Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[CH2:21][C@H:20]([NH:25][S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[CH2:19]3)[C:10]=1[C:11]([F:14])([F:13])[F:12])=O)C.[H-].C([Al+]CC(C)C)C(C)C.CC(C[AlH]CC(C)C)C>C1COCC1>[OH:3][CH2:4][C:6]1[CH:7]=[N:8][N:9]([CH2:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[CH2:21][C@H:20]([NH:25][S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[CH2:19]3)[C:10]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CCOC(=O)c1cnn(Cc2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)c1C(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Cn3ncc(CO)c3C(F)(F)F)cc2C1
Reaction time: 0.5 h

Procedure:
(S)-Ethyl-1-((2-(1-methylethylsulfonamido)-2,3-dihydro-1H-inden-5-yl)methyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.026 mmol, 12 mg) was dissolved in THF (1 mL) and diisobutylaluminium hydride (0.304 mmol, 50 μL, 43.3 mg) added. After 15 min an additional 100 uL of DIBAL added and stirring continued for 30 min before the reaction was quenched with methanol. The mixture was concentrated then partitioned between DCM and Water. The aq. phase was acidified with 5N HCl and the phases mixed and separated using a hydrophobic frit. The organics were concentrated to dryness to give the desired compound as a clear film (10.6 mg, 0.025 mmol, 97%). MS (ESI): m/z [M+H]+ 418.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[NH:11][CH:12]=[N:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26](=[O:29])[CH2:27]Br.O>CN(C=O)C.C(O)CCC.C(O)(=O)C.O.C(OC(=O)C)C>[CH3:24][O:25][C:26](=[O:29])[CH2:27][N:13]1[CH:12]=[N:11][C:10]2[C:14]1=[N:15][CH:16]=[N:17][C:9]=2[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2ncnc3nc[nH]c23)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)Cn1cnc2c(OCc3ccccc3)ncnc21

Procedure:
6-Benzyloxypurine (4.18 g; 18.5 mmol) was added to a suspension of potasiumcarbonate (3.1 g; 22.4 mmol) in DMF (100 ml). After 15 min. bromoacetic acid methyl ester (1.93 ml; 20.4 mmol) was added. The reaction was monitored by TLC in butanol:acetic acid:water 4:1:1. Upon completion, the reaction mixture was portioned between water (600 ml) and ethylacetate (600 ml). The organic phase was dried over magnesium sulphate and evaporated to a volume of ˜10 ml and precipitated with pet. ether. The two products were separated by column chromatography using ethylacetate as the solvent. The products was precipitated in pet. ether. Yield: 2.36 g (43%). Melting point: 111.5-115° C. UV λmax=250 nm (9-alkylated); λmax=260 nm (7-alkylated). 1H-NMR (DMSO-d6): 8.60 (1H, s); 8.43 (1H, s); 7.6-7.35 (5H, m); 5.69 (2H, s); 5.26 (2H, s); 3.75 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.[CH3:57][N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:61]1[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]1)=[O:13])=[CH:5]2
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-chloroindole-2-carboxylic acid (0.234 g), HATU (0.569 g), HOAT (0.203 g) and N,N-diisopropylethylamine (0.191 mL) in DMF (0.6 mL) was treated with N-methylpiperazine (0.1 mL) stirred at ambient temperature for 48 h then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (3-10% 2 M ammonia in methanol/dichloromethane) to give the title compound (0.18 g). 1H NMR (400 MHz, CDCl3): δ 9.60 (br s, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.26 (d, 1.8 Hz, 1H), 6.76 (d, J=1.5 Hz, 1H), 4.0 (br m, 4H), 2.56 (t, J=5.1 Hz, 4H), 2.41 (s, 3H). Analysis: Calc'd for C14H16ClN3O; C, 60.54; H, 5.81; N, 15.13; Found: C, 59.99; H, 5.94; N, 18.87.
Reaction SMILES: [CH3:1][C:2]1([C:19]2[S:23][CH:22]=[C:21]([C:24]([O:26]C)=[O:25])[CH:20]=2)[CH2:6][O:5][C:4]2[CH:7]=[C:8]3[C:13](=[CH:14][C:3]1=2)[C:12]([CH3:16])([CH3:15])[CH2:11][CH2:10][C:9]3([CH3:18])[CH3:17].[OH-].[Li+].CO.O>C1COCC1>[CH3:1][C:2]1([C:19]2[S:23][CH:22]=[C:21]([C:24]([OH:26])=[O:25])[CH:20]=2)[CH2:6][O:5][C:4]2[CH:7]=[C:8]3[C:13](=[CH:14][C:3]1=2)[C:12]([CH3:15])([CH3:16])[CH2:11][CH2:10][C:9]3([CH3:17])[CH3:18]
Reactant: COC(=O)c1csc(C2(C)COc3cc4c(cc32)C(C)(C)CCC4(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)OCC3(C)c1cc(C(=O)O)cs1

Procedure:
A mixture of methyl [5-(3,5,5,8,8-pentamethyl-2,3,5,6,7,8-hexahydronaphtho[2,3-b]furan-3-yl)-thiophene-3-yl]carboxylate (2.1 g, 5.4 mmol), lithium hydroxide (2g, 48 mmol), methanol (1 ml) and water (1 ml) in 30 ml of THF was heated under reflux for 6 h. After concentrating in a rotary evaporator under vacuum at 40° C., adding water, ethyl ether and acidifying with a concentrated hydrochloric acid solution to pH 1, the organic phase was washed twice with water, dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40° C. The solids obtained were washed with heptane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]([CH2:16][CH2:17][C:18]([O:20]C)=[O:19])([N+:13]([O-])=O)[CH2:7][CH2:8][C:9](OC)=[O:10]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:7][CH2:8][C:9](=[O:10])[NH:13]1
Reactant: COC(=O)CCC(CCC(=O)OC)(CCC(=O)OC)[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCC1(CCC(=O)O)CCC(=O)N1

Procedure:
A solution of 160 g of crude γ-carbomethoxyethyl-γ-nitropimelic acid dimethyl ester in 800 ml of methanol is hydrogenated at approximately 50 psi using 2 g of 20% Pd/C as catalyst. The resulting slurry is filtered to remove the catalyst and the filtrate is concentrated at reduced pressure to yield crude 5-oxo-2,2-pyrrolidinedipropanoic acid methyl ester and 5-oxo-2,2-pyrrolidinedipropionic acid monomethyl ester. The crude esters are dissolved in 100 ml of methanol and 100 ml of water and are treated with 120 g of 50% sodium hydroxide solution. The reaction mixture is stirred and is heated to 100° C. with distillation of methanol.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([O:24]C)=[CH:11][CH:10]=3)[CH3:2].B(Br)(Br)Br.ClCCCl.[OH-].[Na+]>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([OH:24])=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(NCC3CCCCC3)c3cc(OC)ccc3nc21
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(O)ccc3nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-ethyl-6-methoxy-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine (5.4 g, 0.016 mol), boron tribromide (48 ml, 0.048 mol) and 1,2-dichloroethane (250 ml) is stirred at room temperature overnight. The reaction mixture is stirred with 1 volume of water, made basic with NaOH, and the layers are separated. The basic layer is acidified with acetic acid and the yellow precipitate that forms is collected by filtration, washed with water and dried. The product is recrystallized from hot acetonitrile/methanol to afford 1-ethyl-6-hydroxy-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as a yellow powder, m.p. 223°-224° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:21]3[N:22]=[C:23]([C:32]([OH:34])=O)[C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:31])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[O:46]1[CH2:51][CH2:50][CH:49]([NH2:52])[CH2:48][CH2:47]1.CCN(CC)CC.Cl>C(Cl)Cl.O>[Cl:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:24]=1[C:23]([C:32](=[O:34])[NH:52][CH:49]1[CH2:50][CH2:51][O:46][CH2:47][CH2:48]1)=[N:22][C:21]([C@@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]1[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH3:20])=[CH:30]2
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(C(=O)O)n1
Reactant: NC1CCOCC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(C(=O)NC2CCOCC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-3-(1-(((9H-fluoren-9-yl)methoxy)carbonylamino)ethyl)-8-chloroisoquinoline-1-carboxylic acid (349) (25.5 g, 54.0 mmol, 1.0 eq) and DMF (1.5 mL, 19.3 mmol, 0.35 eq) in CH2Cl2 (200 mL), oxalyl chloride (30 mL, 177.7 mmol, 3.29 eq) was added dropwise slowly. The resulting mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in CH2Cl2 (100 mL). This solution was added dropwise to a solution of tetrahydro-2H-pyran-4-amine (15 mL, 133 mmol, 2.46 eq) and Et3N (30 mL, 210.9 mmol, 3.90 eq) in CH2Cl2 (200 mL) at 0° C. The mixture was warmed to RT and stirred for 30 min. 5% Hydrochloric acid aqueous solution was added to the reaction mixture until the pH=1˜2. The mixture was poured into water (400 mL), extracted with CH2Cl2 (150 mL×2). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5-10% MeOH-DCM) to afford (S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-1-(tetrahydro-2H-pyran-4-ylcarbamoyl)isoquinolin-3-yl)ethylcarbamate (351).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:40]1[CH2:44][CH2:43][CH2:42][C@@H:41]1[CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:40]1[CH2:44][CH2:43][CH2:42][C@@H:41]1[CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Reactant: C1CN[C@@H](CN2CCCC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cc(C(=O)N3CCC[C@@H]3CN3CCCC3)ccc2[nH]1
Yield: 69 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), (R)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light brown foam (69%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:14][CH:15]([C:17]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[CH2:19][O:18]1)[CH3:16]>CN(C)C=O>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[C:17]([OH:18])([CH:15]([O:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1)[CH3:16])[CH2:19][N:3]1[CH:7]=[N:6][CH:5]=[N:4]1
Reactant: CC(OC1CCCCO1)C1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(OC1CCCCO1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 0 °C
Yield: 49.6 %

Procedure:
To N,N-dimethylformamide (700 ml) was added, at room temperature while stirring, 60% sodium hydride in oil (35.2 g) by portions during 10 minutes. The mixture was stirred for 5 minutes at room temperature, to which was added 1H-1,2,4-triazole (25 g) by portions at room temperature during 20 minutes. The reaction mixture was cooled with ice, to which was added 1H-1,2,4-triazole (44.6 g) during 30 minutes with stirring, followed by stirring at room temperature for further 10 minutes. To the resultant mixture was added dropwise 2-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl]-2-(2,4-difluorophenyl)oxirane (83.4 g) during 5 minutes, which was stirred for 4 hours at 90° C. The reaction mixture was cooled and poured into ice-water (1.5 l), which was subjected to extraction with ethyl acetate (500 ml) for 4 times. The ethyl acetate layer was washed with water (300 ml) 3 times and dried over anhydrous magnesium sulfate. Then the solvent was distilled off to leave a pale yellow oily product. This product was purified by means of a silica gel column chromatography (hexane:acetone=4:1~1:1). The resultant oily product was crystallized from hexane to give 2-(2,4-difluorophenyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxy-1-(1H-1,2,4-triazol-1-yl)-2-butanol (51.4 g) as colorless powder, m.p. 93°-95° C. Elemental Analysis for C17H21F2N3O3 : Calcd.: C, 57.78; H, 5.99; N, 11.89 Found: C, 57.82; H, 6.04; N, 11.77.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:3]=1[O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:19]([OH:21])=[O:20])[CH:11]([C:15]([F:18])([F:17])[F:16])[O:12]2)=[CH:7][CH:6]=1.[OH-].[Na+:28]>C(O)C.C1COCC1.O>[CH3:1][C:2]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:3]=1[O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:19]([O-:21])=[O:20])[CH:11]([C:15]([F:17])([F:18])[F:16])[O:12]2)=[CH:7][CH:6]=1.[Na+:28]
Reactant: Cc1ccc(C)c(Oc2ccc3c(c2)OC(C(F)(F)F)C(C(=O)O)=C3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(C)c(Oc2ccc3c(c2)OC(C(F)(F)F)C(C(=O)[O-])=C3)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 116 mg of 7-(2,5-dimethylphenoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid (0.318 mmol) in 4 mL of ethanol and 2 mL of THF was added 3.15 mL (0.318 mmol) of a 0.1008 N NaOH solution in water. The resulting solution was stirred at room temperature for 15 min. The volatiles were removed. To the solution was added 2 mL of water and the resulting suspension was cooled at −78° C. and solidified then put on high vacuum for lyophilization. The ivory solid was registered as PHA-807535A: 1H NMR (CD3OD/400 MHz) 2.08 (s, 3H), 2.28 (s, 3H), 5.77 (q, 1H, J=7.6 Hz), 6.31 (d, 1H, J=2.0 Hz), 6.41 (dd, 1H, J=2.4 Hz, 8.4 Hz), 6.78 (s, 1H), 6.94 (d, 1H, J=8.0 Hz), 7.11-7.15 (m, 2H), 7.38 (s, 1H); MS (ES+) 365 (M+l, 100); LC-MS purity 100% at 3.575 min. (UV), 100% ELSD.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:6]([CH3:7])[CH2:5][CH2:4][CH:3]1[CH:8]([CH3:11])[CH:9]=[O:10].[CH2:13](O)[C:14](=[CH2:16])[CH3:15].CC1C=CC(S(O)(=O)=O)=CC=1.O.C(O)C(=C)C>C1CCCCC1>[CH3:11][C:8]([CH:3]1[CH2:4][CH2:5][CH:6]([CH3:7])[C:2]1([CH3:1])[CH3:12])([CH2:15][C:14]([CH3:16])=[CH2:13])[CH:9]=[O:10]
Reactant: C=C(C)CO
Reactant: CC(C=O)C1CCC(C)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: C=C(C)CC(C)(C=O)C1CCC(C)C1(C)C

Procedure:
A 1 liter 3 neck flask equipped with a Dean-Stark trap, mechanical agitator, condenser, thermometer and nitrogen sweep was charged with the aldehyde from Example 28, 122.9 g at approximately 90% purity (0.66 mole), 230 g of methallyl alcohol (3.20 moles), 1.0 g of p-TSA, and 500 ml of cyclohexane. The contents were refluxed for 72 hours taking off a water-methallyl alcohol distillate (18 ml). The batch was cooled, washed with 250 ml of 10% sodium carbonate and 250 ml of brine. The mixture was dried, filtered, and concentrated in vacuo to afford 311 g of a mixture of acetal, and starting material. Distillation from 2 g of soda ash afforded 119 g of starting aldehyde. The pot residue 134.8 g contains the crude acetal (IR (Neat), 2980, 1660, 1470, 1150, 1100 cm-1) which was taken up in 200 ml of tetraglyme and 3 g of citric acid. Under nitrogen the flask was heated to 185° C. and 4 ml of methallyl alcohol were collected (approximately 2.5 hours). The flask was cooled and the contents were poured into 500 ml of 10% sodium carbonate and extracted with 2×200 ml of ether. The ether was washed with 200 ml of 10% sodium carbonate, 250 ml of water, and 250 ml of brine. The batch was dried, filtered, and concentrated to afford 124.7 g of crude product. Distillation afforded 58 g of purified product (40% yield). BP 92° C./0.3 mmHg; 1H-NMR (300 MHz), δ0.64 (3H, s), 0.78 (3H, d, J=6.78 Hz), 0.91 (3H, s), 1.05 (3H, s), 1.60 (3H, s), 1.5-1.9 (6H, m), 2.3 (2H, AB quartet, JAB =13.8 Hz), 4.63 (1H, s), 4.81 (1H, s), 9.73 (1H, s); 13C-NMR (75 MHz), δ13.50, 14.67, 16.73, 23.34, 24.23, 27.84, 28.88, 44.24, 45.95, 46.32, 53.13, 56.56, 115.46, 141.53, 207.14; IR (Neat), 2980, 2700, 1720, 1460, 900 cm-1 ; MS (m/e), 222 (M+), 207, 166, 123, 109, 95, 41 (Base);
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:20][CH:21]=[CH2:22])[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18]O)([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)[Br:25]>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:20][CH:21]=[CH2:22])[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][Br:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrP(Br)Br
Reactant: C=CC[C@H](COCc1ccccc1CO)NC(=O)OC(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: C=CC[C@H](COCc1ccccc1CBr)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 161.9 %

Procedure:
A solution of compound 18i (3.0 g, 9 mmol) in CCl4 (10 mL) was cooled in an ice bath. To this mixture was added PBr3 (1.0 g, 4.5 mmol) dropwise and the mixture was stirred at 0° C. for 2 hr. The mixture was quenched with water and extracted with DCM (3×50 mL). The combined organic layers were washed with brine and concentrated. The crude compound 18j (2.8 g, 80% yield) was used in the next step without purification. LCMS (m/z): 385.1 (MH+).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[N+:11]([O-:17])([O:13][CH2:14][CH2:15]Br)=[O:12]>C(O)C>[O:13]([CH2:14][CH2:15][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])[N+:11]([O-:17])=[O:12]
Reactant: O=Cc1cccc(O)c1
Reactant: O=[N+]([O-])OCCBr
Agent: [Na]
Solvent: CCO
Product: O=Cc1cccc(OCCO[N+](=O)[O-])c1
Yield: 19 %

Procedure:
1.42 g of sodium were dissolved in 200 ml of ethanol. 7.5 g of 3-hydroxybenzaldehyde and 10.5 g of bromoethyl nitrate were added and the resulting solution was refluxed for 5 hours. The compound was purified by column chromatography (silica, CH2Cl2). Yield 19%. Melting point: oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:33]=[CH:34][C:35]=1[N+:36]([O-:38])=[O:37])[C:13]([C:15]1[N:23]2[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]2)=[C:17]([NH:24]C(=O)OC(C)(C)C)[C:16]=1[CH3:32])=[O:14].C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(OC(C)C)(C)C>[NH2:24][C:17]1[C:16]([CH3:32])=[C:15]([C:13]([C:12]2[CH:33]=[CH:34][C:35]([N+:36]([O-:38])=[O:37])=[C:10]([O:9][CH3:8])[CH:11]=2)=[O:14])[N:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[CH:22]2
Reactant: COc1cc(C(=O)c2c(C)c(NC(=O)OC(C)(C)C)c3ccccn23)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)c2c(C)c(N)c3ccccn23)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 86.5 %

Procedure:
2.32 ml of trifluoroacetic acid are added dropwise to a solution of 643 mg (1.51 mmol) of tert-butyl 3-(3-methoxy-4-nitrobenzoyl)-2-methylindolizin-1-ylcarbamate in 20 ml of dichloromethane, cooled to 0° C. Once the introduction is complete, the medium is allowed to return to room temperature and it is stirred for 4 hours. The reaction medium is poured over a saturated aqueous potassium carbonate solution and extracted with ethyl acetate. The organic phase is separated after settling out, washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The crystals obtained are taken up in isopropyl ether, filtered off, washed with isopropyl ether and then dried. 425 mg of a brown solid are obtained.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7]([O:9]CC)=[O:8]>[OH-].[Na+]>[CH3:1][C:2]1[O:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1cc(C)oc1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C(=O)O)c(C)o1

Procedure:
Saponification of 0.5 g of the ester was accomplished by refluxing 4 hours in 10 ml of 25% aqueous sodium hydroxide. Acidification precipitated the crude acid, which was recrystallized from water to give 2,5-dimethyl-3-furoic acid as white needles, mp 135.5°-136.0° C.
Reaction SMILES: [CH3:1][C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH3:14])[N:3]=1.[Cl:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1.C(OC(=O)C)(=O)C>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=[CH:1][C:2]3[N:11]([CH3:12])[C:10](=[O:13])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][C:8]=4[CH3:14])[N:3]=3)=[CH:24][CH:23]=2)=[O:21])=[CH:30][CH:31]=1
Reactant: Cc1cccc2nc(C)n(C)c(=O)c12
Reactant: O=Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Solvent: CC(=O)OC(C)=O
Product: Cc1cccc2nc(C=Cc3ccc(C(=O)c4ccc(Cl)cc4)cc3)n(C)c(=O)c12
Temperature: 140 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To a mixture of 2,3,5-trimethyl-4(3H)-quinazolinone (376 mg) and 4-(4-chlorobenzoyl)benzaldehyde (1.1 g) was added acetic anhydride (0.5 ml) and the mixture was stirred at 140° C. for 2 hours. This reaction mixture was concentrated and the residue was washed with diethyl ether and dried to provide 504 mg of yellow powder.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][CH2:21][CH2:22][CH2:23][O:24][N+:25]([O-:27])=[O:26]>CN(C)C=O.ClCCl>[OH:8][C:7]1[CH:9]=[CH:10][C:2]([C:1]([O:12][CH2:20][CH2:21][CH2:22][CH2:23][O:24][N+:25]([O-:27])=[O:26])=[O:11])=[CH:3][C:4]=1[O:5][CH3:6]
Reactant: O=[N+]([O-])OCCCCBr
Reactant: COc1cc(C(=O)O)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)OCCCCO[N+](=O)[O-])ccc1O
Temperature: 0 °C
Reaction time: 69 h

Procedure:
To a solution of vanillic acid (5.0 g, 29.73 mmol) in N,N-dimethylformamide (50 ml), cesium carbonate (9.68 g, 29.73 mmol) was added. The reaction was cooled at 0° C. and a 20% solution of 1-bromo-4-(nitrooxy)butane in dichloromethane (29.45 g) was added. The reaction was stirred at room temperature for 69 hours. The mixture was poured into a 5% aqueous NaH2PO4 solution and extracted with diethyl ether (3×70 ml) The organic layers were washed with water (70 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, Cartridge column FLASH 65+M™ KP-Sil, eluent: gradient n-hexane/ethyl acetate 95/5 (500 ml), to n-hexane/ethyl acetate 1/1 during 4000 ml, n-hexane/ethyl acetate 1/1 (500 ml)). The product (5.88 g) was obtained.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][CH2:22]I)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])[CH3:30]>>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][CH2:22][N:35]4[CH2:36][CH2:37][N:32]([C:29](=[O:31])[CH3:30])[CH2:33][CH2:34]4)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCI)CS3)cc2c1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(CC[C@@H]2CSC(c3cc4cc(CS(C)(=O)=O)cc(NC5CCCC5)c4[nH]3)=N2)CC1

Procedure:
Cyclopentyl-{2-[(R)-4-(2-iodo-ethyl)-4,5-dihydro-thiazol-2-yl]-5-methanesulfonylmethyl-1H-indol-7-yl}-amine prepared in Step A of Example 156 and acetylpiperazine were reacted according to the same procedure as Step B of Example 156 to give the title compound.