Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.Cl[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:29](=[O:30])[CH:28]=[C:21]2[S:22](=[O:27])(=[O:26])[CH2:23][CH2:24][CH2:25][N:20]2[C:19]1=[O:31].[I-].[Na+]>CN(C)C=O.O>[N:12]1[CH:11]=[CH:10][N:9]2[C:4]([S:3][CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:29](=[O:30])[CH:28]=[C:21]4[S:22](=[O:27])(=[O:26])[CH2:23][CH2:24][CH2:25][N:20]4[C:19]3=[O:31])=[CH:5][CH:6]=[CH:7][C:8]=12
Reactant: O=c1cc2n(c(=O)n1CCCCCl)CCCS2(=O)=O
Reactant: Sc1cccc2nccn12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc2n(c(=O)n1CCCCSc1cccc3nccn13)CCCS2(=O)=O
Reaction time: 0.5 h

Procedure:
To a suspension of 0.053 g (2.2 mmol) of 60% oily sodium hydride in 15 ml of N,N-dimethylformamide, 0.33 g (2.2 mmol) of 5-mercaptoimidazo[1,2-a]pyridine was added at room temperature, followed by stirring for 30 minutes. To this mixture, 0.61 g (2.0 mmol) of 7-(4-chlorobutyl)-1,1-dioxo-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione and 0.33 g (2.2 mmol) of sodium iodide were added, followed by stirring at 100° C. for 3 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate 3 times. The organic layer was washed with water and dried, after which the solvent was distilled off. The residue was purified by recrystallization (solvent, chloroform/diethyl ether) to yield 0.442 g (52.6%, light green powder) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([O:21]C)=[O:20])=[N:17][CH:18]=2)=[O:11])=[C:5]([C:23]([F:26])([F:25])[F:24])[CH:4]=1.C1COCC1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[N:17][CH:18]=2)=[O:11])=[C:5]([C:23]([F:25])([F:26])[F:24])[CH:4]=1
Reactant: COC(=O)c1ccc(NC(=O)Cc2ccc(OC)cc2C(F)(F)F)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)O)nc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
Prepared using General Procedure 9: To a stirred solution of methyl 5-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)picolinate INT-14 (74 mg, 0.2 mmol) in MeOH (1 mL) and THF (4 mL) was added 2 N NaOH (1 mL). The reaction mixture was stirred at room temperature overnight then concentrated. The residue was diluted with water (1 mL) and acidified with 1 N HCl to a pH of 2. The resulting precipitate was isolated by filtration and the filter cake was washed with water. Crude product was dried under vacuum to afford 48 mg (67%) of 5-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)picolinic acid INT-15 which was used in the next step without purification. LCMS-ESI (m/z) calculated C16H13F3N2O4: 354; found 355, tR=2.66 min (Method 1). 1H NMR (400 MHz, DMSO) δ 10.71 (s, 1H), 8.83 (d, J=2.2 Hz, 1H), 8.18 (dd, J=8.6, 2.5 Hz, 1H), 8.02 (d, J=8.6 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 7.29-7.10 (m, 2H), 3.92 (s, 2H), 3.82 (d, J=5.3 Hz, 3H), 3.35 (s, 1H).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][C:12]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:13]=2[C:14]([OH:16])=O)=[CH:9][CH:8]=1>O>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[O:11][C:12]3[C:13](=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:14](=[O:16])[C:23]=2[CH:24]=1
Reactant: COc1ccc(Oc2ccc(Br)cc2)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1ccc2oc3ccc(Br)cc3c(=O)c2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Sulfuric acid (41 ml, 765 mmol) was added to 2-(4-bromophenoxy)-5-methoxybenzoic acid (3750 mg, 12 mmol) at RT. The reaction mixture was stirred at 60° C. for 60 min. LCMS showed complete reaction. The reaction mixture was cooled to rt and poured slowly over stirred mixture of ice and water (100 ml). The tan precipitate was filtered and washed with water (3×30 ml), twice with 30 ml of 0.5N NaOH, and with water again. The residue was recrystallized from 40 ml THF to give the title compound. MS m/z=307.2 [M+H]+. Calc'd for C14H9BrO3: 305.1.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([O:16]CC)=[O:15])[CH:13]=[C:8]2[CH:7]=[CH:6]1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O>[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([OH:16])=[O:15])[CH:13]=[C:8]2[CH:7]=[CH:6]1
Reactant: CCOC(=O)c1cc2ccn(Cc3ccc(F)cc3F)c2cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2ccn(Cc3ccc(F)cc3F)c2cn1
Temperature: 100 °C
Yield: 32.9 %

Procedure:
To ethyl 1-(2,4-difluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (0.30 g, 1.58 mmol) in methanol (3 mL) was added sodium hydroxide (0.076 g, 3.16 mmol) in water (0.5 mL). The reaction was heated in a SmithCreator™ (microwave reactor from Personal Chemistry) to 100° C. for five minutes. The reaction solution was poured into water (30 mL) and the pH was adjusted to 2-3 by addition of citric acid. The precipitate that formed was collected by filtration and dried in vacuo to provide the title compound as a white powder (0.15 g, 55%). 1H NMR (DMSO-d6): δ ppm 8.97 (s, 1H), 8.35 (s, 1H), 7.82 (d, 1H, J=3.2 Hz), 7.28-7.38 (m, 2H), 7.09 (t, 1H, J=8.4 Hz), 6.76 (d, 1H, J=3.2 Hz), 5.67 (s, 2H). LCMS (API-ES, M+H+): 289.1
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].CCN(C(C)C)C(C)C.[CH2:30]([N:37]=[C:38]=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCOCC1>[CH2:30]([NH:37][C:38](=[O:39])[NH:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C=NCc1ccccc1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNC(=O)NCc1ccccc1)NC(c1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
A solution of 0.2 mmol rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 0.28 mmol of DIPEA in 2 ml of dioxane was treated with 0.2 mmol of benzylisocyanate. The mixture was stirred at room temperature for 48 hours, concentrated and diluted with diethyl ether. The solid was filtered off, dissolved in dichloromethane and extracted 2 times with a diluted solution of citric acid. The organic phase was dried and concentrated. The residue was triturated with diethyl ether to give the title compound as a colorless solid. Yield=93%.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[OH:7][C:8]([CH3:41])([CH3:40])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:24]=[CH:23][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:20]=2)[CH3:18])[CH2:12][CH2:11]1.Br[C:43]1[CH:44]=[CH:45][C:46](=[O:53])[N:47]([CH2:49][CH:50]2[CH2:52][CH2:51]2)[CH:48]=1>CN(C)C=O>[CH:50]1([CH2:49][N:47]2[C:46](=[O:53])[CH:45]=[CH:44][C:43]([C:22]3[CH:21]=[CH:20][C:19]([C@@H:17]([N:13]4[CH2:12][CH2:11][C@:10]([CH2:9][C:8]([OH:7])([CH3:40])[CH3:41])([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[O:15][C:14]4=[O:16])[CH3:18])=[CH:24][CH:23]=3)=[CH:48]2)[CH2:52][CH2:51]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=c1ccc(Br)cn1CC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(CC3CC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
2 M aqueous Na2CO3 solution (0.84 mL) was added to a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.40 g) and 5-bromo-1-cyclopropylmethyl-1H-pyridin-2-one (0.24 g) in dimethyl-formamide (4 mL). The resulting mixture was sparged with argon for 10 min, before [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex (34 mg) was added. The mixture was heated to 100° C. and stirred at this temperature for 4 h. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (dichloromethane/methanol 99:1->95:5) to afford the title compound that was crystallized with little ethyl acetate. Yield: 0.19 g (46% of theory); Mass spectrum (ESI+): m/z=501 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][N:4]=1.[SH:13][C:14]1[NH:18][C:17]2[CH:19]=[C:20]3[C:24](=[CH:25][C:16]=2[N:15]=1)[C:23]([CH3:27])([CH3:26])[C:22](=[O:28])[C:21]3([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:29][C:21]1([CH3:30])[C:20]2[C:24](=[CH:25][C:16]3[NH:15][C:14]([S:13][CH2:2][C:3]4[C:8]([CH3:9])=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][N:4]=4)=[N:18][C:17]=3[CH:19]=2)[C:23]([CH3:27])([CH3:26])[C:22]1=[O:28]
Reactant: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Reactant: Cc1c([N+](=O)[O-])ccnc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c([N+](=O)[O-])ccnc1CSc1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)C3(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 11.5 g of 2-chloromethyl-3-methyl-4-nitropyridine and 16 g of 5,7-dihydro-2-mercapto-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(lH)-one in 200 ml of absolute acetone was treated with 13 g of finely ground potassium carbonate and the mixture was stirred at room temperature under argon for 18 hours. 100 ml of acetone were distilled off in vacuo, whereupon the residue was poured on to ice. The product which crystallized out was filtered off and dissolved in methylene chloride; the solution obtained was washed with water, dried and concentrated. By recrystallization from ethyl acetate/ether there was obtained 5,7-dihydro-5,5,7,7-tetramethyl-2-[[(3-methyl-4-nitro-2 -pyridyl)methyl]thio]indeno[5,6-d]imidazol-6(lH)-one of melting point 181-183° (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:18][CH:19]1[CH2:21][CH2:20]1)[CH:5]=[O:6]
Reactant: BrCC1CC1
Reactant: O=Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC2CC2)c(Br)c1
Temperature: 60 °C
Yield: 84.6 %

Procedure:
A well stirred mixture of commercially available 3-bromo-4-hydroxy-benzaldehyde (40.2 g; 220 mmol), anhydrous K2CO3 (30.4 g; 220 mmol) and commercially available bromomethyl-cyclopropane (32.4 g; 240 mmol) in dry DMF (200 mL) is heated to 60° C. over night. The reaction mixture is filtered, concentrated under reduced pressure, diluted with water and extracted with tert. BuOMe. The combined organic extracts are washed with brine, dried over Mg2SO4 and concentrated under reduced pressure. The residue is chromatographed on silica gel (cyclohexane/AcOEt 100:0 to 85:15) to yield 47.5 g of the title compound as pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[S:13][C:14]([CH3:18])=[C:15]([CH3:17])[CH:16]=2)=[N:4][N:3]=1.[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([O:31][C:32]3[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=3)=[CH:26][CH:27]=[N:28]2)=[N:23][CH:22]=1>C(O)(C)(C)C>[CH3:17][C:15]1[CH:16]=[C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([NH:38][C:35]3[CH:34]=[CH:33][C:32]([O:31][C:25]4[C:24]5[C:29](=[CH:30][C:21]([O:20][CH3:19])=[CH:22][N:23]=5)[N:28]=[CH:27][CH:26]=4)=[CH:37][CH:36]=3)=[N:3][N:4]=2)[S:13][C:14]=1[CH3:18]
Reactant: Cc1cc(-c2nnc(Cl)c3ccccc23)sc1C
Reactant: COc1cnc2c(Oc3ccc(N)cc3)ccnc2c1
Solvent: CC(C)(C)O
Product: COc1cnc2c(Oc3ccc(Nc4nnc(-c5cc(C)c(C)s5)c5ccccc45)cc3)ccnc2c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
In a nitrogen purged sealed tube, 1-chloro-4-(4,5-dimethylthiophen-2-yl)phthalazine (0.040 g, 0.146 mmol) was dissolved in tert-butanol (1.00 mL). 4-(7-Methoxy-1,5-naphthyridin-4-yloxy)benzenamine (0.039 g, 0.146 mmol) was added, and the reaction mixture in the tube was stirred at 100° C. for 3 h. The mixture was concentrated in vacuo, and the crude material was purified by silica gel chromatography using 0-100% CH2Cl2:MeOH(90:10)/CH2Cl2. Product-containing fractions were concentrated to yield 4-(4,5-dimethylthiophen-2-yl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine as light yellow solid. MS [M+H]=506.0; Calc'd 505.6 for C29H23N5O2S.
Reaction SMILES: [NH2:1][C:2]([C:23]#[N:24])([CH3:22])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[C:8]#[N:9].C(N(C(C)C)C(C)C)C.[F:34][C:35]([F:47])([F:46])[O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1>ClCCl>[C:23]([C:2]([NH:1][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][C:37]([O:36][C:35]([F:34])([F:46])[F:47])=[CH:38][CH:39]=1)([CH3:22])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:8]#[N:9])[CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])#[N:24]
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: CC(N)(C#N)COc1cc(C#N)ccc1Oc1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C#N)(COc1cc(C#N)ccc1Oc1ccc(Cl)cc1Cl)NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
13.04 g of 3-(2-amino-2-cyano-1-propoxy)-4-(2,4-dichlorophenoxy)-benzonitrile and 6.1 g of ethyldiisopropylamine are dissolved in 120 ml of dichloromethane. After cooling the mixture to 0°, 9.9 g of 4-trifluoromethoxybenzoyl chloride is added, the reaction mixture stirred at room temperature for 6 h and then concentrated under vacuum. The residue is dissolved in ethylacetate and washed with a 1N aqueous solution of sodium hydroxide, water, a 1N aqueous solution of hydrogen chloride, again with water and finally with brine. The organic phase is dried over magnesium sulfate, filtered and evaporated. The raw residue is then recrystallized in diethylether/hexane, thus yielding the title compound with a melting point of 151-2°.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[O:12])[C:8]([CH3:19])=[C:7]2[C:3]=1[C:4]1[CH:23]=[C:22]([CH3:24])[CH:21]=[N:20][C:5]=1[NH:6]2.[CH:25]1([NH:28][C:29]([C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=2)=[O:30])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:29]([C:31]2[CH:36]=[C:35]([C:2]3[CH:10]=[C:9]([C:11]([NH:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[O:12])[C:8]([CH3:19])=[C:7]4[C:3]=3[C:4]3[CH:23]=[C:22]([CH3:24])[CH:21]=[N:20][C:5]=3[NH:6]4)[CH:34]=[CH:33][CH:32]=2)=[O:30])[CH2:26][CH2:27]1
Reactant: O=C(NC1CC1)c1cccc(B(O)O)c1
Reactant: Cc1cnc2[nH]c3c(C)c(C(=O)NCCN(C)C)cc(Cl)c3c2c1
Product: Cc1cnc2[nH]c3c(C)c(C(=O)NCCN(C)C)cc(-c4cccc(C(=O)NC5CC5)c4)c3c2c1

Procedure:
The title compound was synthesized from 5-chloro-N-(2-(dimethylamino)ethyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxamide and 3-(cyclopropylcarbamoyl)phenyl boronic acid using an analogous procedure to that described in the preparation of Compound 84. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.57 (dd, J=3.92, 2.40 Hz, 2H) 0.71 (dd, J=6.95, 2.40 Hz, 2H) 1.23 (s, 1H) 2.26 (s, 3H) 2.65 (s, 3H) 2.87 (d, J=5.05 Hz, 6H) 3.29 (q, J=5.98 Hz, 2H) 3.61 (q, J=6.15 Hz, 2H) 7.20 (s, 1H) 7.50 (s, 1H) 7.66 (t, J=7.83 Hz, 1H) 7.77 (d, J=7.83 Hz, 1H) 7.98 (d, J=7.83 Hz, 1H) 8.08 (s, 1H) 8.31 (d, J=1.77 Hz, 1H) 8.57-8.61 (m, 1H) 8.59 (d, J=4.55 Hz, 1H) 12.05 (s, 1H). [M+H] calc'd for C28H31N5O2 470; found, 470.4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[CH2:19][O:20][CH3:21])=[O:13])[CH:11]=1)[C:5]([O:7]C)=[O:6].C([Sn](CCCC)(CCCC)[C:27]1[O:28][CH:29]=[CH:30][N:31]=1)CCC.C(OCC)(=O)C>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][O:20][CH2:19][C@H:15]1[CH2:16][CH2:17][CH2:18][N:14]1[C:12]([C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([C:27]2[O:28][CH:29]=[CH:30][N:31]=2)[CH:11]=1)[C:5]([OH:7])=[O:6])=[O:13]
Reactant: COC[C@H]1CCCN1C(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC[C@H]1CCCN1C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Temperature: 95 °C
Yield: 75.7 %

Procedure:
To a solution of (R)-methyl 3-bromo-5-(2-(methoxymethyl)pyrrolidine-1-carbonyl)benzoate (Step H (1), 350 mg, 1.0 mmol) in dioxane (5 mL) were added Pd(PPh3)4 (173.5 mg, 0.15 mmol) and 2-(tributylstannyl)oxazole (1.8 g, 5.0 mmol) above made and the reaction mixture was stirred at 95° C. with sealed cap for 16 h. Ethyl acetate (200 mL) was added and the mixture was washed with H2O and concentrated under vacuum. The crude mixture was purified by silica gel Flash Chromatography (0% to 30% to 50% to 70% EtOAc/Hexane step gradient) to give 250 mg of the title compound: 1H NMR (CDCl3, 500 MHz) δ ppm 1.75-2.11 (4H, m), 3.08 (1H, brd s), 3.38 (3H, s), 3.50 (1H, m), 3.63 (2H, s), 3.83 (3H, s), 4.43 (1H, s), 7.24 (1H, s), 7.73 (1H, s), 8.22 (1H, s), 8.35 (1H, s), 8.71 (1H, s). MS (ESI) (M+H)+ 345.26.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:21](I)[CH3:22]>CN(C=O)C>[CH2:21]([O:1][C:2]1[CH:9]=[C:8]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:22]
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(N(CC)CC)ccc1C=O
Reaction time: 48 h

Procedure:
To a mixture of 2-hydroxy-4-(diethylamino)benzaldehyde (10.0 g, 51.75 mmol), K2CO3 (14.3 g) and DMF (150 ml) at room temperature was added ethyl iodide (4.1 ml). The reaction mixture was stirred for about two days, filtered and the filtrate was concentrated in vacuo. The residue was partitioned between ether and saturated Na2CO3, and the organic layer was separated, dried over MgSO4, treated with charcoal, filtered and concentrated in vacuo. The solid product was recrystallized from hexane to afford, as a pink crystalline solid, 9.8 g of 2-ethoxy-4-(diethylamino)benzaldehyde, m.p. 58°-59° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[CH3:12][OH:13]>C[O-].[Na+]>[CH3:12][O:13][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cccc(CBr)c1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Product: COCc1cccc(C(=O)O)c1
Reaction time: 0.12 h
Yield: 92 %

Procedure:
12 g (55.75 millimoles) of 3-bromomethyl-benzoic acid are dissolved in 10 ml of anhydrous methanol and to the solution 22.30 ml of sodium methylate (concentration 5 millimoles/ml) are added dropwise at room temperature. The reaction mixture is stirred for 5-10 minutes, the methanol is removed in vacuo. The residue is dissolved in 10 ml of ethyl acetate, to the solution 2 ml of water are added and the pH of the mixture is adjusted to 2-3 with a 2N sodium hydrogen sulfate solution at 0° C. The layers are separated, the organic phase is dried, filtered and the solvent is distilled off in vacuo. Thus 8.55 g of the title compound are obtained, yield 92,3%.
Reaction SMILES: [CH2:1]([C@H:4]1[C@H:8]([CH2:9][O:10][Si](C(C)(C)C)(C)C)[CH2:7][N:6]([C@@H](C2C=CC=CC=2)C)[CH2:5]1)[CH:2]=[CH2:3].Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].Cl.C(O)C>ClCCl>[CH2:1]([C@H:4]1[C@H:8]([CH2:9][OH:10])[CH2:7][N:6]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1CN([C@H](C)c2ccccc2)C[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: C=CC[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1CO
Temperature: 55 °C
Reaction time: 10 h
Yield: 85.9 %

Procedure:
(3S,4S)-3-Allyl-4-(tert-butyldimethylsilyloxy)methyl-1-[(1R)-1-phenylethyl]pyrrolidine (213 g, 592 mmol) was dissolved in dichloromethane (420 mL). Benzyl chloroformate (169.2 mL, 1.19 mol) was added dropwise, and the mixture was stirred at 55° C. for 10 hours and then at room temperature for 14 hours. A 1 M solution of hydrochloric acid in ethanol (250 mL, 250 mmol) was further added to the reaction solution, and the mixture was stirred at room temperature for 24 hours. The reaction solution was extracted with a saturated sodium bicarbonate solution and ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1→1:1) to give 140 g of the title compound as a pale yellow oil.
Reaction SMILES: C([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:26])=[C:18]([CH2:20][NH:21][C:22](=[O:25])[CH2:23][Cl:24])[CH:19]=1)(OC(C)(C)C)=O.Cl.Cl.CCOCC>CO>[ClH:24].[NH:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:26])=[C:18]([CH2:20][NH:21][C:22](=[O:25])[CH2:23][Cl:24])[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(CNC(=O)CCl)c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=C(CCl)NCc1cc(OC[C@@H]2CCN2)cnc1Cl
Yield: 37 %

Procedure:
The product of step 211a (0.34 g, 0.80 mmol) was deprotected and isolated as the free base in 37% yield according to the procedure of Example 20b, followed by conversion to the monohydrochloride with HCl/Et2O: [α]D23 +16.82 (c 0.3, MeOH); 1H NMR (D2O, 300 MHz) δ 2.72 (q, J=8.5, 16.5 Hz, 2H), 4.07-4.43 (m, 4H), 4.45 (s, 2H), 4.48 (d, J=4.5 Hz, 2H), 4.81 (m, 1H), 7.53 (d, J=3.0 Hz, 1H), 8.08 (d, J=3.0 Hz, 1 H); MS (CI/NH3) m/z 304 (M+H)+. Anal. Calcd for C12H15Cl2N3O2.HCl: C, 42.31; H, 4.73; N, 12.33. Found: C, 42.34; H, 5.00; N, 12.25.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[CH:20]=[C:21]([CH2:28][OH:29])[CH:22]=[C:23]([O:26][CH3:27])[C:24]=1[OH:25].C(OCC)(=O)C>C(Cl)Cl>[OH:15][C:10]1[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]2[O:4][C:3]([C:1]#[C:2][C:19]3[CH:20]=[C:21]([CH2:28][OH:29])[CH:22]=[C:23]([O:26][CH3:27])[C:24]=3[OH:25])([CH3:17])[CH2:8][CH2:7][C:6]=2[C:9]=1[CH3:16]
Reactant: COc1cc(CO)cc(I)c1O
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(CO)cc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)c1O

Procedure:
This compound was obtained by reacting rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 3-iodo-4-hydroxy-5-methoxybenzenemethanol [P. Claus et al. Monatsh. Chem. 103, 1178 (1972)]under the conditions described in Example 1. The product was isolated by chromatography over silica gel using 30 % (V/V) of ethyl acetate in methylene chloride. Crystallization from ether/ hexane yielded colorless crystals with m.p. 160°-163°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[H-].[Na+].I[CH3:33]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([N:11]([CH3:33])[C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:21]=[C:22]([O:28][CH3:29])[CH:23]=[C:24]([O:26][CH3:27])[CH:25]=3)[CH2:16][CH2:15]2)=[O:13])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C)c(C)nc3OC)CC2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(N2CCN(C(=O)N(C)c3cc(C)c(C)nc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
1-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(100 mg, 0.25 mmol) was dissolved in dimethylformamide(15 ml) and thereto sodium hydride(6.0 mg, 0.25 mmol) was added. The resulting mixture was stirred at room temperature for 15 min and thereto iodomethane(35 mg, 0.25 mmol) was added. The resulting mixture was stirred at room temperature for 16 hrs, concentrated under the reduced pressure to remove dimethylformamide, and purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.