Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:12]([NH:14][C@H:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=1)[CH3:16])=[O:13].O[Li:32].O>>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:12]([NH:14][C@H:15]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([O-:23])=[O:22])=[CH:25][CH:26]=1)[CH3:16])=[O:13].[Li+:32]
Reactant: [Li]O
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)C2CCCCN2Cc2ccc(F)c(F)c2)cc1
Solvent: O
Product: C[C@H](NC(=O)C1CCCCN1Cc1ccc(F)c(F)c1)c1ccc(C(=O)[O-])cc1
Product: [Li+]

Procedure:
The title compound (E1) (62 mg) was prepared according to the general procedure for esters hydrolysis starting from methyl 4-((1S)-1-(1-(3,4-difluorobenzyl)piperidine-2-carboxamido)ethyl)benzoate (D18) (67 mg). (LiOH H2O: 1.75 eq; reaction time: 3 hrs)
Reaction SMILES: [C:1]([C:3]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1C(OC(C)(C)C)=O)#[N:2].[ClH:27]>CCO>[ClH:27].[N+:24]([C:23]1[CH:22]=[CH:21][CH:20]=[C:4]([O:5][CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)[C:3]=1[C:1]#[N:2])([O-:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCCCC1COc1cccc([N+](=O)[O-])c1C#N
Agent: Cl
Solvent: CCO
Product: N#Cc1c(OCC2CCCCN2)cccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 1 h
Yield: 116 %

Procedure:
To a solution of tert-butyl 2-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate (Example 26e, 1.02 g, 2.83 mmol) in EtOH (20 mL) was added HCl 1.25N in EtOH (11.3 mL, 14.13 mmol) and the reaction mixture was stirred at 80° C. under nitrogen for 1 hour. After cooling to room temperature, the reaction mixture was concentrated in vacuum. The oily residue was washed with Hexane:DCM (1:4) and the solvent concentrated in vacuum to give 2-nitro-6-(piperidin-2-ylmethoxy)benzonitrile hydrochloride (0.982 g. 116%). MS 262 (MH+).
Reaction SMILES: N1CCCCC1.[NH:7](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:8]([C:13]([NH:15][C@H:16]([C:18]([NH:20][C@H:21]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH3:17])=[O:14])[CH2:9][CH2:10][S:11][CH3:12]>CN(C=O)C>[NH2:7][C@H:8]([C:13]([NH:15][C@H:16]([C:18]([NH:20][C@H:21]([C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])[CH2:22][CH:23]([CH3:24])[CH3:25])=[O:19])[CH3:17])=[O:14])[CH2:9][CH2:10][S:11][CH3:12]
Reactant: CSCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
In a round bottom flask (25 mL), Fmoc-Met-Ala-Leu-OBn is dissolved in 5 mL of anhydrous DMF. Piperidine is added to the solution and the mixture is stirred at room temperature for 25 minutes. The reaction is quenched with water and extracted with ethyl acetate. The combined organic layer is further washed by water, brine and dried over sodium sulfate. Solid Met-Ala-Leu-OBn is obtained after removal of solvent.
Reaction SMILES: C1(S[C:8]2([O:11][C:12]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][C:13]=3[CH:14]=[O:15])[CH2:10][CH2:9]2)C=CC=CC=1.[C-]1C2C(=CC=CC=2)C=CC=1.[Li+].O>C1COCC1>[CH:8]1([O:11][C:12]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:16][C:13]=2[CH:14]=[O:15])[CH2:10][CH2:9]1
Reactant: O=Cc1cc(OC(F)(F)F)ccc1OC1(Sc2ccccc2)CC1
Agent: [Li+]
Agent: [c-]1cccc2ccccc12
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(OC(F)(F)F)ccc1OC1CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 6 %

Procedure:
Freshly cut lithium metal (97 mg, 13.9 mmol) was added to a solution of naphthalene (1.77 g, 13.9 mmol) in THF (20 mL) and the mixture was sonicated at room temperature for 30 min. to produce a dark green solution of lithium naphthalenide. A solution of 2-(1-phenylthiocycloprop-1-yl)oxy-5-(trifluoromethoxy)benzaldehyde (Description 1, 96 mg, 0.27 mmol) in THF (2 mL) was cooled to -78° C. and the solution of lithium naphthalenide in THF (2 mL) was added dropwise until the intense green colour persisted. The reaction was then stirred for 5 min., water (6 mL) was added and the mixture was warmed to room temperature. The mixture was extracted with ethyl acetate, the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/Et2O (80:20), to give to give the title compound as a colourless oil (4 mg, 6%). 1H NMR (360 MHz, CDCl3) δ 0.86 (4H, m), 3.82-3.9 (1H, m), 7.42 (2H, m), 7.62 (1H, d, J 2.5 Hz), and 10.36 (1H, s).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)=[O:5].[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>CN(C=O)C.CC(=O)OCC>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[O:19])[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)=[O:5])[CH3:18]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cccc(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)CC(=O)c1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
Sodium hydride (60% oil dispersion, 1.24 g, 31.1 mmol) was added in portions to a solution of 3-chloroacetophenone (4.0 g, 25.9 mmol) and diethyl oxalate (4.54 g, 31.1 mmol) in DMF (32 mL) at 0° C. The mixture was stirred at r.t for 1 h and was then heated at 80° C. for 0.5 h. After cooling, the mixture was treated with 3N HCl and then diluted with EA. The organic layer was washed with water and saturated brine, dried (Na2SO4), filtered and concentrated. The resulting residue was then purified by column chromatography using 0-10% EA in hex to afford the title compound (4.43g, 67%). 1H NMR: 15.12 (br s, 1H), 7.98 (s, 1H), 7.88 (d, 1H), 7.58 (d, 1H), 7.47 (t, 1H), 7.05 (s, 1H), 4.39 (m, 2H), 1.41 (m, 3H).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([N:13](/[CH:17]=[CH:18]/[CH2:19][CH3:20])C(=O)C)[C:7]1[CH:12]=CC=CC=1.[ClH:21]>CN(C=O)C>[Cl:21][C:6]1[CH:7]=[CH:12][C:18]([CH2:19][CH3:20])=[CH:17][N:13]=1
Reactant: Cl
Reactant: CC/C=C/N(Cc1ccccc1)C(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCc1ccc(Cl)nc1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 19 %

Procedure:
To DMF (3.8 mL) at 5° C., was added POCl3 (1.4 mL) dropwise. After 5 minutes, 62b (1 g, 4.9 mmol) was added dropwise in 2 mL of DMF. The mixture was heated to 100° C. overnight. The mixture was allowed to cool to room temperature and was added dropwise to 50 mL of 1N HCl. The solution was extracted 3 times with ethyl acetate. The combined organic layer was dried, evaporated, then purified by column chromatography (eluent: 0 to 30% EtOAc in hexane) to give 0.13 g of 62c (19% yield).
Reaction SMILES: C(=CCO[C:6]1[CH:10]=[C:9]([CH2:11][O:12][CH3:13])[O:8][N:7]=1)=O.[CH3:14]CC(C)[BH-](C(C)CC)C(C)CC.[Li+].[OH-:28].[Na+].OO>O1CCCC1.C(O)C.O>[OH:28][CH2:14][C:6]1[CH:10]=[C:9]([CH2:11][O:12][CH3:13])[O:8][N:7]=1
Reactant: COCc1cc(OCC=C=O)no1
Reactant: CCC(C)[BH-](C(C)CC)C(C)CC
Reactant: [OH-]
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COCc1cc(CO)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6.55 g of 3-carbonylethoxy-5-methoxymethyl-isoxazole in 70 ml dry tetrahydrofuran were added 77.6 ml of a 1 N solution of L-selectride® at 0° C. The solution was stirred overnight at room temperature. After cooling to 0° C. 13 ml of water and 33 ml of ethanol were added, then simultaneously 33 ml of a 6 N solution of sodium hydroxide and 49 ml hydrogen peroxide were added with caution. After stirring for half an hour the supernatant was decanted, the residue washed several times with methylene chloride. The aqueous phase was extracted with dichloromethane in an extraction apparatus for one day. The organic phase was dried over sodium sulfate and the solvent evaporated to give 4.1 g product.
Reaction SMILES: C(O[C:4]([C:6]1[NH:10][C:9]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[O:13][C:8]=2[CH:7]=1)=[O:5])C.[CH2:23]([O:25][C:26](=[O:54])[CH:27](CC)[CH2:28][CH2:29][N:30]1C(=S)N2C3C=C(C4C=CC([N+]([O-])=O)=CC=4)OC=3C=C2[C:31]1=[O:51])[CH3:24].N(CCCC(OCC)=O)=C=O.C(N(CC)CC)C.N(CCCC([O-])=O)=C=O>C(OCC)(=O)C.CCCCCC>[CH2:23]([O:25][C:26](=[O:54])[CH2:27][CH2:28][CH2:29][N:30]1[C:31](=[O:51])[N:10]2[C:9]3[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)[O:13][C:8]=3[CH:7]=[C:6]2[C:4]1=[O:5])[CH3:24]
Reactant: CCOC(=O)C(CC)CCN1C(=O)c2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3n2C1=S
Reactant: CCOC(=O)c1cc2oc(-c3ccc([N+](=O)[O-])cc3)cc2[nH]1
Agent: CCOC(=O)CCCN=C=O
Agent: O=C=NCCCC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCN1C(=O)c2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3n2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
2-(4-Nitro-phenyl)-4H-furo[3,2-b]pyrrole-5-carboxylic acid ethyl ester (25 mg, 0.087 mmol, 1 molequivalent), prepared as described hereinabove (see, preparation of Compound 1), ethyl 4-isocyanatobutyrate (135 mg, 0.87 mmol) and triethylamine (214 μl, 1.74 mmol) were stirred overnight at room temperature. Additional 4-isocyanatobutyrate (130 μl) was added and the mixture was heated to 50° C. and was stirred at this temperature overnight. Once TLC analysis, using a 2:1 hexane:ethyl acetate mixture as eluent, indicated a complete conversion, the crude mixture was purified by column chromatography using a gradient of hexane to hexane:ethyl acetate (9:1) as eluent to give pure Compound 30 (26 mg, 74% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.ClCCl.[CH3:12][N:13](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.[Zn]>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]#[N:13])=[N:3][CH:4]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1ccc(Cl)cn1
Temperature: 25 °C
Yield: 46 %

Procedure:
Slurry 2,5-dichloropyridine (6 g, 40.5 mmol), zinc cyanide (2.9 g, 24.7 mmol), zinc (dust) (116 mg, 1.8 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (720 mg, 0.98 mmol) in anhydrous DMF (40 mL). Heat the mixture to reflux under a nitrogen atmosphere for 4.5 h. Cool the mixture to room temperature, dilute with EtOAc (300 mL), wash with aqueous 10% sodium chloride (3×75 mL). Collect organic layer, dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1 gradient) to obtain the desired intermediate (2.6 g, 46%). GC-MS m/z: 138 (M+).
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>O>[CH3:33][O:32][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[O:9][CH2:8][CH2:7][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)[N:17]=[CH:16][CH:15]=[C:14]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: C1COCCN1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCN1CCOCC1
Temperature: 80 °C
Reaction time: 72 h
Yield: 40.8 %

Procedure:
N,N-Dimethylformamide (1.5 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (50 mg), potassium carbonate (53 mg), and morpholine (33 mg), and the mixture was stirred at 80° C. for 3 days. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (23 mg, yield 41%).
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)[CH2:2][C:3]#[CH:4].C([Li])CCC.[CH2:17]=[O:18]>C1COCC1>[O:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[O:5][CH2:1][CH2:2][C:3]#[C:4][CH2:17][OH:18]
Reactant: C#CCCOC1CCCCO1
Reactant: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCC#CCCOC1CCCCO1
Temperature: -23 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
To a solution of 8.0 mL (51 mmol) of 2-(3-butynyloxy)tetrahydro-2H-pyran in 150 mL of THF under nitrogen atmosphere at −23° C. was added dropwise a solution of 33 mL (53 mmol) of 1.6M butyllithium in hexanes, maintaining the temperature at −23° C. The resulting solution was stirred at 0° C. for 2 h, recooled to −23° C. and 2.4 g (76.5 mmol) of paraformaldehyde was added in several portions. The mixture was stirred at −23° C. for 1 h and let warm to room temperature and stirred for 18 h. The reaction mixture was poured into a large excess of ice water and extracted with ether. The organics were washed with brine until neutral, dried over MgSO4, filtered and concentrated in vacuo. The residue was kugelrohr distilled to provide 7.26 g (77%) of 5-(tetrahydro-2H-pyran-2-yloxy)-2-pentyn-1-ol as a colorless liquid. EI Mass Spec: 185.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][O:9][C:8]2=[O:12])=[CH:4][CH:3]=1.[CH3:15][S:16][CH2:17][C:18](OCC)=[O:19].C(OCl)(C)(C)C.C(N(CC)CC)C.Cl>CC#N.C1COCC1>[CH3:15][S:16][CH:17]1[C:14]2[C:2](=[CH:3][CH:4]=[C:5]([CH2:6][N:7]3[CH2:11][CH2:10][O:9][C:8]3=[O:12])[CH:13]=2)[NH:1][C:18]1=[O:19]
Reactant: CCOC(=O)CSC
Reactant: Nc1ccc(CN2CCOC2=O)cc1
Agent: CC(C)(C)OCl
Agent: Cl
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSC1C(=O)Nc2ccc(CN3CCOC3=O)cc21
Temperature: -50 °C
Reaction time: 1 h

Procedure:
To a solution of the compound obtained in Step B (0.113 mol) in a mixture of CH3CN (200 ml) and THF (200 ml) at −60° C. there is added, dropwise, ethyl (methylsulphanyl)-acetate (0.136 mol) under a nitrogen atmosphere. tBuOCl (0.136 mol) is added dropwise to the reaction mixture over 20 minutes, keeping the temperature between −60° C. and −55° C. After stirring for one hour at −50° C., triethylamine (0.152 mol) is added dropwise. The reaction mixture is brought to 0° C. and then aqueous 3M HCl solution (580 ml) is added dropwise. After stirring for 12 hours at ambient temperature, the organic phases are evaporated in vacuo and then the aqueous phase is extracted with DCM and the organic phases are combined. The organic phase obtained is washed with water and then with saturated aqueous NaCl solution. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness. The product obtained is recrystallised from a mixture of ethyl ether/ethanol. The crystals obtained are filtered off, washed with ether and dried in vacuo at 40° C. to yield the title product, which is used directly in the next Step.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:10])[NH2:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[S:15][C:16]([C:19](=[O:21])[CH3:20])=[CH:17][CH:18]=1)=O.C(O)(=O)C>CN(C=O)C>[C:19]([C:16]1[S:15][C:14]([C:12]2[NH:11][C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([NH2:9])=[O:10])[C:2]=3[N:1]=2)=[CH:18][CH:17]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1ccc(C(=O)Nc2cccc(C(N)=O)c2N)s1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)s1
Temperature: 125 °C
Yield: 95.1 %

Procedure:
To a solution of EXAMPLE 41A (1.70 g) in hot N,N′-dimethylformamide (60 mL) was added acetic acid (50 mL) and the solution heated at 125° C. for 3 hours. After cooling, the solution was filtered, and the yellow solid washed with methanol and dried to give the title compound (1.52 g, 95%). MS (APCI): 286 (M+1)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17]([O:19]CC)=[O:18])[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].O.[OH-].[Li+]>C1COCC1.C(O)C.O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17]([OH:19])=[O:18])[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(-c3ccccc3F)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(C(=O)O)ccc12
Yield: 70.2 %

Procedure:
A suspension of ethyl 8-carbamoyl-5-(2-fluorophenyl)-9H-carbazole-2-carboxylate (Example 3-12, 0.8 g, 2.126 mmol) and lithium hydroxide monohydrate (0.255 g, 6.38 mmol) in THF-ethanol-water (3:1:1) (25.0 mL) was heated at reflux for 4 h. The mixture was concentrated and the residue was suspended in water. The pH was adjusted to 1-2 by addition of 1 M hydrochloric acid. The precipitate was collected by filtration, washed with water and dried to provide 8-carbamoyl-5-(2-fluorophenyl)-9H-carbazole-2-carboxylic acid as a yellow solid (520 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δ 12.77 (br. s., 1 H) 11.87 (s, 1 H) 8.41 (m, 1 H) 8.26 (br. s., 1 H) 8.08 (d, J=7.69 Hz, 1 H) 7.50-7.67 (m, 4 H) 7.40-7.49 (m, 2 H) 7.09-7.17 (m, 2 H). Mass spectrum m/z 349.1 (M+H)+.
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH:15]([CH:18]=O)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH:15]([CH:18]=[CH2:1])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)C1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 70 %

Procedure:
To a suspension consisting of methyl triphenylphosphonium bromide (4.76 g, 13.3 mmol) and THF (20 mL) at 0° C. was added n-butyl lithium (1.6 M solution in hexanes, 8.3 mL). The resulting orange solution was stirred at 0° C. for 5 min. A solution consisting of 3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.50 g, 12.5 mmol) and THF (15 mL) was then added via cannula. The reaction mixture was stirred at 0° C. and was warmed to rt over 2.5 h. The reaction mixture was then cooled to 0° C., quenched with sat. NH4Cl, and extracted with Et2O. The organic layer was combined, dried (MgSO4) and concentrated. The crude residue was suspended in hot hexanes and filtered. The filtrate was concentrated and purified (FCC) to give the title compound (1.7 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.[Cl:33][C:34]1[CH:35]=[C:36]([C:40]2[N:45]=[CH:44][C:43]([NH2:46])=[CH:42][N:41]=2)[CH:37]=[CH:38][CH:39]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:46][C:43]3[CH:44]=[N:45][C:40]([C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([Cl:33])[CH:35]=4)=[N:41][CH:42]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: Nc1cnc(-c2cccc(Cl)c2)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cnc(-c5cccc(Cl)c5)nc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.7 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation B; 45 mg, 0.12 mmol) was diluted with DCM (1 mL) followed by the addition of oxalyl chloride in DCM (2M) (66 μl, 0.13 mmol) and DMF (1 drop). 2-(3-chlorophenyl)pyrimidin-5-amine (25 mg, 0.12 mmol) and DIEA (52 μl, 0.30 mmol) were added and the reaction was stirred at ambient temperature for 4 hours. The reaction was loaded directly onto silica gel and eluted with 5% ethyl acetate/hexanes to 70% ethyl acetate/hexanes to yield the desired compound (45 mg, 0.080 mmol, 67% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][NH2:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:40][CH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=1)=[O:31]
Reactant: O=C(Br)CBr
Reactant: NCc1ccccn1
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)c(OC)c32)cc1OC
Product: COc1ccc(CC2c3c(cc(OC)c(OC)c3OC)CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-picolylamine
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:18])=[CH:4][CH:3]=1.[OH2:19].[CH2:20]([CH:22]1[O:24][CH2:23]1)[Cl:21]>C(O)(=O)C>[Cl:21][CH2:20][CH:22]([OH:19])[CH2:23][NH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH:18][CH2:23][CH:22]([OH:24])[CH2:20][Cl:21])=[CH:4][CH:3]=1
Reactant: O
Reactant: ClCC1CO1
Reactant: Nc1ccc(N)c2c1C(=O)c1ccccc1C2=O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)c2c(NCC(O)CCl)ccc(NCC(O)CCl)c21
Temperature: 50 °C
Reaction time: 16 h

Procedure:
1,4-Diaminoanthraquinone (20.00 g, 0.084 mole) was slurried in 200 ml of glacial acetic acid containing 12 ml of water. This mixture was heated to 50° C. and treated with 8.0 ml of epichlorohydrin. The reaction temperature was raised to between 90° and 100° C. and the remaining 32 ml of epichlorohydrin was dripped in slowly during 3.5 hours while maintaining this temperature range. A total of 40 ml (0.511 mole) of epichlorohydrin was added to the reaction mixture. After addition was complete, the external heating source was removed and the reaction mixture was allowed to cool to ambient temperature and stir overnight (about 16 hours). 200 ml of acetic acid containing 20% water was added to the reaction mixture and stirring was continued for 2 hours. The precipitated product was isolated by filtration. The filter-cake was rinsed with 20% aqueous acetic acid, followed by distilled water and then air-dried. This material was further dried in-vacuo over P2O5 to afford 19.08 g of 1,4-bis-(3-chloro-2-hydroxypropylamino)-9,10-anthracenedione.