Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([O:18][CH3:19])[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]>C(OCC)(=O)C.C(O)C.[Pd]>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([O:18][CH3:19])[CH:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCN1CCN(c2ccc(N)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
4.05 g (15.27 mmol) of the product prepared in step 18.1 in 25 mL of an ethyl acetate/ethanol mixture (v/v=1/1) are placed in a hydrogenation autoclave, and 0.32 g of 10% palladium-on-charcoal is added, under an inert atmosphere. The mixture is stirred under a hydrogen pressure of 2.5 bar at room temperature for 2 hours. After filtering through thin glass fibre paper and evaporating under reduced pressure, 3.51 g of the expected product are obtained in the form of a violet solid, which is used as obtained in the following step. Yield=98%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2.[H-].[Na+].[C:27](Cl)(=[O:29])[CH3:28].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:27](=[O:29])[CH3:28])[CH:20]=[CH:19]2
Reactant: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1OC
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc4c(ccn4C(C)=O)c3)c2cc1OC
Reaction time: 0.5 h
Yield: 41 %

Procedure:
6,7-Dimethoxy-4-[(1H-5-indolyl)oxy]quinoline (50 mg) was dissolved in N,N-dimethylformamide (1 ml), and 60% sodium hydride (7 mg) was added to the solution, followed by stirring under ice cooling for 30 min. Acetyl chloride (16.6 μl) was added to the reaction solution, and the mixture was stirred under ice cooling for additional one hr. Further, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (23 mg, yield 41%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5](Br)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].Cl.[CH3:15][NH:16][CH3:17].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([N:16]([CH3:17])[CH3:15])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)C(Br)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(c1cccnc1)N(C)C
Yield: 53 %

Procedure:
Bromopyridin-3-yl-acetic acid ethyl ester (2.54 g; 10.2 mmol) was reacted in a sealed tube, at rt., in CH2Cl2, overnight with N,N-dimethylamine hydrochloride (3.34 g; 41.0 mmol; 4 equiv) and Et3N (5.8 mL; 41.0 mmol; 4 equiv). The reaction solution was evaporated to dryness, dissolved in CH2Cl2, washed five times with saturated NaHCO3 (aq), washed once with saturated NaCl (aq), dried with Na2SO4, filtered, and concentrated in vacuo. The resulting brown oil was purified with silica gel chromatography in a 3×25 cm glass column using a 0.5% methanol/chloroform (v/v) mobile phase. The desired product was isolated as a yellow oil (1.12 g; 53% yield). MS(ES) calc'd: [M+H]+=208.1 m/z. Found: 208.1 m/z.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])=[O:5].[Cl:19][CH2:20][C:21](Cl)=O>C(O)(=O)C>[Cl:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:2]2[C:3]=1[C:4](=[O:5])[N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])[C:21]([CH2:20][Cl:19])=[N:1]2
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc(Cl)c1C(=O)Nc1ccccc1F
Solvent: CC(=O)O
Product: O=c1c2c(Cl)cccc2nc(CCl)n1-c1ccccc1F
Yield: 39.6 %

Procedure:
Prepared according to Procedure B with 1k (1.0 g, 3.78 mmol) and chloroacetyl chloride (0.90 mL, 11.3 mmol) in acetic acid (20 mL). Purified by chromatography in CH2Cl2 to afford 484 mg of a pale pink solid (40%). 1H NMR (CDCl3) δ: 7.69 (s, 1H); 7.68 (d, J=3.2 Hz, 1H); 7.56 (d, J=3.0 Hz, 1H); 7.54 (d, J=3.0 Hz, 1H); 7.40-7.47 (m, 1H); 7.35-7.38 (m, 1H); 7.27-7.32 (m, 1H); 4.35 (d, J=12 Hz, 1H); 4.18 (d, J=12 Hz, 1H). MS (ES): m/z 323.0 (M+).
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:6][CH2:5][CH2:4][N:3]1[C@@H:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=O.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.C(N=C=N)C.[CH2:38]([N:45]1[CH2:49][C@H:48]2[C@H:50]([NH2:53])[CH2:51][CH2:52][C@H:47]2[CH2:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl>[CH2:38]([N:45]1[CH2:49][C@H:48]2[C@H:50]([NH:53][C:8](=[O:10])[C@@H:7]([N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:51][CH2:52][C@H:47]2[CH2:46]1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: CC(C)C[C@@H](C(=O)O)N1CCCS1(=O)=O
Agent: CCN=C=N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)N1CCCS1(=O)=O
Reaction time: 0.25 h

Procedure:
(2S)-2-(1,1-Dioxidoisothiazolidin-2-yl)-4-methylpentanoic acid (359 mg, 1.526 mmol) was combined with triethylamine (0.387 mL, 2.77 mmol) in dichloromethane (10 mL). 1-Hydroxybenzotriazole (234 mg, 1.526 mmol) and N43-dimethylaminopropyl)-N′-ethylcarbodiimide (0.270 mL, 1.526 mmol) were added, and the reaction mixture was stirred for 15 minutes. Then (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine (300 mg, 1.387 mmol) from Example 16 Step E was added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched with 10 mL of aqueous sodium bicarbonate and extracted with 3×20 mL of dichloromethane. The solvent was removed in vacuo. The crude material was applied to a silica gel cartridge (Analogix®, Burlington, Wis., RS15-24) and eluted with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.76 (d, J=6.9, 1H), 7.46-7.39 (m, 2H), 7.40-7.33 (m, 2H), 7.26 (dd, J=9.9, 17.2, 1H), 4.52 (t, J=7.7, 1H), 4.44-4.34 (m, 1H), 3.93 (dt, J=7.0, 14.5, 1H), 3.57 (dd, J=5.4, 13.1, 1H), 3.49-3.36 (m, 2H), 3.30-3.20 (m, 2H), 2.83-2.74 (m, 1H), 2.62-2.45 (m, 2H), 2.44-2.37 (m, 1H), 2.33-2.17 (m, 4H), 2.11 (qd, J=6.5, 12.5, 1H), 1.92-1.78 (m, 3H), 1.77-1.59 (m, 2H), 1.45-1.32 (m, 1H), 0.88 (d, J=6.6, 3H), 0.83 (dd, J=2.5, 6.5, 3H); MS (ESI+) m/z 434 (M+H)+.
Reaction SMILES: Cl.[S:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[C:11]([C:13]1[CH:26]=[CH:25][C:16]([CH2:17][N:18]2[C:22]([CH:23]=O)=[CH:21][N:20]=[CH:19]2)=[CH:15][CH:14]=1)#[N:12].C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(C(Cl)Cl)(Cl)Cl.CCOC(C)=O>[C:11]([C:13]1[CH:14]=[CH:15][C:16]([CH2:17][N:18]2[C:22]([CH2:23][CH:9]3[CH2:10][C:5]4[CH:4]=[CH:3][S:2][C:6]=4[NH:7][CH2:8]3)=[CH:21][N:20]=[CH:19]2)=[CH:25][CH:26]=1)#[N:12]
Reactant: c1cc2c(s1)CCNC2
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)C(Cl)Cl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Cn2cncc2CC2CNc3sccc3C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (Halczenko and Hartman; Synthetic Commun., 1996, 26, 1363; 0.439 g, 2.5 mmol) in CHCl2CHCl2 (15 mL) was added 1-(4-cyanobenzyl)-5-imidazole carboxaldehyde (0.58 g, 2.75 mmol), 4 Å sieves and triethylamine (0.35 mL, 2.5 mmol) followed by NaBH(OAc)3 (1.59 g, 7.5 mmol). The mixture was stirred at room temperature for 16 h., the mixture was diluted with EtOAc, filtered through celite, washed with brine, dried (Na2SO4) and concentrated. The residue was stirred in 2N HCl (50 mL) for 2 h. then extracted with ether. The aqueous layer was basified with 40% NaOH solution and extracted 3× CH2Cl2 which was then washed with brine, dried (Na2SO4) and the solvent evaporated in vacuo. Chromatography (silica gel; 2.5% MeOH in CHCl3) followed by crystallization from ether afforded the title compound as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O.C(N1CCOCC1)C>C(Cl)Cl>[O:12]=[C:10]1[NH:1][CH:2]2[CH2:6][CH2:5][CH2:4][CH:3]2[CH2:7][CH2:8][CH2:9]1
Reactant: NC1CCCC1CCCC(=O)O
Agent: CCN1CCOCC1
Solvent: ClCCl
Product: O=C1CCCC2CCCC2N1
Reaction time: 14 h

Procedure:
4.1 g of amino acid hydrochloride from Example I (5) are suspended in 40 ml of methylene chloride, 12.8 ml of N-ethylmorpholine are added, while cooling with ice, and 12.8 ml of 50% strength n-propanephosphonic acid anhydride in methylene chloride are added dropwise at 0° C. The solution is left to stand at room temperature for 14 hours. It is then diluted with 200 ml of CH2Cl2 and extracted with water, 2N HCl and saturated NaHCO3 solution. The CH2Cl2 phase is dried and evaporated.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([Cl:21])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(NC(=O)c2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cccc(NC(=O)c2ccccc2)c1
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 1.5 g of 3-(benzoylamino) benzoic acid suspended in 10 ml of toluene was added 2 ml of thionyl chloride, and the resulting mixture was stirred under a reflux condition for 2 hours. The reaction solution was returned to room temperature, and then the solvent was removed under a reduced pressure to obtain 1.53 g of the desired product (Yield: 95%) as a white solid.
Reaction SMILES: [N:1]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[CH:22]=[C:23]5[CH:29]=[CH:28][N:27]([Si](C(C)C)(C(C)C)C(C)C)[C:24]5=[N:25][CH:26]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[F-].[Cs+]>C(#N)C.ClCCl>[N:1]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[CH:22]=[C:23]5[CH:29]=[CH:28][NH:27][C:24]5=[N:25][CH:26]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(-c3ccc4ncnc(N5CCCc6ccccc65)c4c3)cnc21
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: CC#N
Product: c1ccc2c(c1)CCCN2c1ncnc2ccc(-c3cnc4[nH]ccc4c3)cc12
Yield: 14.1 %

Procedure:
0.20 g of 4-(3,4-dihydro-2H-quinolin-1-yl)-6-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)quinazoline and 0.08 g of caesium fluoride in 1 ml of acetonitrile and 1 ml of dichloromethane are stirred at 25° C. in a flask until the reaction is complete (HPLC check, about 24 hours). A precipitate precipitates out of the reaction solution. This is filtered off, rinsed with water and dried, giving 0.02 g of 4-(3,4-dihydro-2H-quinolin-1-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinazoline (“A3”) as white solid (yield 13%, content 95%); MS-FAB (M+H+)=377.9; Rf (polar method): 1.79 min;
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([Br:18])[CH:8]=[CH:9][C:10]=2[NH:14][C:15](=[O:17])[CH3:16])[CH2:5]1)(=[O:3])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([Br:18])[CH:8]=[C:9]([N+:19]([O-:21])=[O:20])[C:10]=2[NH:14][C:15](=[O:17])[CH3:16])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Br)c2c1CCN(C(C)=O)C2
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1c([N+](=O)[O-])cc(Br)c2c1CCN(C(C)=O)C2
Temperature: 25 °C

Procedure:
The product from Example 21 (31 g) was dissolved in trifluoroacetic acid (450 mL). The solution was treated dropwise with 33 mL of fuming 90% nitric acid and stirred at room temperature. The reaction mixture was concentrated, the residue was dissolved in chloroform and then washed well with sodium bicarbonate solution. A solid formed, and was dissolved in 3 L chloroform and dried over magnesium sulfate. After evaporation, the residue was crystallized from ethyl acetate to give a white solid (19.32 g), and the filtrate concentrated to give an additional 16.3 g.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(N1C=CN=C1)=[O:2].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[CH:21]1[C:26](C(O)=O)=[C:25]([CH3:30])[NH:24][C:23]([CH3:31])=[C:22]1[C:32]([O:34][CH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:33].C1(C)C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[CH:21]1[C:26]([C:1]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[O:2])=[C:25]([CH3:30])[NH:24][C:23]([CH3:31])=[C:22]1[C:32]([O:34][CH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:33]
Reactant: CC1=C(C(=O)O)C(c2c(F)cccc2Cl)C(C(=O)OC2CCCC2)=C(C)N1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1=C(C(=O)OC2CCCC2)C(c2c(F)cccc2Cl)C(C(=O)n2ccnc2)=C(C)N1

Procedure:
13.6 g (83 mmol) of carbonyldiimidazole are added to 33.0 g (83 mmol) of 4-(2-chloro-6-fluorophenyl)-3-cyclopentyloxycarbonyl-1.4-dihydro-2,6-dimethylpyridine-5-carboxylic acid in 350 ml of tetrahydrofuran and the mixture is heated to reflux for 3 h. Thin-layer chromatographic checking (silica gel, toluene/ethyl acetate 1:1) shows complete reaction, after which the reaction mixture is concentrated, the residue is taken up in ethyl acetate, and the solution is washed twice with water, dried over sodium sulphate and concentrated again. The target compound precipitates from ether in the form of white crystals of m.p. 150° C.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.C[O-].[Na+]>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[CH:4][C:3](=[O:2])[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[CH3:12])=[O:8]
Reactant: COC(=O)C=CC(C(=O)OC)=C(C)NCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(=O)n(Cc2ccccc2)c1C
Temperature: 25 °C
Yield: 98.7 %

Procedure:
A mixture of 4-(1-benzylamino-ethylidene)-pent-2-enedioic acid dimethyl ester (3 g, 10.4 mmol), triethylamine (1.5 mL, Et3N) and MeOH (200 mL) was refluxed for 23 h. NaOMe solution (0.12 mL, 0.52 mmol, 25 wt % in MeOH) was added, and the mixture was refluxed for 16 h. The mixture was cooled to r.t. and concentrated in vacuo. The residue was partitioned between saturated NH4Cl (100 mL) and CH2Cl2 (100 mL). 1M HCl was added until pH was about 1. The aqueous layer was extracted with additional CH2Cl2, and the combined organic layer was dried over MgSO4 and concentrated to give 2.64 g of the title compound as a white solid. MS: (+) m/z 258.13 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH:10]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][C:16]([F:15])([F:25])[F:26])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: Nc1cccc(OC(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(tert-Butoxycarbonyl)-L-prolinal (200 mg, 1.00 mmol) and 3-trifluoromethoxy-phenylamine (186.8 mg, 1.05 mmol) were mixed in 1,2-dichloroethane (10 mL) and treated with sodium triacetoxyborohydride (314 mg, 1.41 mmol). The mixture was stirred at RT under nitrogen overnight, then quenched by addition of water, extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated. The crude oil was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1) to give the desired material. MS (LC/MS): 361.1 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]2[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=2)[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+].C(OCC)(=O)C>O1CCOCC1>[CH:6]1([CH2:5][CH:4]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[N:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][N:20]=3)[CH:13]=[N:12]2)[C:3]([OH:29])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)n1ncc(Oc2nccc(C(F)(F)F)n2)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2nccc(C(F)(F)F)n2)cc1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 3-cyclopentyl-2-[6-oxo-4-(4-trifluoromethyl-pyrimidin-2-yloxy)-6H-pyridazin-1-yl]-propionic acid methyl ester (0.2 g, 0.48 mmol) in dioxane (2 mL) was treated with a 6N aqueous sodium hydroxide solution (2 mL). The reaction was stirred at 25° C. for 2 d. At this point, ethyl acetate (20 mL) was added and then the aqueous phase was back extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Preparative HPLC afforded 3-cyclopentyl-2-[6-oxo-4-(4-trifluoromethyl-pyrimidin-2-yloxy)-6H-pyridazin-1-yl]-propionic acid as a light oil (20 mg, 10%); 1H NMR (300 MHz, DMSO-d6): δ 9.13 (d, 1H, J=4.8 Hz), 8.24 (d, 1H, J=2.4 Hz), 7.96 (d, 1H, J=4.8 Hz), 7.04 (d, 1H, J=2.4 Hz), 5.38 (dd, 1H, J1=4.5 Hz, J2=10.5 Hz), 2.25˜2.15 (m, 1H), 2.06˜1.97 (m, 1H), 1.71˜1.44 (m, 7H), 1.17˜1.04 (m, 3H). LC-MS: 399.1 [M+1]+, tR=3.04 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:22]([CH3:24])[CH3:23]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([F:13])([F:14])[F:12])=[N:9][N:8]([CH:22]([CH3:24])[CH3:23])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)I
Reactant: CCOC(=O)c1cn[nH]c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C(C)C)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a suspension of 5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (13 g, 62.5 mmol) and cesium carbonate (61.1 g, 187.5 mmol) in DMF (70 mL) was added 2-iodo-propane (6.86 mL, 68.75 mmol) and the resulting mixture allowed to stir at room temperature for 16 hours. The crude reaction mixture was poured onto water (100 mL) and extracted with EtOAc (100 mL×3). The combined organics were washed with water (50 mL×2), brine (50 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to afford the title compound as an off-white solid in 65% yield, 10.2 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[C:15]([CH3:16])=[CH:14][S:13][CH:12]=1)[C:5]([OH:7])=O.[NH2:17][C:18](=[N:30]O)[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=1[F:29]>>[F:29][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:19]=1[C:18]1[N:17]=[C:5]([C:4]2[CH:8]=[CH:9][C:10]([C:11]3[C:15]([CH3:16])=[CH:14][S:13][CH:12]=3)=[C:2]([CH3:1])[CH:3]=2)[O:7][N:30]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: Cc1cc(C(=O)O)ccc1-c1cscc1C
Reactant: COC(=O)c1ccc(C(N)=NO)c(F)c1
Product: COC(=O)c1ccc(-c2noc(-c3ccc(-c4cscc4C)c(C)c3)n2)c(F)c1

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 6 (116.2 mg; 0.50 mmol) and Intermediate 2 (106.1 mg; 0.50 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was suspended in ACN, filtrated and washed with cHex dried under vacuo, affording the title compound. 1H NMR (DMSO-d6, 300 MHz) δ 8.35-8.30 (m, 1H), 8.17 (d, J=1.3 Hz, 1H), 8.08-8.01 (m, 2H), 7.95 (dd, J=11.0, 1.3 Hz, 1H), 7.46-7.42 (m, 2H), 7.35 (dd, J=3.2, 1.1 Hz, 1H), 3.93 (s, 3H), 2.24 (s, 3H), 2.01 (s, 3H). LC/MS (Method B): 409.1 (M+H)+. HPLC (Method A) Rt 6.06 min (Purity: 93.6%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1([CH2:19][CH3:20])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8](O)[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[CH2:22]([Mg]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.CCOCC.Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1([CH2:19][CH3:20])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: CCC1(CC(=O)OC)OCC(O)c2c1[nH]c1ccccc21
Reactant: Br[Mg]Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCC1(CC(=O)OC)OCC(Cc2ccccc2)c2c1[nH]c1ccccc21
Temperature: -78 °C
Yield: 51.5 %

Procedure:
To a solution of 1-ethyl-4-hydroxy-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid methyl ester (1 g, 3.6 mmol) in 60 mL of dry methylene chloride at -78° C. under nitrogen was added TiCl4 in one portion and then after ~10 minutes, a solution of benzyl magnesium bromide in ether was added in one portion and the reaction mixture was allowed to stir at -78° C. for ~30 minutes. The reaction was quenched with methanol (3 mL) at -78° C. and then poured into water (10 mL). The two layers were separated and the aqueous layer was then extracted with methylene chloride (2×100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was passed through a pad of silica gel, eluting with 10% EtOAc in hexane to give 0.67 g (51.5%) of the product as an oil, which had isomer ratio of 75:25 by HPLC.
Reaction SMILES: [C:1](=[N:14][NH2:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.II.ClC1C=C(C=CC=1)C(OO)=O>C(Cl)Cl.CN(C)C(N(C)C)=N>[C:2]1([C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N+:14]=[N-:15])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: CN(C)C(=N)N(C)C
Agent: II
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [N-]=[N+]=C(c1ccccc1)c1ccccc1

Procedure:
To a solution of benzophenone hydrazone (10 g) in CH2Cl2 (51 mL) is added a 1% w/v solution of iodine in CH2Cl2 (2.05 mL) and 1,1,3,3-tetramethylguanidine (6.43 g). 3-Chloroperoxybenzoic acid (9.7 g) is then added in small portions at room temperature. The solvent is removed in vacuo to provide diphenyl diazomethane. A solution of diphenyl diazomethane (8.78 g) in EtOAc (19 mL) is then added to a cooled (5° C.) solution of Compound 3 in THF (150 mL) and EtOAc (150 mL). The mixture is stirred until completion whereupon it is evaporated to dryness in vacuo. THF (64 mL) is added and the insolubles are filtered off. The filtrate is evaporated in vacuo until crystals begin to form. EtOAc (64 mL) is then added and the mixture is stirred for 1.5 hours at 0°-5° C. The resulting solid is filtered to provide Compound 4.