Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([CH:16]=O)[C:8](=[O:15])[N:9]2[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.O.[NH2:20][NH2:21].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[NH:21][N:20]=[CH:16][C:7]=3[C:8](=[O:15])[N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1
Reactant: NN
Reactant: CC(C)n1c(=O)c(C=O)c(Cl)c2ccc(Br)cc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1c(=O)c2cn[nH]c2c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
As described in Step 1.3., to a solution of 7-bromo-4-chloro-2-oxo-1-(propan-2-yl)-1,2-dihydroquinoline-3-carbaldehyde (1.0 g, 3.08 mmol) in 30 mL of DMF at 0° C. is added hydrazine hydrate (0.19 mL, 3.70 mmol). After stirring for 8 hours at room temperature, the reaction mixture is poured into water. The orange-coloured precipitate formed is filtered off and washed with water and then dried under vacuum to give 859 mg of an orange-coloured solid (yield: 73%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=1)[C:10]([OH:12])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:49]1[CH2:54][CH2:53][O:52][CH2:51][CH:50]1[C:55]1[C:63]2[S:62][C:61]([NH2:64])=[N:60][C:59]=2[C:58]([O:65][CH3:66])=[CH:57][CH:56]=1>C1COCC1.C(Cl)(Cl)Cl>[O:49]1[CH2:54][CH2:53][O:52][CH2:51][CH:50]1[C:55]1[C:63]2[S:62][C:61]([NH:64][C:10](=[O:12])[C:9]3[CH:13]=[CH:14][N:15]=[C:7]([CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:8]=3)=[N:60][C:59]=2[C:58]([O:65][CH3:66])=[CH:57][CH:56]=1
Reactant: COCCOCc1cc(C(=O)O)ccn1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COCCOCc1cc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)ccn1

Procedure:
From 2-(2-methoxy-ethoxymethyl)-isonicotinic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+69.2° (c=1.04, CHCl3), ES-MS m/e (%): 460 (M+H+, 100).
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:28][C:29]([F:41])([F:40])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([NH2:39])(=[O:38])=[O:37]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:39][S:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[C:29]([F:28])([F:40])[F:41])(=[O:38])=[O:37])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: NS(=O)(=O)c1ccccc1C(F)(F)F
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccccc2C(F)(F)F)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 2-(trifluoromethyl) benzenesulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method B described hereinabove. Yield (14%); 1H NMR (d6-DMSO) δ 12.49 (br s, 1H), 7.98-7.90 (m, 3H), 7.39-7.08 (m, 13H), 6.85 (d, J=8.0 Hz, 2H), 6.47 (d, J=15.7 Hz, 1H), 2.36 (q, J=7.3 Hz, 2H), 0.82 (t, J=7.3 Hz, 3H); APcI m/z: 562 (M+H+)
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:22]([Cl:27])[CH:21]=[CH:20]2>>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([Cl:27])[CH:21]=[CH:20]3)[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccc2cc(CBr)ccc2n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc3nc(Cl)ccc3c2)C1=O

Procedure:
The title compound is prepared from (2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester as described in EXAMPLE 1, Part H using 6-bromomethyl-2-chloro-quinoline in place of 7-bromomethyl-1-chloroisoquinoline. The crude product is purified by column chromatography eluting with a gradient of 2% MeOH/CH2Cl2 to 4% MeOH/CH2Cl2 to afford the title compound as a beige solid.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN.[CH2:36]([NH:38][C:39]([NH:41][C:42]1[N:47]=[CH:46][C:45]([C:48]2[CH:49]=[N:50][CH:51]=[C:52]([C:54]([OH:56])=O)[CH:53]=2)=[C:44]([C:57]2[S:58][CH:59]=[C:60]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[N:61]=2)[CH:43]=1)=[O:40])[CH3:37]>CN(C=O)C>[CH2:36]([NH:38][C:39]([NH:41][C:42]1[N:47]=[CH:46][C:45]([C:48]2[CH:49]=[N:50][CH:51]=[C:52]([C:54]([NH:2][CH3:1])=[O:56])[CH:53]=2)=[C:44]([C:57]2[S:58][CH:59]=[C:60]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[N:61]=2)[CH:43]=1)=[O:40])[CH3:37]
Reactant: CCNC(=O)Nc1cc(-c2nc(-c3ccccc3)cs2)c(-c2cncc(C(=O)O)c2)cn1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1cc(-c2nc(-c3ccccc3)cs2)c(-c2cncc(C(=O)NC)c2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (73.7 mg, 0.19 mmol), DIEA (78.6 mg, 0.45 mmol) and methylamine (2M soln in THF, 0.15 mL, 0.30 mmol) were added to a solution of 6′-{[(ethylamino)carbonyl]amino}-4′-(4-phenyl-1,3-thiazol-2-yl)-3,3′-bipyridine-5-carboxylic acid (Example 132, 66.4 mg, 0.15 mmol) in DMF (1.5 mL). The resulting light yellow solution was stirred at room temperature for three hours. The reaction mixture was partitioned between water and ethyl acetate and layers separated. The organic layer was washed with saturated NaHCO3, water, brine, then dried over magnesium sulfate. The solvent was removed and the resulting residue was washed with acetonitrile and filtered to yield 33 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:18]([C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=1[F:14])=[O:5].Cl[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[C:18]([C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][N:26]=2)[CH:10]=[CH:9][C:8]=1[F:14])=[O:5]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(O)ccc3F)c2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc([N+](=O)[O-])cn4)ccc3F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
A mixture of 2-chloro-3-(1-cyanocyclopropyl)-N-(2-fluoro-5-hydroxyphenyl)benzamide (23.0 g, 69.6 mmol), 2-chloro-5-nitropyridine (12.2 g, 77.1 mmol), potassium carbonate (11.5 g, 83.1 mmol) and N,N-dimethylformamide (70 mL) was stirred at room temperature for 4 hr. To the reaction mixture were added N,N-dimethylformamide (130 mL) and water (250 mL), and the mixture was stirred at room temperature for 1 hr. The precipitate was collected by filtration, washed with water (200 mL), and dried under reduced pressure to give the title compound (29.3 g, 93%) as a gray powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[CH:22][N:21]=[C:20]([C:24]([OH:26])=[O:25])[CH:19]=2)[CH2:14][C@H:13]1[O:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[CH:22][N:21]=[C:20]([C:24]([O:26][CH3:29])=[O:25])[CH:19]=2)[CH2:14][C@H:13]1[O:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CO[C@@H]1CN(c2cc(C(=O)O)ncn2)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
cis(±)-6-(4-{[(Benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)pyrimidine-4-carboxylic acid obtained in Example (174b) (420 mg, 1.09 mmol) was dissolved in DMF (10 mL). Potassium carbonate (180 mg, 1.3 mmol) and methyl iodide (185 mg, 1.3 mmol) were added, and the mixture was stirred at room temperature overnight. Potassium carbonate (180 mg, 1.3 mmol) and methyl iodide (185 mg, 1.3 mmol) were further added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water and brine, and then dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane/methanol=40/1, 20/1, 10/1) to obtain 112 mg of the title compound as a brown oily substance (26%).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:24]=[C:23]([C:25]([NH:27][C:28]3[C:37]([CH3:38])=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][C:29]=3[CH3:39])=[O:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:24]=[C:23]([C:25]([NH:27][C:28]3[C:29]([CH3:39])=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][C:37]=3[CH3:38])=[O:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:13][CH2:14]1
Reactant: COC(=O)c1cc(C)c(NC(=O)c2cc(N3CCC(O[Si](C)(C)C(C)(C)C)CC3)nc3ccccc23)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(NC(=O)c2cc(N3CCC(O)CC3)nc3ccccc23)c(C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 78.9 %

Procedure:
To a solution of methyl 4-(2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)quinoline-4-carboxamido)-3,5-dimethylbenzoate (0.21 g, 0.00038 mol) in THF (4 ml) is added Bu4NF 1.0 M in THF (4.0 ml) at 0° C. The reaction mixture is gradually warmed to ambient temperature. After 14 hours, the reaction mixture is diluted with ice-water and extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by flash chromatography (silica gel) over a gradient using 0-40% ethyl acetate in hexanes to afford the title compound as a light yellow solid (0.13 g, 78%). Mass spectrum (m/z): 434.2 (M+1).
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[H][H]>CO.[Pd]>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: [H][H]
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)O
Yield: 75.8 %

Procedure:
2.0 g (4.51 mmoles) of Z-Glp-Leu-piperidine are dissolved in 40 ml of methanol, 0.4 g of a 10% palladium-on-carbon catalyst are added to the solution, and hydrogen is bubbled through the mixture for one hour. The catalyst is filtered off, the filtrate is evaporated, and the residue is crystallized from ether. 1.12 g (81%) of Glp-Leu-piperidine are obtained; m.p.: 99°-100° C., Rf5 =0.71, [α]D25 =+30.4° (c=1%, in acetic acid). Analysis for amino acids: Glu=0.95 (1.0), Leu=1.00 (1.0).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[N:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[N:17]3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:34][NH:35][C@H:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38][CH2:37]1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH3:34][N:35]([C@H:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38][CH2:37]1)[C:21]([C:19]1[CH:18]=[N:17][N:16]([CH:13]2[CH2:12][CH2:11][N:10]([C:8](=[O:9])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:24]([F:26])([F:25])[F:27])=[N:5]3)[CH2:15][CH2:14]2)[N:20]=1)=[O:23]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(n2ncc(C(=O)O)n2)CC1
Reactant: CN[C@@H]1CCCc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(n2ncc(C(=O)N(C)[C@@H]3CCCc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a slurry of 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-2H-1,2,3-triazole-4-carboxylic acid (0.070 g, 0.18 mmol) (i.e. the product of Example 32, Step C) in dichloromethane (2 mL) was added oxalyl chloride (0.05 mL, 0.35 mmol) and one drop of N,N-dimethylformamide. After 45 minutes the reaction mixture was concentrated in vacuo and the resulting residue was dissolved in dichloromethane (10 mL). The reaction mixture was then added to a solution of (R)—N-methyl-1,2,3,4-tetrahydronaphthalen-1-ylamine (32 mg, 0.20 mmol) and triethylamine (0.033 mL, 0.24 mmol) in dichloromethane (2 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. The organic layer was washed with saturated aqueous sodium bicarbonate, dried (Na2SO4) and the solvent was removed with a rotary evaporator. The residue was purified by medium pressure liquid chromatography (MPLC) using 35-60% ethyl acetate in hexanes as eluant to afford 74 mg of the title product, a compound of the present invention as an oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]([CH3:31])([C:18](=[O:30])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:29])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[C:14]([O:16][CH3:17])=[O:15].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:9]1[C:26]([CH3:28])([CH3:27])[CH:25]1[CH2:24][CH2:23][C:22]([CH3:29])=[CH:21][CH2:20][CH2:19][C:18](=[O:30])[C:13]([CH3:31])([CH3:12])[C:14]([O:16][CH3:17])=[O:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C(C)(C)C(=O)CCC=C(C)CCC=C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(=O)CCC=C(C)CCC1OC1(C)C
Temperature: -50 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
A solution of 1.32 g of m-chloroperbenzoic acid in 50 ml of methylene chloride was added to a solution of 1.93 g of the product of Step A in 50 ml of methylene chloride cooled to -50° C. and the mixture was stirred for 1 hour at -40° C. and 21/2 hours at -5° C. The mixture was poured into a saturated aqueous sodium bicarbonate solution and the organic phase was decanted. The aqueous phase was extracted with methylene chloride and the combined organic phases were washed with water, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed over silica and was eluted with a 95-5 mixture of benzene and ethyl acetate to obtain 0.88 g of methyl 10-epoxy-2,2,7,11-tetramethyl-3-oxo-6-dodecenoate in the form of a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:10]2[C:11]([NH2:14])=[N:12][O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1.O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:19][C:17]1[CH:16]=[CH:15][C:3]([O:4][C:5]2[C:10]3[C:11]([NH2:14])=[N:12][O:13][C:9]=3[CH:8]=[CH:7][CH:6]=2)=[C:2]([F:1])[CH:18]=1
Reactant: Nc1noc2cccc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2cccc3onc(N)c23)c(F)c1
Temperature: 70 °C

Procedure:
120 mg (0.41 mmol) of 4-(2-fluoro-4-nitrophenoxy)-1,2-benzisoxazole-3-amine (from example VI) and 468 mg (2.07 mmol) of tin(II) chloride dihydrate are dissolved in 8 ml of ethyl acetate and heated at 70° C. for 4 hours. After cooling to room temperature, the reaction solution is adjusted to pH 9 using saturated sodium bicarbonate solution, which gives a colorless precipitate. 5 g of kieselguhr are added to the suspension, and the mixture is filtered. The filtrate is extracted repeatedly with ethyl acetate. The combined organic phases are washed with water and dried over sodium sulfate. Removal of the solvent under reduced pressure gives the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13]O)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.CS(Cl)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[CH2:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(CO)c1ccc(Cl)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: C=C(C(=O)OC)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
Methyl 2-(4-chlorophenyl)-3-hydroxypropanoate (39.4 g, 184 mmol) was dissolved in DCM (500 mL) and treated with TEA (64.0 mL, 459 mmol). The solution was cooled to 0° C. and slowly treated with MsCl (15.6 mL, 202 mmol), then allowed to stir for 30 minutes to completion by TLC analysis. The solution was partitioned with 1N HCl solution, and the aqueous layer was extracted once with DCM. The combined organic layer washed once more with 1N HCl solution, separated, washed with diluted NaHCO3 solution, and separated. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford an orange oil. The residue was loaded onto a large fritted filter with a plug of silica gel and eluted with 9:1 hexanes:ethyl acetate affording the pure desired product by TLC analysis. The concentrated pure fractions yielded the methyl 2-(4-chlorophenyl)acrylate as a colorless oil (30.8 g, 85%). This methyl 2-(4-chlorophenyl)acrylate (500 mg, 2.54 mmol) was added as a solution in THF (1.35 mL) to a stirring solution of i-PrNH2 (217 uL, 2.54 mmol) in THF (5.0 mL) at 0° C. The reaction was allowed to stir at room temperature overnight to completion by LCMS analysis. The Boc2O (584 uL, 2.54 mmol) was added to the stirring amine via pipet. The reaction was allowed to stir overnight to completion by LCMS and TLC analysis of the mixture. The solution was concentrated in vacuo to afford methyl 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoate as a colorless oil (854 mg, 94%). LC/MS (APCI+) m/z 256.1 [M-Boc]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2.Br[CH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25].C(#N)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[C:24]([C:23]1[CH:22]=[C:21]([CH:28]=[CH:27][CH:26]=1)[CH2:20][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)#[N:25]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(O)cccc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(cccc2OCc2cccc(C#N)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.8 %

Procedure:
tert-Butyl 5-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.025 g, 0.10 mmol) was combined with 3-(bromomethyl)benzonitrile (Aldrich, 145610) (0.029 g, 0.15 mmol), acetonitrile (2.0 mL) and cesium carbonate (0.065 g, 0.20 mmol) and was stirred at r.t. overnight. This was diluted with ethyl acetate, filtered to remove the solids and concentrated under reduced pressure to give crude tert-butyl 5-(3-cyanobenzyloxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.040 g) as a semisolid. Analytical LCMS (M+Na)+: m/z=387.0.
Reaction SMILES: C([N:8]1[C@H:13]([CH3:14])[CH2:12][CH:11]([N:15]([CH2:40][CH3:41])[C:16]2[C:17]([CH3:39])=[C:18]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=2)[C:19]([NH:21][CH2:22][C:23]2[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=2[CH3:29])=[O:20])[CH2:10][C@H:9]1[CH3:42])C1C=CC=CC=1>CO.[Pd]>[CH3:29][C:28]1[CH:27]=[C:26]([CH3:30])[NH:25][C:24](=[O:31])[C:23]=1[CH2:22][NH:21][C:19](=[O:20])[C:18]1[CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=[C:16]([N:15]([CH:11]2[CH2:12][C@@H:13]([CH3:14])[NH:8][C@H:9]([CH3:42])[CH2:10]2)[CH2:40][CH3:41])[C:17]=1[CH3:39]
Reactant: CCN(c1cc(C(F)(F)F)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1C[C@@H](C)N(Cc2ccccc2)[C@H](C)C1
Agent: [Pd]
Solvent: CO
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1C[C@@H](C)N[C@H](C)C1
Reaction time: 2 h
Yield: 56.2 %

Procedure:
To a stirred solution of 3-{[(2R,6R)-1-benzyl-2,6-dimethylpiperidin-4-yl](ethyl)amino}-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2-methyl-5-(trifluoromethyl)benzamide (267 mg, 0.459 mmol) in MeOH (5 mL) was added Pd/C (250 mg). The reaction mixture was stirred at et for 2 hour under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (1. NAM-300H silica gel produced by Nagara Science Co., Ltd., ethylacetate/MeOH=4/1 to ethylacetate/MeOH/triethylamine=1/1/0.01, 2. NH—SiO2, heptane/ethylacetate=30/1 to 8/1) to give the titled compound as a white solid (127 mg, 56% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.30 (s, 1H), 7.26 (s, 1H), 7.14 (t, J=6.1 Hz, 1H), 5.94 (s, 1H), 4.54 (dd, J=5.9, 1.6 Hz, 2H), 3.41-3.49 (m, 1H), 3.01-3.13 (m, 3H), 2.85-2.92 (m, 1H), 2.40 (s, 3H), 2.32 (s, 3H), 2.22 (s, 3H), 1.63-1.80 (m 4H), 1.13 (d, J=7.0 Hz, 3H), 1.02 (d, J=6.2 Hz, 3H), 0.83 (t, J=7.0 Hz, 3H); LC-MS: m/z [M+H] 493.1, [M+Na] 515.3; HPLC; 97.2% purity.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:10]2[N:22]([C:25](=[O:42])[CH:26]([NH:31]C(OCC3C=CC=CC=3)=O)[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:24][CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:10]2[N:22]([C:25](=[O:42])[CH:26]([NH2:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:24][CH:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(OCc2ccc(F)cc2)C2C1CCN2C(=O)C(NC(=O)OCc1ccccc1)C(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(OCc2ccc(F)cc2)C2C1CCN2C(=O)C(N)C(C)(C)C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
A solution containing 46 (4.10 g, 7.02 mmol) and NH4OAc (275 mg, 3.50 mmol) in MeOH (70 mL) was treated with 10% Pd-on-carbon (wet, 745 mg, 0.70 mmol) and the stirred mixture was purged with hydrogen. After 3 h stirring under a balloon of hydrogen, TLC analysis (1:1 hexanes/EtOAc) indicated the reaction was complete. The catalyst was removed by filtration and the solvent was concentrated in vacuo. The residue was dissolved in Et2O and washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to provide 3.30 g of 47 as colorless oil which was used without further purification. Mass spectrum, m/z [449.9] (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[BH4-].[Na+].B(F)(F)F.CCOCC.Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[CH2:7][OH:8]
Reactant: O=C(O)c1cc(Cl)ccc1I
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1cc(Cl)ccc1I
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
A solution of 120 g of 5-chloro-2- iodobenzoic acid (K. Pelz et al., Collect.Czech.Chem.Commun. 33, 1852, 1968) in 145 ml of tetrahydrofuran is stirred and treated at 10°-20° C. for 45 minutes with 16.1 g of sodium borohydride. The mixture is then stirred for 30 minutes at this temperature and treated with a solution of 80.3 g (71.4 ml) of boron trifluoride etherate in 40 ml of tetrahydrofuran. It is stirred for another 3 hours and while cooling with ice-cold water it is decomposed at a maximum temperature of 8° C. with 50 ml of 5% hydrochloric acid added dropwise. It is diluted with water and extracted with benzene. The extract is washed with a 5% sodium hydroxide solution and water, dried with magnesium sulfate and evaporated. There are obtained 100 g (96%) of crude 5-chloro-2-iodobenzyl alcohol with m.p. of 115°-117° C. The analytically pure substance is obtained by crystallization from ethanol; m.p. 116°-117° C.