Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][NH2:19].O>CS(C)=O>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][NH:19][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(O)c2n1
Yield: 40.7 %

Procedure:
4-Chloro-8-hydroxy-2-methylquinoline (500 mg, 2.58 mmole) and 3,4-dichlorobenzylamine (910 mg, 5.16 mmole) in dimethylsulfoxide (5 mL) were stirred at 140° C. for 90 min in a microwave oven. Water was added and the mixture was decanted to obtain an oily residue. The residue was washed with ethyl acetate to give a brownish solid (350 mg, 41%). ESI-MS [M+H]+=333.1/337.0 calculated for C17H14Cl2N2O=333 g/mole
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]3[C:15](=[CH:16][CH:17]=1)[C:14]([CH2:18][CH3:19])=[C:13]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:22][CH:21]=1)[C:12]3=[C:34]([CH2:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]Cl)[CH:35]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[NH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1.C(O)C>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[C:10]2[N:11]3[C:15](=[CH:16][CH:17]=1)[C:14]([CH2:18][CH3:19])=[C:13]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:22][CH:21]=1)[C:12]3=[C:34]([CH2:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)[CH:35]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(COCCCCCCl)cc3c(OCc4ccccc4)ccc1n32
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(COCCCCCN3CCCCC3)cc3c(OCc4ccccc4)ccc1n32
Reaction time: 120 h
Yield: 36.4 %

Procedure:
5-Benzyloxy-2-(4-benzyloxyphenyl)-3-((5-chloropentyloxy)methyl)-1-ethylpyrrolo[2,1,5-cd ]indolizine (0.41 g, 0.69 mmol) was dissolved in 50 ml of dry dimethylformamide under a nitrogen atmosphere. Sodium hydride (60% in oil) (0.40 g, 10 mmol) and piperidine (0.93 g, 11mmol) was added, and the mixture was stirred at 60° for 5 days. Ethanol (10 ml) was added dropwise, and the reaction mixture was diluted with 200 ml of water. The organic material was extracted into ethyl acetate (3×100 ml), and the combined organic layers were washed with brine and dried over sodium sulfate. The solvent was evaporated and the crude produce was purified by column chromatography over silica gel 60, using 10% of methanol in dichloromethane as the eluent. Fractions containing the product were collected and crystallised from diethyl ether and dichloromethane to afford 161 mg (36%) of 5-benzyloxy-2-(4-benzyloxyphenyl)-1-ethyl-3-((5-piperidinopentyloxy)methyl)pyrrolo[2,1,5-cd ]indolizine as yellow crystals. M.p. 106-107° C. MS(SP): m/z 627 (M+1). 1H-NMR (DMSO-d6, 300 MHz) δ: 1.16-1.75 (m, 15H); 2.61-2.95 (m, 4H); 3.07 (q, 2H); 3.21-3.24 (m, 4H); 4.71 (s, 2H); 5.20 (s, 2H); 5.56 (s, 2,H); 7.30-7.64 (m, 14H); 7.99 (d, 1H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[C:6]([CH:8]=[CH:9][C:10](Cl)=[O:11])[CH:5]=[N:4][CH:3]=1.[CH3:13][C:14]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:15]=1[NH2:16].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:13][C:14]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:15]=1[NH:16][C:10](=[O:11])[CH:9]=[CH:8][C:6]1[CH:7]=[N:2][CH:3]=[N:4][CH:5]=1
Reactant: O=C(Cl)C=Cc1cncnc1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])cc1NC(=O)C=Cc1cncnc1
Reaction time: 0.5 h

Procedure:
To a suspension of the product of step 3 (2.05 g) in anhydrous dichloromethane (30 ml), a solution of 2-methyl-5-nitroaniline (3.04 g) and triethylamine (8 ml, excess allowed) in dichloromethane (15 ml) was added dropwise slowly in an ice-bath with the temperature no more than 5° C. After addition, the reaction was carried out for 30 min in an ice-bath, and then at room to temperature for 3 h. Completion of reaction was indicated by TLC. Potassium carbonate solution (10%) was added to the mixture. Then the mixture was extracted with EtOAc (20 ml*3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to recover the solvent. The residue was purified on silica gel column (EtOAc/petroleum ether 4:1). The eluent was collected, concentrated under reduced pressure to give a yellow powdered solid.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:21](O)[CH3:22]>CCOCC>[C:1]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Solvent: CCOCC
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC
Reaction time: 40 h
Yield: 90 %

Procedure:
A mixture containing Catalyst A (0.05 g) and oleic acid (1.41 g, 5 mmol) and ethanol (10 ml) was refluxed with stirring for 40 h. On cooling ether (30 ml) was added and the catalyst was filtered off. The organic washings were combined and concentrated to give ethyl oleate as an oil (1.39 g, 90% yield).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:30])=[C:20]([CH:29]=1)[O:21][CH2:22][C:23]1[N:24]=[N:25][N:26]([CH3:28])[CH:27]=1>>[F:1][C:2]1[C:3]2[N:4]([C:12]([C:16]3[CH:17]=[CH:18][C:19]([F:30])=[C:20]([O:21][CH2:22][C:23]4[N:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:29]=3)=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: Fc1c(C(F)(F)F)ccn2ccnc12
Reactant: Cn1cc(COc2cc(Br)ccc2F)nn1
Product: Cn1cc(COc2cc(-c3cnc4c(F)c(C(F)(F)F)ccn34)ccc2F)nn1

Procedure:
8-Fluoro-7-trifluoromethylimidazo[1,2-α]pyridine was coupled to 4-(5-bromo-2-fluorophenoxymethyl)-1-methyl-1H-[1,2,3]triazole as described in Example 6 to give 8-fluoro-3-[4-fluoro-3-(1-methyl-1H-[1,2,3]triazol-4-ylmethoxy)phenyl]-7-trifluoromethylimidazo[1,2-α]pyridine as an off-white solid: δH (400 MHz, d6-DMSO) 4.07 (3H, s), 5.53 (2H, s), 7.14 (1H, dd, J 7 and 7), 7.29-7.31 (1H, m), 7.44 (1H, dd, J 11 and 8), 7.73 (1H, dd, J 8 and 2), 8.06 (1H, s), 8.23 (1H, s), 8.62 (1H, d, J 7); m/z (ES+) 410 [MH+].
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.O>[O-]CC.[Na+]>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=2)=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(OCc2ccc(Cl)cc2)cc1
Yield: 58.5 %

Procedure:
To a solution of ethyl 4-hydroxybenzoate (8.3g.) in sodium ethoxide solution (1.15g. sodium in 70 ml. of absolute ethanol) was added p-chlorobenzylchloride (8.1g.) in one portion. The mixture was heated under reflux for 16 hours, allowed to cool and poured into water (500 mls.) and the product extracted into ether. The organic layer was separated and dried (anhydrous MgSO4) and filtered. Evaporation of the solvent under reduced pressure gave the crude product which on recrystallization from ethanol, yielded by 4-ethoxycarbonylphenoxy-4-chlorophenyl methane (8.5g.) m.pt. 83°-84° C.
Reaction SMILES: C([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7](N)=[N:8][C:9]=2[Cl:13])(=O)C.[Cl:15][Si](Cl)(C)C.N(OCCC(C)C)=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Cl:15][C:7]1[N:6]=[C:5]2[C:10]([NH:11][CH:12]=[N:4]2)=[C:9]([Cl:13])[N:8]=1
Reactant: C[Si](C)(Cl)Cl
Reactant: CC(=O)n1cnc2c(Cl)nc(N)nc21
Agent: CC(C)CCON=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: Clc1nc(Cl)c2[nH]cnc2n1
Temperature: 27.5 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
9-Acetyl-2-amino-6-chloropurine (2.50 g, 11.8 mmol), dichlorodimethylsilane (4.57 g, 35.4 mmol), benzyltriethylammonium chloride (0.16 g, 0.70 mmol) and isoamyl nitrite (2.07 g, 17.7 mmol) were added to o-dichlorobenzene (10 ml), and the mixture was heated to 25-30° C. and stirred for 8 hr. After the completion of the reaction, the mixture was filtrated. The obtained crystals were diluted with water (4.0 ml), and the reaction mixture was added dropwise to 2M aqueous sodium hydroxide solution (20 ml) and partitioned. The aqueous layer was adjusted to pH 4-5 with 35% hydrochloric acid. After aging under ice-cooling for 1 hr, the mixture was filtrated, and the obtained crystals were dried under reduced pressure at 80° C. to give 2,6-dichloropurine as a white powder (1.62 g, yield 72.6%). The properties of the obtained compound were the same as in Example 1(2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.C(Cl)Cl.[C:19](Cl)(Cl)=[S:20].N1C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]=[C:19]=[S:20])=[N:10][CH:11]=1
Reactant: Nc1ccc(Oc2cccc(F)c2)cn1
Reactant: S=C(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Fc1cccc(Oc2ccc(N=C=S)nc2)c1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 77.2 %

Procedure:
5-(3-Fluorophenoxy)-2-pyridinamine (210 mg, 1 mmol) was dissolved in dry degassed methylene chloride (5 ml) and thiophosgene (0.11 ml, 1.3 mmol) was added through syringe during 5-10 min to the stirred solution. Pyridine (0.18 ml, 2 mmol) was added to the reaction mixture right after the addition of thiophosgene and the reaction mixture was stirred at ambient temperature for 1.5-2 h. Then the reaction mixture was poured into water (15 ml) and extracted into methylene chloride (3×20 ml). Organic extract was washed with water and brine and dried over magnesium sulfate. Solvent was then removed by rotary evaporation and the oil obtained was purified by column chromatography on silica (30 g, EtOAc/hexane 1:3) to give 190 mg of pure product as dark brown-purple solid. Yield 75%.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8].N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8])(=[O:19])[CH3:18]
Reactant: Cc1csc(N)c1C(N)=O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1scc(C)c1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-amino-4-methyl-thiophene-3-carboxylic acid amide (5 g, 32 mmol) in DCM (100 mL) is cooled to 0° C. Dry pyridine (3.6 mL, 45 mmol) is added, followed by acetylchloride (11 mL, 156 mmol) which is added dropwise to the solution. The resulting mixture is stirred at room temperature overnight, then diluted with DCM and washed with aqueous NaHCO3. The organic phase is dried over MgSO4, filtered and concentrated. The obtained residue is triturated in di-isopropylether, filtered, and the cake is dried to afford the desired product.
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([C:14]([OH:16])=[O:15])[O:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]3[CH:9]=[C:10]([C:14]([OH:16])=[O:15])[O:11][C:12]=3[CH3:13])=[CH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1oc(C(=O)O)cc1COc1ccc(I)cc1
Product: COc1cccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)c1

Procedure:
Compound (116) was prepared from compound (26) and (3-methoxy-phenyl)-boronic acid by adapting the procedure of Example 27B. LC/MS System B; Rt=1.79 mins, m/z (ES−)=337 (M−H for C20H18O5).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[C:5]1(=O)[CH:10]=[CH:9][C:8](=[O:11])[CH:7]=[CH:6]1>C(O)C.Cl>[NH2:1][C:2]1[S:3][C:10]2[CH:9]=[C:8]([OH:11])[CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: O=C1C=CC(=O)C=C1
Reactant: NC(N)=S
Agent: Cl
Solvent: CCO
Product: Nc1nc2ccc(O)cc2s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The intermediate 2-amino-1,3-benzothiazol-6-ol was prepared according to a slightly modified literature procedure by Lau and Gompf: J. Org. Chem. 1970, 35, 4103-4108. To a stirred solution of thiourea (7.6 g, 0.10 mol) in a mixture of 200 mL ethanol and 9 mL concentrated hydrochloric acid was added a solution of 1,4-benzoquinone (21.6 g, 0.20 mol) in 400 mL of hot ethanol. The reaction was stirred for 24 hours at room temperature and then concentrated to dryness. The residue was triturated with hot acetonitrile and the resulting solid was filtered and dried.
Reaction SMILES: [OH:1][CH:2]1[CH2:14][CH2:13][C:5]2([CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.[O:15]=[C:16]1[CH:20]=[C:19]([CH2:21]P(=O)(OC)OC)[CH2:18][O:17]1>>[OH:1][CH:2]1[CH2:14][CH2:13][C:5]2([CH2:10][CH2:9][CH:8]([CH:11]=[CH:21][C:19]3[CH2:18][O:17][C:16](=[O:15])[CH:20]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3]1
Reactant: COP(=O)(CC1=CC(=O)OC1)OC
Reactant: O=CC1CCC2(CCC(O)CC2)CC1
Product: O=C1C=C(C=CC2CCC3(CCC(O)CC3)CC2)CO1

Procedure:
Using the same reaction conditions described in Ex. 2 and 9-hydroxy-3-formyl-spiro[5.5]undecane (I-bc, Ex. 50) and dimethyl (2-oxo-[5H]-4-furyl)methylphosphonate (intermediate described in Ex. 2) as starting materials, the title compound (EZ)-9-hydroxy-3-(2-(2-oxo-[5H]-4-furyl)vinyl)-spiro-[5.5]undecane (I-ai) was obtained as an amorphous solid, identical to the one above described.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([OH:17])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([N:20]([CH2:25][CH3:26])[C:21](=[O:24])[CH2:22]Cl)[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>CC(=O)CC>[CH2:18]([N:20]([CH2:25][CH3:26])[C:21](=[O:24])[CH2:22][O:17][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH3:19]
Reactant: CCN(CC)C(=O)CCl
Reactant: Oc1nc(-c2ccccc2)cc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCN(CC)C(=O)COc1nc(-c2ccccc2)cc2ccccc12
Yield: 6.5 %

Procedure:
The procedure is as in Example 47, starting with 3-phenyl-1-isoquinolinol (5.1 g), N,N-diethylchloroacetamide (3.8 g), sodium carbonate (4.8 g) and cuprous iodide (1.15 g) in 2-butanone (100 cc). After 2 chromatographic separations on silica gel with chloroform as eluant and crystallization of the product in petroleum ether, N,N-diethyl-(3-phenyl-1-isoquinolyl)oxyacetamide (0.5 g), m.p. 102° C., is obtained.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:21][CH3:22])=[C:7]([CH:9]2[CH2:18][C:17]3[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=3[C:11](=O)[CH2:10]2)[CH:8]=1.[C:23]([NH:26][NH2:27])([NH2:25])=[NH:24].Cl.Cl>C(O)C>[ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:21][CH3:22])=[C:7]([CH:9]2[CH2:18][C:17]3[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=3[C:11](=[N:27][NH:26][C:23]([NH2:25])=[NH:24])[CH2:10]2)[CH:8]=1
Reactant: COc1ccc(F)cc1C1CC(=O)c2c(C)ccnc2C1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: COc1ccc(F)cc1C1CC(=NNC(=N)N)c2c(C)ccnc2C1
Temperature: 110 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a mixture of 7-(5-fluoro-2-methoxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one hydrochloride (1.2 g) and aminoguanidine hydrochloride (0.477 g) were added ethanol (15 ml) and concentrated hydrochloric acid (0.1 ml), and the mixture was stirred at 110° C. (bath temperature) for 2 hours. The reaction solution was cooled to room temperature, and the resulting crystals were filtered and dried to give 7-(5-fluoro-2-methoxyphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 168) (1.4 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].[CH:12]1([C:18](O)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][NH:8][C:18]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:19])[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc(CCN)c1
Reactant: O=C(O)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1cccc(CCNC(=O)C2CCCCC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
A mixture of 3-methoxyphenethylamine (1.000 g, 6.61 mmol), cyclohexanecarboxylic acid (0.847 g, 6.61 mmol), 1-hydroxybenzotriazole hydrate (1.340 g, 9.92 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.330 g, 6.94 mmol) in anhydrous CH2Cl2 (20 ml) was stirred at 0° C. under N2 for 1 hr, then warmed to rt and stirred at rt for 18 hr. The reaction mixture was washed sequentially with 1M NaOH (10 ml), 1M HCl (10 ml), and H2O (10 ml), then dried over MgSO4 and concentrated in vacuo to give 1.301 g of off-white solid. Purification by flash chromatography, eluting with hexane:EtOAc (6:4) gave 1.107 g (64% yield) of white solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:24]([O:25][CH3:26])=[CH:23][C:13]2[O:14][C:15](=[O:22])[C:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:12]=2[CH:11]=1)(=O)=O.[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CC(OC)(C)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O.C(O)C.C(O)(C)C>[CH3:26][O:25][C:24]1[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:36]2[CH2:37][CH2:38][N:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:34][CH2:35]2)=[CH:11][C:12]2[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=3[C:15](=[O:22])[O:14][C:13]=2[CH:23]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCOS(C)(=O)=O)CCCC3
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)=O
Solvent: CCO
Solvent: CC(C)O
Product: COc1cc2oc(=O)c3c(c2cc1OCCCN1CCN(c2ccccc2)CC1)CCCC3
Yield: 94 %

Procedure:
Method B (24 h at 60° C.); starting materials: 7,8,9,10-tetrahydro-2-[3-(methanesulfonyloxy)propoxy]-3-methoxy-6H-dibenzo[b,d]pyran-6-one (example 80) and 1-phenylpiperazine; yield 94%; fusion point 104°-106° C. (from TBME and isopropanol). Fumarate: method E; yield 92%; fusion point 160°-161° C. (from ethanol and acetone).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20](=[O:23])[CH2:21]Br>CN(C)C=O>[CH3:18][O:19][C:20](=[O:23])[CH2:21][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 4-chloro-3-nitrophenol (25 g), N,N-dimethylformamide (200 mL), potassium carbonate (60 g) and bromoacetic acid methyl ester (15.5 mL) was stirred at room temperature for 2.5 hours. The mixture was partitioned between ethyl acetate and water, and the aqueous phase extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated under reduced pressure. The residue was washed with diethyl ether to afford title compound as a white solid (30 g).
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[N:13]=[N:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1.CO.C(=O)([O-])O.[Na+]>ClCCl.CN(C)C=O>[CH3:1][O:15][C:14]([C:11]1[N:12]=[N:13][C:8]([Cl:7])=[CH:9][CH:10]=1)=[O:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Cl)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Oxalyl chloride (1.14 mL, 13.09 mmol), was added dropwise to an ice-cold suspension of 6-chloro-pyridazine-3-carboxylic acid [(1.9 g, 11.9 mmol), J. Het. Chem. 29(6), 1583-92; 1992] in a mixture of dichloromethane (50 mL) and N,N-dimethylformamide (1 drop) and the mixture was stirred for 1 hour at room temperature. The reaction mixture was then evaporated under reduced pressure and the residue was diluted with dichloromethane (30 mL) and cooled to 0° C. Methanol (485 μL, 11.9 mmol) was added and the mixture was stirred at 0° C. for 1 hour. Sodium hydrogen carbonate solution was then added to the reaction mixture and the aqueous layer was separated and extracted with dichloromethane (×2). The combined organic solutions were washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound as a white solid in 65% yield, 1.33 g.
Reaction SMILES: Br[C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:10]([OH:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([C:29]#[N:30])[CH:24]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([C:29]#[N:30])[CH:24]=2)[C:3]([O:13][CH3:14])=[C:4]([CH:10]([OH:12])[CH3:11])[CH:5]=1
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1Br
Reactant: CC1(C)OB(c2ccnc(C#N)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: COc1c(C(C)O)cc(Cl)c(C)c1-c1ccnc(C#N)c1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol (0.30 g, 1.1 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (from Combi-Blocks, 0.27 g, 1.2 mmol), sodium carbonate (230 mg, 2.1 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (100 mg, 0.13 mmol) in acetonitrile (8 mL)/water (2 mL) was degassed and then refilled with N2. The reaction was stirred at 95° C. for 2 hours, then cooled and diluted with ethyl acetate, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with 0 to 40% EtOAc in hexanes (0.249 g, 75%). LCMS calculated for C16H16ClN2O2 (M+H)+: m/z=303.1; Found: 303.0
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[NH:35][C:36]([NH:38][C:39]1[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][C:40]=1[F:46])=[O:37])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[O:18])[CH:13]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:46][C:40]1[CH:41]=[CH:42][C:43]([CH3:45])=[CH:44][C:39]=1[NH:38][C:36]([NH:35][C:34]1[CH:33]=[CH:32][C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([C:12]3[NH:16][CH:15]=[C:14]([C:17]([N:19]4[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]4)=[O:18])[CH:13]=3)[CH:7]=2)=[CH:3][C:2]=1[F:1])=[O:37]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)N5CCN(C(=O)OC(C)(C)C)CC5)c[nH]4)c3)cc2F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)N5CCNCC5)c[nH]4)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of tert-butyl 4-[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]piperazine-1-carboxylate (200 mg, 0.32 mmol) in 10 ml of methylene chloride was added 3 ml of TFA. The mixture was stirred at room temperature for 30 minutes, and evaporated to dryness under reduced pressure. The residue was re-dissolved in 5 ml of methanol and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=9. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 12% methanol in chloroform to give 1-(2-fluoro-5-methylphenyl)-3-[2-fluoro-4-({2-[4-(piperazin-1-ylcarbonyl)-1H-pyrrol-2-yl]pyridin-4-yl}oxy)phenyl]urea as white solid. Yield: 145 mg, 86%