Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:14]([N:21]([S:28](Cl)(=[O:30])=[O:29])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>C(Cl)Cl>[CH2:14]([N:21]([S:28]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)(=[O:29])=[O:30])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)N1CCOCC1
Yield: 6 %

Procedure:
A solution of morpholine (1.05 ml, 12 mmol) and triethylamine (1.84 ml, 12 mmol) in methylene chloride (10 ml) was added to a solution of ethyl 2-[benzyl-(chlorosulfonyl)amino]acetate (2.3 g, 8.3 mmol), [prepared as described in Step 1 above], in methylene chloride (30 ml) at 0° C. The reaction mixture was slowly allowed to warm to RT and after 6 h 1M HCl was added. The product was extracted into methylene chloride, washed with brine, and dried over MgSO4. The organics were removed in vacuo and the crude product was chromatographed (PTLC, SiO2, 25% ethyl acetate/hexane) to give ethyl 2-[benzyl-(morpholine-4-sulfonyl)amino]acetate as a colorless oil (6%). Proceeding as described in Example 1 above, but substituting morpholine with:
Reaction SMILES: [C:1]1([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.[CH2:32]([NH:38][C:39]([NH:41][C:42]1[CH:47]=[CH:46][N:45]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]O)[C:44](=[O:55])[N:43]=1)=[O:40])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(Cl)Cl>[CH2:32]([NH:38][C:39](=[O:40])[NH:41][C:42]1[CH:47]=[CH:46][N:45]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][O:21][C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:1]2[C:14]3[C:15]4=[C:16]5[C:11](=[CH:12][CH:13]=3)[CH:10]=[CH:9][CH:8]=[C:7]5[CH:6]=[CH:5][C:4]4=[CH:3][CH:2]=2)[C:44](=[O:55])[N:43]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCNC(=O)Nc1ccn(CCCCCCO)c(=O)n1
Reactant: O=C(O)CCCc1ccc2ccc3cccc4ccc1c2c34
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCCCNC(=O)Nc1ccn(CCCCCCOC(=O)CCCc2ccc3ccc4cccc5ccc2c3c45)c(=O)n1
Reaction time: 1 h

Procedure:
To a solution of pyrene butyric acid (commercially available) (0.05 g, 0.17 mmol) in CH2Cl2 (5 ml) was added at 0° C., dicyclohexylcarboimide (0.044 g, 0.210 mmol) and dimethylaminopyridine (4 mg). The mixture was stirred for 1 h. 1-Hexyl-3-[1-(6-hydroxy-hexyl)-2-oxo-1,2-dihydro-pyrimidinyl]-urea) (J) was then added to the mixture and the solution was stirred at room temperature for 16 h. The solid was filtered off and the filtrate washed with water (2×10 ml) then saturated sodium chloride solution (5 ml). The organic phase was then dried (MgSO4) and the solvent evaporated in vacuo. The crude solid was purified using flash silica gel chromatography using a gradient: 1) (CHCl3) 2) (CHCl3/EtOAc, 5:1) and 3) (CHCl3/EtOAc/Et3N, 5:1:0.2). 4-Pyren-1-yl-butyric acid 6-[4-(3-hexyl-ureido)-2-oxo-2H-pyrimidin-1-yl]-hexyl ester (K) was obtained as a yellow solid (0.025 mg, 23%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]1[CH:33]=[CH:32][C:14]2[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][C:21]=3[O:29][CH3:30])=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:42]([O:44][CH2:45][CH3:46])=[O:43]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]1[CH:33]=[CH:32][C:14]2[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:22][C:21]=3[O:29][CH3:30])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccn1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OCC)cc1OC)n2C)c1ccccn1
Yield: 43 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and ethyl chloroformate. Yield: 43% of theory, C31H35N7O6 (601.7) Rf value: 0.44 (silica gel; dichloromethane/ethanol=9:1) ##EQU142##
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C@@H:15]([NH:18]S(C(C)(C)C)=O)[CH2:16][CH3:17])=[N:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl.O1CCOCC1>CO>[C:1]1([CH3:25])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C@@H:15]([NH2:18])[CH2:16][CH3:17])=[N:11]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1ccn(S(=O)(=O)c2ccc(C)cc2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC[C@H](N)c1ccn(S(=O)(=O)c2ccc(C)cc2)n1
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid {(S)-1-[l-(toluene-4-sulfonyl)-1H-pyrazol-3-yl]-propyl}-amide (1.00 g, 2.61 mmol) in MeOH was added a 4 M solution of HCl in dioxane (1 mL, 4 mmol). After 2 hours, the solvent was concentrated in vacuo. The residue was made basic with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N:21]=[C:22]4[CH2:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([F:11])[F:10]>Cl.O1CCOCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N:21]=[C:22]4[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([F:11])[F:10]
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(OC(F)F)c(Cl)c4)n3)cccc12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)CCc1nccc2c(-c3noc(-c4ccc(OC(F)F)c(Cl)c4)n3)cccc12
Reaction time: 2 h
Yield: 44.9 %

Procedure:
1,1-Dimethylethyl 3-[5-(5-{3-chloro-4-[(difluoromethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]propanoate (D46; 32 mg, 0.064 mmol) was dissolved in 4M hydrogen chloride in 1,4-dioxane, and the solution allowed to stand at room temperature for 2 h. The solvent was evaporated in vacuo to give a white solid which was triturated under dry ether (3×5 ml) to give a white solid. The sample was dissolved in 1:1 MeOH:DMSO (1 ml) and purified by Mass Directed Preparative HPLC (Supelcosil ABZ+Plus column, eluting with solvents NB (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid)). The solvent was evaporated in vacuo to give the title compound as a white solid (12.8 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH2:16][CH3:17])[N:12]=[N:11]1.Br[CH2:19][C:20]#[CH:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH2:21][C:20]#[CH:19])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH2:16][CH3:17])[N:12]=[N:11]1
Reactant: CCn1nnn(-c2cc(O)c(F)cc2Cl)c1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1cc(-n2nnn(CC)c2=O)c(Cl)cc1F
Yield: 65.2 %

Procedure:
In the manner of Example 8, Step B, the reaction of 0.8 g (0.0031 mole) of 1-(2-chloro-4-fluoro-5-hydroxyphenyl)-1,4-dihydro-4-ethyl-5H-tetrazol-5-one with 0.9 g (0.0062 mole) of 1-bromo-2-propyne and 0.63 g (0.0046 mole) of potassium carbonate in 25 mL of acetone produced 0.6 g of 1-[2-chloro-4-fluoro-5-(2-propynyloxy)phenyl]-1,4-dihydro-4-ethyl-5H-tetrazol-5-one, mp 88°-89° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH:23]1[O:26][CH:24]1[CH3:25]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[N:12]([CH2:21][CH2:22][CH:23]4[O:26][CH:24]4[CH3:25])[C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1c2ccc(Cl)cc2nc2[nH]c3ccccc3n12
Reactant: CC1OC1CCBr
Product: CC1OC1CCn1c2ccccc2n2c(=O)c3ccc(Cl)cc3nc12

Procedure:
3-Chloro-6-(3,4-epoxypentyl)benzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 3-chlorobenzimidazo[2,1-b]quinazolin-12(6H)one and 1-bromo-3,4-epoxypentane.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[O:4]C1C=CC=CC=1.[CH3:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=3)[CH:20]=2)[NH:15][CH:14]=1.[H-].[Na+].CN(C)C=O>O>[CH3:1][NH:2][C:3]([N:15]1[C:16]2[C:21](=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=3)=[CH:18][CH:17]=2)[C:13]([CH3:12])=[CH:14]1)=[O:4]
Reactant: Cc1c[nH]c2ccc(Oc3ccnc(N)c3)cc12
Reactant: CNC(=O)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)n1cc(C)c2cc(Oc3ccnc(N)c3)ccc21
Reaction time: 0.75 h
Yield: 58.9 %

Procedure:
Phenyl N-methylcarbamate (350 mg, Production example 2-1) was added to a solution of 4-(3-methyl-1H-5-indolyl)oxy-2-pyridinamine (500 mg), sodium hydride (93 mg) and N,N-dimethylformamide (5 ml) at room temperature; and the reaction mixture was stirred for 2 hours and 45 minutes. Water was added to the reaction mixture; extraction was performed with ethyl acetate; and purification was performed by NH-silica gel column chromatography (Fuji Silysia, hexane:ethyl acetate=1:2, sequentially, ethyl acetate) to yield the title compound as a pale yellow amorphous solid (365 mg).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.NCC([N:55]1[CH2:60][CH2:59][CH:58]([O:61][C:62]2[CH:69]=[CH:68][CH:67]=[CH:66][C:63]=2[C:64]#[N:65])[CH2:57][CH2:56]1)=O>CN(C=O)C.O>[C:64]([C:63]1[CH:66]=[CH:67][CH:68]=[CH:69][C:62]=1[O:61][CH:58]1[CH2:59][CH2:60][N:55]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]2[CH:17]=[C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:20][N:19]=2)=[O:22])[CH2:56][CH2:57]1)#[N:65]
Reactant: N#Cc1ccccc1OC1CCN(C(=O)CN)CC1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reaction time: 0.03 h
Yield: 6 %

Procedure:
DIPEA (1.3 g, 0.01 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (720 mg, 2.9 mmol) in DMF (4 mL) followed by HOBt (459 mg, 3.4 mmol) and EDCI.HCl (664 mg, 3.4 mmol). After 2 minutes of stirring, 2-[1-(2-amino-acetyl)-piperidin-4-yloxy]-benzonitrile hydrochloride (prepared by method used for the synthesis of Intermediate 15) (600 mg, 2.9 mmol) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (using neutral alumina and 5% MeOH in CHCl3 as eluent) afforded 87 mg (6% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-cyano-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 430.18, 96.4%, 1H NMR (300 MHz, DMSO-d6): δ8.0 (m, 1H), 7.8 (m, 3H), 7.2 (m, 1H), 7.4 (m, 4H), 7.2 (m, 2H), 4.9 (m, 1H), 4.2 (bs, 2H), 3.7 (m, 2H), 3.5 (m, 2H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10](NN)=[O:11])[N:9]=1)[C:2]([NH2:4])=[NH:3].C(=N)([O:17]CC)CC.Cl.C(=N)(OCC)CC>C(O)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]([OH:11])=[O:17])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(C(=O)NN)cs1
Reactant: CCOC(=N)CC
Agent: Cl
Solvent: CCO
Product: N=C(N)Nc1nc(C(=O)O)cs1
Yield: 103.9 %

Procedure:
2.90 g (14.48 mmol) of 2-guanidino-4-thiazole carboxylic acid hydrazide in 50 ml dry ethanol was slurried with 29.1 mmol of ethyl propionimidate (prepared from 4.0 g (29.1 mmol) of ethyl propionimidate hydrochloride) for 5 days at 25°. The slurry was filtered and the resulting solid was dried for 2 hours at 60° in vacuo to give 2.802 g (75%) of 2-guanidino-4-thiazole carboxylic acid 2-propioniminohydrazide.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([OH:17])=O.[CH2:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:19].ClP(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:19][CH2:18][N:20]([C:15]([C:3]1[C:4](=[O:14])[N:5]([CH3:13])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([Cl:12])[C:11]=2[C:2]=1[OH:1])=[O:17])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCNc1ccccc1
Reactant: Cn1c(=O)c(C(=O)O)c(O)c2c(Cl)cccc21
Agent: ClP(Cl)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Temperature: 27.5 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
1,2-Dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid (2 gm) and N-ethyl aniline (1 gm) were taken in toluene (50 ml) and stirred for 30 minutes at 25-30° C. under nitrogen atmosphere. The resulting mass was followed by the addition of dichlorotriphenyl phosphorane (10.5 gm) at 25-30° C., followed by heating to reflux (110-115° C.) and then maintained for 3 hours at reflux. Toluene was distilled out from the reaction mass under vacuum at below 60° C. The resulting residue was dissolved in ethyl acetate (100 ml) at 25-30° C. followed by the addition of water (100 ml) at 25-30° C. and then pH of the resulting mass was adjusted to 10-12 with 10% sodium hydroxide solution at 25-30° C. The resulting mass was stirred for 30 minutes at 20-25° C. followed by separation of the layers. The resulting aqueous layer was cooled to 15-20° C. and pH was adjusted to 2 by using concentrated hydrochloric acid. The resulting mass was stirred for 30 minutes at 15-20° C. The separated solid was filtered, washed with water and then dried to yield 2 gm of laquinimod (HPLC purity: 98.4%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH2:14][CH:15]([N:30]1[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[N:31]1)[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][C:18]=1[OH:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>CN(C)C=O>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][C:18]1[O:29][CH2:14][CH:15]([N:30]3[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[N:31]3)[CH2:16][C:17]2=1
Reactant: COc1ccc2ncc(O)c(CC(CO)n3cc([N+](=O)[O-])cn3)c2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2ncc3c(c2c1)CC(n1cc([N+](=O)[O-])cn1)CO3
Reaction time: 3 h
Yield: 63.4 %

Procedure:
Diethyl azodicarboxylate (250 μL, 1.87 mmol, 6.43 eq) is added at room temperature to a stirred solution of 4-[3-hydroxy-2-(4-nitro-pyrazol-1-yl)-propyl]-6-methoxy-quinolin-3-ol (100 mg, 0.29 mmol, 1.0 eq) and triphenylphosphine (122 mg, 0.46 mmol, 1.6 eq) in N,N-dimethylformamide (38 mL). After 3 hours stiffing at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3×20 mL) and water (20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 1:1, v/v) to afford 6-methoxy-3-(4-nitro-pyrazol-1-yl)-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene as a light yellow solid (60 mg, 63% yield).
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:2].[Cl:11][C:12]([O:15]C(Cl)=O)(Cl)Cl>C(OCC)(=O)C>[CH:4]1([N:3]([CH2:1][CH3:2])[C:12]([Cl:11])=[O:15])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCNC1CCCCCC1
Solvent: CCOC(C)=O
Product: CCN(C(=O)Cl)C1CCCCCC1
Yield: 56.4 %

Procedure:
N-ethylcycloheptylamine (21.15 g) was added with ice bath cooling to a mixture consisting of trichloromethylchloroformate (29.7 g) end ethyl acetate (300 ml). Thereafter, the temperature was gradually elevated and heated with refluxing for 6 hours. After distilling off the solvent, the obtained oil was distilled under reduced pressure to obtain N-cycloheptyl -N-ethylcarbamoyl chloride (17.20 g). b.p. 125°-128° C./4.0 mbar.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[N:14][NH:13][C:12](=[O:24])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:13]1[C:12](=[O:24])[CH:11]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[C:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[N:14]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(-c2n[nH]c(=O)cc2-c2ccc(OC)c(F)c2)cc1
Product: COc1ccc(-c2nn(Cc3ccccc3)c(=O)cc2-c2ccc(OC)c(F)c2)cc1
Yield: 95.6 %

Procedure:
Using 5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one and benzyl bromide as starting materials, the procedures of Example 12 were repeated likewise, whereby the title compound was obtained in a yield of 95.6%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]([F:37])([F:36])[C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[C:29]([C:28]([F:27])([F:36])[F:37])[CH:30]=3)=[O:21])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(C)cccc3Cl)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(C)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)(F)F)c1
Yield: 22.3 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2-chloro-6-methylphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-27, 0.100 g, 0.268 mmol), 3-(trifluoromethyl)aniline (0.040 g, 0.403 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.030 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 2.33 (s, 3H), 3.95 (s, 3H), 7.41-7.59 (m, 4H), 7.68 (t, J=6.9 Hz, 1H), 7.75 (d, 1H), 7.77-7.82 (m, 2H), 7.95 (d, J=8.4 Hz, 1H), 8.25 (s, 1H), 10.36 (s, 1H), 12.53 (br s, 1H); MS (m/z): 503.17 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([C:16]#[N:17])[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:16][NH2:17])[CH2:12][CH2:13][CH2:14][CH2:15]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2(C#N)CCCC2)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccc(C2(CN)CCCC2)cc1OC
Temperature: 0 °C
Reaction time: 16 h
Yield: 87.9 %

Procedure:
(3,4-Dimethoxy-phenyl)-acetonitrile (5.00 g, 28.2 mmol) was dissolved in 60 mL of anhydrous tetrahydrofuran in a 250 mL round bottom flask. Sodium hydride (2.03 g, 84.6 mmol) was slowly added and the reaction mixture was warmed to 50-60° C. 1,4-Dichlorobutane (4.30 g, 33.9 mmol) was then added and the reaction mixture was heated to reflux for 16 hours. An additional aliquot of 1,4-dichlorobutane (4.30 g, 33.9 mmol) was added and the reaction mixture was refluxed for an additional 24 hours. The reaction mixture was cooled to room temperature and quenched with the slow addition of methanol. The reaction mixture was evaporated to dryness and purified by column chromatography on silica gel to yield a pale yellow oil (1.61 g, 6.98 mmol, 24.8%). The resulting 1-(3,4-dimethoxy-phenyl)-cyclopentanecarbonitrile (363 mg, 1.57 mmol) was dissolved in dry ether (4 mL) and cooled to 0° C. under an atmosphere of nitrogen. Lithium aluminum hydride (1.57 mL, 1 M in ether) was slowly added and the reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was quenched with the slow addition of methanol. The reaction mixture was washed with a saturated aqueous sodium chloride solution, separated, and evaporated to dryness to give a colorless oil (356 mg, 1.38 mmol, 87.9%). ESI-MS m/z calc. 235.3, found 236.2 (M+1)+. Retention time of 1.64 minutes.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:26]=1)[CH3:2].C(OO)(=[O:36])C.C(O)(=O)C.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(OCC)(=O)C.O>[CH2:1]([C:3]1[N:4]([CH2:27][CH:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[CH:10][C:9]=3[N+:8]([O-:36])=[CH:7][C:6]=2[N:26]=1)[CH3:2]
Reactant: CCc1nc2cnc3cc(OCCNC(=O)OC(C)(C)C)ccc3c2n1CC1CCOCC1
Reactant: CC(=O)OO
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCc1nc2c[n+]([O-])c3cc(OCCNC(=O)OC(C)(C)C)ccc3c2n1CC1CCOCC1
Temperature: 50 °C

Procedure:
tert-Butyl 2-{[2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate (2.3 g, 5.06 mmol) was slurried in ethyl acetate (20 mL). 32% Peracetic acid in acetic acid (1.06 mL, 5.06 mmol) was added in one portion and the reaction was heated to 50° C. for 2 hours. Another 0.250 mL (1.19 mmol) peracetic acid solution was added and the reaction was stirred for 1 additional hour. Sodium metabisulfite (1.2 g, 6.33 mmol) in water (2.5 mL) was added over 3 minutes and the reaction was stirred for 30 minutes. The heat was removed and the reaction was brought to pH 10 with saturated aqueous sodium carbonate (˜10 mL). The milky slurry was cooled in an ice bath and subsequently filtered. The solid was washed with water and dried for 1 hour. Roughly 2.0 g of tert-butyl 2-{[2-ethyl-5-oxido-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate was isolated as an off-white solid with water still remaining.
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:7]OC[CH2:4]1.[CH2:8]([OH:20])[CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19]>O>[CH2:7]([O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][OH:20])[CH:3]=[CH2:4]
Reactant: C1CCOC1
Reactant: OCCOCCOCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: C=CCOCCOCCOCCOCCO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
Under nitrogen atmosphere, NaH (1.2 g, 50 mmol) was charged into a flask, and then dry THF (15 mL) was added thereto and stirred at 0° C. for 15 minutes. Tetraethyleneglycol (10.7 g, 55 mmol) was added to the NaH mixture at 0° C. The mixture was stirred at room temperature for 1 hour. Next, the mixture was diluted with water (20 mL) and an organic material was extracted with methylene chloride (3×10 mL). The resulting organic layer was collected, dried on MgSO4 and concentrated to obtain a crude product as yellow liquid. The crude product was purified with a column chromatography (Hex:EA=1:2 (10% MeOH)) to obtain the target product (3.8 g, 32%) in a colorless oily phase. The NMR analysis result of the obtained product is as follows.