Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:14]([NH:16][C@H:17]([C:21]([OH:23])=O)[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:3][C:4]1[N:5]=[C:6]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[S:7][CH:8]=1.[NH2:24][C@@H:25]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:26][C@H:27]([OH:46])[C@@H:28]([NH:36][C:37]([O:39][CH2:40][C:41]1[O:45][N:44]=[CH:43][CH:42]=1)=[O:38])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:1][N:2]([C:14]([NH:16][C@H:17]([C:21]([NH:24][C@@H:25]([CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[CH2:26][C@H:27]([OH:46])[C@@H:28]([NH:36][C:37]([O:39][CH2:40][C:41]1[O:45][N:44]=[CH:43][CH:42]=1)=[O:38])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:23])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH2:3][C:4]1[N:5]=[C:6]([N:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)[S:7][CH:8]=1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccno1
Reactant: CC(C)[C@H](NC(=O)N(C)Cc1csc(N2CCCC2)n1)C(=O)O
Product: CC(C)[C@H](NC(=O)N(C)Cc1csc(N2CCCC2)n1)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccno1

Procedure:
Using the procedure of Example 1U, but replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with N-((N-methyl-N-((2-(1-pyrrolidinyl)-4-thiazolyl)methyl)amino)carbonyl)-L-valine and replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-5-amino-2-(N-((5-isoxazolyl)methoxy-carbonyl)amino)-1,6-diphenyl-3-hydroxyhexane provided, after purification by silica gel chromatography using 2% methanol in chloroform, the desired compound (Rf 0.30, 4% methanol in chloroform).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH:11]([C:15]([OH:17])=[O:16])[CH:12]([CH3:14])[CH3:13].[OH-].[Na+].S(=O)(=O)(O)O>O1CCCC1>[C:1]([NH:10][CH:11]([C:15]([OH:17])=[O:16])[CH:12]([CH3:14])[CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)C(N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)c1ccccc1)C(=O)O
Reaction time: 3 h

Procedure:
5.1 kg. (36.28 moles) of benzoyl chloride is added portionwise to a mixture of 3.5 kg. (29.88 moles) of DL-valine, 39.0 1. of 2N. sodium hydroxide solution (78 moles) and 7 1. of tetrahydrofuran stirred at ~10° C. at a rate such that the temperature is maintained at 10° -15° C., and the reaction mixture is warmed to ~20° C. and stirred at ~20° C. for 3 hours, the reaction mixture being stirred under nitrogen throughout. 1.4 1. of concentrated sulfuric acid is carefully added at a rate such that the temperature does not exceed 25° C., and the mixture is cooled to ~5°-10° C. and stirred at this temperature for about 30 minutes to obtain a solid. (If necessary, the mixture is seeded.) The resulting solid is collected by filtration, washed three times with 20 1. portions of hot water, washed three times with 20 1. portions of hexane and dried at 40° C. and reduced pressure for ~12 hours to obtain the product (6.4 kg.), m.p. 123°-126° C.
Reaction SMILES: [C:1]([C:3](=[CH:8][CH:9]([CH3:11])[CH3:10])[CH2:4][C:5]([OH:7])=[O:6])#[N:2].[H][H].C(N(CC)CC)C.C([C@@H](CC(C)C)CC(O)=O)#N>CO>[C:1]([CH:3]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:4][C:5]([OH:7])=[O:6])#[N:2]
Reactant: CC(C)C=C(C#N)CC(=O)O
Reactant: [H][H]
Agent: CC(C)C[C@H](C#N)CC(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)CC(C#N)CC(=O)O
Reaction time: 16 h
Yield: 51 %

Procedure:
The above procedure was followed to react 250 mg (1.634 mmol) of 3-cyano-5-methylhex-3-enoic acid with hydrogen (50 psi) in the presence of 8 mg (0.01634 mmol) of [(S,S)-Et-BPE]Rh(COD)+BF4− and 0.023 mL (0.1634 mmol; 0.1 eq) of triethylamine in 5 mL of methanol at 24° C. for 40 hours. The reaction mixture was filtered, the solvent was removed by evaporation, and the product was shown by proton NMR to be 71% (S)-3-cyano-5-methylhexanoic acid with 84% e.e. for the S-enantiomer. C. The above procedure was repeated, except that no base was added to the reaction mixture. The product was shown by proton NMR to be 26%, (S)-3-cyano-5-methylhexanoic acid having 91% e.e. for the S-enantiomer. D. The above procedure was followed to react 200 mg (1.307 mmol) of 3-cyano-5-methylhex-3-enoic acid with hydrogen (50 psi, 100 hours) in the presence of 10 mg (0.01307 mmol) of [(S,S)-Et-DuPHOS]Rh(COD)+BF4−. The product was shown by proton NMR to be 82% (S)-3-cyano-5-methylhexanoic acid having 56% e.e. for the S-enantiomer. E. The procedure of Example 5D was repeated, except that 0.1 eq. (0.02 mL, 0.1307 mmol) of triethylamine was added to the reactive mixture. The reaction was stopped after 16 hours, and the product was shown to be 86% (S)-3-cyano-5-methylhexanoic acid with 68% e.e. for the S-enantiomer. F. The procedure of Example 5E was repeated, except that 1 eq. (0.18 mL, 1.307 mmol) of triethylamine was added to the reaction mixture, and the reaction was stopped at 16 hours. The product was shown by proton NMR to be 92% converted to (S)-3-cyano-5-methylhexanoic acid having 56% e.e. for the S-enantiomer. G. By following the general procedures from above, 250 mg (1.634 mmol) of 3-cyano-5-methylhex-3-enoic acid was reacted with hydrogen (50 psi, 16 hours. 24° C.) in the presence of 12 mg (0.01634 mmol) of [(R,R)-DIPAMP]Rh(COD)+BF4− in methanol (10 mL) to provide 51% of 3-cyano-5-methylhexanoic acid having 72% e.e. for the R-enantiomer.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:3][CH2:2]1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH:1]1([C:4]2[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:28]4[CH2:29][CH2:30][O:26][C:27]4=[O:31])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:3][CH2:2]1
Reactant: O=C1NCCO1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C2CC2)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3)CC2)c(C2CC2)c1
Yield: 27.1 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using [4-(2-cyclopropyl-4-methylphenyl)piperazin-1-yl](4-iodophenyl)methanone (280 mg) described in Preparation Example 17 and oxazolidin-2-one (313 mg), the title compound (69 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C[Al](C)C.[O:14]=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]#[N:25])[CH:22]=2)[CH2:17][O:16]1>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:15](=[O:14])[C:23]2[CH:22]=[C:21]([C:24]#[N:25])[CH:20]=[CH:19][C:18]=2[CH2:17][OH:16])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Br
Reactant: N#Cc1ccc2c(c1)C(=O)OC2
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1c(Br)cccc1NC(=O)c1cc(C#N)ccc1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
Step 1 A solution of 3-bromo-2-methylaniline (0.67 g, 3.60 mmol) in DCM (18 mL) was treated dropwise with trimethylaluminum (2 M in toluene, 1.801 mL, 3.60 mmol) and the resulting solution was stirred at rt for 30 min. A solution of 3-oxo-1,3-dihydroisobenzofuran-5-carbonitrile (0.573 g, 3.60 mmol) in DCM (18.00 mL) was added and the resulting mixture was stirred at rt overnight. The mixture was diluted with DCM, washed with an aqueous solution of sodium potassium tartrate (Fehling's Reagent II) and water, then was dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 80:20 hexane-EtOAc to EtOAc) to provide N-(3-bromo-2-methylphenyl)-5-cyano-2-(hydroxymethyl)benzamide as a white solid (170 mg, 14%) which was used without further purification. Mass spectrum m/z 345, 347 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].IC.[CH3:27]N(C)C(=O)C>C1COCC1>[CH3:27][CH:8]([CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: CC(=O)N(C)C
Reactant: O=C(CC(c1ccccc1)c1ccccc1)c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C(=O)c1ccncc1)C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3,3-diphenyl-1-pyridin-4-yl-propan-1-one (200 mg, example 14, step 1) in THF (11 ml) was added NaH (33 mg as a 55% suspension in mineral oil) at room temperature. The mixture was stirred for 1.5 h and placed in an ice bath. Iodomethane (109 mg) was added. The mixture was stirred for 1 h at 0° C. and for 2 h at room temperature. N,N-dimethylacetamide (0.5 ml) was added and the mixture was stirred overnight at room temperature. Ice water was added and the mixture was extracted with ethyl acetate. The organic phase was dried using MgSO4, filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 1:0 to 0:1) to give the title compound (148 mg) as an off-white solid, MS (ESI+): m/z=302.3 [M+H]+.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:26][C@H:25]([C:27]4[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=4)[C@H:24]4[C@@H:15]([CH2:16][CH:17]=[C:18]5[C@@H:23]4[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C[S-].[Na+]>CN(C)C=O>[CH2:11]1[CH2:10][O:9][C:8]23[O:13][CH2:14][CH2:1][O:2][C:3]2([C@:4]2([CH2:26][C@H:25]([C:27]4[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=4)[C@H:24]4[C@@H:15]([CH2:16][CH:17]=[C:18]5[C@@H:23]4[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:12]1
Reactant: COc1ccc([C@H]2C[C@@]3(C)[C@@H](CC45OCCOC43OCCO5)[C@@H]3CC=C4CCCC[C@@H]4[C@H]32)cc1
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]12C[C@H](c3ccc(O)cc3)[C@H]3[C@@H](CC=C4CCCC[C@@H]43)[C@@H]1CC13OCCOC12OCCO3

Procedure:
17,17-bis-(ethylenedioxy)-11β-(4-methoxyphenyl)-5-estrene is dissolved in 100 ml of absolute dimethylformamide, mixed with 5.6 g of sodium methanethiolate and the reaction mixture is refluxed for 3 hours. After cooling, it is poured on water and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed several times with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel with a mixture of ethyl acetate/hexane and 8.67 g of 3,3;17,17-bis-(ethylenedioxy)-11β-(4-hydroxyphenyl)-5-estrene is obtained as white foam.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(Cl)(Cl)=O.CN(C=O)C.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](/[CH:31]=[CH:32]/[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[NH2:39])=[N:23]1.C(N(CC)CC)C>C1COCC1.ClCCl>[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](/[CH:31]=[CH:32]/[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[NH:39][C:10]([C:8]2[S:9][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[O:12])=[N:23]1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)s1
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccccc2/C=C/c2n[nH]c3ccccc23)s1
Yield: 31.8 %

Procedure:
In a similar manner to Example 29, 5-(methylsulfonyl)thiophene-2-carboxylic acid (97 mg, 0.47 mmol) was treated with thionyl chloride (53 μL, 0.72 mmol), DMF (5.0 μL, 0.085 mmol) and dichloromethane (2.0 mL), followed by reacting with Compound 2 (0.10 g, 0.43 mmol), triethylamine (60 μL, 1.1 mmol) and THF (2.0 mL) to obtain Compound 354 (58 mg, 32%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[N:24]1[CH2:28][C:27](=[O:29])[NH:26][S:25]1(=[O:31])=[O:30])[CH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16])C1C=CC=CC=1>CCO.O.[Pd]>[NH2:16][CH2:15][C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[CH2:12][C:11]1[CH:21]=[CH:22][C:23]([N:24]2[S:25](=[O:31])(=[O:30])[NH:26][C:27](=[O:29])[CH2:28]2)=[C:9]([OH:8])[CH:10]=1
Reactant: N#Cc1ccccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: NCc1ccccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
A solution of 2-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzyl]-benzonitrile in EtOH/water (1:1) is hydrogenated at 1 atm over 10% Pd/C for 40 min. The catalyst is filtered, the solvent evaporated and the residue purified by preparative HPLC to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:11]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[C:11]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=4[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Fc1ccc(CNc2nc(Cl)nc3sc4c(c23)CCCC4)cc1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1nc(NCc2ccc(F)cc2)c2c3c(sc2n1)CCCC3

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6,7,8-tetrahydro-4-(4-fluorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6,7,8-tetrahydro-4-(4-fluorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl[C:18]1[N:19]=[N:20][C:21]([C:24]2[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=2)=[CH:22][CH:23]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[N:19]=[N:20][C:21]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)=[CH:22][CH:23]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2cnn(C3CCNCC3)c2c1
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc(N3CCC(n4ncc5ccc(F)cc54)CC3)nn2)cn1

Procedure:
6-Fluoro-1-(piperidin-4-yl)-1H-indazole (260 mg, 1.19 mmol), 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine (230 mg, 1.19 mmol) and DIEA (269 uL) in DMSO (4 ml) under Ar were heated in a microwave reactor at 200° C. for 1 hour. After removal of most of the DMSO in vacuo, water (10 mL) was added and the aqueous layer extracted several times with CHCl3 (50 mL). The organic layer was washed with brine, dried (MgSO4), decolorized with NORITE, filtered and the solvent removed in vacuo. The resulting residue was purified via ISCO column chromatography (Amine “Redisep” 14 gram column eluded 0-100% EtOAc/hexane over 20 column volumes), then re-crystallized from DCM with heptanes to yield 6-fluoro-1-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-yl)-1H-indazole.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=2)(=O)=O)=CC=1.[I-:29].[Na+]>CC(=O)CC>[I:29][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=1
Reactant: [I-]
Reactant: CCCCCCCC(=O)c1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCCCCCC(=O)c1ccc(CCI)cc1
Yield: 99.6 %

Procedure:
2-(4-Octanoyl phenyl)ethyl p-toluene sulfonate (1.23 g) prepared in the above-described procedure was dissolved in 2-butanone (18 ml) to obtain a solution. Sodium iodide (550 mg) was added to the solution, and the solution was heated to reflux for 40 minutes. The reaction solution was concentrated, and the solution was partitioned with water-dichloromethane. The dichloromethane layer was washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain 4′-(2-iodoethyl)octanophenone (1.09 g) in the form of white crystal.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8](O)=[C:7]([O:13][CH3:14])[C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2].[CH2:17](Cl)[C:18](=[CH2:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH2:19][C:18]([CH3:20])=[CH2:17])=[C:7]([O:13][CH3:14])[C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2]
Reactant: COc1c(O)cc(C)c(OC(C)=O)c1OC
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)Cc1cc(C)c(OC(C)=O)c(OC)c1OC
Yield: 84 %

Procedure:
A suspension (200 ml) of 4-acetoxy-2,3-dimethoxy-5-methylphenol (26 g), methallyl chloride (13 ml) and potassium carbonate (18 g) in N,N-dimethylformamide was stirred under an atmosphere of argon at 65° C. for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to obtain the title compound (27 g, 84%) as an oil.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[N:13]1([CH2:11][C:3]2[CH:2]=[N:1][C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: O=Cc1cnc2c(c1)CCCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: c1nc2c(cc1CN1CCOCC1)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A 100 mL three-neck round bottom flask equipped with a nitrogen inlet, bubbler, and glass stopper is charged with 1,2-dichloroethane (45 mL), 5,6,7,8-tetrahydroquinoline-3-carbaldehyde (Preparation 15, 2.39 g) and morpholine (1.42 mL). To the above solution is added NaBH(OAc)3 (5.01 g) in one portion. After 1 hour at room temperature, the reaction is quenched via slow addition of Na2CO3 (50 mL of a saturated aqueous solution). The resulting biphasic solution is stirred for two hours at room temperature then poured into methylene chloride (100 mL). The resulting layers are separated, and the organic layer is dried with Na2SO4, filtered, and concentrated in vacuo. The crude product is purified by flash chromatography (10% methanol/CH2Cl2) to give 2.60 g (76%) of the title compound as an oil which crystallizes on standing. Physical characteristics: M.p. 40.9° C.; 1H NMR (CDCl3): δ8.24, 7.31, 3.68, 3.41, 2.88, 2.74, 2.41, 1.87, 1.78; 13C NMR (CDCl3) δ156.4, 147.5, 137.6, 131.9, 130.1, 66.9, 60.4, 53.5, 32.2, 28.7, 23.1, 22.7.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][O:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>C1COCC1.CCOC(C)=O>[CH3:34][O:35][CH:36]1[CH2:41][CH2:40][N:39]([S:20]([C:16]2[CH:15]=[C:14]([C:10]3[N:9]=[C:8]([C:6]4[CH:5]=[C:4]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=5)[CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:13]=[CH:12][CH:11]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:21])=[O:22])[CH2:38][CH2:37]1
Reactant: COC1CCNCC1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC1CCN(S(=O)(=O)c2cccc(-c3cccc(-c4cc(-c5ccc(C(F)(F)F)cc5)cc(C)n4)n3)c2)CC1
Yield: 38.8 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available 4-methoxypiperidine [CAS-no. 4045-24-3] (0.236 g, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.090 g, 39%) as a white foam. MS (ISP) 568.3 [(M+H)+]; mp 107° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[O:11][C:12](=O)[C@@H:13]1[O:15][C@H:14]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.O>CS(C)=O>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C@@H:14]2[O:15][C@H:13]2[C:12]([NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:11])=[CH:21][CH:20]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)[C@@H]1O[C@H]1c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc([C@@H]2O[C@H]2C(=O)Nc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
To a mixture of sodium hydride (62.5% oil dispersion, 0.46 g) and dimethyl sulfoxide (3 ml) is added a solution of aniline (1.02 g) in dimethyl sulfoxide (1 ml) at room temperature under nitrogen atmosphere, and the mixture is stirred for 30 minutes. To the mixture is added a solution of (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxypropionic acid methyl ester (2.08 g) in dimethyl sulfoxide (4 ml) at room temperature over a period of 15 minutes. The mixture is further stirred at the same temperature for one hour, and thereto is added water (50 ml). The precipitated yellow crystals are collected by filtration, and recrystallized from ethyl acetate (60 ml) to give (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxy-N-phenylpropionamide (1.50 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=O)[C:7]2([CH3:13])[CH3:12].COCCO[AlH2-]OCCOC.[Na+].[OH-].[Na+].O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][C:7]2([CH3:13])[CH3:12]
Reactant: CC1(C)C(=O)Nc2c(F)cccc21
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CNc2c(F)cccc21
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 81.4 %

Procedure:
A mixture of 7-fluoro-3,3-dimethyloxindole (EXAMPLE 99, step 5, 2.24 g 12.5 mmol) in toluene (15 mL) under nitrogen was heated at 80° C. Vitride (65 wt % in toluene, 6 mL, 19.3 mmol) was added dropwise via an addition funnel. The resulting solution was stirred at 80° C. for an additional 1.5 hours, then cooled in an ice bath. Aqueous sodium hydroxide solution (1N, 15 mL) was added slowly to quench the reaction. Water (15 mL) was added and the reaction mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried (anhydrous sodium sulfate), filtered through a pad of silica gel, and concentrated under reduced pressure to yield 1.68 g (82%) of 7-fluoro-3,3-dimethylindoline as a colorless oil. MS (ES) m/z 166.1 ([M+H]+); HRMS: calcd for C10H12FN+H+, 166.1032; found (ESI, [M+H]+), 166.1040.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[CH3:12][C:13]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)=[O:14].[OH-].[Na+]>CO>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[CH:12]/[C:13]([C:15]2[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)=[O:14])=[CH:6][CH:5]=1)[CH3:2]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: CCOc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.3 %

Procedure:
To a stirred solution of 4-ethoxybenzaldehyde (1.32 ml, 9.5 mmol) and 3,4,5-trimethoxyacetophenone (2.0 g, 9.5 mmol) in methanol (30 ml) was added 50% w/v of aqueous sodium hydroxide (7.6 ml, 0.095 mol). The reaction was stirred for 24 h at room temperature. A precipitate was isolated by filtration, washed with pet:ether and subsequently recrystallised from ethanol. 1.8 g (55%) of a pale yellow powder was isolated. 1H-NMR (CDCl3) δ 7.8 (d, 1H), 7.6 (d, 2H), 7.3 (d, 1H), 6.9 (d, 2H), 4.1 (q, 2H), 3.9 (s×2, 9H), 1.4 (t, 3H). 13C-NMR (CDCl3) δ 189.2, 161.1, 153.1, 142.3, 133.8, 127.4, 63.4. Mass Spectrum m/e (M+1) 343.