Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]2[CH:11]=[C:10]([C:12]#[N:13])[C:9]([CH3:14])=[CH:8][N:7]2[CH:15]=1)([CH3:3])[CH3:2].[I:16]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[I:16][C:15]1[N:7]2[CH:8]=[C:9]([CH3:14])[C:10]([C:12]#[N:13])=[CH:11][C:6]2=[N:5][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cn2cc(C(C)C)nc2cc1C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn2c(I)c(C(C)C)nc2cc1C#N
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.1 %

Procedure:
2-Isopropyl-6-methylimidazo[1,2-a]pyridine-7-carbonitrile (500 mg, 2.51 mmol) obtained in step 2 was dissolved in DMF (3.0 mL), and the solution was stirred at room temperature for 6 hours under light shielding after adding N-iodosuccinimide (621 mg, 2.76 mmol). A sodium carbonate aqueous solution was added to the reaction mixture. The precipitated crystals were collected by filteration, and dried under reduced pressure to give 3-iodo-2-isopropyl-6-methylimidazo[1,2-a]pyridine-7-carbonitrile (752 mg, yield 92%).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[Cl:18][CH2:17][CH2:16][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:12]=1
Reactant: ClCCBr
Reactant: Oc1ccc(Cc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: ClCCOc1ccc(Cc2ccccc2)cc1
Yield: 86 %

Procedure:
A solution of 4-(benzyl)phenol (638 mg, 3.46 mmol), 1-bromo-2-chloroethane (2.3 mL, 27.7 mmol) and cesium carbonate (4.5 g, 27.7 mmol) in 35 mL of acetonitrile was heated at reflux for 12 hours. After cooling, water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 734 mg of 1-(2-chloroethoxy)-4-(benzyl)benzene, 1H NMR (300 MHz, CDCl3) δ 7.29 (dd, 2H), 7.19 (dd, 1H), 7.18 (d, 2H), 7.12 (d, 2H), 6.85 (d, 2H), 4.21 (t, 2H), 3.93 (s, 2H), 3.80 (t, 2H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOC(C)=O>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCOc2ccc(O)cc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C1CCOc2ccc(OCc3ccccc3)cc21

Procedure:
A mixture of 6-hydroxy-4-chromanone (18.6 g, 113 mmol), benzyl bromide (20 g, 116 mmol), and K2CO3 (21 g, 152 mmol) in acetone (110 ml) was refluxed for 20 hrs. The mixture was cooled, diluted with EtOAc, and filtered through celite. The filtrate was concentrated to an oil, which was triturated with 10% Et2O in hexane (150 ml) to gives, after filtration and washing, 28 g (87%) of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([NH2:10])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[CH2:12]([N:19]([CH2:23][CH2:24]Cl)[CH2:20][CH2:21]Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>ClC1C=CC=CC=1>[CH2:12]([N:19]1[CH2:23][CH2:24][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[CH:2][NH:1]3)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cccc2[nH]ccc12
Reactant: ClCCN(CCCl)Cc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Clc1ccccc1
Product: c1ccc(CN2CCN(c3cccc4[nH]ccc34)CC2)cc1
Temperature: 130 °C
Yield: 24.9 %

Procedure:
A mixture of 500 mg (3.78 mmole) 1H-indol-4-yl-amine, 993 mg (3.78 mmole) N-benzyl-bis(2-chloroethyl)amine hydrochloride, and 1.32 mL (7.6 mmole) diisopropylethylamine in 10 mL chlorobenzene was heated at 130° C. for 24 hours. Another 0.66 mL (3.8 mmole) diisopropylethylamine was added and the mixture was heated at 130° C. for an additional 5 hours. The mixture was partitioned between 25 mL ethyl acetate and 10 mL 5% sodium hydroxide. The organic phase was extracted with 10 mL 3 N hydrochloric acid. The aqueous phase was washed with 15 mL ethyl ether, then made basic with 50% sodium hydroxide. The product was extracted with 25 mL dichloromethane, the organic phase was washed with 10 mL water, dried (magnesium sulfate) and concentrated under reduced pressure. 4-(4-benzyl-piperazin-1-yl)-1H-indole (274 mg) was isolated as the hydrochloride salt from ethyl ether.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[N:31]1([C:23]([C:22]2[CH:21]=[CH:20][C:19]([N:16]3[CH2:15][CH2:14][N:13]([CH2:12][C:9]4[CH:10]=[N:11][C:5]5[N:4]6[CH2:28][CH2:29][CH2:30][C@H:3]6[C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)[CH2:18][CH2:17]3)=[CH:27][CH:26]=2)=[O:25])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C1Nc2cc(CN3CCN(c4ccc(C(=O)N5CCCC5)cc4)CC3)cnc2N2CCC[C@@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
In a 1 dram vial, (S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (100 mg, 0.245 mmol) was suspended in DMF (Volume: 1.227 mL) then added pyrrolidine (0.024 mL, 0.295 mmol), HATU (140 mg, 0.368 mmol) and N-methylmorpholine (0.108 mL, 0.982 mmol). The r×n was stirred at RT overnight. The mixture was purified by prep HPLC-MS (acidic mode, 15-35%). The pH of the combined fractions was adjusted to pH=8-9 and extracted with EtOAc (3×30 ml), washed with brine, dried with MgSO4, filtered and concentrated to dryness. The residue was taken up with water/ACN (1:1), and concentrated in vacuo to provide the title compound as a fluffy white solid (29 mg, 26% yield). m.p.=121.3° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.73-1.87 (m, 4 H) 1.87-2.01 (m, 3 H) 2.14-2.21 (m, 1 H) 2.43-2.49 (m, 4 H) 3.15-3.23 (m, 4 H) 3.35 (br. s., 2 H) 3.37-3.49 (m, 5 H) 3.54-3.65 (m, 1 H) 3.95-4.04 (m, 1 H) 6.91 (d, J=9.09 Hz, 2 H) 6.99 (d, J=2.02 Hz, 1 H) 7.42 (d, J=8.84 Hz, 2 H) 7.62 (d, J=1.77 Hz, 1 H) 10.44 (s, 1 H). [M+H] calc'd for C26H32N6O2, 461; found, 461.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[N:11]=[C:12]([NH:23][C:24]([C:26]3[N:27]([CH2:37][C:38]([O:40]C)=[O:39])[C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=4[CH3:36])=[O:25])[S:13][C:14]=2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:4]([O:42][CH3:43])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl>O.C(O)CCC>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[N:11]=[C:12]([NH:23][C:24]([C:26]3[N:27]([CH2:37][C:38]([OH:40])=[O:39])[C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=4[CH3:36])=[O:25])[S:13][C:14]=2[CH2:15][CH2:16][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[C:4]([O:42][CH3:43])[CH:3]=1
Reactant: COC(=O)Cn1c(C(=O)Nc2nc(-c3cc(OC)c(Cl)cc3OC)c(CCC3CCCCC3)s2)cc2cc(C)cc(C)c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: COc1cc(-c2nc(NC(=O)c3cc4cc(C)cc(C)c4n3CC(=O)O)sc2CCC2CCCCC2)c(OC)cc1Cl
Temperature: 90 °C
Yield: 79.3 %

Procedure:
A mixture of 4 g of the compound obtained in step A of Example 5a, 2.65 g of K2CO3 in 9.2 ml of water and 16 ml of n-butanol is heated at 90° C. for 12 hours. After cooling to RT, 19.2 ml of 2N HCl are added. The white precipitate formed is washed with 3 times 200 ml of water and then 3 times 200 ml of ethyl ether. 3.1 g of the expected product are obtained: m.p.=241° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[N:35]=[C:34]([CH3:36])[O:33][N:32]=2)[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.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.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:29]4[CH:30]=[CH:25][CH:26]=[C:27]([C:31]5[N:35]=[C:34]([CH3:36])[O:33][N:32]=5)[CH:28]=4)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nc(-c2cccc(I)c2)no1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(-c4noc(C)n4)c3)CCCC(=O)C2)cc1OC1CCCC1
Temperature: 80 °C
Yield: 79.7 %

Procedure:
To a solution of the compound from Example 3 (E1) (0.125 g, 0.4 mmol) and 1-iodo-3-(5-methyl-[1,2,4]oxadiazol-3-yl)benzene (0.09 g, 0.32 mmol) in triethylamine (3 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C. for 0.2 h, was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, followed by trituration from hexanes/ethyl acetate, provided the title compound as colorless crystals (0.12 g, 67%), m.p. 116-118° C.
Reaction SMILES: C1(=O)[N:5]([CH:6]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:7][P:8]([NH:13][CH:14]2[CH2:19][S:18][C@H:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:16]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:15]2=[O:32])([O:10][CH2:11][CH3:12])=[O:9])[C:4](=[O:40])[C:3]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:2]12.O.NN>O1CCOCC1>[C:4]([NH:5][CH:6]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:7][P:8]([NH:13][CH:14]1[CH2:19][S:18][C@H:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:16]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:15]1=[O:32])([O:10][CH2:11][CH3:12])=[O:9])(=[O:40])[C:3]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:2]=1
Reactant: CCOC(=O)CN1C(=O)C(NP(=O)(CC(Cc2ccccc2)N2C(=O)c3ccccc3C2=O)OCC)CS[C@@H]1c1ccccc1
Agent: NN
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CN1C(=O)C(NP(=O)(CC(Cc2ccccc2)NC(=O)c2ccccc2)OCC)CS[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of (R)-dihydro-5-[[[2-phthalimido-3-phenylpropyl]ethoxyphosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester in dioxane is treated with hydrazine hydrate and stirred for 24 hours at room temperature. The mixture is then partitioned between ethyl acetate-water and the ethyl acetate phase was washed with water and saturated sodium chloride, dried (Na2SO4), and evaporated. The residue is taken up in dry toluene and refluxed for one hour. The mixture is filtered, treated with triethylamine and benzoyl chloride and stirred at room temperature for 30 minutes. The mixture is diluted with ethyl acetate, washed successively with 5% potassium bisulfate, saturated sodium bicarbonate, and saturated sodium chloride, dried (Na2SO4), and evaporated. The residue is chromatographed on silica gel to give (R)-dihydro-5-[[[2-(benzoylamino)-3-phenylpropyl]ethoxyphosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([OH:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:13][CH3:14])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C#N)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(C(C)(C)C)ccc1C#N
Temperature: 50 °C
Reaction time: 2 h
Yield: 32.4 %

Procedure:
4-t-Butyl-2-hydroxybenzonitrile (1.16 g) and potassium carbonate (376 mg) were dissolved in dimethylformamide (4 ml) and to the solution was added dropwise iodomethane (226 μl), followed by stirring at 50° C. for 2 hours. The resulting mixture was filtered to remove the remaining potassium carbonate and concentrated under reduced pressure. The obtained residue was purified by column-chromatography (hexane/ethyl acetate=10/1) to yield the compound 13-2a (167 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[H-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15].C(OCC=C)C=C.C1(C)C=C(C)C=C(C)C=1>>[CH2:15]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([O:9][CH3:10])[C:5]=1[OH:8])[CH:14]=[CH2:13]
Reactant: COc1cc(Cl)ccc1O
Reactant: C=CCBr
Agent: C=CCOCC=C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1cc(C)cc(C)c1
Product: C=CCc1cc(Cl)cc(OC)c1O

Procedure:
Treatment of 4-chloro-2-methoxyphenol (30.0 g, 0.19 mol) with sodium hydride (9.1 g, 0.23 mol, 60 wt. %) and allyl bromide (27.46 g, 0.23 mol) followed by treatment of the resultant allyl ether in refluxing mesitylene generally according to the procedure described for Intermediate 8 gave 2-allyl-4-chloro-6-methoxyphenol as a yellow oil. Treatment of 2-allyl-4-chloro-6-methoxyphenol with sodium hydride (7.08 g, 0.177 mol, 60 wt. %) and benzyl bromide (30.27 g, 0.177 mol) generally according to the procedure described for Intermediate 13 provided 1-allyl-2-(benzyloxy)-5-chloro-3-methoxybenzene as a pale yellow oil. Treatment of the olefin (35.5 g, 0.123 mol) of with AD-mix-α (132.0 g) generally according to the procedure described for Intermediate 2 gave 35 g (54%) of (±)-3-[2-(benzyloxy)-5-chloro-3-methoxyphenyl]propane-1,2-diol as a white solid. mp. 65-68° C. Anal. calcd. for C17H19ClO4: C, 63.26; H, 5.93. Found: C, 65.29; H, 6.23.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C:13](=O)[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]=1[CH2:18][C:19]([CH3:21])=[CH2:20].[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>ClCCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([N:27]=[C:13]2[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]([CH2:18][C:19]([CH3:21])=[CH2:20])=[C:8]2[CH3:7])=[CH:25][CH:24]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: C=C(C)CC1=C(C)C(=O)C(C)=C(C)C1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: C=C(C)CC1=C(C)C(=Nc2ccc(Cl)cc2)C(C)=C(C)C1=O
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
Titanium tetrachloride (2.42 ml, 22.1 mmol) was added dropwise to a solution of pyridine (7.13 ml, 88.2 mmol) in 1,2-dichloroethane (40 ml) and, after completion of addition, the reaction mixture was heated under reflux for 20 minutes in an argon atmosphere. After cooling of the reaction mixture, to the mixture was added a solution of 3,5,6-trimethyl-2-(2-methyl-2-propenyl)-1,4-benzoquinone (3.00 g, 14.7 mmol) and p-chloroaniline (5.62 g, 44.1 mmol) in 1,2-dichloroethane (20 ml) and the mixture was stirred at 90° C. for 45 minutes in an argon atmosphere. The reaction mixture was cooled and filtered through Cerite and the filtrate was washed with a saturated saline solution, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate, 93:7) to obtain the desired compound as oil (4.43 g, yield: 96.0%).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][CH:22]=[C:23]([CH3:25])[N:24]=2)=[CH:16][CH:15]=1)C1C=CC=CC=1.C1CC=CCC=1>CO.[Pd]>[CH3:25][C:23]1[N:24]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][NH2:10])=[CH:15][CH:16]=2)[O:21][CH:22]=1
Reactant: Cc1coc(-c2ccc(OCCNC(=O)OCc3ccccc3)cc2)n1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CO
Product: Cc1coc(-c2ccc(OCCN)cc2)n1
Yield: 90 %

Procedure:
The title compound of Example 1, {2-[4-(4-Methyl-oxazol-2-yl)-phenoxy]-ethyl}-carbamic acid benzyl ester, (166 mg, 0.47 mmol) was dissolved in methanol (5 ml) and 10% Pd/C (50 mg) and 1,4-cyclohexadiene (192 mg, 2.4 mmol) were added to the resulting solution. The mixture was allowed to stir for about sixteen hours, and then it was filtered through diatomaceous earth, and the filter pad was washed with methanol. The filtrate was concentrated in vacuo to dryness, and the resulting material (92 mg, 90% yield), which was determined to be pure by 1H NMR, was used directly without further purification. LRMS ([M+H]+)=219.2.
Reaction SMILES: C(O)(=O)C.Cl.[NH2:6][C@H:7]1[C:15]2[C:10](=[CH:11][C:12]([C:17]([O:19][CH3:20])=[O:18])=[C:13]([F:16])[CH:14]=2)[CH2:9][CH2:8]1.[CH3:21][C:22]([CH3:24])=O.[BH4-].[Na+]>CO>[F:16][C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][C@H:7]2[NH:6][CH:22]([CH3:24])[CH3:21])=[CH:11][C:12]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cc2c(cc1F)[C@H](N)CC2
Reactant: CC(C)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc2c(cc1F)[C@H](NC(C)C)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
Glacial acetic acid (0.33 ml) was added to a mixture of (R)-methyl 1-amino-6-fluoro-2,3-dihydro-1H-indene-5-carboxylate hydrochloride (A-05) [see above] (4.1 g, 19.6 mmol, 1 eq) and acetone (28.8 ml, 392.3 mmol, 20 eq) in methanol (100 ml), and the reaction mixture was stirred for 3 h at room temperature. It was then cooled to 0° C. and NaBH4 (2.23 g, 58.8 mmol, 3 eq) was added in portions. Stirring was carried out for a further 2 h at room temperature. After monitoring by TLC, concentration was carried out under reduced pressure and the residue was diluted with water (100 ml). Extraction with dichloromethane (150 ml) was carried out and the organic phase was washed with sat. sodium hydrogen carbonate solution (100 ml) and dried over sodium sulfate. The solvent was distilled off under reduced pressure and then the crude product was purified by column chromatography (Alox, 10% ethyl acetate/hexane) to yield the desired product in the form of a light-brown liquid. Yield: 76% (3.75 g, 19.61 mmol)
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH:18]([C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1)=[CH2:19]>CN1CCCC1=O.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:19][CH2:18][C:20]3[CH:21]=[N:22][CH:23]=[N:24][CH:25]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cncnc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2cncnc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.3 %

Procedure:
To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.49 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.14 g, 2.5 mmol) and allowed to stir for 10 min at RT. 5-vinyl pyrimidine (0.132 g, 1.25 mmol) was added and stirred for further 5 h at 60 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200, mesh, Diameter of column—2.5 cm, Height of silica approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.050 g, 32.6% yield). 2,8-Dimethyl-5-(2-pyrimidin-5-yl-ethyl)-2,3,4,5-tetrahydro-1-pyrido[4,3-b]indole (0.040 g, 0.13 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.015 g, 0.119 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.046 g, 90% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])[CH:14]=3)=[CH:11][C:10]([NH2:27])=[N:9]2)=[CH:4][CH:3]=1.[O:28]=[C:29]1[NH:33][CH2:32][C@@H:31]([C:34](O)=[O:35])[CH2:30]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:24])([F:23])[F:25])[CH:14]=3)=[CH:11][C:10]([NH:27][C:34]([C@H:31]3[CH2:30][C:29](=[O:28])[NH:33][CH2:32]3)=[O:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1C[C@H](C(=O)O)CN1
Reactant: C[C@@H](OCc1cccc(-c2cc(N)nn2-c2ccc(Cl)cc2)c1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](OCc1cccc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccc(Cl)cc2)c1)C(F)(F)F
Reaction time: 3 h

Procedure:
To a solution of 1-(4-chlorophenyl)-5-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (about 0.125 mmol) prepared in the previous step in N,N-dimethylformamide (1 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid prepared according to the same procedures as preparation 14 (18 mg) and WSC.HCl (29 mg) at room temperature, and the mixture was stirred for 3 hours. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. The resulting organic layer was concentrated under reduced pressure, the resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=10/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (33 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5]([O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:6][C:7]([N+:13]([O-:15])=[O:14])=[C:8]([CH:12]=1)[C:9](O)=[O:10].C[N:26](C=O)C>S(Cl)(Cl)=O>[CH3:2][O:3][C:4]1[C:5]([O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:6][C:7]([N+:13]([O-:15])=[O:14])=[C:8]([CH:12]=1)[C:9]([NH2:26])=[O:10]
Reactant: CN(C)C=O
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OCCCN1CCCC1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OCCCN1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
A solution of 5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)benzoic acid hydrochloride (9.63 g, 24 mmol) in thionyl chloride (20ml) and DMF (50 μl) was heated at 45° C. for 1.5 hours. The excess thionyl chloride was removed by evaporation and by azeotroping with toluene (×2). The resulting solid was suspended in THF (250 ml) and methylene chloride (100 ml) and ammonia was bubbled though the mixture for 30 minutes and the mixture stirred for a further 1.5 hours at ambient temperature. The volatiles were removed by evaporation, the residue was dissolved in water and applied to a Diaion (trade mark of Mitsubishi) HP20SS resin column and eluted with water/methanol (100/0 to 95/5). The solvent was removed by evaporation from the fractions containing product and the residue was dissolved in a minimum of methanol and the solution was diluted with ether. The resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 5-methoxy-2-nitro4-(3-(pyrrolidin-1-yl)propoxy)benzamide (7.23 g, 73%).