Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:15]3[N:16]=[CH:17][NH:18][C:14]=3[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[O:7]2)[CH2:3][CH2:2]1.[CH:19]([O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=1[CH3:32])([CH3:21])[CH3:20].C(N(CC)CC)C.CCN=C=NCCCN(C)C>ClCCl>[CH:19]([O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:1]2[CH2:6][CH2:5][C:4]3([C:15]4[N:16]=[CH:17][NH:18][C:14]=4[C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[O:7]3)[CH2:3][CH2:2]2)=[O:28])=[CH:25][C:24]=1[CH3:32])([CH3:21])[CH3:20]
Reactant: c1ccc2c(c1)OC1(CCNCC1)c1nc[nH]c1-2
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2[nH]cnc23)ccc1OC(C)C
Reaction time: 16 h
Yield: 12 %

Procedure:
A mixture of 1H-spiro[chromeno[3,4-d]imidazole-4,4′-piperidine] (210 mg, 0.88 mmol), 4-isopropoxy-3-methyl-benzoic acid (170 mg, 0.89 mmol), triethylamine (370 μL, 2.6 mmol), and EDCI (170 mg, 0.89 mmol) in dichloromethane (5 mL) was stirred for 16 h. The reaction mixture was diluted with dichloromethane and was washed with 1M HCl, saturated solution of NaHCO3, and brine. The organics were dried over sodium sulfate and evaporated to dryness. The crude product was purified by silica gel chromatography eluting with 0-100% methanol in dichloromethane to yield (4-isopropoxy-3-methylphenyl)(1H-spiro[chromeno[3,4-d]imidazole-4,4′-piperidine]-1′-yl)methanone (44 mg, 12%). ESI-MS m/z calc. 417.5. found 418.5 (M+1)+; Retention time: 1.44 minutes (3 min run).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH2:24]([C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:9]3[N:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=3)=[CH:13][CH:14]=2)=[CH:19][CH:20]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCc1ccc(-c2ccc(-c3ncc(C(=O)OCC)cn3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCc1ccc(-c2ccc(-c3ncc(C(=O)O)cn3)cc2)cc1

Procedure:
5.12 g. of 2-(4'-n-hexyl-4-biphenylyl)-pyrimidine-5-carboxylic acid ethyl ester are boiled under reflux for 3 hours with 150 ml. of ethanol and 6.1 g. of sodium hydroxide in 45 ml. of water and the reaction mixture is evaporated in vacuo. 50 ml. of water and 100 ml. of 20% strength hydrochloric acid are added to the residue. Filtering, washing with water and drying gives 2-(4'-n-hexyl-4-biphenylyl)-pyrimidine-5-carboxylic acid, which can be converted into the acid chloride by boiling for 2 hours with 30 ml. of thionyl chloride. The excess reagent is removed in vacuo and the residual acid chloride is suspended in 60 ml. of absolute dioxane and added to a solution of 80 ml. of dioxane saturated with ammonia at room temperature, with stirring. Ammonia is passed into the reaction mixture for 4 hours and the mixture is allowed to stand overnight at room temperature. After this, the mixture is evaporated to dryness and the residue is stirred for 30 minutes with 100 ml. of water, filtered, rinsed with water and dried. Colorless 2-(4'-n-hexyl-4-biphenylyl)-pyrimidine-5-carboxylic acid amide is thus obtained, which can be sublimed at 205° in a high vacuum for purification, m.p. >260°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:13]=2[C:14](Cl)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([F:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:13]=2[C:14]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([F:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Reactant: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)Cl)cc1OC
Solvent: Cc1ccccc1
Product: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)Nc2ccc(S(=O)(=O)F)cc2)cc1OC

Procedure:
10.00 g (25.6 mmol) of 2-(4-Chloro-phenylsulfonylamino)4,5-dimethoxy-benzoyl chloride were mixed with 300 ml of toluene, 4.49 g (25.6 mmol) of 4-aminobenzenesulfonyl fluoride were added and the mixture was heated under reflux for 4 h. After cooling the precipitated solid was filtered off with suction and washed with toluene. 11.71 g (87%) of the title compound having a melting point of 216-219° C. were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([F:23])([F:22])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:26][N:27]([CH3:32])[C:28](=[O:31])[CH2:29]Cl>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:9][C:10]([F:22])([F:23])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=1)[CH2:29][C:28]([N:27]([CH3:32])[CH3:26])=[O:31])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCOc1cccc(C(F)(F)CNC(=O)OC(C)(C)C)c1
Reactant: CN(C)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOc1cccc(C(F)(F)CN(CC(=O)N(C)C)C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.5 %

Procedure:
150 mg (0.46 mmol) of N-(tert-butoxycarbonyl)-2,2-difluoro-2-(3-butoxyphenyl)ethylamine are dissolved in dry DMF (2.5 mL) and the solution was cooled to 0° C. NaH (60% in mineral oil; 22 mg; 0.55 mmol) is added and the reaction mixture stirred for 10 minutes at 0° C. and for further 10 minutes at room temperature. The reaction mixture is cooled again at 0° C., then N,N-dimethylchloroacetamide (73 mg; 0.60 mmol) is added and stirring is continued for 24 hours at room temperature. The reaction is quenched with water, extracted three times with EtAc, washed with brine. The organic phases are dried over anhydrous Na2SO4, filtered and evaporated. The residue is flash-chromatographed on silica gel (eluant: DCM/EtAc, from 98/2 to 95/5). 2-[N′-(tert-butoxycarbonyl)-2,2-difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethyl-acetamide (165 mg; 87%) is obtained as a white solid.
Reaction SMILES: OS(O)(=O)=O.[O:6]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:19].[CH3:20][OH:21]>>[CH3:20][O:21][C:18](=[O:6])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][OH:19]
Reactant: CO
Reactant: O=C1CCCCCCCCCCCO1
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCCCCCCCO
Reaction time: 24 h
Yield: 88 %

Procedure:
Concentrated H2SO4 (0.2 mL) was added to a solution of oxacyclotridecan-2-one (850 mg, 4.3 mmol) in 20 mL of methanol and stirred for 1 day. Methanol was removed under reduced pressure and the aqueous residue was extracted with diethyl ether 3 times. The combined organic layers were washed with saturated NaHCO3, saturated NaCl, and then dried over MgSO4. The diethyl ether was removed under reduced pressure to yield 874 mg (88%) of 14c as a white solid. 1H-NMR (400 MHz, CDCl3, δH ppm): 3.65 (3H, s, CO2CH3), 3.63 (2H, t, 3JH—H=6.6 Hz, HO—CH2), 2.29 (2H, t, 3JH—H=7.6 Hz, CH2CO2), 1.50-1.66 (4H, m, 2CH2), 1.22-1.38 (14H, m, 7CH2). HRMS (EI): m/z calcd 231.1955 ([M+H]+, C13H27O3), found 231.1954 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[C:18](=O)([O-])[O-].[Na+].[Na+]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12][CH3:18])=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cn1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])cn1
Yield: 89 %

Procedure:
5-Nitropyridine-2-carboxylic acid (100 g, 0.60 mol) was heated at reflux in methanol (1 L) and sulfuric acid (57 mL) for 5 hours. The reaction mixture was coded, reduced to half volume in vacuo, and the residue neutralized with a solution of sodium carbonate. The resulting precipitate was filtered to give methyl 5-nitropyridine-2-carboxylate (yield 89%, 98 g).
Reaction SMILES: [CH2:1]([C:8]1(O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=[O:11])O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([NH2:22])[CH2:20][NH2:21]>>[CH2:1]([C:8]12[NH:22][CH2:19][CH2:20][N:21]1[C:10](=[O:11])[C:12]1[C:17]2=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: O=C1OC(O)(Cc2ccccc2)c2ccccc21
Product: O=C1c2ccccc2C2(Cc3ccccc3)NCCN12

Procedure:
Condense 3-benzyl-3-hydroxyphthalide (15 g.) and ethylenediamine (30 ml.) by the procedure of Example 1 to obtain 9b-benzyl-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one, m.p. 115°-117° C. (elemental analysis confirms the empirical formula C17H16N2O), reduce with lithium aluminum hydride and treat with hydrogen chloride as described in Example 1 to obtain 1-benzyl-1,2,3,4,5,6-hexahydro-2,5-benzodiazocine dihydrochloride, m.p. 238°-40° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:10]1[CH:33]=[CH:32][CH:31]=[CH:30][C:11]=1[O:12][C@@H:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C@@H:14]1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:35].O>CN(C)C=O>[CH2:3]([C:10]1[CH:33]=[CH:32][CH:31]=[CH:30][C:11]=1[O:12][C@@H:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C@@H:14]1[N:22]([CH3:35])[C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1ccccc1Cc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@H]1Cc2ccccc2[C@H]1Oc1ccccc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92.5 %

Procedure:
To a suspension of sodium hydride (80% disp. in oil, 43 mg, 1.4 mmol) in dry N,N-dimethylformamide (2 ml) under nitrogen was added dropwise a solution of (±)cis-1-(2-benzylphenoxy)-2-tert-butoxycarbonylaminoindane (492 mg, 1.2 mmol) in dimethylformamide (5 ml). After stirring the mixture for 45 minutes at room temperature, iodomethane (88 μl, 1.4 mmol) was added dropwise and stirring continued for a further 45 minutes. The reaction mixture was then poured into a large excess of water and extracted with diethyl ether (3×30 ml). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The residue was subjected to column chromatography on silica gel eluting with 10% diethyl ether in hexanes to afford the title compound as a colourless oil (477 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14](O)[C@@H:13]([CH2:17][Br:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[F:30]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([F:30])[C@@H:13]([CH2:17][Br:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C(OCc1ccccc1)N1C[C@H](CBr)[C@@H](O)C1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(OCc1ccccc1)N1C[C@H](CBr)[C@H](F)C1
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
Process B: (3S,4R)-1-Benzyloxycarbonyl-3-bromomethyl-4-hydroxypyrrolidine (492 mg) was dissolved in toluene (1 mL). To this solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL) was added and perfluoro-1-octanesulfonylfluoride (0.42 mL) was subsequently added dropwise while the mixture was chilled in an ice water bath. The reaction mixture was stirred at 2° C. for 30 min and then at room temperature for 5 hours. Subsequently, the mixture was poured on a silica gel pad and was eluted with ethyl acetate (80 mL). The eluate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=2:1) to give (3S,4S)-1-benzyloxycarbonyl-3-bromomethyl-4-fluoropyrrolidine as a milky white syrup (421 mg).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[C:19]2[C:25]#[CH:26])=[O:15].[O:27]1[CH:32]=[CH:31][CH2:30][CH2:29][CH2:28]1>COCCOC>[C:25]([C:19]1[C:18]2[C:22](=[CH:23][CH:24]=[C:16]([C:14]([O:13][CH3:12])=[O:15])[CH:17]=2)[N:21]([CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][O:27]2)[N:20]=1)#[CH:26]
Reactant: C#Cc1n[nH]c2ccc(C(=O)OC)cc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCOC
Product: C#Cc1nn(C2CCCCO2)c2ccc(C(=O)OC)cc12

Procedure:
PTSA (0.99 g; 5.77 mmol; 0.11 eq.) was added to a solution of 3-Ethynyl-1H-indazole-5-carboxylic acid methyl ester (10.1 g; 50.2 mmol; 1.0 eq.) and 3,4-dihydro-2H-pyran (10.5 mL; 116 mmol; 2.3 eq.) in DME (100 mL). The reaction mixture was refluxed for 3 h, then cooled and concentrated. The residue was redissolved in DCM and washed sequentially with NaHCO3 (sat) and NaCl (sat) solutions, dried over magnesium sulfate, filtered and concentrated. The crude was triturated with Et2O to give the title compound as a yellow solid
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[NH:23][C:22](=[O:24])[N:21]=[CH:20][CH:19]=3)=[N:13][CH:14]=2)=[CH:4][C:3]=1[C:25]([F:28])([F:27])[F:26].Cl.Cl[CH2:31][C:32]1[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[CH:19]=[CH:20][N:21]([CH2:31][C:32]4[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=4)[C:22](=[O:24])[N:23]=3)=[N:13][CH:14]=2)=[CH:4][C:3]=1[C:25]([F:26])([F:27])[F:28]
Reactant: O=c1nccc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cn2)[nH]1
Reactant: Cn1cc(CCl)cn1
Agent: Cl
Product: Cn1cc(Cn2ccc(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cn3)nc2=O)cn1

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 6-{[2-(5-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-2-pyridinyl)ethyl]oxy}-2(1H)-pyrimidinone and 4-(chloromethyl)-1-methyl-1H-pyrazole hydrochloride. LC-MS (ESI): m/z 506 [M+H]+; 2.90 min (ret time).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:37]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>>[NH2:37][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:7][CH:8]=1)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Yield: 99.5 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (9H-fluoren-9-yl)methyl(S)-3-(4-tert-butoxyphenyl)-1-(((S)-1,1-diethoxypropan-2-yl)(naphthalen-1-ylmethyl)amino)-1-oxopropan-2-ylcarbamate (Compound III-6) (1.34 g, 1.84 mmol) was treated with piperidine and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound (928 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[C:19]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[Cl:1])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc([N+](=O)[O-])cc1Cl)c1ccccc1
Temperature: 25 °C
Yield: 28.4 %

Procedure:
A mixture of 2-chloro-4-nitroaniline (15.0 g, 86.9 mmol), triethylamine (13.3 ml, 95.6 mmol) and benzoyl chloride (11.1 ml, 95.6 mmol) were heated in toluene (200 ml) at reflux for 2 hours under an inert atmosphere. The reaction was allowed to cool to ambient temperature overnight, causing precipitation of a white solid. The solid was collected by suction filtration, washed with toluene (3×50 ml) and dried in vacuo. The crude product was taken up in dichloromethane (300 ml) and washed with 2.0 N aqueous hydrochloric acid (3×100 ml), water (100 ml), saturated aqueous sodium bicarbonate solution (3×100 ml) and water (100 ml). Drying of the organic layer over magnesium sulphate, followed by solvent evaporation in vacuo, yielded N-benzoyl 2-chloro-4-nitroaniline (6.83 g, 28% yield) as a yellow crystalline solid:
Reaction SMILES: [OH:1][CH:2]1[O:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.N1C(C)=CC=CC=1C.[Si:17](OS(C(F)(F)F)(=O)=O)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(Cl)Cl>[Si:17]([O:1][CH:2]1[O:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O=C1C=CC(O)OC1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1C=CC(=O)CO1
Temperature: -78 °C
Yield: 54.9 %

Procedure:
6-Hydroxy-2H-pyran-3(6H)-one (9 g, 79 mmol) was dissolved in DCM (250 mL), placed under a nitrogen atmosphere, and cooled to −78° C. 2,6-Lutidine (13.78 mL, 118 mmol) was then added in one portion, followed by slow addition of t-butyldimethylsilyltrifluoromethanesulfonate (21.74 mL, 95 mmol). The reaction was allowed to slowly warm to 0° C. over 4 h. The reaction was quenched by addition of ˜20 mL of water. The solution turned pale yellow upon quenching. After transferring to a separatory funnel, the organic phase was washed successively with 10% citric acid and brine. The organic layer was then dried over sodium sulfate, filtered and condensed to give a yellow oil. The crude material was purified on a 340G SNAP Biotage column (0-20% ethyl acetate in hexane) to give 6-(tert-butyldimethylsilyloxy)-2H-pyran-3(6H)-one (9.90 g, 43.4 mmol, 55.0% yield) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ ppm 6.87 (dd, J=10.54, 3.12 Hz, 1H), 6.08 (d. J=10.15 Hz, 1H), 5.53 (d, J=3.12 Hz, 1H), 4.51 (d, J=16.79 Hz, 1H), 4.08 (d, J=16.79 Hz, 1H), 0.92 (s, 9H), 0.17 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8]Cl)=[C:4]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[NH:23][CH:24]=[CH:25][N:26]=2)[N:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][N:26]2[CH:25]=[CH:24][N:23]=[C:22]2[C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[N:17]=2)=[C:4]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:3]=1
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Reactant: CCN(CC)c1cc(Cl)nnc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)c1cc(Cl)nnc1Cn1ccnc1-c1cccc(F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
A mixture of (6-chloro-3-chloromethyl-pyridazin-4-yl)-diethyl-amine (crude, 180 mg, 0.77 mmol), 2-fluoro-6-(1H-imidazol-2-yl)-pyridine (78 mg, 0.48 mmol) and K2CO3 (330 mg, 2.4 mmol) in DMF (5 mL) is stirred at room temperature overnight. The reaction is quenched with brine (4 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers are dried and solvent removed. PTLC separation (10% MeOH in DCM) gives 39 mg of {6-chloro-3-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-pyridazin-4-yl}-diethyl-amine as a solid. 1H NMR (CDCl3) 8.12 dd, 1H), 7.90 (dd, 1H), 7.19 (s, 1H), 7.07 (s, 1H), 6.79 (s, 1H), 6.77 (dd, 1H), 6.04 (s, 2H), 3.28 (q, 4H), 1.17 (t, 6H).
Reaction SMILES: [Cl-:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH:9]([NH3+:13])[CH2:8][CH:7]2[CH2:14][C:15]([O:17]C)=[O:16]>Cl>[Cl-:1].[C:15]([CH2:14][CH:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([O:3][CH3:2])[CH:5]=2)[CH:9]([NH3+:13])[CH2:8]1)([OH:17])=[O:16]
Reactant: COC(=O)CC1CC([NH3+])c2ccc(OC)cc21
Agent: Cl
Agent: [Cl-]
Product: COc1ccc2c(c1)C(CC(=O)O)CC2[NH3+]

Procedure:
5-Methoxy-3-methoxycarbonylmethyl-indan-1-yl-ammonium chloride (12.5 g) dissolved in 2 M hydrochloric acid (120 mL) is stirred at reflux temperature for 3 h. Then, the solvent is removed and the residue is azeotropically dried using toluene and further purified by washing with diisopropylether. The product is dried at 50° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[C:14](=[O:22])[NH:15][C:16]([CH2:19][CH2:20][CH3:21])=[CH:17][CH:18]=1>O1CCOCC1.[OH-].[Na+].O.C(=O)(O)[O-].[Na+]>[CH2:5]([O:4][C:2]([NH:12][C:13]1[C:14](=[O:22])[NH:15][C:16]([CH2:19][CH2:20][CH3:21])=[CH:17][CH:18]=1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCCc1ccc(N)c(=O)[nH]1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCc1ccc(NC(=O)OCc2ccccc2)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
Benzyl chloroform ate (1.8 ml; 12.6 mmol) was added to a solution of 3-amino-6-propyl-2-(1H)-pyridinone (1.63 g, 10.8 mmol) in a mixture of dioxane (25 ml) and 1N NaOH at 0° C. Within minutes a white precipitate formed. The reaction mixture was stirred at the same temperature for 1 hr then at room temperature for an additional hour. The reaction mixture was diluted with water and extracted with ethyl acetate then methylene chloride. Each extract was washed with brine then combined and dried over magnesium sulfate. Removal of the solvents in vacuo gave a yellow semi-solid which was a mixture of starting material and product. This was redissolved in a mixture of dioxane (24 ml) and 10% aqueous sodium bicarbonate (12 ml) and cooled to 0° C. Benzyl chloroformate (1.5 ml, 10.5 mmol) was once again added and after stirring for 30 min, the reaction mixture was allowed to stir at room temperature for 3 h. After dilution with water, the precipitate was filtered off and washed thoroughly, first with water and then with ether. Drying gave 2.64 g of the title compound as a white powder: 1H NMR (CDCl3) δ 0.96 (t, J=7.3 Hz, 3 H), 1.68 (m, 2 H), 2.52 (t, J=7.5 Hz, 2 H), 5.22 (s, 2 H), 6.07 (d, J=7.5 Hz, 1 H), 7.34-7.43 (m, 4 H), 7.68 (s, 1 H), 8.05 (br d, J=5.3 Hz, 1 H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:19]3=[C:20]([C:22](=[O:32])[C:23]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[CH:24][N:18]3[C:17]3[CH:16]=[CH:15][C:14]([O:33][CH3:34])=[CH:13][C:12]2=3)[CH:21]=1)C1C=CC=CC=1.C([O-])(=O)C.[Na+].[H][H]>C(O)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:19]3=[C:20]([C:22](=[O:32])[C:23]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[CH:24][N:18]3[C:17]3[CH:16]=[CH:15][C:14]([O:33][CH3:34])=[CH:13][C:12]2=3)[CH:21]=1
Reactant: COc1ccc2c(c1)c1cc(OCc3ccccc3)cc3c(=O)c(Cc4cccnc4)cn2c31
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)c1cc(O)cc3c(=O)c(Cc4cccnc4)cn2c31
Yield: 68.5 %

Procedure:
2-benzyloxy-10-methoxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (470 mg) obtained in Example 252 was dissolved in acetic acid. To the solution were added sodium acetate (259 mg) and palladium carbon (116 mg), and the mixture was heated under reflux in a hydrogen atmosphere for 3 hours. The reaction mixture was filtered, and the filtrate was distilled to remove the solvent under reduced pressure. To the residue was added an aqueous solution of sodium hydrogencarbonate until the termination of foaming. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:methylene chloride/methanol=20:1) to obtain the title compound (257 mg, 62%).