Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10](=O)[C:11]([O:13]CC)=O.[C:17]1([NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>CCO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:11]([OH:13])=[N:23][C:18]2[C:17]([N:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: CCOC(=O)C(=O)c1cc2ccccc2o1
Reactant: Nc1ccccc1N
Solvent: CCO
Product: Oc1nc2ccccc2nc1-c1cc2ccccc2o1
Temperature: 90 °C
Reaction time: 16 h
Yield: 93.8 %

Procedure:
To a solution of ethyl 2-(benzofuran-2-yl)-2-oxoacetate (Example 15a, 237 mg, 1.09 mmol) in EtOH (2.7 mL) was added o-phenylenediamine (117 mg, 1.09 mmol). The reaction mixture was stirred at 90° C. for 16 h (a yellow solid appeared quickly). The mixture was cooled to 0° C., filtered, and the solid rinsed with cold EtOH. The yellow solid was azeotroped with CHCl3 and benzene and dried to provide the title compound (268 mg, 94% yield).
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][O:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)[CH2:26][CH2:27]1)#[N:2]
Reactant: CC(C)C(C#N)(CCCI)c1cccs1
Reactant: c1ccc(OCCN2CCNCC2)nc1
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2ccccn2)CC1)c1cccs1

Procedure:
The title compound was synthesized in accordance with Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and 1-[2-(2-pyridyloxy)ethyl)piperazine. The physico-chemical data of the compound was as below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH2:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH:15][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: NNc1ccc(-c2ccc(Cl)cc2)nn1
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)NNc1ccc(-c2ccc(Cl)cc2)nn1

Procedure:
A mixture of 1.0 g. of 6-(p-chlorophenyl)-3-hydrazinopyridazine and 0.65 g. of diisopropylethylamine in 25 ml. of dioxane are placed in a flask and warmed slightly. To this is added 0.5 g. (0.45 ml.) of ethyl chloroformate and the reaction is stirred for one hour. The dioxane is removed on a rotating evaporator and ethanol is added to the residue resulting in a precipitate. This precipitate is recrystallized from ethanol giving a yellow solid, m.p. 176°-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][S:6](N1CCN(C2C(Cl)=CN=CC=2Cl)CC1)(=[O:8])=[O:7].[Cl:27]C1C=NC=C(Cl)C=1N1CCNCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][S:6]([Cl:27])(=[O:8])=[O:7])[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: Clc1cncc(Cl)c1N1CCNCC1
Reactant: O=S(=O)(Cc1ccc(Cl)c(Cl)c1)N1CCN(c2c(Cl)cncc2Cl)CC1
Product: O=S(=O)(Cl)Cc1ccc(Cl)c(Cl)c1
Yield: 61 %

Procedure:
In an analogous manner to Example 1F, step 1Q 1-[(3,4-dichlorobenzyl)sulfonyl]-4-(3,5-dichloropyridin-4-yl)piperazine was prepared from 1-(3,5-dichloro-4-pyridyl)piperazine (0.1 g, 0.43 mmol) and 3,4-dichlorophenylmethyl sulfonyl chloride (61% yield).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:9]=[C:10]([OH:17])[CH:11]=[CH:12][C:13]=2[N+:14]([O-:16])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>>[CH3:18][O:19][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:17][C:10]1[CH:11]=[CH:12][C:13]([N+:14]([O-:16])=[O:15])=[C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=1
Reactant: COC(=O)CCCCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1Nc1ccccc1
Product: COC(=O)CCCCCOc1ccc([N+](=O)[O-])c(Nc2ccccc2)c1

Procedure:
13.3 g of 3-phenylamino-4-nitrophenol was reacted with 6-bromohexanoic acid methyl ester according to general operating instructions 2. 11.2 g was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([O:13][C:14](=[O:23])[C@H:15]([CH3:22])[NH:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])C>>[CH3:11][O:13][C:14](=[O:23])[C@H:15]([CH3:22])[N:16]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: CCOC(=O)[C@H](C)NCCCOC
Product: COCCCN(c1ccccc1[N+](=O)[O-])[C@@H](C)C(=O)OC

Procedure:
The same procedure as in Example 22 is repeated except that 2-chloronitrobenzene is used in place of 2,4-dichloronitrobenzene and that (21) is used in place of (20) to obtain (25) in the form of orange oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[OH:4].Cl[CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+].OP([O-])(O)=O.[K+]>C(#N)C.C(OCC)(=O)C>[Br:11][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH2:2][NH:1][CH2:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CCl)Nc1ccccc1
Reactant: NCC(O)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(CNCC(O)c1cccc(Br)c1)Nc1ccccc1
Temperature: 80 °C
Yield: 42.3 %

Procedure:
To a solution of 2-amino-1-(3-bromo-phenyl)-ethanol (example 33, step 1, 1.34 g) and crude 2-chloro-N-phenyl-acetamide (example 33, step 2, 1.0 g) in acetonitrile (15 mL) was added potassium carbonate (1.03 g). The mixture was heated to 80° C. overnight. A 1M solution of KH2PO4 was added, followed by ethyl acetate. The phases were separated, and the inorganic one was extracted with ethyl acetate (x2). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. Column chromatography (SiO2, CH2Cl2/MeOH 95:5) followed by precipitation from a mixture of diethylether/n-heptane (1:4) gave 2-[2-(3-bromo-phenyl)-2-hydroxy-ethylamino]-N-phenyl-acetamide (0.87 g, 42%) as a white solid, MS: 349.1 (M+H, 1Br)+.
Reaction SMILES: [C:1]([N:4]1[CH2:8][C@H:7]([O:9][CH2:10][CH3:11])[C@H:6]([NH:12][C:13]2[C:18]([CH2:19][CH3:20])=[N:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:15]([CH2:29][CH3:30])[N:14]=2)[CH2:5]1)(=[O:3])C.[N:31]1(C(Cl)=O)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:16]1[N:17]=[C:18]([CH2:19][CH3:20])[C:13]([NH:12][C@H:6]2[C@@H:7]([O:9][CH2:10][CH3:11])[CH2:8][N:4]([C:1]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:3])[CH2:5]2)=[N:14][C:15]=1[CH2:29][CH3:30]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CN(C(=O)N2CCOCC2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting 4-morpholinecarbonyl chloride and making non-critical variations provided the title compound as an oil: 1H NMR (400 MHz, CDCl3) δ) 7.50, 7.34, 7.28, 5.23, 4.69, 4.10, 3.90, 3.80-3.68, 3.58-3.28, 2.70, 2.49, 1.33-1.26, 1.16; IR (liq.) 2970 (s), 2934 (s), 2874 (s), 2353 (w), 1996 (w), 1956 (w), 1642 (s), 1567 (s), 1552 (s), 1500 (s), 1469 (s), 1414 (s,b), 1397 (s), 1118 (s), 1102 (s), cm−1HRMS (FAB) calcd for C25H33Cl2N5O3+H 522.2039, found 522.2038.
Reaction SMILES: Cl.Cl.[CH2:3]([C:7]1[N:12]=[N:11][C:10]([O:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH:15]2[CH2:20][OH:21])=[CH:9][C:8]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1)[CH2:4][CH2:5][CH3:6].C=O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(Cl)Cl>[CH2:3]([C:7]1[N:12]=[N:11][C:10]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:37])[CH2:16][CH:15]2[CH2:20][OH:21])=[CH:9][C:8]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:26][CH:27]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OC2CCNCC2CO)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCN(C)CC2CO)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 0.08 h

Procedure:
A suspension of {4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidin-3-yl}-methanol dihydrochloride (0.059 mmol, 30 mg), 37% paraformaldehyde (0.205 mmol, 16 mg), and 1 drop of acetic acid in 3 mL of DCM was stirred for 5 min then added sodium triacetoxyborohydride (0.205 mmol, 43 mg) and continued stirring for 0.5 h at room temperature. Quenched with water, solvent was evaporated, the residue was diluted with ethyl acetate, and then washed with saturated NaHCO3 solution, brine. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The resultant residue was purified by column chromatography using 5% methanolic solution of ammonia (2.0 M ammonia in methanol) in DCM to provide {4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-1-methyl-piperidin-3-yl}-methanol.
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.[Cl:8][C:9]1[S:21][C:12]2[NH:13][C:14](=[O:20])[C:15]([C:18]#[N:19])=[C:16]([OH:17])[C:11]=2[C:10]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2([OH:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:24][CH:23]=1.CCN(CC)CC.CC(OC(C)=O)=O>C(Cl)Cl>[C:2]([N:33]1[CH2:34][CH2:35][C:30]([CH2:29][O:28][C:25]2[CH:24]=[CH:23][C:22]([C:10]3[C:11]4[C:16]([OH:17])=[C:15]([C:18]#[N:19])[C:14](=[O:20])[NH:13][C:12]=4[S:21][C:9]=3[Cl:8])=[CH:27][CH:26]=2)([OH:36])[CH2:31][CH2:32]1)(=[O:1])[CH3:4]
Reactant: N#Cc1c(O)c2c(-c3ccc(OCC4(O)CCNCC4)cc3)c(Cl)sc2[nH]c1=O
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(O)(COc2ccc(-c3c(Cl)sc4[nH]c(=O)c(C#N)c(O)c34)cc2)CC1

Procedure:
An ambient solution of 2-chloro-4-hydroxy-3-{4-[(4-hydroxypiperidin-4-yl)methoxy]phenyl}-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile TFA salt (40 mg, 0.073 mmol), Et3N (0.015 mL, 0.11 mmol), and Ac2O (0.007 mL, 0.073 mmol) in DCM (0.5 mL) was stirred for 18 h. The reaction was then quenched by the addition of saturated NaHCO3 (1 mL) and EtOAc (1 mL). The layers were separated, and the aqueous was extracted with additional EtOAc (2×1 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by RPLC to give the title compound. MS (ESI) m/e 474 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.61 (m, 4H), 2.01 (s, 3H), 2.94 (m, 2H), 3.4 (m, 2H), 3.81 (s, 2H), 6.95 (d, J=8.81 Hz, 2H), 7.22 (d, J=8.48 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[C:4]([CH3:12])[CH:3]=1.C(Cl)(=O)C(Cl)=O.CCN(CC)CC.[N:26]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27]1>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:6]([N:34]2[CH2:35][CH2:36][CH:31]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:32][CH2:33]2)=[O:8])=[C:9]([CH3:11])[CH:10]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1cc(Br)cc(C)c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A suspension of 0.344 g (1.5 mmol) 4-bromo-2,6-dimethyl-benzoic acid [Fuson, R. C.; Scott, S. L.; Lindsey, R. V., Jr. Journal of the American Chemical Society (1941), 63, 1679-82] in 5 ml of CH2Cl2 was treated at RT with two drops of DMF; then, a solution of 0.14 ml=0.21 g (1.6 mmol) of oxalyl chloride in 3 ml of CH2Cl2 was added drop by drop below 25° C. and the reaction mixture was stirred of 1 hour. After removal of the solvents by evaporation in a high vacuum, the residue was dissolved again in 10 ml of CH2Cl2 and the solution cooled down to 0° C.; then, 0.42 ml=0.30 g (3.0 mmol) of Et3N was added while stirring, followed by 0.23 g (1.5 mmol) of 4-pyrrolidin-1-yl-piperidine. The reaction mixture was subsequently warmed up to RT. After 60 hours, it was poured into crashed ice and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 95:5) to give 0.42 g (76%) of the title compound as light yellow oil. MS: 365.0 (MH+, 1 Br).
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[CH2:7][O:6][CH2:5][C:4](=[O:8])[NH:3]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1O.[OH-].[Na+]>O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]2[N:18]=[C:12]([C:11]3[CH:10]=[C:9]([C:2]4([CH3:1])[NH:3][C:4](=[O:8])[CH2:5][O:6][CH2:7]4)[CH:17]=[CH:16][CH:15]=3)[O:14][C:20]=2[CH:21]=1
Reactant: Nc1ccc(Cl)cc1O
Reactant: CC1(c2cccc(C(=O)O)c2)COCC(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(c2cccc(-c3nc4ccc(Cl)cc4o3)c2)COCC(=O)N1
Temperature: 130 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
A mixture of 3-((RS)-3-methyl-5-oxo-morpholin-3-yl)-benzoic acid (intermediate XXVI-1) (250 mg, 1.1 mmol) and 2-amino-5-chloro-phenol (230 mg, 1.6 mmol) in polyphosphoric acid (1 g) was heated under stirring at 130° C. for 3 hours. For the workup, the reaction mixture was cooled and water was added. The mixture was neutralized with an aqueous solution of sodium hydroxide (10%), then extracted with dichloromethane. The organic layer was dried over sodium sulphate and evaporated to yield the (RS)-5-[3-(6-chloro-benzooxazol-2-yl)-phenyl]-5-methyl-morpholin-3-one (316 mg, 87% of theory) in a quality suited to be engaged in the next step without further purification. MS (ISP): m/z=343 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2=[N:6][C:7]([C:14]([O:16]C)=[O:15])=[C:8]([C:10]([O:12]C)=[O:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[OH-].[K+].O>CO>[S:1]1[C:5]2=[N:6][C:7]([C:14]([OH:16])=[O:15])=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: COC(=O)c1cc2ccsc2nc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2ccsc2nc1C(=O)O

Procedure:
A solution containing dimethyl thieno[2,3-b]-pyridine-5,6-dicarboxylate (27.75 g, 0.11 mol) and potassium hydroxide (30.98 g, 0.55 mol) in methanol (200 mL) under a N2 atmosphere is heated at reflux for two hours. The reaction mixture is cooled and sufficient water added to dissolve any solids present before evaporating the mixture to dryness. The resulting solid is dissolved in a minimum volume of water, cooled in an ice bath and acidified with concentrated H2SO4 to pH~1. Thieno[2,3-b]pyridine-5,6-dicarboxylic acid is filtered off and dried overnight to give 23.36 g mp 272°-275° C.
Reaction SMILES: [C:1]1([NH:7]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>>[CH:4]1[CH:5]=[CH:6][C:1]([NH:7][C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][CH:12]=2)=[CH:2][CH:3]=1
Reactant: Nc1ccccc1
Reactant: ONc1ccccc1
Agent: Cl
Product: Nc1ccc(Nc2ccccc2)cc1

Procedure:
It is disclosed that phenylhydroxylamine and aniline in the presence of concentrated HCl, HZSM-5, HY zeolites, Nafion, filtrol (acid clay), NaHSO4/SiO4, or montmorillonite yield p-aminodiphenylamine. In each case, the predominant isomer of aminodiphenylamine was the para isomer.
Reaction SMILES: [CH3:1][C:2](N(C1OC2C=CC=CC=2N=1)[C@H](C(O)=O)CC1C=CC(OCCCC(OCC)=O)=CC=1)([CH3:4])[CH3:3].[O:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[NH:44][C@H:45]([C:66]([OH:68])=[O:67])[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH2:55][CH2:56][C:57](=[O:65])[NH:58][C:59]2[NH:60][CH2:61][CH2:62][CH2:63][N:64]=2)=[CH:49][CH:48]=1.NC1NCCCN=1>C(Cl)Cl>[O:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[NH:44][C@H:45]([C:66]([O:68][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:67])[CH2:46][C:47]1[CH:48]=[CH:49][C:50]([O:53][CH2:54][CH2:55][CH2:56][C:57](=[O:65])[NH:58][C:59]2[NH:60][CH2:61][CH2:62][CH2:63][N:64]=2)=[CH:51][CH:52]=1
Reactant: O=C(CCCOc1ccc(C[C@H](Nc2nc3ccccc3o2)C(=O)O)cc1)NC1=NCCCN1
Reactant: CCOC(=O)CCCOc1ccc(C[C@@H](C(=O)O)N(c2nc3ccccc3o2)C(C)(C)C)cc1
Agent: NC1=NCCCN1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)Nc1nc2ccccc2o1
Reaction time: 6 h
Yield: 96.8 %

Procedure:
The ester 6-1 (370 mg) is mixed with 2-amino-1,4,5,6-tetrahydropyrimidine (200 mg) in 5 ml of CH2Cl2 and agitation is carried out at ambient temperature for 6 hours. The reaction medium is then evaporated under reduced pressure and the dry extract obtained is purified by chromatography eluting with a CH2Cl2/MeOH/water/AcOH mixture 90/10/1/1. 200 mg of the expected product 6-2 is obtained.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[OH:12])[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:13]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[C:10]([OH:12])[CH:9]=[CH:8][CH:7]=3)=[O:15])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cnc2cccc(O)c2c1O
Reactant: NCc1ccc(Cl)cc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cccc(O)c2c1O
Temperature: 180 °C
Yield: 28.4 %

Procedure:
A mixture of 3-aminophenol (5.457 g) and diethyl ethoxymethylenemalonate (10.81 g) is heated to 130° C. for 2 h with removal of ethanol by a Dean-Stark trap. The reaction is cooled to 80° C. and 50 ml of diphenyl ether is added. The mixture is heated to 250° C. for 30 min with removal of ethanol by a Dean-Stark trap. The solution is cooled to 80° C. and the resulting solid is collected and washed with hexanes. A portion of this solid is adsorbed onto silica and chromatographed, eluting with 5% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and concentrated in vacuo to yield ethyl 4,5-dihydroxyquinoline-3-carboxylate as a gold solid. A mixture of this ester (0.125 g) and 4-chlorobenzylamine (0.379 g) are heated to 180° C. for 1 h. The solution is cooled to room temperature. The crude reaction is chromatographed on silica, eluting with 2% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and concentrated in vacuo. The residue is sonicated with CH2Cl2 /hexanes. The resulting solid is collected and dried to yield 0.050 g of the desired product as a pale-yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])=[CH:6][CH:5]=1)([O-])=O.[H][H]>N.O[V](=O)=O.[O-2].[O-2].[Ti+4].[Pd].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])=[CH:8][CH:9]=1
Reactant: O=C1c2ccccc2C(=O)N1c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: O=[V](=O)O
Agent: [Pd]
Agent: [Ti+4]
Solvent: O
Product: Nc1ccc(N2C(=O)c3ccccc3C2=O)cc1
Temperature: 60 °C
Yield: 79.6 %

Procedure:
0.002 g of ammonium vanadate and 2 g of titanium dioxide extrudate containing 1% by weight of palladium and having a particle size of 3 mm (from Johnson Matthey) are added to a suspension consisting of 250 ml of water and 13.3 g of N-(4-nitrophenyl)phthalimide. After displacing the air with nitrogen, the latter is replaced by hydrogen at atmospheric pressure and the suspension is stirred at 60° C. At a hydrogen absorption of 40% of theory (after 42 hours), the suspension is transferred to an autoclave together with a catalyst and is then stirred at 100° C. under a hydrogen pressure of 10 bar for another 21 hours. During this time, a total of 115% of the theoretical amount of hydrogen, based on N-(4-nitrophenyl)phthalimide, is absorbed. After cooling to room temperature, the resulting suspension is sieved through a sieve having a mesh width of 1 mm. The material remaining on the sieve is washed with 50 ml of water and the combined aqueous phases are then filtered through a paper filter and washed with 250 ml of water. Drying at 80° C. under reduced pressure (125 mbar) gives 9.4 g (80%) of N-(4-aminophenyl)phthalimide.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:7]=1.C(N(CC)CC)C.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30].N#N>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(C)=O.CCCCCC>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][C@H:10]1[CH2:9][O:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:7]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(C#C[Si](C)(C)C)c1
Yield: 99.3 %

Procedure:
A 50 mL round-bottom flask with stir bar was charged with 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]pyridine (564 mg, 1.64 mmol), copper(I) iodide (25 mg, 0.13 mmol, 0.08 equiv.), bis(triphenylphosphine)palladium(II) chloride (49 mg, 66 μmol, 0.04 equiv.), and triphenylphosphine (34 mg, 0.13 mmol, 0.08 equiv.). Anhydrous triethylamine (5 mL) and trimethylsilylacetylene (0.63 mL, 4.45 mmol, 2.7 equiv.) were added. The flask was equipped with a reflux condenser topped by a N2 balloon, and the reaction mixture was heated to gentle reflux (heating mantle) for 16 h. A black color appeared soon after heating. After cooling, the mixture consisted of an amber solution and a black precipitate. TLC (silica gel, EtOAc/hexane 55:45) demonstrated complete conversion (Rf 0.6; starting material: Rf 0.55). The reaction mixture was evaporated and the residue was taken up in DMPU (0.8 mL+0.4 mL rinse) and was chromatographed on silica gel (25×2.5 cm, EtOAc/hexane 35:65 switching to 45:55 after appearance of the product). After evaporation of the product-containing fractions, the residue was twice evaporated with CH3CN and the solution before the final evaporation was filtered over a cotton plug to remove a small amount of solid. Drying (50° C./14 torr) afforded 587 mg (99%) of the product as a light-amber glass of sufficient purity to be used in the subsequent step. 1H NMR (CDCl3, TMS, 250 MHz) δ 8.30 (d, 1H, J=1.4 Hz), 8.27 (d, 1H, J=2.8 Hz), 7.30 (dd, 1H, 1.6, 2.7 Hz), 4.51 (m, 1H), 4.32 (m, 1H), 4.12 (dd, 1H, J=2.8, 10.1 Hz), 3.88 (t, 2H, J=7.6 Hz), 2.43-2.20 (m, 2H), 1.43 (s, 9H), 0.26 (s, 9H); 13C NMR (CDCl3, 62.5 MHz) δ 156.1, 154.3, 145.0, 138.1, 133.9, 123.2, 120.3, 101.2, 98.0, 79.6, 68.6, 59.9, 46.9 (br), 28.3, 18.9, 0.1.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:26])=[C:8]([CH3:25])[C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:13]=1)=[O:11].B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:26])=[C:8]([CH3:25])[C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:13]=1)=[O:11]
Reactant: COc1ccc(C(=O)c2c(Cc3ccccc3Br)oc(C)c2C)cc1C1CCCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1oc(Cc2ccccc2Br)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Yield: 49.7 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using [2-(2-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3-cyclopentyl-4-methoxy-phenyl)-methanone (2.82 g, 6.03 mmol) and 1M boron tribromide/CH2Cl2 (18.7 mL) in CH2Cl2. Purification on Biotage KP-Sil eluting with a 2, 5 & 10% EtOAc/pet. ether step gradient gave 1.36 g (50%) of the title compound. (DMSO-d6) δ 1.42-1.44 (m, 2 H), 1.58-1.72 (m, 4 H), 1.79 (s, 3 H), 1.87-1.92 (m, 2 H), 2.16 (s, 3 H), 3.17 (quintet, 1 H), 3.92 (s, 2 H), 6.85 (d, 1 H), 7.12-7.17 (m, 2 H), 7.29 (t, 1 H), 7.45 (dd, 1 H), 7.50-7.52 (m, 2 H), 10.31 (s, 1 H).