Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[O:4].O1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[C:7]1[CH:15]=O.[I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+]>CCCCCC>[CH:13]([C:12]1[O:4][C:3]2[CH:15]=[CH:7][CH:8]=[CH:9][C:10]=2[CH:11]=1)=[CH2:14]
Reactant: O=Cc1cc2ccccc2o1
Reactant: CN(C)C=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [I-]
Solvent: CCCCCC
Product: C=Cc1cc2ccccc2o1
Yield: 25 %

Procedure:
To 20 ml of N,N-dimethylformamide were added 1.60 g of 2-benzofurancarbaldehyde and 4.90 g of methyltriphenylphosphonium iodide. Thereto was added 0.50 g of 60% sodium hydride with stirring under ice cooling. The mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 100 ml of n-hexane. The resulting mixture was washed with water and an aqueous saturated sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: n-hexane) to obtain 0.40 g (yield: 25%) of 2-vinylbenzofuran as a colorless oily material.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[CH3:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:17][C:16]=1[C:3]1[C:2]([O:1][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[CH:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[CH:4]=1
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2O)C(C)(C)CCC3(C)C)c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: COc1ccc(C=CC(=O)O)cc1-c1cc2c(cc1OCCN1CCOCC1)C(C)(C)CCC2(C)C
Yield: 89.4 %

Procedure:
In a manner similar to that of Example 16(a), by reaction of 1.4 g (3.4 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylate obtained in Example 13(f) with 760 mg (4.08 mmol) of 4-(2-chloroethyl)morpholine hydrochloride, 1.5 g (85%) of the expected compound was obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:13]=[CH:12][C:11]2[NH:10][C:9]3[N:14]=[CH:15][C:16](Br)=[CH:17][C:8]=3[C:7]=2[CH:6]=1)=[O:4].[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=2)[CH2:22][CH2:21]1.C([O-])(=O)C.[K+]>C(#N)C.C(=O)(O)[O-].[Na+].C(Cl)Cl.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>[CH3:1][O:2][C:3]([C:5]1[N:13]=[CH:12][C:11]2[NH:10][C:9]3[N:14]=[CH:15][C:16]([C:29]4[CH:28]=[CH:27][C:26]([N:23]5[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]5)=[CH:31][CH:30]=4)=[CH:17][C:8]=3[C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ncc(Br)cc12
Reactant: CN1CCN(c2ccc(B(O)O)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)c1cc2c(cn1)[nH]c1ncc(-c3ccc(N4CCN(C)CC4)cc3)cc12

Procedure:
3-Bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester (100 mg, 0.327 mmol), 4-(4-methylpiperazin-1-yl)phenylboronic acid, pinacol ester (104 mg, 0.343 mmol) and bis(triphenylphosphine)palladium(II) dichloride (11.5 mg, 0.016 mmol) were suspended in acetonitrile (1.8 mL) and 1N aqueous potassium acetate solution (1.8 mL) and heated under microwave irradiation at 140° C. for 30 minutes. The cooled reaction mixture was diluted with saturated sodium bicarbonate solution and DCM, and the solid removed by filtration. The layers of the resultant filtrate were separated and the aqueous phase was further extracted with DCM. The combined organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The resultant residue was purified by flash chromatography (silica, 0-20% (MeOH containing 1% triethylamine) in DCM).
Reaction SMILES: [Br:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:19][C@H:18]([CH2:20][O:21]CC3C=CC=CC=3)[C@@H:13]([O:14]C(=O)C)[C@@H:12]2[F:29])=[C:4](Br)[N:3]=1.O.[OH-].[Li+].C(Cl)(Cl)Cl.CO.C(O)(=O)C.[NH3:44]>>[Br:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@@H:12]2[F:29])=[C:4]([NH2:44])[N:3]=1
Reactant: N
Reactant: CC(=O)O[C@H]1[C@H](F)[C@H](n2cnc3c(Br)nc(Br)nc32)O[C@@H]1COCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Nc1nc(Br)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 1a (5.84 g, 10.5 mmol) in 400 mL of ethanolic ammonia (saturated at 0° C.) was sealed in a glass-lined stainless steel bomb and left at room temperature for 3 days. The solution was evaporated to dryness and evaporated with ethanol to remove ammonia. The residue, containing the desired product and 5'-benzoyl compound, was dissolved in 440 mL of acetonitrile and 120 mL of water. Lithium hydroxide monohydrate (881 mg, 21 mmol) was added, and the solution was stirred for 16 hours at room temperature. Thin-layer chromatography (5:1 CHCl3 -MeOH) indicated complete reaction. The chilled solution was carefully neutralized with glacial acetic acid and evaporated to dryness. The white solid residue was recrystallized from water. The product was dried in vacuo at room temperature at 100° C. for 2 hours: 2.15 g (59.2%). Mp 209-210° C., TLC 5:1 CHCl3 -MeOH Rf 0.47; HPLC 99.8% 9:1; H2O-MeCN; MS, 3.48 (M+1)+ ; UV λmax pH 1 264 (14.3), pH 7 264 (14.9), pH 13 264 (15.2). Anal. Calcd. for C10H11BrFN5O3 : C, 34.50; H, 3.18; N, 20.12. Found: C, 34.36; H, 3.28; N, 19.93.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][N:11]([CH:13]=O)[CH3:12]>>[CH3:10][N:11]([CH3:13])[CH:12]=[CH:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1C#N
Reactant: CN(C)C=O
Product: CN(C)C=Cc1ncccc1C#N

Procedure:
N,N-dimethyl-2-(3-cyano-2-pyridyl)ethenamine was prepared using the procedure of 4 A from 2-methyl-3-cyanopyridine (9.0 g, 0.076 m), DMF acetal (11.0 g, 0.092 m) and DMF (50 mL) yielding N,N-dimethyl-2-(3-cyano-2-pyridyl) ethenamine b.p.=133°-135° (0.3 mm), m.p.=49°-50° after sublimation at 50° (0.3 mm).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:8]=[C:7](Cl)[N:6]=[C:5]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])[N:4]=1>O1CCCC1>[Cl:2][C:3]1[N:4]=[C:5]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])[N:6]=[C:7]([NH2:1])[CH:8]=1
Reactant: N
Reactant: COc1ccc(Cl)cc1-c1nc(Cl)cc(Cl)n1
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1-c1nc(N)cc(Cl)n1
Temperature: 0 °C
Yield: 71 %

Procedure:
A pressure bottle was charged with tetrahydrofuran (50 ml) and cooled to 0° C. Ammonia gas was passed through the tetrahydrofuran until saturated. To this solution was added 4,6-dichloro-2-(5-chloro-2-methoxy-phenyl)-pyrimidine (0.15 g, 0.52 mmol) and the mixture was heated at 75-80° C. for 18 hours. Evaporation of volatiles under reduced pressure provided the hydrochloride salt of 6-chloro-2-(5-chloro-2-methoxy-phenyl)-pyrimidin-4-yl-amine (0.10 g, 71%).
Reaction SMILES: C([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:6]1(=[O:29])=[O:28])(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[F:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[CH2:40][CH2:41]Br>C(O)(C(F)(F)F)=O.CC#N>[F:36][C:37]1[CH:38]=[C:39]([CH2:40][CH2:41][N:5]2[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[S:6]2(=[O:28])=[O:29])[CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)(C)N1C(=O)C(NCCCCc2ccccc2)=C(c2ccccc2)S1(=O)=O
Reactant: Fc1cccc(CCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C1C(NCCCCc2ccccc2)=C(c2ccccc2)S(=O)(=O)N1CCc1cccc(F)c1
Temperature: 120 °C
Yield: 65.6 %

Procedure:
2-tert-Butyl-5-phenyl-4-[(4-phenylbutyl)amino]isothiazol-3(2H)-one 1,1-dioxide (Example 1) (0.150 g, 0.36 mmol) was dissolved in TFA (3 ml) and heated in a microwave reactor at 120° C. for 20 mins. The solvent was evaporated and the crude product was reevaporated from DCM (2×5 ml). The crude product, potassium carbonate (0.251 g, 1.82 mmol) and 3-fluorophenethylbromide (0.221 g, 1.09 mmol) was dissolved in dry MeCN (3 ml) and heated at in a microwave reactor 140° C. for 10 mins. The reaction mixture was purified by silica gel column chromatography using a 85:15 mixture of heptane and EtOAc as eluant, to give the title compound (0.113 g, 65%). 1H NMR (500 MHz, CDCl3): δ 7.55-7.41 (m, 5H), 7.34-7.25 (m, 3H), 7.23-7.17 (m, 1H), 7.14-7.01 (m, 4H), 7.00-6.93 (m, 1H), 5.28-5.19 (m, 1H), 3.98-3.90 (m, 2H), 3.18-3.10 (m, 2H), 2.91-2.83 (m, 2H), 2.50-2.43 (m, 2H), 1.44-1.36 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 164.1, 162.2, 159.1, 141.7, 140.3, 140.2, 135.6, 131.8, 130.4, 130.3, 130.0, 128.9, 128.6, 128.5, 126.2, 125.0, 124.8, 116.2, 116.0, 114.1, 113.9, 107.0, 44.2, 41.1, 35.4, 34.4, 29.2, 28.3; Mass Spectrum: M−H+ 479.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([C:15](=[O:21])[CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH:11]=[CH:10][C:9]=2[OH:22])=[O:5].[H][H]>CO.[Pd]>[CH3:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH:15]([OH:21])[CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH:11]=[CH:10][C:9]=2[OH:22])=[O:5]
Reactant: [H][H]
Reactant: COC(=O)c1cc2c(C(=O)CNC(C)C)ccc(O)c2[nH]1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc2c(C(O)CNC(C)C)ccc(O)c2[nH]1
Temperature: 0 °C
Yield: 98.5 %

Procedure:
A solution of 1.6 g of 7-hydroxy-4-isopropylaminoacetylindole-2-carboxylic acid methyl ester hydrochloride in 80 ml of methanol is combined with 300 mg of 10% palladium-animal charcoal and shaken for 21/4 hours under normal pressure with hydrogen. The reaction mixture is then filtered and the filtrate evaporated to dryness under vacuum. The residue is triturated with acetonitrile, cooled to 0° C., and filtered, thus obtaining 1.41 g of 4-(1-hydroxy-2-isopropylaminoethyl)-7-hydroxyindole-2-carboxylic acid methyl ester, decomposition point 137°-139° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[S:27][C:26](Cl)=[N:25][C:24]=23)=[O:18])=[O:8])[N:6]=1>CO.[Pd]>[CH3:1][C:2]1[S:3][C:4]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[S:27][CH:26]=[N:25][C:24]=23)=[O:18])=[O:8])[N:6]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3sc(Cl)nc23)c1
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3scnc23)c1
Reaction time: 3 h

Procedure:
A solution of 2-Chloro-benzothiazole-4-carboxylic acid[(1S,2S,5R)-3-(2-methyl-5-m-tolyl-thiazole-4-carbonyl)-3-aza-bicyclo[3.1.0]hex-2-ylmethyl]-amide (0.04 mmol) in MeOH (2.0 mL) is treated with Pd/C (10%, 50 mg) and stirred under a hydrogen atmosphere (1 bar) for 3 h. After filtration through celite and removal of the solvents the desired product is obtained. LC-MS: tR=0.98 min; [M+H]+=489.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH2:11].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C(O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]=[CH:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=1
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: O=Cc1cccc(Br)c1
Solvent: CCO
Product: COC(=O)c1cc(Cl)ccc1N=Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 23.9 %

Procedure:
A mixture of 2-amino-5-chloro-benzoic acid methyl ester (11.7 g, 63 mmol) and 3-bromo-benzaldehyde (11.7 g, 63 mmol) in ethanol (200 mL). The reaction mixture was heated to reflux for 2 hours. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 2-{[1-(3-bromo-phenyl)-methylidene]-amino}-5-chloro-benzoic acid methyl ester (5.3 g, 24%) as a white solid: LC/MS m/e calcd for C15H11BrClNO2 M+: 353.6, observed: 353.6.
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH:32]([CH3:34])[CH3:33])[C:11]([N:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:14][C:15]([NH:17][C@H:18]([CH:23]=[O:24])[CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)CN(C(=O)[C@@H](NC(=O)C1C=CC=CC=1)C(C)C)CC1C=CC=C(NC(OC(C)(C)C)=O)C=1)C.C(OC(=O)CN(C(=O)[C@@H](NC(=O)C1C=CC=CC=1)C(C)C)CC1C=CC=C([NH:85][C:86]([NH2:88])=[O:87])C=1)C>>[C:1]([NH:9][C@@H:10]([CH:32]([CH3:34])[CH3:33])[C:11]([N:13]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([NH:85][C:86]([NH2:88])=[O:87])[CH:31]=1)[CH2:14][C:15]([NH:17][C@H:18]([CH:23]=[O:24])[CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN(Cc1cccc(NC(N)=O)c1)C(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@H](C=O)CC(=O)O)Cc1ccccc1
Agent: CCOC(=O)CN(Cc1cccc(NC(=O)OC(C)(C)C)c1)C(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@H](C=O)CC(=O)O)Cc1cccc(NC(N)=O)c1

Procedure:
Compound 741 was prepared by a method similar to the method used to prepare compound 706, except compound 703 was replaced with compound 740. ##STR120##
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].Cl.[C:6]1([C@H:16]([NH:18][C@H:19]2[CH2:23][CH2:22][N:21]([C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[CH2:20]2)[CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[OH:4][CH2:3][CH2:2][NH:1][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([N:21]2[CH2:22][CH2:23][C@H:19]([NH:18][C@@H:16]([C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=[CH:8][CH:7]=3)[CH3:17])[CH2:20]2)=[CH:25][CH:26]=1
Reactant: NCCO
Reactant: C[C@@H](N[C@H]1CCN(c2ccc(C(=O)O)cc2)C1)c1cccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](N[C@H]1CCN(c2ccc(C(=O)NCCO)cc2)C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.5 %

Procedure:
To a mixed solution of 7.7 mg of 2-aminoethanol and 50 mg of 4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzoic acid hydrochloride (the compound obtained in Example 3.001) dissolved in 8 ml of dimethylformamide were added 22.2 mg of 1-hydroxybenzotriazole, 70 μl of triethylamine and 31.4 mg of EDC hydrochloride, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated, a saturated aqueous sodium bicarbonate solution and chloroform were added to the residue, and the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by NH thin layer silica gel chromatography (chloroform:methanol=39:1) and thin layer silica gel chromatography (chloroform:methanol=9:1) to give 22.6 mg of N-(2-hydroxyethyl)-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamide. (2) To a solution of 22.6 mg of N-(2-hydroxyethyl)-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]-benzamide dissolved in 1 ml of methylene chloride was added dropwise 3 ml of a solution of 4M hydrochloric acid in dioxane, and the mixture was stirred for a while. The reaction mixture was evaporated; and, to the residue was added tert-butanol to dissolve the same, and freeze-dried to obtain 25.6 mg of N-(2-hydroxyethyl)-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamide hydrochloride (the following Table A3, Example 3.017).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:30][C:29](=O)[CH:28]=[C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([N:38]3[CH:42]=[CH:41][N:40]=[C:39]3[CH3:43])[CH:33]=2)[O:26]1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:29](=[O:30])[CH2:28][C:27]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[CH:41][N:40]=[C:39]2[CH3:43])[CH:33]=1)=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nccn1-c1cccc(C2=CC(=O)OC(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2F)cc1N
Product: Cc1nccn1-c1cccc(C(=O)CC(=O)Nc2cc(-c3ccc(F)cc3F)ccc2NC(=O)OC(C)(C)C)c1

Procedure:
Prepared from (3-amino-2′,4′-difluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G43) and 2,2-dimethyl-6-[3-(2-methyl-imidazol-1-yl)-phenyl]-[1,3]dioxin-4-one (Example J15) according to the general procedure K. Obtained as a yellow oil (145 mg).
Reaction SMILES: O1CCC[CH2:2]1.[OH:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8]1.[H-].[Na+].CI>C(OCC)(=O)C>[CH3:2][O:6][CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:11][CH2:12]1
Reactant: C1CCOC1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: COC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 94 %

Procedure:
To a 20 ml tetrahydrofuran solution of 1.87 g (7.95 mmol) of benzyl 4-hydroxy-1-piperidinecarboxylate, 413 mg (60% in oil, 10.33 mmol) of sodium hydride and 792 μl (12.72 mmol) of methyl iodide were added at 0° C., and the mixture was stirred at room temperature for 16.5 hours. Then, the reaction mixture was diluted with ethyl acetate, and washed with water. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 2.08 g (94%) of the captioned compound.
Reaction SMILES: [C:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[N:16][N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][CH2:28][NH:29]C(OC(C)(C)C)=O)[N:18]=2)=[CH:10][CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[ClH:37]>>[ClH:37].[C:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[N:16][N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][CH2:28][NH2:29])[N:18]=2)=[CH:10][CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1ccccc1Cn1nnc(-c2ccc(OC(=O)C(C)(C)C)cc2)n1
Agent: Cl
Product: CC(C)(C)C(=O)Oc1ccc(-c2nnn(Cc3ccccc3OCCN)n2)cc1
Reaction time: 15 h
Yield: 93 %

Procedure:
Hydrogen chloride (10 ml, 4N solution in ethyl acetate) was added to 4-[2-[2-[2-(t-butoxycarbonylamino)ethoxy]benzyl]tetrazol -5-yl]phenyl pivalate (200 mg), obtained in example 34, and the solution was allowed to stand in an ice box for 15 h. After the ethyl acetate was concentrated in vacuo, the resulting crystals were filtered and dried to give 160 mg (93%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.F[C:17]1[C:18]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:19]([CH3:35])[C:20]([C:33]#[N:34])=[C:21]2[C:25]=1[O:24][C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32])=[N:22]2>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:17]2[C:18]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[C:19]([CH3:35])[C:20]([C:33]#[N:34])=[C:21]3[C:25]=2[O:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])=[N:22]3)[CH2:4]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(-c3ccccc3O)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(-c3ccccc3O)nc2c1C#N
Temperature: 120 °C
Yield: 24.7 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (100 μl, 0.79 mmol) and triethylamine (220 μl) were added to a dimethyl sulfoxide (5 ml) solution of 7-fluoro-2-(2-hydroxyphenyl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-212) (204 mg, 0.59 mmol). The system was purged with nitrogen, then sealed up, and heated at 120° C. for 30 minutes. After cooling, the solvent was evaporated away under reduced pressure, then the resulting residue was dissolved in chloroform, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated away under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. Elution with a mixed solvent of chloroform/methanol (97:3, v/v) gave a main product. This was washed with a mixed solvent of isopropyl ether and ethanol, and the solid was collected by filtration to obtain the entitled compound (64 mg, 24%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][NH2:43])=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:19])[NH:43][CH2:42][CH2:41][CH2:40][C:37]3[CH:36]=[CH:35][C:34]([Cl:33])=[CH:39][CH:38]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NCCCc1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCCc4ccc(Cl)cc4)cc3)c(Cl)cc21
Reaction time: 0.17 h
Yield: 83.3 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl) chroman-7-yloxy)benzoic acid (Preparation 1) (67 mg, 0.18 mmol) was diluted with DCM (1 mL) followed by the addition of oxalyl chloride in DCM (2M) (98 μl, 0.20 mmol) and DMF (1 drop). After stirring for 10 minutes, 3-(4-chlorophenyl)propan-1-amine (33 mg, 0.20 mmol) and DIEA (68 μl, 0.39 mmol) were added and the reaction was stirred at ambient temperature for 2 hours. The reaction was loaded directly onto a biotage 25 cartridge and eluted with 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes to yield ethyl 6-chloro-7-(4-(3-(4-chlorophenyl)propylcarbamoyl)phenoxy)chroman-4-carboxylate (80 mg, 0.15 mmol, 85% yield).
Reaction SMILES: [I-].[C:2]([O:6][C:7]([NH:9][CH2:10][CH2:11][C:12]1[N:13]([CH3:24])[CH:14]=[C:15]([C:17]2[CH:18]=[N+:19](C)[CH:20]=[CH:21][CH:22]=2)[N:16]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].CN1C=CN=C1>O>[CH3:24][N:13]1[CH:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=[C:12]1[CH2:11][CH2:10][NH:9][C:7](=[O:8])[O:6][C:2]([CH3:4])([CH3:3])[CH3:5]
Reactant: Cn1cc(-c2ccc[n+](C)c2)nc1CCNC(=O)OC(C)(C)C
Agent: Cn1ccnc1
Agent: [I-]
Solvent: O
Product: Cn1cc(-c2cccnc2)nc1CCNC(=O)OC(C)(C)C
Reaction time: 9 h
Yield: 167 %

Procedure:
A solution of 3-(2-(2-(tert-butoxycarbonylamino)ethyl)-1-methyl-1H-imidazol-4-yl)-1-methylpyridinium iodide (655 mg, 2.06 mmol) in 1-methylimidazole (2 mL, 25.1 mmol) was heated to 160° C. and stirred for 9 h. The reaction mixture was poured into water (5 mL) and extracted with dichloromethane (2×5 mL). The organic layers were combined, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (using silica gel amine phase and an ethyl acetate/heptane gradient) to give 1.04 g of a light yellow liquid. The residual 1-methylimidazole was distilled of in a “Kugelrohr” (ball tube) vacuum distillation apparatus at 100-120° C. at ˜0.2 mbar to yield the product as light yellow oil (102 mg, 337 μmol, 16.3%). MS: M=303.1 (M+H)+