Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(P(Cl)(C2C=CC=CC=2)=O)=CC=1.C([O:19][C:20]1[C:21]([CH3:29])=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([OH:25])=O)(=O)C.[C:30]([NH:34][C:35]([C@@H:37]1[C:41]([CH3:43])([CH3:42])[S:40][CH2:39][N:38]1[C:44](=[O:58])[C@@H:45]([OH:57])[C@@H:46]([NH2:56])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>CCOC(C)=O>[C:30]([NH:34][C:35]([C@@H:37]1[C:41]([CH3:42])([CH3:43])[S:40][CH2:39][N:38]1[C:44](=[O:58])[C@@H:45]([OH:57])[C@@H:46]([NH:56][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([OH:19])[C:21]=1[CH3:29])[CH2:47][C:48]1[CH:49]=[CH:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=1)=[O:36])([CH3:31])([CH3:32])[CH3:33]
Reactant: CC(=O)Oc1cccc(C(=O)O)c1C
Reactant: COc1ccc(C[C@H](N)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NC(C)(C)C)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(C[C@H](NC(=O)c2cccc(O)c2C)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NC(C)(C)C)cc1
Reaction time: 1 h
Yield: 80.4 %

Procedure:
DPP-Cl (43 μl) and TEA (31 μl) were added to a solution of 3-acetoxy-2-methylbenzoic acid (41 mg) in EtOAc (2 ml), and the mixture was stirred for one hour. After the addition of the compound obtained in Step 2 (85 mg) and TEA (34 μl), the mixture was stirred overnight. The reaction mixture was washed with 5% Na2CO3 (×2), 1N HCl, and 5% NaCl. After concentration, MeOH (1.5 ml) and 1N NaOH (300 μl) were added. After stirring for one hour, IN HCl was added to make the reaction mixture acidic. The resulting mixture was extracted with EtOAc. The extract was washed with 5% Na2CO3 (×2), 1N HCl, and 5% NaCl, dried over MgSO4, filtered and concentrated. The residue was recrystallized from a mixture of EtOAc and n-hexane to obtain the title compound (90 mg, 81%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][OH:8].[H-].[Na+].[N+:11]([C:14]1[CH:15]=[N:16][CH:17]=[C:18]([N+]([O-])=O)[CH:19]=1)([O-:13])=[O:12]>CN(C=O)C.O.[Cl-].[Na+].O>[N+:11]([C:14]1[CH:19]=[C:18]([O:8][CH2:7][C@@H:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])[CH:17]=[N:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cncc([N+](=O)[O-])c1
Reactant: CN1CCCC1CO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC[C@H]1COc1cncc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.6 %

Procedure:
1-Methylpyrrolidinylmethanol (0.46 ml, 3.9 mmol) was added to a suspension of NaH in DMF at room temperature. After stirring at room temperature for 30 minutes, 3,5-dinitro-pyridine (0.34 g, 4 mmol) was added, and the mixture was allowed to stir at room temperature for 16 hours. The mixture was diluted with 1:1 water/brine, and the aqueous solution was extracted with ether. The combined ether layers were dried over MgSO4, filtered and concentrated. The residue was chromatographed, eluting with CH2Cl2 : methanol (10:0.5) to afford 70 mg of the title compound. MS (DCI/NH3) m/e: 238 (M+1). 1H NMR (CDCl3, 300MHz) δ: 9.06 (m, 1H), 8.62 (d, 1H), 7.97 (m, 1H), 4.07 (m, 2H), 3.50 (s, 3H), 3.13 (m, 1H), 2.73 (m, 1H), 2.35 (m, 1H), 2.05 (m, 1H), 1.82 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=1)=[O:27]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=1)=[O:27]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: O=C(CBr)c1ccc(Cl)cn1
Product: COC(=O)Cc1c(C(=O)c2ccc(Cl)cn2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-5-chloropyridine*.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:7])[CH3:6].[Cl-].[CH3:18][O:19][C:20](=[O:26])[CH2:21][CH2:22][C:23](O)=[O:24]>C(Cl)Cl>[O:24]=[C:23]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][NH:8][C:5](=[O:7])[CH3:6])=[CH:12][CH:13]=1)[CH2:22][CH2:21][C:20]([O:19][CH3:18])=[O:26]
Reactant: CC(=O)NCCc1ccccc1
Reactant: COC(=O)CCC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1ccc(CCNC(C)=O)cc1
Temperature: 25 °C

Procedure:
272.7 g. (2.04 mol) aluminium chloride are introduced portionwise at 0° C. into a solution of 110.97 g. (0.68 mol) N-acetylphenethylamine and 93 ml. (0.75 mol) succinic acid methyl ester chloride in 1200 ml. anhydrous methylene chloride, the reaction mixture is further stirred for 1 hour at 0° C. and then warmed to ambient temperature. The reaction mixture is poured into hydrochloric acid/ice water, the organic phase is separated off, dried over anhydrous magnesium sulphate and evaporated. The residue is stirred up with hot diethyl ether, filtered off with suction and afterwashed with a little cold diethyl ether. Yield 154 g. (82% of theory); colourless crystals; m.p. 119.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1B(O)O.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:33]4[S:32][CH:36]=[CH:35][CH:34]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Reactant: OB(O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cccs4)cc3)oc2C)cc1

Procedure:
To a 25 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.410 mmoles, 200 mg) (see Ex. 2, part B), 2-thiophenyl boronic acid (0.451 mmoles), toluene (5 mL), ethanol (5 mL), and sodium carbonate (0.819 mmoles, 0.410 mL of a 2M solution). This mixture was vacuum degassed and nitrogen was added in at a positive pressure. Pd(PPh3)4 (catalytic, spatula tip) was added and the reaction was heated to reflux for 3 h. Distilled water was added to the mixture. Subsequently, this was extracted with ethyl acetate and washed with brine. The organic layer was collected, filtered over a thin pad of silica gel, and concentrated in-vacuo. The crude mixture was then purified by chromatography on silica gel affording 2-(4-{2-[2-(4-thiophen-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:10]1([NH2:14])[CH2:13][CH2:12][CH2:11]1>>[CH:10]1([NH:14][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:13][CH2:12][CH2:11]1
Reactant: NC1CCC1
Reactant: N#Cc1ccccc1F
Product: N#Cc1ccccc1NC1CCC1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and cyclobutylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][O:8][C:4]=2[CH:3]=1.[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ncoc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2ncoc2c1
Yield: 38.2 %

Procedure:
A mixture of 6-methylbenzoxazole (422 mg, 3.17 mmol), N-bromosuccinimide (677 mg, 3.80 mmol), and 2,2′-azobisisobutyronitrile (78 mg, 0.48 mmol) in CCl4 (6.3 mL) was heated at reflux for 22 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. Purification of the crude material on silica gel (4% EtOAc/hexanes) gave the title compound as colourless crystals (257 mg, 38%). 1H NMR (CDCl3) δ 4.64 (s, 2H), 7.42 (dd, 1H, J=8.1, 1.5 Hz), 7.64 (d, 1H, J=1.2 Hz), 7.76 (d, 1H, J=8.4 Hz), 8.12 (s, 1H).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[C:28]([S:32]([NH:35][CH2:36][CH2:37][OH:38])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[C:28]([S:32]([NH:35][CH2:36][CH2:37][OH:38])(=[O:33])=[O:34])[CH:29]=[CH:30][CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(NCCO)c1cccc(Br)c1
Product: O=S(=O)(NCCO)c1cccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 3-bromo-N-(2-hydroxy-ethyl)-benzenesulfonamide (example B.34) (252 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (300 mg, 55%). MS (ISP) 537.3 [(M+H)+]; mp 113-115° C.
Reaction SMILES: [C:1]([N:11](C)[C@H:12]([C:16]([NH:18][C@H:19]([C:32]([NH2:34])=[O:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])(OCC1C=CC=CC=1)=O.[H][H]>[OH-].[OH-].[Pd+2].CO>[NH:11]([CH3:1])[C@H:12]([C:16]([NH:18][C@H:19]([C:32]([NH2:34])=[O:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:29])([CH3:31])[CH3:30])[CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14]
Reactant: [H][H]
Reactant: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN[C@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Yield: 87.1 %

Procedure:
A mixture of the thus obtained Z-N-Me-Val-Tyr(3-tBu)-NH2 (1.7 g), 20% palladium hydroxide/carbon (0.15 g) and methanol (30 ml) was stirred at room temperature in a hydrogen atmosphere for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:methanol=10:1), giving the titled compound (1.07 g, 88%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([OH:17])[CH2:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[F:19][C:2]([F:1])([F:18])[C:3](=[O:17])[CH2:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6]
Reactant: COc1cc(F)ccc1C(C)(C)CC(O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cc(F)ccc1C(C)(C)CC(=O)C(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of 2.3 g (8.42 mmol) of 1,1,1-trifluoro-4-(4-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol in dichloromethane was added the 4.96 (11.70 mmol) of Dess-Martin periodinane. After 1 hour, the mixture was concentrated and diluted with ether-hexanes (1:9) and filtered through a pad of silica gel washing with 1:1 ether-hexanes. A second pad of silica gel using EtOAc-hexanes (1:9) afforded the title compound as an oil. The product was dried under vacuum to a constant weight of 2 g (85%).
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([OH:18])=O)[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2].[NH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(CCCN=C=NCC)C>C(Cl)Cl>[C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([NH:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2]
Reactant: Nc1cccnc1
Reactant: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)O)NC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)Nc2cccnc2)NC1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid (0.100 g, 0.35 mmol), 3-aminopyridine (0.036 g, 0.38 mmol), 1-hydroxybenzotriazole (0.047 g, 0.035 mmol), and 4-methylmorpholine (0.077 mL, 0.70 mmol) are dissolved in methylene chloride (2.5 mL), and the reaction is cooled to 0° C. To this solution is added N-(dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.134 g, 0.70 mmol), and the reaction is allowed to warm up to room temperature and then stirred overnight. The reaction is partitioned between methylene chloride and water, the organic layer is dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (70% ethyl acetate/hexane) to give 3-{N-[[trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecan-10-yl]-carbonyl]-amino}-pyridine, MS: M+1=364.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:14])=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[CH2:15]([O:17][C:18]1[C:22]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][N:20]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[N:19]=1)[CH3:16].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:15]([O:17][C:18]1[C:22]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][N:20]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH2:2][C:3]3[C:4]([CH3:14])=[N:5][N:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[CH:7]=3)=[CH:35][CH:36]=2)[N:19]=1)[CH3:16]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Reactant: Cc1nn(-c2ccccn2)cc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cn(-c4ccccn4)nc3C)cc2)nc1OCC
Temperature: 80 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
A mixture of 2-(4-chloromethyl-3-methyl-1H-pyrazol-1-yl)pyridine (350 mg), ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (500 mg), potassium carbonate (500 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[4-[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-ylmethoxy]benzyl]-1H-pyrazol-4-yl]propionate (700 mg, yield: 91%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.O[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)=[O:13])=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC1(C)CCSc2cc(C(=O)O)ccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)SCCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A solution of 103.5 mg (0.466 mmol) of 4,4-dimethyl-7-carboxythiochroman and 77.8 mg (0.468 mmol) of ethyl 4-hydroxybenzoate in 10 ml of methylene chloride was treated sequentially with 14.2 mg (0.116 mmol) of 4-dimethylaminopyridine and 96.9 mg (0.47 mmol) of 1,3-dicyclohexylcarbodiimide. The reaction mixture was stirred at room temperature for 120 hours and then filtered and the residue washed with 10 ml of methylene chloride. The filtrate was concentrated in-vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexanes) to give the title compound as a colorless oil. PMR (CDCl3): δ1.38 (6H, s), 1.42 (3H, t, J~7.1 Hz), 2.02 (2H, m), 3.08 (2H, m), 4.41 (2H, q, J~7.1 Hz), 7.29 (2H, d, J~8.7 Hz), 7.51 (1H, d, J~8.3 Hz), 7.81 (1H, dd, J~8.3 Hz, 1.9 Hz), 7.95 (1H, d, J~1.9 Hz), 8.14 (2H, d, J~8.7 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:12][CH:11]=1.[C:32](Cl)(=[O:41])[C:33]1[C:34]([O:39][CH3:40])=[CH:35][CH:36]=[CH:37][CH:38]=1.O>O1CCCC1.[H-].[Na+]>[CH3:40][O:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:32]([N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9](=[O:31])[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:14][CH:15]=1)=[O:41]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)NCc2ccccn2)cc1
Reactant: COc1ccccc1C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(=O)c2ccccc2OC)cc1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a solution of 1 g of product from Example 4 in 15 ml of dry tetrahydrofuran is added in one portion 0.0622 g of sodium hydride. The mixture is heated at reflux temperature for 2 hours, cooled to room temperature and 0.442 g o-anisoyl chloride is added. The reaction is then heated at reflux for 1.5 hours, cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel: 35% ethyl acetate/hexane) to give 1.27 g of the desired product.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH3:6][O:7][CH:8](Cl)Cl.C[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH:18]([CH2:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1)[CH2:17][CH2:16]2.[OH-].[NH4+]>C(Cl)Cl.O>[NH:26]1[CH:27]=[C:23]([CH2:22][CH:18]2[C:19]3[C:15](=[CH:14][C:8]([O:7][CH3:6])=[C:21]([CH:13]=[O:12])[CH:20]=3)[CH2:16][CH2:17]2)[N:24]=[CH:25]1
Reactant: COC(Cl)Cl
Reactant: COc1ccc2c(c1)CCC2Cc1c[nH]cn1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(cc1C=O)C(Cc1c[nH]cn1)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Tin(IV)chloride (800 mg) is added dropwise to a stirred solution of dichloromethyl methyl ether (343 mg) in methylene chloride (8 ml) with ice cooling under a nitrogen atmosphere. The solution is stirred at 0° C. for one hour before adding a solution of 4-(5-methoxyindan-1-ylmethyl)-1H-imidazole (300 mg) in methylene chloride (4 ml). The resulting mixture is allowed to warm to ambient temperature while being stirred for 4 hours. The mixture is then poured into cold water and is made basic with ammonium hydroxide solution. Work-up of the mixture gives the crude product which is purified by flash chromatography and recrystallized from ethyl acetate.
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]([F:13])([F:12])[F:11])=[N:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[Cl:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]([F:13])([F:12])[F:11])=[N:4][CH:3]=1
Reactant: COc1ccc(B(O)O)c(Cl)c1
Reactant: N#Cc1cc(C(F)(F)F)ncc1Br
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: C1COCCO1
Solvent: O
Product: COc1ccc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)c1
Temperature: 85 °C
Reaction time: 6 h
Yield: 41.9 %

Procedure:
To a mixture of 5-bromo-2-trifluoromethyl-isonicotinonitrile 1-1 (2.51 g, 10 mmol) in dioxane (3.3 mL) and water (3.3 mL), were added 2-chloro-4-methoxyphenylboronic acid (2.3 g, 12.5 mmol) and Na2CO3 (6.3 g). The mixture was purged with nitrogen gas for 10 min, then Pd(PPh3)4 (1.2 g, 1.0 mmol) was added. The mixture was stirred in a sealed vessel at 85° C. for 6 hrs, then extracted by ethyl acetate. The organic layer was washed with water, dried over MgSO4. Concentration and purification by silica gel column chromatography eluting with hexane/ethyl acetate (10/1) yielded 5-(2-chloro-4-methoxy-phenyl)-2-trifluoromethylisonicotinonitrile (1.31 g). tR=2.96 min (method 1).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[C:12]([O:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH:26](O)[CH2:25][CH2:24]2)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O-]S([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[C:12]([O:20][C:21]1[CH:22]=[C:23]2[C:27]([CH:26]=[CH:25][CH2:24]2)=[CH:28][CH:29]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Oc1ccc2c(c1)CCC2O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: O=C(Oc1ccc2c(c1)CC=C2)c1ccccc1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
TsOH (850 mg, 9.449 mmol) was added to a stirred mixture of 1-hydroxy-2,3-dihydro-1H-inden-5-yl benzoate (120 g, 472.441 mmol) and MgSO4 (113.4 g, 944.882 mmol) in toluene at rt under nitrogen, and the reaction mixture was stirred at 90-100° C. overnight. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE) to give the title compound. 1H-NMR (400 MHz, CDCl3): δ 8.22-8.24 (m, 2H), 7.62-7.66 (m, 1H), 7.50-7.54 (m, 2H), 7.42 (d, J=8.1 Hz, 1H), 7.34 (d, J=1.2 Hz, 1H), 7.12 (dd, J=8.1 Hz, J=2.0 Hz, 1H), 6.88-6.90 (m, 1H), 6.57-6.59 (m, 1H), 3.44 (s, 2H) ppm.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:31])=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C@@H:17]3[C@@H:22]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=4[F:30])[CH2:21][CH2:20][NH:19][CH2:18]3)=[O:16])[CH2:11][CH2:10]2)[CH:8]=1.Cl.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=1>C(Cl)(Cl)Cl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:31])=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C@@H:17]3[C@@H:22]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=4[F:30])[CH2:21][CH2:20][N:19]([S:39]([C:35]4[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=4)(=[O:41])=[O:40])[CH2:18]3)=[O:16])[CH2:13][CH2:14]2)[CH:8]=1
Reactant: Cc1ccc(Cl)cc1N1CCN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(F)cc2F)CC1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Cl)cc1N1CCN(C(=O)[C@H]2CN(S(=O)(=O)c3cccnc3)CC[C@@H]2c2ccc(F)cc2F)CC1

Procedure:
In analogy to example 63, step 4, from (3S,4R) or (3R,4S)-[4-(5-chloro-2-methyl-phenyl)-piperazin-1-yl]-[4-(2,4-difluoro-phenyl)-piperidin-3-yl]-methanone hydrochloride and pyridine-3-sulfonyl chloride hydrochloride was prepared (3S,4R) or (3R,4S)-[4-(5-chloro-2-methyl-phenyl)-piperazin-1-yl]-[(3S,4R)-4-(2,4-difluoro-phenyl)-1-(pyridine-3-sulfonyl)-piperidin-3-yl]-methanone as a white foam, MS: 575.4 ([M+H, 1Cl])+; [α]D=−66.76 (c=0.454 g/100 mL, CHCl3).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:26]([O:1][CH2:2][C@@H:3]([NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2ncnc(N[C@H](CO)c3ccccc3)c2cc1OC
Solvent: O
Product: COc1cc2ncnc(N[C@H](COC(C)=O)c3ccccc3)c2cc1OC
Yield: 90 %

Procedure:
A solution of (S)-4-[α-(hydroxymethyl)benzylamino]-6,7dimethoxyquinazoline (70 mg, 0.21 mmol) in acetic anhydride (2 ml) was stirred at room temperature for 3 h. Then water was added to the reaction mixture, the precipitate was filtered, washed with water and dried under vacuum. Thus pure title compound was obtained in 90% yield (71 mg).