid was collected. The solid was dissolved in EtOAc. The organic phase was washed with brine, dried (MgSO4) and the solvent was removed under reduced pressure. The product was purified by SiO2 chromatography eluting with 10% EtOAc/hexane to afford 0.61 g (70%) of 12a: LCMS RT 3.48 min, M+H.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:23][OH:24].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:23][OH:24])=[CH:4][CH:3]=1
Reactant: CC(C)CC(CC(=O)c1ccncc1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)CC(CC(=NO)c1ccncc1)c1ccc(Br)cc1

Procedure:
In analogy to example 74, step 7, from 3-(4-bromo-phenyl)-5-methyl-1-pyridin-4-yl-hexan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (2.7:1) as a colorless oil, MS (ESI+): m/z=361.2 ([M+H]+, 1Br).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:18][CH2:19][CH3:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[CH:8][CH:7]=[C:6]([OH:17])[CH:5]=2.[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[C:25]([CH3:27])([O:17][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:2]([CH3:1])[N:3]2[CH2:18][CH2:19][CH3:20])=[CH:8][CH:7]=1)[CH3:26])[CH3:22]
Reactant: CCCn1c(C)c(-c2ccncc2)c2ccc(O)cc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCn1c(C)c(-c2ccncc2)c2ccc(OC(C)(C)C(=O)OCC)cc21

Procedure:
In accordance with a procedure analogous to that of Example 10, the above compound was prepared from 2-methyl-1-propyl-3-(4-pyridyl)-1H-indole-6-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)=[O:4].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: O=Cc1cccc(F)c1
Reactant: COC(=O)c1ccc(N)cn1
Solvent: c1ccccc1
Product: COC(=O)c1ccc(N=Cc2cccc(F)c2)cn1

Procedure:
The starting material is prepared as follows: The mixture of 11.25 g of 5-aminopyridine-2-carboxylic acid methyl ester, 10.0 g of m-fluorobenzaldehyde and 50 ml of benzene is refluxed for 22 hours on a water trap. It is evaporated and the residue recrystallized from acetonitrile, to yield the 5-(m-fluorobenzylideneamino)-pyridine-2-carboxylic acid methyl ester, melting at 111°-114°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:13]([O-:15])=O)CO2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N-:16]=[N+:17]=[N-:18].[Na+].[CH:20]([O:22][CH2:23][CH3:24])=[O:21]>CCO.O.CCOC(C)=O>[N:16]([CH:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH:13]([OH:15])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C([O-])C1(c2ccc([N+](=O)[O-])cc2)CO1
Reactant: CCOC=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(O)C(N=[N+]=[N-])c1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of ethyl (2RS,3RS)-3-(4-nitrophenyl-2-oxirane carboxylate [prepared by the method of Moyna, G., Williams, H. J., Scott, A. I., Synth. Commun, (1996) 26, 2235-9] (2.5 g, 10.5 mmol) sodium azide (3.4 g, 52.5 mmol), ethyl formate (10 ml) in EtOH/water (8:1, 50 ml) was heated at 50° overnight. The mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4) and evaporated in vacuo. Column chromatography (SiO2; MeOH/DCM, 1:99) gave the title compound as a yellow oil (2.34 g) (less polar regioisomer). δH (CDCl3) 8.24 (2H, d, J 8.8 Hz, ArH), 7.55 (2H, d, J 8.9 Hz, ArH), 5.02 (1H, d, J 3.7 Hz, CHN3), 4.57 (1H, dd, J 5.3, 3.7 Hz, CHOH), 4.25-4.14 (2H, m, CO2CH2), 3.15 (1H, d, J 5.5 Hz, OH), 1.21 (3H, t, J 7.2 Hz, CO2CH2CH3). m/z (ES+, 70V) 253 (M+−N2).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:12]([C:14]2[CH:18]=[C:17]([CH2:19][N:20]([S:22]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([O:32][CH3:33])=[CH:27][C:26]=3[CH3:34])(=[O:24])=[O:23])[CH3:21])[O:16][CH:15]=2)=[O:13])[CH3:10])=[CH:5][CH:4]=1)=O.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.CC(O)=O.ClCCCl>C(Cl)Cl>[CH3:33][O:32][C:28]1[CH:29]=[C:30]([CH3:31])[C:25]([S:22]([N:20]([CH2:19][C:17]2[O:16][CH:15]=[C:14]([C:12]([NH:11][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:4][CH:5]=3)[CH3:10])=[O:13])[CH:18]=2)[CH3:21])(=[O:24])=[O:23])=[C:26]([CH3:34])[CH:27]=1
Reactant: C1CCNC1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NC(C)c3ccc(C=O)cc3)co2)c(C)c1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NC(C)c3ccc(CN4CCCC4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BF using N-[1-(4-formylphenyl)ethyl]-5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxamide (39 mg, 0.08 mmol), pyrrolidine (6.8 mg, 0.1 mmol), AcOH (7 mg, 0.12 mmol), STAB (34 mg, 0.16 mmol) and DCE (1 mL). The reaction was diluted with DCM (1 mL) and washed with saturated aqueous NaHCO3 solution (5 mL). The organic phase was dried over Na2SO4 and the solvent removed in vacuo. The crude product was purified by FCC eluting with 2-10% MeOH in DCM to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]3[CH2:25][CH2:24][CH:23]=[CH:22]3)[C:11](=[O:26])[C@:10]([CH2:28][CH:29]3[CH2:33][O:32]C(C)(C)[O:30]3)([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]3[CH2:25][CH2:24][CH:23]=[CH:22]3)[C:11](=[O:26])[C@:10]([CH2:28][CH:29]([OH:30])[CH2:33][OH:32])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OCC(C[C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)cc3)N(C3C=CCC3)C2=O)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@]1(CC(O)CO)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C2C=CCC2)C1=O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of (3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methylpiperidin-2-one (Example 28, Step C) (310 mg, 0.603 mmol) in THF (3 mL) at room temperature was added aq. HCl (1 M) (3013 μL, 3.01 mmol). The reaction mixture was stirred at room temperature for 19 h. The reaction mixture was diluted with EtOAc and the layers were separated. The organic layer was washed with sat. NaHCO3, sat. aq. NaCl solution and dried over Na2SO4 and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[F:5][C:6]1[C:11](O)=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=1[F:16].C1(N=C=NC2CCCCC2)CCCCC1>CCOC(C)=O>[F:5][C:6]1[C:11]([O:3][C:1](=[O:4])[CH3:2])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=1[F:16]
Reactant: CC(=O)O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 0.40 M solution of acetic acid (46 μL, 0.800 mmol) in EtOAc (2.00 mL, filtered through activated alumina) were added pentafluorophenol (162 mg, 0.880 mmol) and 1,3-dicyclohexylcarbodiimide (182 mg, 0.88 mmol). The reaction mixture was stirred for 12 h at rt at which time it was filtered (washing with EtOAc) and concentrated. Ester 19 was used immediately without further purification.