Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C([CH:9]([C:27](=[O:29])[OH:28])[C@H:10]([C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[CH2:16][CH2:15]1)=[O:13])[NH2:11])C1C=CC=CC=1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:39](O)=[O:40])[CH:37]=2)[CH:32]=[CH:31]1.[Li+].[OH-].Cl>>[ClH:1].[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:39]([NH:11][C@@H:10]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH:20]4[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]4)[CH2:16][CH2:15]3)=[O:13])[CH2:9][C:27](=[O:29])[OH:28])=[O:40])[CH:37]=2)[CH:32]=[CH:31]1
Reactant: CN1CCC(C2CCN(C(=O)[C@H](N)C(Cc3ccccc3)C(=O)O)CC2)CC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: CN1CCC(C2CCN(C(=O)[C@@H](CC(=O)O)NC(=O)c3ccc4cc[nH]c4c3)CC2)CC1

Procedure:
Prepared from 1-[(β-benzyl)-D-aspartyl]-4-(1-methylpiperidin-4-yl)piperidine Hydrochloride and indole-6-carboxylic acid using methods substantially equivalent to General Coupling Method 1. Ester deprotection with 2 eq LiOH and final purification and HCl salt formation via prep HPLC.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]([F:15])([F:14])[F:13])[CH:9]=2)[N:4]([CH3:16])[N:3]=1.C([Mg]Cl)(C)C.[CH2:22]([Sn:26]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:28][CH2:29][CH2:30][CH3:31])Cl)[CH2:23][CH2:24][CH3:25]>C1COCC1>[CH3:16][N:4]1[C:5]2[C:10](=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=2)[C:2]([Sn:26]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:22][CH2:23][CH2:24][CH3:25])=[N:3]1
Reactant: Cn1nc(I)c2cc(OC(F)(F)F)ccc21
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(OC(F)(F)F)cc12
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
3-Iodo-1-methyl-5-(trifluoromethoxy)-1H-indazole (0.141 g, 412 μmol) was dissolved in THF (3.00 mL). The colorless solution was cooled to −16° C. (NaCl/ice bath), then isopropylmagnesium chloride 2M in THF (231 μL, 462 μmol) was added dropwise at −16° C. The reaction mixture was stirred at −16° C. for 20 min. Tributylchlorostannane (154 mg, 129 μL, 474 μmol) was added slowly. The reaction mixture was warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with dichloromethane (3×30 mL), the organics dried over MgSO4 and concentrated to a yellow oil. The residue was dried under high vacuum and taken into the next step without further purification.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1.[I:21]I>O1CCCC1.O>[F:13][C:14]1[CH:19]=[C:18]([I:21])[C:17]([F:20])=[CH:16][N:15]=1
Reactant: II
Reactant: Fc1ccc(F)nc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: Fc1cc(I)c(F)cn1
Reaction time: 1 h
Yield: 44.4 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 18.6 mL, 46.5 mmol) was added to a solution of diisopropylamine (6.51 mL, 46.1 mmol) in anhydrous tetrahydrofuran (85 mL) at −78° C. and stirred at this temperature for 1 hour. A solution of 2,5-difluoropyridine (5.0 g, 43 mmol) in anhydrous THF (12 mL) was added dropwise via cannula and the reaction was stirred at −78° C. for 3 hours. After this time, iodine (12.1 g, 47.8 mmol) in tetrahydrofuran (50 mL) was added dropwise via cannula to the reaction at −78° C. and stirred at this temperature for 1 hour after complete addition. Water (100 mL) was added to the reaction and the temperature was allowed to come to RT. The reaction was extracted with diethyl ether (3×100 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), filtered and concentrated. The crude was purified via flash chromatography using an Analogix SF40-80g column and an eluant of ethyl acetate in heptane (0-10%) to afford the title compound as a yellow solid (4.60 g, 44%). LC-MS m/z 242.0 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.39 (t, J=3.71 Hz, 1H) 7.96 (d, J=1.56 Hz, 1H).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[F:21][C:22]1[C:27]([Si:28]([CH3:31])([CH3:30])[CH3:29])=[C:26]([F:32])[C:25]([F:33])=[CH:24][C:23]=1[C:34]1[O:35][CH2:36][C:37]([CH3:40])([CH3:39])[N:38]=1.CI>C1COCC1.O>[F:21][C:22]1[C:27]([Si:28]([CH3:31])([CH3:29])[CH3:30])=[C:26]([F:32])[C:25]([F:33])=[C:24]([CH3:1])[C:23]=1[C:34]1[O:35][CH2:36][C:37]([CH3:40])([CH3:39])[N:38]=1
Reactant: CC(C)NC(C)C
Reactant: CC1(C)COC(c2cc(F)c(F)c([Si](C)(C)C)c2F)=N1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(F)c(F)c([Si](C)(C)C)c(F)c1C1=NC(C)(C)CO1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 90.6 %

Procedure:
A solution of 0.64 ml (4.57 mmol) of diisopropylamine in 20 ml of dry THF under argon was cooled to -78° C. and treated with 2.1 ml (4.20 mmol) of 2.0N n-butyllithium. The LDA solution was stirred at -78° C. for 15 minutes, then warmed to 0° C. To this solution was added a solution of 1.05 g (3.5 mmol) of 2-(2,4,5-trifluoro-3-trimethylsilylphenyl)-4,4-dimethyl-2-oxazoline in 5 ml of THF; the reaction mixture was stirred at 0° C. for 45 minutes, then quenched with 1.50 g (10.6 mmol) of methyl iodide. The solution was stirred at room temperature for three hours and diluted with water. The organic layer was washed with water, dried over magnesium sulfate, and concentrated to give 1.00 g of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[OH2:15].[OH:16]OS([O-])=O.[K+]>CC(C)=O>[CH3:1][C:2]1[C:3]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:4][C:5]([S:8]([CH3:9])(=[O:16])=[O:15])=[N:6][CH:7]=1
Reactant: O
Reactant: CSc1ncc(C)c(-c2cccs2)n1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cnc(S(C)(=O)=O)nc1-c1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Methyl-2-(methylthio)-4-(thiophen-2-yl)pyrimidine (0.15 g, 0.67 mmol) was dissolved in acetone (10 mL) and then water (10 mL) was added. Oxone (1.2 g, 2.02 mmol) was added in small portions to the reaction mixture, which was allowed to stir overnight at ambient temperature. The white precipitate that formed during the course of the reaction was collected by suction filtration and washed several times with water and then dried in a vacuum oven at 60° C. Yield=0.12 g. MS (M+H)+ 255.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:21](=O)[CH2:22][CH2:23][CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:21]([N:18]1[CH2:17][CH2:16][N:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:1]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)[CH2:20][CH2:19]1)[CH2:22][CH2:23][CH3:24]
Reactant: C1=C(c2ccccc2N2CCNCC2)CCCCCC1
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCCN1CCN(c2ccccc2C2=CCCCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.5 %

Procedure:
To a solution of 1-(2-cyclooct-1-enylphenyl)piperazine (11 mg, 0.0407 mmol) produced in Example (46a) in tetrahydrofuran (1 mL) were added butyraldehyde (0.0047 mL, 0.0529 mmol), sodium triacetoxyborohydride (11.2 mg, 0.0529 mmol) and acetic acid (0.0044 mL, 0.0773 mmol), followed by stirring for 14 hours and 20 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed three times with ethyl acetate. The organic layer was concentrated to produce a residue, which was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 9.9 mg of 1-butyl-4-(2-cyclooct-1-enylphenyl)piperazine as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=2)[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[N:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[C:13]([CH3:24])=[N:12][CH:11]=2)[CH2:5][CH2:4]1.B1([O-])O[O:38]1.O.O.O.O.[Na+]>CO.O>[OH:1][CH2:2][C:3]1([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:34])([F:35])[F:36])[CH:27]=2)[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[N:14]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([NH2:21])=[O:38])=[CH:22][CH:23]=3)[C:13]([CH3:24])=[N:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: [O-]B1OO1
Reactant: Cc1ncc(CN2CCC(CO)(Cc3cccc(OC(F)(F)F)c3)CC2)n1Cc1ccc(C#N)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ncc(CN2CCC(CO)(Cc3cccc(OC(F)(F)F)c3)CC2)n1Cc1ccc(C(N)=O)cc1
Temperature: 50 °C

Procedure:
A solution of 4-{5-[4-hydroxymethyl-4-(3-trifluoromethoxy-benzyl)-piperidine-1-ylmethyl]-2-methylimidazol-1-ylmethyl}benzonitrile (71 mg, 0.142 mmol; Example 31) and sodium perborate tetrahydrate (92.8 mg, 0.6 mmol) in a mixture of methanol (2.5 mL) and water (1 mL) was heated at 50° C. for 7 h. The resultant mixture was concentrated under vacuum, and the residue was partitioned between chloroform and dilute hydrochloric acid (0.5M). The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 10% methanol in chloroform. Collection and concentration of appropriate fractions provided the title compound as white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20]([OH:22])=O)=[CH:10]2)[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][NH:25][O:26][CH3:27].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(#N)C>[CH3:27][O:26][N:25]([CH3:24])[C:20]([C:11]1[C:12](=[O:19])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[CH:10]=1)=[O:22]
Reactant: CNOC
Reactant: Cc1cccc(Cn2cc(C(=O)O)c(=O)c3ccccc32)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CON(C)C(=O)c1cn(Cc2cccc(C)n2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 5 of Example 60, from crude 1-(6-Methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 1.27 g (12.7 mmol) of N,O-dimethylhydroxylamine hydrochloride, 9 mL (6.5 g, 64.7 mmol) of triethylamine and 9.2 mL (9.83 g, 15.5 mmol) of 50% 1-propanephosphonic acid cyclic anhydride in 50 mL acetonitrile to give 2.30 g of the product as an off-white solid.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:8]=[C:9]([NH:14][C:15]([C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[CH:20]=[CH:21]C=2O)=[O:16])[CH:10]=[CH:11][C:12]=1[F:13].Cl>O1CCCC1.N1C=CC=CC=1>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[C:19]1[CH:20]=[CH:21][C:5]2[O:4][C:2](=[O:3])[N:14]([C:9]3[CH:10]=[CH:11][C:12]([F:13])=[C:7]([F:6])[CH:8]=3)[C:15](=[O:16])[C:17]=2[CH:18]=1
Reactant: COC(=O)Cl
Reactant: O=C(Nc1ccc(F)c(F)c1)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=c1oc2ccc(-c3ccc(F)cc3F)cc2c(=O)n1-c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 25 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 3 (1.44 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 15.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][C:3]=1[F:10].[F:11][CH:12]([F:15])[CH2:13][NH2:14].C(N(CC)CC)C>C(#N)C.Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:14][CH2:13][CH:12]([F:15])[F:11])=[CH:4][C:3]=1[F:10]
Reactant: Fc1cc(CCl)cnc1Cl
Reactant: NCC(F)F
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Fc1cc(CNCC(F)F)cnc1Cl
Yield: 57 %

Procedure:
At 45° C., 520 mg (2.89 mmol) of 6-chloro-3-chloromethyl-5-fluoropyridine (VII-3), 1.05 ml (14.44 mmol) of 2,2-difluoroethylamine and 400 μL (2.89 mmol) of triethylamine are stirred in 50 ml of acetonitrile for about 48 hours. After about 16 and 32 hours, in each case another 0.42 ml (5.78 mmol) of 2,2-difluoroethylamine are added. After concentration of the reaction mixture under reduced pressure, the residue is taken up in 1 N aqueous hydrochloric acid and the mixture is washed with ethyl acetate. The aqueous phase is made alkaline using 2.5 N aqueous sodium hydroxide solution and extracted repeatedly with ethyl acetate. The combined organic phase is dried over sodium sulphate and concentrated under reduced pressure, giving 370 mg (57% of theory) of N-[(6-chloro-5-fluoropyridin-3-yl)methyl]-2,2-difluoroethylamine.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(OC([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=O)(C)(C)C.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([C@H:58]([NH2:60])[CH3:59])=[CH:54][CH:53]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:32][C:33]1([C:48]([NH:60][C@@H:58]([C:55]2[CH:56]=[CH:57][C:52]([Cl:51])=[CH:53][CH:54]=2)[CH3:59])=[O:50])[CH2:34][CH2:35][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: C[C@@H](N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 52.9 %

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.418 g, 1.10 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.361 g, 1 mmol), (R)-1-(4-chlorophenyl)ethanamine (0.156 g, 1.00 mmol) and DIPEA (0.524 mL, 3.00 mmol) in DMA (10 mL) at 25° C. under nitrogen. The resulting solution was stirred at 60° C. for 4 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness. The crude material was treated with a 10% solution of TFA in DCM (5 mL) and stirred at room temperature. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness. The crude product was purified by preparative LCMS using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (R)-4-amino-N-(1-(4-chlorophenyl)ethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (0.211 g, 52.9%) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[C:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]1=2.Cl.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])=[C:19]([CH:22]=1)[C:20]#[N:21]>C(N(CC)CC)C>[C:20]([C:19]1[CH:22]=[C:15]([NH:14][C:6]([C:4]2[C:3]3[CH2:9][CH2:10][CH2:11][CH2:12][C:2]=3[S:1][CH:5]=2)=[O:8])[CH:16]=[CH:17][C:18]=1[O:23][CH2:24][C:25]([CH3:28])([CH3:29])[CH2:26][OH:27])#[N:21]
Reactant: O=C(O)c1csc2c1CCCC2
Reactant: CC(C)(CO)COc1ccc(N)cc1C#N
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)(CO)COc1ccc(NC(=O)c2csc3c2CCCC3)cc1C#N
Yield: 58.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.78 g) and 5-amino-2-(2,2-dimethyl-3-hydroxypropoxy)benzonitrile monohydrochloride (1.0 g) and triethylamine (0.6 ml), the title compound (0.87 g) was obtained. melting point: 148-150° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]=[CH:5]2.C([Li])CCC.[CH:19]12S[CH:20]1[CH:21]1[S:25][CH:22]1[CH:23]=[CH:24]2>C1COCC1>[CH3:12][C:7]1([CH3:13])[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([S:25][C:22]3[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=3)[CH:3]=2)[O:8]1
Reactant: CC1(C)C=Cc2cc(Br)ccc2O1
Reactant: C1=CC2SC2C2SC12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)C=Cc2cc(Sc3ccccc3)ccc2O1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
6-Bromo-2,2-dimethyl-2H-chromene (10 mmoL) in THF (20 mL) was treated with n-butyl lithium (15 mmoL) dropwise at −78° C. The resulting solution was stirred at −78° C. for 30 min. Benzene disulfide (10 mmoL) in THF (10 mL) was then added dropwise into the reaction over about 15 min. The reaction mixture was kept at −78° C. and slowly warmed to room temperature over 2 hrs. The solvent was removed and the residue was partitioned between diethyl ether and water. The combined organic layer was washed with brine, filtered, dried over anhydrous Na2SO4 and concentrated to yield crude material, which was purified by silica gel chromatography to yield the title compound as a white solid.
Reaction SMILES: Br[C:2]1[N:6](S(C2C=NC=CC=2)(=O)=O)[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[C:2]1[NH:6][CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
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+]
Product: CN(Cc1c[nH]c(-c2ccc(F)cc2F)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2,4-difluorophenyl)boronic acid (198 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (220 mg), the title compound was obtained as a colorless oil (yield 113 mg, 50%).
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.[S:16]([CH2:23][C:24]([OH:26])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.BrC(Br)=[O:36].C1CCN2C(=NCCC2)CC1>C(#N)C>[OH:36][C:2]1([CH3:15])[O:25][C:24](=[O:26])[C:23]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:3]1[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CC(Br)C(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: O=C(Br)Br
Reactant: O=C(O)CSc1ccccc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Product: CC1(O)OC(=O)C(Sc2ccccc2)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 2-bromo-1-(4-(methylsulfonyl)phenyl)propan-1-one (6.0 g, 20.6 mmol) and thiophenoxyacetic acid (3.8 g, 22.6 mmol) in acetonitrile (60 mL) was added triethylamine (4.0 mL, 28.8 mmol). The mixture was stirred at r.t. for 3 h. T.L.C. showed no bromoketone remaining and DBU (4.0 mL) was added. The mixture was stirred at r.t. for 1 h., then air was bubbled through the mixture for another hour. After dilution with water, the mixture was extracted with EtOAc. The EtOAc extract was washed with 1 N aquous HCl, brine, dried over MgSO4, filtered and the solvent evaporated under vacuum. The residue was swished in Et2O to give the title compound (6.0 g) as a pale yellow powder.
Reaction SMILES: C(O[C:5]([C:7]1[CH:15]=[CH:14][C:12]([OH:13])=[C:9]([O:10][CH3:11])[CH:8]=1)=O)(=O)C.[CH:16]([C:18]1C=CC=CC=1P(=C)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:17].C1C[O:41][CH2:40][CH2:39]1>>[C:40]([O:13][C:12]1[CH:14]=[CH:15][C:7]([CH:5]=[CH:18][CH:16]=[O:17])=[CH:8][C:9]=1[O:10][CH3:11])(=[O:41])[CH3:39]
Reactant: COc1cc(C(=O)OC(C)=O)ccc1O
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1C=O
Reactant: C1CCOC1
Product: COc1cc(C=CC=O)ccc1OC(C)=O
Yield: 54 %

Procedure:
Acetoxy vanillin (5.0 g, 2.6×10-2M) is dissolved in dry THF (300 ml) with formyl methylenetriphenylphosphorane (78 g, 2.6×10-2M) and refluxed under an atmosphere of argon for 80 hours. The reaction mixture is concentrated to dryness and chromatographed on flash silica to afford 4-acetoxy-3-methoxycinnamaldehyde (3 g, 54% yield); mp=83°-86° C.
Reaction SMILES: Br[C:2]1[C:3]([F:36])=[C:4]([CH:12]2[C:17]3([C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[NH:19][C:18]3=[O:27])[CH:16]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)[CH2:15][C:14](=[O:35])[NH:13]2)[C:5]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1.[C:37]([Si:39]([CH3:42])([CH3:41])[CH3:40])#[CH:38].C(N(CC)CC)C>CN(C)C=O.O>[Cl:26][C:22]1[CH:21]=[C:20]2[NH:19][C:18](=[O:27])[C:17]3([CH:16]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=4)[CH2:15][C:14](=[O:35])[NH:13][CH:12]3[C:4]3[C:5]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=[C:2]([C:38]#[C:37][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:3]=3[F:36])[C:25]2=[CH:24][CH:23]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2c(OCCO)ccc(Br)c2F)N1
Reactant: C#C[Si](C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc(OCCO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1F
Temperature: 100 °C
Yield: 40.5 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-2′-[3-bromo-2-fluoro-6-(2-hydroxy-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.12 g, 0.202 mmol) prepared in example 183d in N,N-dimethyl formamide (1 mL) was added ethynyl-trimethyl-silane (0.28 mL, 2.0 mmol) (Aldrich) and triethylamine (0.127 g, 2.0 mmol). After the reaction mixture was degassed for 5 min, dichloro-bis-(triphenyl-phosphine) (14 mg, 0.02 mmol) (Strem) was added and the reaction mixture was heated at 100° C. under nitrogen for overnight. The reaction mixture was cooled to room temperature and diluted with water, extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, filtered and concentrated. The residue was purified with chromatography to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-fluoro-6-(2-hydroxy-ethoxy)-3-trimethylsilanylethynyl-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as brown solid (Yield: 50 mg, 40.6%).
Reaction SMILES: Br.Br[CH:3]1[C:8]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=2[O:19][CH3:20])=[CH:7][CH2:6][N:5]([CH3:21])[CH2:4]1.[OH2:22]>>[OH:22][CH:3]1[C:8]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=2[O:19][CH3:20])=[CH:7][CH2:6][N:5]([CH3:21])[CH2:4]1
Reactant: COc1cc(OC)c(C2=CCN(C)CC2Br)c(OC)c1
Reactant: O
Agent: Br
Product: COc1cc(OC)c(C2=CCN(C)CC2O)c(OC)c1

Procedure:
treating the reaction mixture containing the compound (VI) directly with water and reacting by stirring at 50°-100° C., preferably at 60°-80° C., to give 3(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine (VII), and
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([OH:19])[CH:3]=1.[OH-].[Li+].O>O1CCCC1>[Br:1][C:2]1[C:11]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:19])[CH:3]=1
Reactant: COC(=O)c1cc(CN2CCOCC2)c(Br)cc1O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(CN2CCOCC2)c(Br)cc1O
Temperature: 50 °C

Procedure:
Methyl 4-bromo-2-hydroxy-5-(4-morpholinylmethyl)benzoate (may be prepared as described in Description 17; 350 mg, 0.96 mmol) was redissolved in tetrahydrofuran (4 ml) and lithium hydroxide (69 mg, 2.87 mmol) was added followed by water (1 ml). The mixture was heated at 50° C. for 1 hour. The mixture was cooled and the solvent removed in vacuo to yield the title compound as a brown oil. 302 mg.