Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:3]1=[O:26].[C:27]1([CH3:36])[CH:32]=[CH:31][CH:30]=[C:29]([N:33]=[C:34]=[O:35])[CH:28]=1>ClCCl>[CH2:24]([O:23][C:21]([CH2:20][N:4]1[C:5]2[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[N:8][CH:2]([NH:1][C:34]([NH:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([CH3:36])[CH:28]=2)=[O:35])[C:3]1=[O:26])=[O:22])[CH3:25]
Reactant: CCOC(=O)CN1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Reactant: Cc1cccc(N=C=O)c1
Solvent: ClCCl
Product: CCOC(=O)CN1C(=O)C(NC(=O)Nc2cccc(C)c2)N=C(c2ccccc2F)c2ccccc21
Yield: 56.6 %

Procedure:
To a solution of (3RS)-3-amino-2,3-dihydro-1-ethoxycarbonylmethyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (1.972 g) in dichloromethane (15 ml) was added dropwise a solution of m-tolyl isocyanate (0.884 g) in dichlromethane (5 ml) under stirring. After completion of the addition, the mixture was stirred for 4 hours at ambient temperature. The resultant white precipitates were collected by suction to give N-[(3RS)-2,3-dihydro-1-ethoxycarbonylmethyl-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea as a colorless crystalline solid (1.533 g). The filtrate was concentrated in vacuo. The residue was treated with chloroform and isopropyl ether to recover the desired compound (0.897 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[O:26]1[CH:30]=[CH:29][N:28]=[CH:27]1.CC(C)([O-])C.[Li+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:18][C:14]1[CH:13]=[C:12]([C:10](=[O:11])[CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:27]3[O:26][CH:30]=[CH:29][N:28]=3)=[CH:3][CH:4]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH:17]=[CH:16][N:15]=1
Reactant: c1cocn1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccccc2C)ccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: [Li+]
Product: Cc1cc(C(=O)CC(c2ccc(-c3ncco3)cc2)c2ccccc2C)ccn1
Temperature: 120 °C

Procedure:
To a solution of (−)-3-(4-bromophenyl)-1-(2-methylpyridin-4-yl)-3-o-tolylpropan-1-one (120 mg; example 142, step 2), oxazole (126 mg) and tetrakis(triphenylphosphine) palladium(0) (68 mg) was added lithium tert-butoxide (141 mg) and the reaction mixture heated by microwave irradiation to 120° C. for 30 min. The reaction mixture was extracted over a sat. solution of sodium hydrogencarbonate (50 mL) with ethyl acetate (3×50 mL) and the combined organic phases dried over sodium sulfate. The crude reaction product was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane/ethyl acetate (1:1 to 2:1) to give the title compound as a colorless oil. MS (ESI+): m/z=383.0 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CN(C=O)C.Cl[CH2:20][C:21](=[O:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24].C([O-])([O-])=O.[K+].[K+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:13][CH2:20][C:21](=[O:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: COc1cc(S)cc(C(F)(F)F)c1
Reactant: COC(=O)CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(=O)CSc1cc(OC)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-methoxy-5-(trifluoromethyl)benzenethiol (1.36 g) and DMF (dry) (10 mL) were added methyl 4-chloroacetoacetate (1.146 mL) and K2CO3 (1.806 g) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with 1N HCl and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (1.120 g).
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([C@H:10]([NH:17][C:18](=[O:32])[C:19]([CH2:30][CH3:31])([CH2:28][CH3:29])[NH:20][C:21]([O:23]C(C)(C)C)=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:9].C(N(CC)CC)C.C([CH:47]([C:63]([O-:65])=[O:64])[C@@H:48](C([O-])=O)[NH:49]C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1.O.C1C=CC2N(O)N=NC=2C=1>>[CH2:8]([C@H:10]([NH:17][C:18](=[O:32])[C:19]([CH2:28][CH3:29])([CH2:30][CH3:31])[NH:20][C:21](=[O:23])[C@H:48]([CH2:47][C:63](=[O:64])[OH:65])[NH2:49])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:9]
Reactant: O=C(N[C@H](C(=O)[O-])C(Cc1ccccc1)C(=O)[O-])OCc1ccccc1
Reactant: CC[C@H](NC(=O)C(CC)(CC)NC(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CC[C@H](NC(=O)C(CC)(CC)NC(=O)[C@@H](N)CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.3 %

Procedure:
19 ml of 4N-HCl/dioxane solution were added to 1.31 g (3.76 mmols) of N-t-butoxycarbonyl-α,α-diethylglycine (S)-α-ethylbenzylamide, and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, 30 ml of ether was added to the residue, and this was again concentrated. The residue was dissolved in 25 ml of methylene chloride, and 0.55 ml (4.13 mmols) of triethylamine and 1.48 g (4.13 mmols) of β-benzyl-N-benzyloxycarbonyl-L-aspartate were added thereto. Under cooling, 0.79 g (4.13 mmols) of water-soluble carbodiimide hydrochloride and 0.51 g (3.76 mmols) of HOBt were added thereto, and these were stirred for one hour under cooling and then overnight at room temperature. The reaction mixture was concentrated under reduced pressure and 50 ml of aqueous 5% citric acid were added. The resulting residue was extracted two times each with 50 ml of ethyl acetate and then washed with 20 ml of water, 25 ml of aqueous 5% sodium hydrogencarbonate and 20 ml of brine, in that order. The resulting organic layer was dried with anhydrous magnesium sulfate and filtered, and the resulting filtrate was concentrated under reduced pressure. The residue was dissolved in 30 ml of methanol, 0.30 g of 10% Pd-carbon (water content 50) was added thereto, and the mixture was reduced under hydrogen. 40 ml of water was added to this, the catalyst was removed by filtration, and the resulting filtrate was concentrated to about 1/4. This was then stored in a refrigerator overnight. The crystal thus precipitated was removed by filtration and dried to obtain 0.40 g (1.10 mmols) of α-L-aspartyl-α,α-diethylglycine (S)-α-ethylbenzylamide.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:15][C:16]([CH3:18])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH:16]([CH3:18])[CH3:15])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CC(C)NC1CCN(Cc2ccccc2)CC1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A solution of 4-amino-1-benzylpiperidine (45.8 g, 0.24 mol) and acetone (531 mL) was stirred at room temperature for 12 hours. The reaction mixture was then reduced to ca. 150 mL in vacuo. To this mixture was added methanol (100 mL) and the resulting mixture was cooled to 5° C. in an ice/water bath. Sodium triacetoxyborohydride (61.2 g, 0.29 mol) in methanol (350 mL), previously cooled to 5° C. in an ice/water bath, was added and this reaction mixture was stirred at 5° C. for 0.5 hours. The ice/water bath was removed and the reaction mixture was stirred for 2 hours at room temperature and then re-cooled to 5° C. in ice/water bath. To this mixture was added concentrated hydrochloric acid (75 mL) until the pH of the reaction mixture was about 3. This mixture was stirred for 1 hour and then concentrated in vacuo to about 600 mL and 1 N aqueous hydrochloric acid (200 mL) was added to dissolve the solids. The aqueous layer was washed with isopropyl acetate (400 mL) and the layers were separated. The aqueous layer was adjusted to pH 12 with 10 N aqueous sodium hydroxide (200 mL) and isopropylacetate (600 mL) was added. This mixture was stirred for 1 hour at room temperature and then the layers were separated and the organic layer washed with saturated aqueous sodium chloride solution (600 mL) and dried over sodium sulfate (80 g). The sodium sulfate was filtered off and washed with ethyl acetate (20 mL). The solvent was removed in vacuo to give 52.0 g of the title intermediate as a yellow oil (95% yield).
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[CH2:3].[CH2:6]([C:8]1[CH:20]=[C:19]2[C:11]([C:12]3[CH2:13][CH2:14][N:15]=[C:16]([CH3:21])[C:17]=3[NH:18]2)=[CH:10][C:9]=1[O:22][CH3:23])[CH3:7].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C=O)C>[CH3:23][O:22][C:9]1[CH:10]=[C:11]2[C:12]3[CH2:13][CH2:14][N:15]4[C:16]([C:17]=3[NH:18][C:19]2=[CH:20][C:8]=1[CH2:6][CH3:7])=[CH:21][CH2:3][CH2:2][C:1]4=[O:5]
Reactant: C=CC(=O)O
Reactant: CCc1cc2[nH]c3c(c2cc1OC)CCN=C3C
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCc1cc2[nH]c3c(c2cc1OC)CCN1C(=O)CCC=C31
Reaction time: 6 h
Yield: 23 %

Procedure:
Acrylic acid (0.23 mL) is added to a solution of 7-ethyl-6-methoxy-1-methyl-3,4-dihydro-β-carboline (740 mg, 3.05 mmol) in DMF (6 mL), followed by dropwise addition of diphenylphosphoryl azide dissolved in DMF (1.5 mL). The medium is left stirring for 6 h. Separation on silica gel allows the 9-methoxy-10-ethyl-2,3,4,6,7,12-hexahydroindolo[2,3-a]quinolizin4-one to be recovered (23% yield).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Br:17])(C)(C)C.[NH:28]1[C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[C:31]=2[CH:30]=[CH:29]1>>[Br:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][CH:8]([NH:7][S:37]([C:32]1[C:31]2[CH:30]=[CH:29][NH:28][C:36]=2[CH:35]=[CH:34][CH:33]=1)(=[O:38])=[O:39])[C:18]([N:20]1[CH2:21][CH2:22][CH:23]([CH3:26])[CH2:24][CH2:25]1)=[O:19]
Reactant: CC1CCN(C(=O)C(CCc2ccccc2Br)NC(=O)OC(C)(C)C)CC1
Reactant: O=S(=O)(Cl)c1cccc2[nH]ccc12
Product: CC1CCN(C(=O)C(CCc2ccccc2Br)NS(=O)(=O)c2cccc3[nH]ccc23)CC1

Procedure:
Example 67 is subsequently prepared from tert-butyl{3-(2-bromophenyl)-1-[(4-methylpiperidin-1-yl)carbonyl]propyl}carbamate and indole-4-sulfonyl chloride in the same manner that Example 5 is synthesized. ESI MS Calc. 517.1; Found: 518.2 (M+H)+.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2]([CH:7]=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: O=Cc1ccccc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2-c2ccccc2)CC1
Reaction time: 3 h
Yield: 102.1 %

Procedure:
To a solution of biphenyl-2-carbaldehyde (5.01 g, 27.5 mmol) in dichloromethane (150 ml) at rt under nitrogen was added piperazine-1-carboxylic acid tert-butyl ester (5.63 g, 30.2 mmol) followed by glacial acetic acid (1.90 ml, 33.2 mmol). The reaction was stirred for 1 h before sodium triacetoxyborohydride (11.65 g, 55.0 mmol) was introduced. After 3 h, a solution of 5% NaOH (˜15 ml) was added and the mixture was extracted with dichloromethane. The organic layer was separated, washed with H2O (×2), brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give 4-biphenyl-2-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester as an oil (9.9 g, 100%) which was used without further purification. HPLC-MS 353 [M+1]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N+:16]([O-:18])=[O:17])=[C:12]([CH:15]=1)[CH:13]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.Cl>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N+:16]([O-:18])=[O:17])=[C:12]([CH:15]=1)[CH2:13][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)cc1CN1CCOCC1
Reaction time: 16 h
Yield: 73.9 %

Procedure:
To a solution of morpholine (2.8 mL, 32.3 mmol) in THF (100 mL) is added 5-chloro-2-nitrobenzaldehyde (5 g, 26.9 mmol) followed by sodium triacetoxyborohydride (11.4 g, 53.9 mmol) and HOAc (3.2 mL, 53.9 mmol). The reaction is stirred for 16 h. The reaction is poured into a saturated aqueous Na2CO3 solution and extracted with ethyl acetate. The combined extracts are washed with water, brine, dried (Na2SO4) and concentrated to afford a clear oil. The residue is taken up in 1N aqueous HCl and the insoluble material is removed by filtration. The filtrate is neutralized with 2M aqueous K2CO3 and partitioned into ethyl acetate. The organic layer is dried (Na2SO4) and concentrated to afford the title compound (5.1 g, 74%) as an oil.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]1([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.F[B-](F)(F)F.[CH2:27]([N+:34]1[CH2:35][CH2:36][CH2:37][C:38]=1OCC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[CH2:27]([N:34]1[CH2:35][CH2:36][CH2:37][C:38]1=[C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:18]([O:20][CH3:21])=[O:19])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)Cc1ccccc1
Reactant: CCOC1=[N+](Cc2ccccc2)CCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(=C1CCCN1Cc1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Lithium hexamethyldisilazide solution (8.39 mL of 1M in tetrahydrofuran, 8.39 mmol) was added to dry THF and cooled to −78° C. Methyl phenylacetate (1.15 mL, 7.99 mmol) was added dropwise, and the reaction stirred for 15 minutes. A solution of 1-benzyl-5-ethoxy-3,4-dihydro-2H-pyrrolium tetrafluoroborate in 5 mL of tetrahydrofuran was added dropwise, and after one hour the reaction was allowed to warm to room temperature. The mixture was quenched with saturated NaHCO3 solution, warmed to ambient temperature and poured into water. The aqueous layer was extracted with EtOAc and the organic extract was washed with brine, dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (25-30% EtOAc/hexane), providing methyl 2-(1-benzylpyrrolidin-2-ylidene)(phenyl)acetate. ESI+MS: 308.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.[CH3:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.C(N(CC)CC)C>O1CCOCC1>[CH3:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:7][C:5]2[S:6][C:2]([CH3:1])=[CH:3][N:4]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1cnc(N)s1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)Nc2ncc(C)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Methyl-thiazol-2-ylamine (22.8 mg, 0.200 mmol) and 4-methyl-benzoyl chloride (30.9 mg, 0.200 mmol) were dissolved in 1,4-dioxane (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). The reaction mixture was stirred overnight at room temperature. The crude product was filtered, evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (9.29 mg, 0.0400, 20.0%). ESI-MS m/z calc. 232.1. found 233.2 (M+1)+ Retention time 2.65 minutes.
Reaction SMILES: C(OP([CH2:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])(OCC)=O)C.[H-].[Na+].[CH:22]1([C:28]2[CH:43]=[CH:42][C:31]([CH2:32][O:33][C:34]3[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=3[CH:36]=O)=[CH:30][CH:29]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)C1C(=CC=CC=1)O.C1(C2C=CC(CCl)=CC=2)CCCCC1>C1COCC1.O>[CH:22]1([C:28]2[CH:43]=[CH:42][C:31]([CH2:32][O:33][C:34]3[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=3/[CH:36]=[CH:9]/[C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:30][CH:29]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: O=Cc1ccccc1OCc1ccc(C2CCCCC2)cc1
Reactant: CCOP(=O)(CC(=O)CCCCC(=O)OC)OCC
Agent: ClCc1ccc(C2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: O=Cc1ccccc1O
Solvent: C1CCOC1
Product: COC(=O)CCCCC(=O)/C=C/c1ccccc1OCc1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, a solution of 3.00 g (10.19 mmol) of methyl 7-(diethoxyphosphoryl)-6-oxo-heptanoate XIIb in 10 ml of THF was added dropwise to a suspension of 0.25 g (10.19 mmol) of sodium hydride in 20 ml of THF. After 30 min, a solution of 2.50 g (8.49 mmol) of 2-[(4-cyclohexylbenzyl)oxy]benzaldehyde (obtainable from salicylaldehyde and 4-cyclohexylbenzyl chloride in 10 ml of THF was added dropwise. The mixture was stirred at room temperature for 2 days. Water was added, the mixture was extracted with ethyl acetate and the combined organic phases were dried over Na2SO4. The product was purified chromatographically (silica gel, cyclo-hexane/ethyl acetate 10:1).
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([N:15]2[C:23](=[O:24])[C:18]3=[CH:19][CH2:20][CH2:21][CH2:22][N:17]3[C:16]2=[O:25])=[C:8]([F:26])[CH:7]=1>C(OCC)(=O)C>[NH2:12][C:11]1[C:6]([Cl:5])=[CH:7][C:8]([F:26])=[C:9]([N:15]2[C:23](=[O:24])[C:18]3=[CH:19][CH2:20][CH2:21][CH2:22][N:17]3[C:16]2=[O:25])[CH:10]=1
Reactant: O=C1C2=CCCCN2C(=O)N1c1cc([N+](=O)[O-])c(Cl)cc1F
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc(N2C(=O)C3=CCCCN3C2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
After an acetic acid (172 mL) solution of reduced iron (21.0 g) was stirred for one hour under reflux, an ethyl acetate (113 mL) solution of 2-(4-chloro-2-fluoro-5-nitrophenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (5.14 g, 0.016 mol) was dropwise added to the mixture at the same temperature. The reaction mixture was stirred for 2 hours under reflux and cooled down to room temperature. After filtration of the resulting mixture, 1N hydrochloric acid (250 mL) was added to the filtrate, and the organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL×2 times). The organic layer combined was washed with water (300 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane =1/1) to obtain a white solid of 2-(5-amino-4-chloro-2-fluorophenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (2.81 g, yield:59.4%).
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[N+:19]([C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25])([O-:21])=[O:20]>>[N+:19]([C:22]1[CH:23]=[C:24]([NH:25][C:2]2[CH:17]=[C:6]3[C:7]4[C:12]([CH2:13][CH2:14][N:5]3[C:4](=[O:18])[N:3]=2)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=4)[CH:26]=[CH:27][CH:28]=1)([O-:21])=[O:20]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2cccc([N+](=O)[O-])c2)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 3-nitro-aniline as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 10.10 (s, 1H), 8.87 (s, 1H), 8.13 (d, 1H), 7.88 (m, 1H), 7.73 (d, 1H), 7.63 (t, 1H), 7.02 (m, 2H), 6.38 (s, 1H), 4.01 (t, 2H), 3.85 (s, 3H) and 2.99 (t, 2H); MS (ESI) (M+H)+ 365.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:18][C@H:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C@@H:20]([NH2:22])[CH3:21])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:18][C@H:19]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C@@H:20]([NH:22][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:21])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1O[C@H](c1ccccc1)[C@H](C)N
Product: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1O[C@H](c1ccccc1)[C@H](C)NC(=O)C(C)(C)C

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-[1-(4-fluorophenyl)-6-methyl-indazol-5-yl]oxy-1-phenyl-propan-2-amine (50 mg, 0.13 mmol) and pivaloyl chloride (0.065 mL, 0.53 mmol). Yield 53 mg (87%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br-:19].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>C1COCC1>[C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:19])[CH:15]=2)[NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [Br-]
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2C1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CNc2ccc(Br)cc2C1
Yield: 1863.5 %

Procedure:
To a solution of XXIII (2.7 g, 10.9 mmol) in THF was added dropwise a solution of pyridinium tribromide (3.83, 0.41 mmol) in 50 mL of THF at rt. The reaction mixture was stirred for 15 min before 60 mL of water was added into the flask. The aqueous phase was extracted with EtOAc. The combined organic phase was washed with saturated NaCl, dried over Na2SO4 and concentrated. The residue was purified by flash silica gel chromatography to give (6-bromo-1,2,3,4-tetrahydro-quinoline-3-yl)-carbamic acid tert-butyl ester XXIV (2.5 g, 70%) as white solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH3:9])=[N:6][CH:5]=[C:4]([CH2:10][CH3:11])[N:3]=1.C1(C)C=CC=CC=1.[CH2:19]([CH:21]([NH2:24])[CH2:22][CH3:23])[CH3:20].CC(C)([O-])C.[Na+]>C([O-])(O)=O.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[CH2:8]([C:7]1[C:2]([NH:24][CH:21]([CH2:22][CH3:23])[CH2:19][CH3:20])=[N:3][C:4]([CH2:10][CH3:11])=[CH:5][N:6]=1)[CH3:9]
Reactant: CCc1cnc(CC)c(Cl)n1
Reactant: CCC(N)CC
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: CCc1cnc(CC)c(NC(CC)CC)n1
Temperature: 100 °C
Yield: 83.7 %

Procedure:
A 250 mL dry round bottom flask equipped with a magnetic stir bar and reflux condenser was charged with 2-chloro-3,6-diethylpyrazine (9.22 g, 54 mmol), dry toluene (108 mL), 1-ethyl propylamine (12.6 mL, 108 mmol), 2-(di-tert-butylphosphino)biphenyl (0.966 g, 3.24 mmol), sodium tert-butoxide (7.26 g, 75.6 mmol), and tris (dibenzylidineacetone)dipalladium (0) (1.48 g, 1.62 mmol) respectively. The mixture was heated to 100° C. for 4 hours. After cooling to ambient temperature, the reaction was poured in saturated aqueous NaHCO3 and extracted twice with ethyl acetate. The organics were combined, dried with Na2SO4, filtered and concentrated to 14.1 g of a dark crude oil. The crude was purified by Biotage MPLC in two batches (120 g columns, 10% ethyl acetate in heptane.) Like fractions were combined to give 10.0 g (84%) of 3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine as an orange oil.