Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O>>[CH3:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=3)[N:13]=2)[CH2:2][CH2:3]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Reactant: Cc1ccccc1C=O
Product: Cc1ccccc1CN1CCCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-methylbenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(2-methylphenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C=O)C>[O:7]=[C:6]1[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[C:3](=[O:12])[N:2]1[O:1][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
A mixture of N-hydroxyphthalimide (10 g, 61.3 mmol), K2CO3 (16.9 g, 122 mmol) and tert-butyl bromoacetate (12 g, 9 mL, 61.3 mmol) in DMF (60 mL) was stirred at room temperature for 3 hours and the solvent was evaporated under high vacuum. The residue was dissolved in EtOAc, washed with brine, dried over Na2SO4 and filtered. The residue after evaporation of the solvent was recrystallized from a mixture of CH2Cl2/EtOAc/hexane to give the title compound (12 g, 71% yield) as a white solid. Mp 140–141° C. 1H NMR (300 MHz, CDCl3) δ 7.80–7.90 (m, 2H), 7.74–7.77 (m, 2H), 4.71 (s, 2H), 1.49 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 166.0, 163.0, 134.7, 128.9, 123.7, 83.0, 73.5, 28.1. Mass spectrum (API-TIS) m/z 278 (MH+), 295 (MNH4+). Anal. calcd. for C14H15NO5: C, 60.64; H, 5.45; N, 5.05. Found: C, 60.47; H, 5.31; N, 4.96.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH:24]([NH:27][C:28]([CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])=[O:29])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:28](=[O:29])[CH2:30][CH2:31][CH2:32][C:33]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:34])([CH3:26])[CH3:25]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CC(C)NC(=O)CCCC(=O)O
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CCCC(=O)NC(C)C

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-isopropylcarbamoyl-butyric acid to yield (3aR,4S,7aR)-methyl 4-(5-(isopropylamino)-5-oxopentanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [2M+H]=938; RT=1.18 min; UPLC Method I
Reaction SMILES: C(N(CC)C(C)C)(C)C.Br[CH2:11][CH2:12][OH:13].[I-].[K+].[CH3:16][C:17]1([CH3:30])[CH:26]=[C:25]([CH3:27])[C:24]2[C:19](=[CH:20][C:21]([O:28][CH3:29])=[CH:22][CH:23]=2)[NH:18]1>>[OH:13][CH2:12][CH2:11][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[C:21]([O:28][CH3:29])[CH:20]=2)[C:25]([CH3:27])=[CH:26][C:17]1([CH3:30])[CH3:16]
Reactant: COc1ccc2c(c1)NC(C)(C)C=C2C
Reactant: OCCBr
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)N(CCO)C(C)(C)C=C2C
Temperature: 115 °C
Reaction time: 24 h

Procedure:
51 g (0.4 mol) N,N-diisopropylethylamine, 72.5 g (0.57 mol) 2-bromoethanol and a spatula tip of potassium iodide were added to 50 g (0.24 mol) 2,2,4-trimethyl-7-methoxy-1,2-dihydroquinoline. The solution was stirred for 24 hours at 110 to 120° C. The organic phase was subsequently washed with dilute sodium hydroxide solution and water and dried over sodium sulfate. The solvent was then completely removed by distillation. A light-green oil was obtained as the product.
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.Br[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:34])=[C:23]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1.C(OCC)(=O)C>CN(C=O)C>[Cl:34][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:8]([C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)[N:6]2[CH:5]=[N:4][N:3]=[CH:7]2)=[CH:24][C:23]=1[O:25][C:26](=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: O=C(Oc1cc(CBr)ccc1Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(Cc2ccc(Cl)c(OC(=O)c3ccccc3)c2)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 200 mg, 5.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMF (20 mL) at r.t. The mixture was stirred for 1 hour at this temperature and benzoic acid 5-bromomethyl-2-chloro-phenyl ester (CAB02138, 1.63 g, 5.0 mmol) was added. The reaction mixture was stirred overnight and ethyl acetate (75 mL) was added. The mixture was transferred into a separation funnel and washed with water (2×50 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc, Rf: 0.31) to give a white solid. Yield: 1.773 g (82%). 1H-NMR (400 MHz, CDCl3) δ=4.93 (s, 2H), 6.66 (d, 9.0 Hz, 2H), 7.06 (dd, J=8.2, 2.0 Hz, 1H), 7.27 (d, J=2.0 Hz, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.47-7.58 (m, 4H), 7.60-7.69 (m, 1H), 8.16-8.21 (m, 2H), 8.24 (s, 2H). LRMS (FAB+): 430.1 (100, [M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClC1C=C(C=CC=1)C(OO)=[O:26]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)/[C:12]#[N+:13][O-:26])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(/C(C#N)=C/c2ccncc2)cc1OC
Solvent: ClCCl
Product: COc1ccc(/C(C#[N+][O-])=C/c2ccncc2)cc1OC
Yield: 94 %

Procedure:
Compound 30 (266 mg) was dissolved in anhydrous dichloromethane (50 mL). m-chloroperoxybenzoic acid (266 mg) was added dropwise to the solution under stirring in an ice bath. The mixture was stirred for about 15 minutes under argon which was fed by means of a separately provided balloon filled with argon. The mixture was returned to room temperature, followed by stirring for 3 hours. The reaction mixture was extracted with purified water and chloroform. The organic layer was washed with brine, and the washed organic layer was dried over sodium sulfate anhydrate. The solvent was evaporated to dryness. The residue was purified by silica gel column chromatography (chloroform-methanol), to thereby yield the target product (yield: 265 mg, 94%).
Reaction SMILES: C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[NH2:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=1)=[O:23].[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([C:48](O)=[O:49])[CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl>[O:23]=[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:32])([F:33])[F:34])[CH:25]=1)[CH2:21][NH:20][C:48]([CH:45]1[CH2:46][CH2:47][N:42]([C:40]([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:41])[CH2:43][CH2:44]1)=[O:49]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NCC(=O)c1cccc(OC(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2cccc(OC(F)(F)F)c2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 57.1 %

Procedure:
Add triethylamine (1.1 mL, 7.89 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.51 g, 7.87 mmol) to a solution of 2-amino-1-(3-(trifluoromethoxy)phenyl)ethanone (1.56 g, 6.10 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1.66 g, 7.24 mmol) in CH2Cl2 (15 mL) at 0° C. Stir at 0° C. for 3 h, then at room temperature overnight. Concentrate the mixture in vacuo. Purify the residue by silica gel chromatography (80 g SiO2 eluting with 50% ethyl acetate/hexanes, 1 L) to provide tert-butyl 4-(2-oxo-2-(3-(trifluoromethoxy)phenyl)ethylcarbamoyl)piperidine-1-carboxylate (1.50 g, 57%).
Reaction SMILES: [Br-].[C:2]1([CH2:8][N+:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:10]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([S:28]([CH:31]=[CH2:32])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO.C1(C=CC(O)=CC=1)O>[C:22]1([S:28]([CH:31]2[CH2:32][C:10]3([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:9]([CH2:8][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:14]2[CH:13]=[CH:12][C:11]3=[O:15])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C=CS(=O)(=O)c1ccccc1
Reactant: Oc1ccc[n+](Cc2ccccc2)c1-c1ccccc1
Agent: Oc1ccc(O)cc1
Agent: [Br-]
Solvent: CO
Product: O=C1C=CC2C(S(=O)(=O)c3ccccc3)CC1(c1ccccc1)N2Cc1ccccc1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
To 7.35 gm (21.5 mmol) 1-phenylmethyl-2-phenyl-3-hydroxypyridinium bromide in 20 ml of methanol was added 8.69 gm Amberlyst AG1-X8 resin —OH form 20–40 mesh. The mixture was stirred for a short period and then filtered and the resin washed with methanol. The solvent was removed in vacuo. The solid residue was taken up in toluene (150 ml) and treated with 50 mg of hydroquinone and 6.84 gm (37.1 mmol) phenyl vinylsulfone. The reaction mixture was heated under reflux for 18 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with 8:2/hexane:ethyl acetate to afford 5.87 gm (64%) of a light yellow solid. 1H NMR (CDCl3, 400 MHz) δ 7.71–7.61 (m, 5H), 7.46 (t, 2H, J=8 Hz), 7.37–7.23 (m, 8H), 6.84 (dd, 1H), J=9 Hz, J=5 Hz), 6.20 (d, 1H, J=9 Hz), 4.22 (d, 1H, J=5 Hz), 3.63 (d, 1H, J=14 Hz), 3.54 (dd, 1H, J=9 Hz, J=4 Hz), 3.40 (d, 1H, J=13 Hz), 2.80 (dd, 1H, J=15 Hz, J=3 Hz), 2.53 (dd, 1H, J=15 Hz, J=5 Hz) ppm. 13C NMR (CDCl3, 125 MHz) δ 196.9, 144.9, 138.3, 138.0, 137.7, 134.3, 130.9, 129.9, 129.8, 129.5, 129.2, 129.2, 129.0, 129.0, 128.9, 128.7, 128.2, 128.1, 127.9, 75.1, 66.3, 57.9, 49.1, 38.1 ppm. Mass spectrum APCI m/z 430 (p+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][N:19]=3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(Nc2ccc(C(F)(F)F)cn2)nn1-c1ncccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(Nc2ccc(C(F)(F)F)cn2)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.9 %

Procedure:
855 mg (2.15 mmol) of methyl 1-(3-chloropyridin-2-yl)-3-{[5-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-5-carboxylate were dissolved in 10.0 ml of ethanol, and 248 mg (2.79 mmol) of 45% strength aqueous sodium hydroxide solution were added. After 24 hours of stirring at room temperature, the mixture was diluted with water and acidified with dilute hydrochloric acid. The aqueous phase was extracted repeatedly with ethyl acetate and dried over magnesium sulphate. The solvent was distilled off under reduced pressure, which gave 758 mg (92% of theory) of 1-(3-chloropyridin-2-yl)-3-{[5-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-5-carboxylic acid. (logP: 2.79; MH+: 384.0; 1H-NMR (400 MHz, CD3CN, δ, ppm): 7.28 (m, 1H), 7.38 (m, 1H), 7.55 (m, 1H), 7.89 (m, 1H), 8.05 (m, 1H), 8.51 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].CS(O[C@H:17]1[CH2:32][N:20]2[CH2:21][CH2:22][N:23]([C:25]3[N:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=3)[CH2:24][C@@H:19]2[CH2:18]1)(=O)=O>CN(C=O)C.O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][C@@H:17]2[CH2:32][N:20]3[CH2:21][CH2:22][N:23]([C:25]4[N:26]=[CH:27][C:28]([F:31])=[CH:29][N:30]=4)[CH2:24][C@@H:19]3[CH2:18]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O[C@@H]1C[C@H]2CN(c3ncc(F)cn3)CCN2C1
Reactant: OCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(CO[C@H]2C[C@H]3CN(c4ncc(F)cn4)CCN3C2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
A solution of 1.15 mL (10.2 mmol) of 4-fluorobenzyl alcohol in 35 mL of dry DMF was treated with 0.48 g (12 mmol) of sodium hydride (60% oil dispersion), and the mixture was stirred at 50° C. for 30 min. A solution of 1.15 g (3.64 mmol) of (7R,8aS)-7-methanesulfonyloxy-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 7) in 35 mL of dry DMF was added and the solution stirred at 100° C. for 18 h. The solution was cooled, diluted with water, and extracted with diethyl ether (2×). The combined organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with ethyl acetate gave 0.25 g (20%) of the title compound. mp (.D-(-)-tartrate) 76°-81° C. 13C NMR (base, CDCl3): δ 36.3, 43.6, 48.8, 51.3, 60.2, 61.9, 70.4, 76.6, 115.0, 115.3, 129.43, 129.53, 134.0, 144.9, 145.2, 149.9, 153.2, 158.9, 160.6, 163.9. HRMS calcd for C18H20F2N4O (MH+): 347.1683, found: 347.1706.
Reaction SMILES: [CH3:1][C:2]([N+:15]([O-])=O)([CH2:13][CH3:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[H][H]>[Pd].C(O)C>[NH2:15][C:2]([CH3:1])([CH2:13][CH3:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CCC(C)(Cc1c[nH]c2ccccc12)[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCC(C)(N)Cc1c[nH]c2ccccc12
Temperature: 70 °C
Reaction time: 7 h
Yield: 95.3 %

Procedure:
Reduction: A mixture of 90.0 g (388 mM) of the nitro intermediate and 9.0 g of palladium catalyst (5% on carbon) and 1000 ml of absolute ethanol was covered with hydrogen at a pressure of 25 atmospheres gauge in the autoclave whereupon it was heated to 70°C. and agitation was continued at this temperature for 7 hours. Filtration, evaporation in vacuo, recrystallisation from xylene and processing of the mother liquor yielded 74.7 g of 3-(2'-amino-2'-methylbutyl)-indole. (Yield: 95% of the theoretical).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[OH-].[Na+].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1>CN(C=O)C.O>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[N:2]2)=[CH:15][CH:14]=1
Reactant: c1ccc2[nH]nnc2c1
Reactant: Fc1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Cn2nnc3ccccc32)cc1
Reaction time: 0.5 h

Procedure:
To a solution of benzotriazole (12 g) in DMF (150 mL) at r.t. was added a solution of 10N NaOH (11 mL). After stirring for 30 min., 4-fluorobenzyl bromide (3.9 mL) was added. The mixture was further stirred for 3 hrs, diluted with H2O, and extracted with EtOAc. The EtOAc extract was washed water (2×), dried (MgSO4) and concentrated. The residue was stirred in diethyl ether/hexane to afford the title compound as a white solid.
Reaction SMILES: Cl.[C:2]1([CH:8]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][NH2:28])=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9][C:10]([O:12]CC)=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]1[C:35]([N+:36]([O-:38])=[O:37])=[CH:34][CH:33]=[CH:32][N:31]=1>C(N(CC)CC)C>[N+:36]([C:35]1[C:30]([NH:28][CH2:27][CH2:26][CH2:25][O:24][C:20]2[CH:19]=[C:18]3[C:23]([C:15]([CH:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][C:10]([OH:12])=[O:11])=[CH:16][NH:17]3)=[CH:22][CH:21]=2)=[N:31][CH:32]=[CH:33][CH:34]=1)([O-:38])=[O:37]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)CC(c1ccccc1)c1c[nH]c2cc(OCCCN)ccc12
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(O)CC(c1ccccc1)c1c[nH]c2cc(OCCCNc3ncccc3[N+](=O)[O-])ccc12

Procedure:
Analogously to Example 18, the compound 35, prepared in accordance with Example 14.2, is reacted with 2-chloro-3-nitropyridine and triethylamine, giving 3-{6-[3-(3-nitropyridin-2-ylamino)propoxy]-1H-indol-3-yl}-3-phenylpropionic acid. After preparative HPLC: 3-{6-[3-(3-nitropyridin-2-yl-amino)propoxy]-1H-indol-3-yl}-3-phenylpropionic acid trifluoroacetate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1>C1COCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CCCCCCCCCCCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
12-Hydroxydodecanoic acid (2.16 g, 10.0 mmol) was suspended in 20mL of dry THF. After the addition of 1.39g (16.5 mmol) of dihydropyran, the solution was stirred for 10 min. at room temperature. Twenty mg (0.105 mmol) of crystalline p-toluenesulfonic acid monohydrate was then added. The mixture became clear immediately, and was stirred for an additional 2 hours at room temperature. Evaporation of solvent under reduced pressure afforded a crude product which was purified by flash chromatography (CHCl3) to yield 2.40 g (80%) of 12-(tetrahydropyranyloxy)dodecanoic acid as a colorless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:9][CH:10]([CH2:19][CH3:20])[CH2:11][CH2:12][CH2:13][C:14](OCC)=[O:15])[CH3:8]>O1CCCC1>[CH2:7]([O:9][CH:10]([CH2:19][CH3:20])[CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH3:8]
Reactant: CCOC(=O)CCCC(CC)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(CC)CCCCO
Temperature: 25 °C

Procedure:
A solution of tetrahydrofuran (2000 ml) and lithium aluminum hydride (46 g, 1.21 moles) is cooled in a -60° C. dry ice/ethanol bath. The starting material prepared in Example 36, ethyl 5-ethoxyheptanoate (302 g ,1.49 moles) is diluted in tetrahydrofuran (300 ml) and added dropwise to the stirring reaction. After the addition is complete the reaction is warmed to room temperature and stirred for an additional hour. The solution is cooled in a -78° C. dry ice/ethanol bath and the excess hydride is destroyed by adding dropwise the following: water (46 ml), 15% sodium hydroxide solution (46 ml), and water (136 ml). The reaction is filtered and the solids washed several times with tetrahydrofuran (3×500 ml). The volume of the filtrate is reduced under vacuum and the residue dried over anhydrous magnesium sulfate. The remaining solvent is then removed leaving a clear, colorless oil suitably pure for the next reaction (238 g, 1.49 moles).
Reaction SMILES: CO.[O:3]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[C].[Pd].C(O)(=O)C>[O:3]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C1=C(c2ccc(Oc3ccccc3)cc2)CCNC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Yield: 66 %

Procedure:
To a 100 ml methanol solution of 3.51 g of the compound (8) synthesized in Example 1 were added 200 mg of palladium carbon and 1 ml of acetic acid for hydrogenation at atmospheric pressure and room temperature. After the completion of the reaction, the insolubles were filtered off, then the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methylene chloride and adjusted by a 10% aqueous solution of sodium hydroxide to a pH 9 to 10, then was shaken. The organic layer was dried, filtered, then condensed under reduced pressure to obtain a residue which was then purified by silica gel column chromatography (methylene chloride:methanol=20:1) to obtain the above-referenced compound (9) in an amount of 2.32 g (yield 66%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][C:29]=3I)[CH2:26][CH2:25][CH2:24]4)[C@@H:15]([CH3:31])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([CH3:46])([CH3:45])[CH2:43][OH:44])=[CH:38][C:37]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][C:29]=3[C:37]3[CH:38]=[C:39]([C:42]([CH3:46])([CH3:45])[CH2:43][OH:44])[CH:40]=[CH:41][C:36]=3[O:35][CH3:34])[CH2:26][CH2:25][CH2:24]4)[C@@H:15]([CH3:31])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1ccc(C(C)(C)CO)cc1B1OC(C)(C)C(C)(C)O1
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc2c(cc1I)CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)CO)cc1-c1cc2c(cc1CN1C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@@H]1C)CCC2

Procedure:
(4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[(6-iodo-2,3-dihydro-1H-inden-5-yl)methyl]-4-methyl-1,3-oxazinan-2-one (Intermediate 25; 30 mg; 0.052 mmol) was treated with 2-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylpropan-1-ol (Intermediate 26; 20 mg; 0.067 mmol), 1-1′-bis(di tert-butylphosphino)ferrocene palladium dichloride (3.4 mg; 0.0052 mmol), 1 N K2CO3 (1.2 mL) and THF (1.2 mL) as described in Example 38 to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-({6-[5-(2-hydroxy-1,1-dimethylethyl)-2-methoxyphenyl]-2,3-dihydro-1H-inden-5-yl}methyl)-4-methyl-1,3-oxazinan-2-one as a clear glass. LCMS=636.1 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers): δ 7.84-7.79 (m, 2H), 7.75 (s, 1H), 7.33 (dd, J=8.7, 2.5 Hz, 1H), 7.29 (s, 1H), 7.23 (d, J=2.3 Hz, 1H), 7.13 (s, 1H), 6.95-6.92 (m, 1H), 5.41 (d, J=15.3 Hz, 1H), 4.93 (d, J=10.5 Hz, 1H), 3.93 (d, J=15.4 Hz, 1H), 3.81 (s, 3H), 3.65-3.61 (m, 1H), 3.57-3.54 (m, 1H), 3.44-3.36 (m, 1H), 2.99-2.94 (m, 4H), 2.20-2.10 (m, 3H), 1.76-1.64 (m, 1H), 1.33-1.25 (m, 6H), 1.05-1.02 (m, 3H).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.CON(C)[C:18]([C:20]1[S:24][CH:23]=[N:22][CH:21]=1)=[O:19]>C1COCC1>[CH3:14][O:13][C:10]1[N:11]=[CH:12][C:7]([C:18]([C:20]2[S:24][CH:23]=[N:22][CH:21]=2)=[O:19])=[CH:8][CH:9]=1
Reactant: CON(C)C(=O)c1cncs1
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cncs2)cn1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A n-BuLi solution (1.89 mL, 3.03 mmol, 1.6 M solution in hexane) was slowly added to a −78° C. solution of 5-bromo-2-methoxypyridine (0.392 mL, 3.03 mmol) in dry THF (10 mL). After addition, stirring was continued for an additional 40 minutes and N-methoxy-N-methylthiazole-5-carboxamide (0.600 g, 3.48 mmol, Intermediate 11: step a) dissolved in THF (10 mL) was slowly added. The mixture was stirred at −78° C. for 10 minutes then warmed to 0° C. and stirred for 1 hour. The cold solution was quenched with saturated aqueous NH4Cl and warmed to room temperature. H2O was added and layers were separated. The aqueous layer was extracted with EtOAc (3×) and the combined organic extracts washed with brine, dried (Na2SO4), filtered, evaporated in vacuo, preabsorbed onto silica gel and chromatographed (CH2Cl2/EtOAc) to provide product. The pure white solid title compound was precipitated from MeOH, filtered and dried under reduced pressure.