Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:18][C@H:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:29])[CH2:21][CH2:20]2)=[N:4][C:5]([N:8]2[C:12]3[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=3[N:10]=[CH:9]2)=[N:6][CH:7]=1.C1N=CN([C:35](N2C=NC=C2)=[O:36])C=1>C1COCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]2[N:10]=[CH:9][N:8]([C:5]3[N:4]=[C:3]4[C:2]([NH:1][C:35](=[O:36])[N:18]4[C@H:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:22](=[O:29])[CH2:21][CH2:20]4)=[CH:7][N:6]=3)[C:12]=2[CH:13]=1
Reactant: Nc1cnc(-n2cnc3ccc(F)cc32)nc1N[C@@H]1CCC(=O)c2ccccc21
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1CC[C@@H](n2c(=O)[nH]c3cnc(-n4cnc5ccc(F)cc54)nc32)c2ccccc21
Yield: 26.4 %

Procedure:
A solution of (4R)-4-(5-amino-2-(6-fluoro-1H-benzo[d]imidazol-1-yl)pyrimidin-4-ylamino)-3,4-dihydronaphthalen-1(2H)-one (32 mg) and CDI (100 mg) in THF (6 mL) was stirred at room temperature overnight and refluxed for 2.5 h. Volatiles were removed in vacuo and the residue was purified by preparative HPLC to afford 9 mg of the title compound as the TFA salt. 1H NMR (CD3OD) δ 9.20 (s, 1H), 8.36 (s, 1H), 8.20 (m, 1H), 7.68 (m, 1H), 7.58-7.47 (m, 3H), 7.20-7.14 (m, 2H), 6.10 (m, 1H), 3.09-2.93 (m, 3H), 2.49 (m, 1H); MS (MH+) 415.1.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24]([OH:26])=[O:25].C(N(CC)CC)C>O>[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[C:23]([C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)[C:24]([OH:26])=[O:25])=[CH:12][CH:11]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: O=C(O)Cc1cccs1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CSc1ccc(C=C(C(=O)O)c2cccs2)cc1
Temperature: 85 °C
Yield: 37.3 %

Procedure:
A mixture of acetic anhydride (90 mL), 4-(methylthio)benzaldehyde (13.17 g, 82.2 mmol), 2-(2-thienyl)acetic acid (12.09 g, 83.3 mmol), and triethylamine (8.60 g, 85 mmol) was heated to reflux for 4 hours. The reaction was cooled to 85° C., and water (80 mL) was added through an addition funnel. A brown solid was isolated by filtration and air dried to afford the propenoic acid (8.48 g, 37%): mp 201°-206° C. 1H NMR (DMSO-d6) 300 MHz 12.80 (br s, 1H), 7.77 (s,1H), 7.60 (d, J=5.2 Hz, 1H), 7.09 (m, 5H), 6.92 (d, J=3.3 Hz, 1H), 2.42 (s, 3H). 13C NMR (DMSO-d6) 168.24, 141.60, 141.30, 136.84, 131.08, 130.86, 128.46, 127.86, 125.51, 125.28, 14.52. Mass spectrum: M+H=277.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:3]12.[CH2:32]([N:34](C(C)C)C(C)C)[CH3:33].Cl.C(N)C>CN(C=O)C>[CH2:32]([NH:34][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][CH2:31][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:14][CH2:15]2)=[CH:27][CH:26]=1)[CH3:33]
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.8 %

Procedure:
(S)-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (122 mg, 0.29 mmol) was taken up in DMF (2.9 mL). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (152 μl, 0.87 mmol), O-(7-azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (165 mg, 0.434 mmol), and ethanamine hydrochloride (26.0 mg, 0.318 mmol). The reaction was stirred at room temperature overnight. The reaction was purified via HPLC (10-80 MeCN/H2O, TFA buffered). The fractions were collected and lyophilized to yield 135 mg (85%) of the product as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.82 (s, 1H), 9.83 (br. s., 1H), 8.25 (t, J=5.6 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.77 (d, J=8.8 Hz, 2H), 6.94-7.12 (m, 3H), 4.59 (d, J=13.1 Hz, 1H), 4.27 (br. s., 2H), 3.85-4.10 (m, 3H), 3.43 (d, J=10.4 Hz, 2H), 3.21-3.30 (m, 2H), 2.95-3.19 (m, 4H), 2.61-2.72 (m, 1H), 2.05 (d, J=11.8 Hz, 1H), 1.87 (d, J=12.4 Hz, 1H), 1.66 (d, J=12.1 Hz, 1H), 1.31-1.62 (m, 3H), 1.09 (t, J=7.2 Hz, 3H). [M+H] calc'd for C, 23; H, 27; N, 5; O, 3, 449; found, 449. MP: 232.6° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C@H:11]([CH3:35])[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:25](=[O:26])[C:24]2[N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=[N:21][C:20]=2[N:19]([CH3:34])[C:17]1=[O:18])(=O)C>CO>[CH2:27]([N:23]1[C:24]2[C:25](=[O:26])[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]([OH:10])[CH3:35])[C:17](=[O:18])[N:19]([CH3:34])[C:20]=2[N:21]=[CH:22]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@@H](O)CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Yield: 89.4 %

Procedure:
Potassium carbonate (30 g) was added to a solution of (R)-1-(5-acetoxyhexyl)-7-benzyl-3-methylxanthine (33.7 g, 84.7 mmol) in methanol (400 ml) and refluxed for 12 hours. After concentration under reduced pressure, the residue was partitioned between ethyl acetate (500 ml) and water (300 ml). The organic layer was washed with water (100 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide (R)-7-benzyl-1-(5-hydroxyhexyl)-3-methylxanthine (27 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[O:17])=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:2]=1.O.[CH3:19][N:20](C)[C:21]1C=CC(B(O)O)=CN=1>>[CH3:19][N:20]([CH3:21])[C:6]1[N:1]=[CH:2][C:3]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[O:17])=[CH:13][CH:14]=3)[NH:9][N:8]=2)=[CH:4][CH:5]=1
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: O=Cc1ccc2c(-c3cccnc3)n[nH]c2c1
Solvent: O
Product: CN(C)c1ccc(-c2n[nH]c3cc(C=O)ccc23)cn1

Procedure:
According to the procedure for the synthesis of 3-(pyridin-3-yl)-1H-indazole-6-carbaldehyde, except substituting 2-(dimethylamino)pyridine-5-boronic acid hydrate (41 mg, 0.22 mmol), the title compound was prepared as a yellow powder (14 mg, 29%). 1H NMR (400 MHz, d6-DMSO) δ ppm 10.13 (s, 1H), 8.72 (d, J=2.4 Hz, 1H), 8.17-8.16 (m, 2H), 8.09 (dd, J=8.4, 2.1 Hz, 1H), 7.62 (d, J=8.9 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 3.09 (s, 6H); MS ESI 267.0 (100) [M+H]+, calcd for [C15H14N4O+H]+ 267.12.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17](=[O:42])[C@@H:18]([CH2:27][C:28]1[CH:33]=[CH:32][C:31](OS(C(F)(F)F)(=O)=O)=[CH:30][CH:29]=1)[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C1(C)C=CC=CC=1>[CH3:15][O:16][C:17](=[O:42])[C@@H:18]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[CH:32][CH:33]=1)[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21]
Reactant: COC(=O)[C@@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Reactant: OB(O)c1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](Cc1ccc(-c2ccsc2)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of N-t-butoxycarbonyl-D-tyrosine methyl ester (2.5 g, 9.48 mmol) in 10 mL of methylene chloride and pyridine (1.9 mL, 23.7 mmol) at -15° C. is added triflic anhydride (1.9 mL, 11.4 mmol). The reaction is stirred 30 minutes. The mixture is washed with water, 0.5 N NaOH, 15% aqueous citric acid, brine dried over MgSO4, filtered and concentrated giving N-t-butoxycarbonyl-4-trifluoromethanesulfonyloxy-D-phenyl alanine methyl ester. A solution of 3-thiopheneboronic acid (1.4 g, 10.9 mmol), potassium carbonate (1.13 g, 8.2 mmol) in 25 mL of toluene is heated to 80° C. and the catalyst tetrakis (triphenyl phosphine)-Pd (0.19 g, 0.16 mmol) is added. N-t-Butoxycarbonyl-4-trifluoro methanesulfonyloxy-D-phenylalanine methyl ester (2.34 g, 5.47 mmol) in 25 mL of toluene is added dropwise and stirred at 80° C. for 3 hours. The mixture is filtered through Celite and washed with ethyl acetate. The organic layer is washed with 0.5 N NaOH (2×), 15% citric acid, water, brine, dried over MgSO4, filtered and concentrated. Chromatography on silica gel with ethyl acetate/toluene (1:5) gives N-t-butoxy carbonyl-4-(3-thienyl)-D-phenylalanine methyl ester. Treatment of the above with dilute HCl in 1,4-dioxane at room temperature overnight yields 4-(3-thienyl)-D-phenylalanine methyl ester hydrochloride.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([C:17]3[CH:18]=[N:19][N:20]([CH2:23][CH3:24])[C:21]=3[OH:22])=[O:16])[C:12]=2[CH3:14])[S:7](=[O:26])(=[O:25])[CH2:6][CH2:5]1.N1C=CC=N1.[CH2:32](Br)[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][N:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([C:17]3[CH:18]=[N:19][N:20]([CH2:23][CH3:24])[C:21]=3[O:22][CH2:32][C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:34])=[O:16])[C:12]=2[CH3:14])[S:7](=[O:25])(=[O:26])[CH2:6][CH2:5]1
Reactant: O=C(CBr)c1ccccc1
Reactant: CCn1ncc(C(=O)c2ccc3c(c2C)C(=NOC)CCS3(=O)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1cn[nH]c1
Solvent: CC(C)=O
Product: CCn1ncc(C(=O)c2ccc3c(c2C)C(=NOC)CCS3(=O)=O)c1OCC(=O)c1ccccc1
Yield: 52 %

Procedure:
0.4 Gram (1.1 mmol) of 4-methoxyimino-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide corresponding to pyrazole derivative (I-H), 0.23 g (1.2 mmol) of phenacyl bromide corresponding to compound B-A-Hal and 0.15 g of potassium carbonate were added to 10 ml of acetone, and the mixture was stirred under heat for 8 hours. Insolubles were removed by filtration, and then the acetone was distilled off. The residue was dissolved in ethyl acetate, and the mixture was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was subjected to column chromatography (hexane/ethyl acetate) to give 4-methoxyimino-5-methyl-6-(1-ethyl-5-phenacyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound Ib-2) at a yield of 52%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[NH:14][CH:15]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)[C:16]([N:18]1[CH2:21][C:20]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:19]1)=[O:17])(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:14][CH:15]([CH2:34][C:35]1[CH:36]=[CH:37][C:38]([OH:41])=[CH:39][CH:40]=1)[C:16]([N:18]1[CH2:19][C:20]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:21]1)=[O:17]
Reactant: CCCCOC1(c2ccccc2C)CN(C(=O)C(Cc2ccc(O)cc2)NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOC1(c2ccccc2C)CN(C(=O)C(N)Cc2ccc(O)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 ml of trifluoroacetic acid are added to a solution of 410 mg (0.8 mmol) of tert-butyl[2-(3-butoxy-3-o-tolyl-azetidin-1-yl)-1-(4-hydroxybenzyl)-2-oxoethyl]carbamate in 5 ml of dichloromethane. After stirring for 1 hour at ambient temperature, the solvent is evaporated off. 440 mg of 2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-hydroxyphenyl)propan-1-one trifluoroacetate are obtained with a quantitative yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[CH3:13][N:14]([CH3:20])[C:15](=[O:19])[C:16]([CH3:18])=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1C=CC=CC=1>[CH3:13][N:14]([CH3:20])[C:15]([C:16]1([CH3:18])[C:9]2=[CH:10][CH:11]=[CH:12][N:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1]1)=[O:19]
Reactant: CC(=O)C(=O)N(C)C
Reactant: Oc1ccccc1-n1cccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: c1ccccc1
Product: CN(C)C(=O)C1(C)Oc2ccccc2-n2cccc21

Procedure:
A mixture of 1-(o-hydroxyphenyl)pyrrole (500 mg), N,N-dimethyl-pyruvamide (580 mg), described by W. F. Gresham in U.S. Pat. No. 2,429,877, issued Oct. 28, 1947, 1.7 g of phosphorus pentoxide, 0.5 g of diatomaceous earth (Celite) in 75 ml of benzene is stirred at room temperature for 15 min. and then at 70° C for 11/2 hr. The reaction mixture is filtered. The filtrate is washed with water, dried (MgSO4) and concentrated to give the title compound, identical to the product of Example 15.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:22]=[CH:21][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17](=[O:20])[CH2:18][NH2:19])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.CCN(CC)CC.[C:30]([O:34][C:35]([NH:37][C:38]1[CH:46]=[C:45]([F:47])[C:44]([F:48])=[CH:43][C:39]=1[C:40](O)=[O:41])=[O:36])([CH3:33])([CH3:32])[CH3:31].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>[OH-].[Na+]>[C:30]([O:34][C:35]([NH:37][C:38]1[CH:46]=[C:45]([F:47])[C:44]([F:48])=[CH:43][C:39]=1[C:40]([NH:19][CH2:18][C:17]([NH:16][CH2:15][CH:12]1[CH2:11][CH2:10][N:9]([CH2:8][C:7]2[CH:21]=[CH:22][C:4]([Cl:3])=[CH:5][CH:6]=2)[CH2:14][CH2:13]1)=[O:20])=[O:41])=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.6 %

Procedure:
A solution of 1-(4-chlorobenzyl)-4-{(glycylamino)methyl}piperidine dihydrochloride (738 mg, 2 mmol) in CH2Cl (20 mL) was treated with Et3N (1.1 mL, 8 mmol), 2-(tert-butoxycarbonylamino)-4,5-difluorobenzoic acid (607 mg, 2.2 mmol), EDCI (422 mg, 2.2 mmol) and HOBt (337 mg, 2.2 mmol). After the reaction mixture was stirred at room temperature for 14 h, 0.6 N aqueous NaOH solution (50 mL) was added, and the mixture was extracted with dichloromethane (3 times). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (SiO2, ethyl acetate then ethyl acetate/methanol=92/8) afforded the desired 4-[{(N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl)amino}methyl]-1-(4-chlorobenzyl)piperidine (1.01 g, 92%): ESI/MS m/e 551.3 (M++H, C27H33ClF2N4O4).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[NH2:11][CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1.CN1CCOCC1.Cl.[CH3:31][N:32]([CH3:50])[C:33]1([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[CH2:38][CH2:37][C:36](=[CH:39][C:40](O)=[O:41])[CH2:35][CH2:34]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH-].[Na+]>O.CN(C)C=O>[CH3:50][N:32]([CH3:31])[C:33]1([C:43]2[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=2)[CH2:38][CH2:37][C:36](=[CH:39][C:40]([NH:11][CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=[O:41])[CH2:35][CH2:34]1
Reactant: CN(C)C1(c2ccc(F)cc2)CCC(=CC(=O)O)CC1
Reactant: NCCc1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(C)C1(c2ccc(F)cc2)CCC(=CC(=O)NCCc2c[nH]c3ccccc23)CC1
Temperature: 0 °C
Reaction time: 96 h
Yield: 95 %

Procedure:
1-Hydroxybenzotriazole (864 mg, 6.4 mmol), tryptamine (512 mg, 3.2 mmol) and N-methylmorpholine (0.703 ml, 6.4 mmol) were added to a solution of (4-dimethylamino-4-(4-fluorophenyl)cyclohexylidene)acetic acid hydrochloride (840 mg, 3.2 mmol) in abs. dimethylformamide (25 ml) under argon. The solution was cooled to 0° C., dicyclohexylcarbodiimide (1.32 g, 6.4 mmol) was added and the mixture was stirred at RT for 4 d. Working up of the mixture was carried out by separating off the urea which had precipitated out and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Still further urea thereby precipitated out and was separated off. The filtrate was diluted with water (400 ml), 5 M sodium hydroxide solution (5 ml, 25 mmol) was added and the mixture was stored at 5° C. for 4 d. The product thereby precipitated out as a beige-coloured oily solid in a yield of 95% (1.27 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.N=C=N.[CH:23]1[CH:24]=[CH:25][C:26]2N(O)N=[N:29][C:27]=2[CH:28]=1.CCN(C(C)C)C(C)C.CC1CCCCN1.C(=O)([O-])[O-]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[CH:13][C:14]([C:15]([N:29]3[CH2:25][CH2:24][CH2:23][CH2:28][CH:27]3[CH3:26])=[O:17])=[CH:18][CH:19]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(F)cc2)cc1
Reactant: On1nnc2ccccc21
Agent: CC1CCCCN1
Agent: N=C=N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CCCCN1C(=O)c1ccc(C(=O)Nc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 383.5 %

Procedure:
To a solution of 4-(4-fluorophenylcarbamoyl)benzoic acid (50 mg, 0.19 mmol) in DMF (1 mL) was added PS-Carbodiimide (125 mg, 0.25 mmol), HOBt (26 mg, 0.19 mmol), DIPEA (52 mg, 0.40 mmol) and 2-methylpiperidine (25 mg, 0.25 mmol). The reaction was agitated at room temperature for 18 h. To the reaction was added MP-carbonate and agitated for a further 8 h. The reaction was filtered and concentrated under vacuum to afford diluted with water (10 mL) and isolated the white precipitate by vacuum filtration to afford N-(4-fluorophenyl)-4-(2-methylpiperidine-1-carbonyl)benzamide (248 mg, 95%). 1H-nmr (400 MHz, d6-DMSO) δ 10.37 (br s, 1H), 8.00 (d, J=7 Hz, 2H), 7.83-7.72 (m, 2H), 7.49 (d, J=7 Hz, 2H), 7.21 (t, J=8 Hz, 2H), 3.52-3.01 (m, 3H), 1.75-1.29 (m, 6H), 1.21 (m, 3H); MS (ESI) m/z 341.4.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].Cl.[CH2:20]([O:22][C:23](=[O:26])[CH2:24][NH2:25])[CH3:21]>CO>[CH2:20]([O:22][C:23](=[O:26])[CH2:24][NH:25][CH:15]1[CH2:16][CH2:17][N:12]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:13][CH2:14]1)[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CNC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 16 h
Yield: 83.5 %

Procedure:
Sodium cyanoborohydride (189 mg, 3.01 mmol) was added to a solution of 1-boc-4-piperidone (500 mg, 2.51 mmol) and glycine ethyl ester hydrochloride (350 mg, 2.51 mmol) in methanol (12.5 mL). After 16 h, the mixture was quenched with saturated ammonium chloride solution, concentrated, and partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/5% (10% ammonium hydroxide/methanol)] gave the title compound (600 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11]C([O-])=O>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:11][C:10]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=Cc1ccc(Cl)cc1
Product: CCOC(=O)C=Cc1ccc(Cl)cc1
Yield: 89.9 %

Procedure:
4-Chlorobenzaldehyde (4.20 g, 30 mmol) and mono-ethyl malonate (4.60 ml, 39 mmol) were reacted as described under General Procedure A to furnish the title compound (5.68 g, 89%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.63 (d, J=16.0 Hz, 1H), 7.46-7.42 (m, 2H), 7.38-7.32 (m, 2H), 6.41 (d, J=16.0 Hz, 1H), 4.26 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:10]=[CH:11][C:12]2[C:18](=[O:19])[C:17]3[CH:20]=[CH:21][CH:22]=[C:23]([O:24][CH2:25][C@H:26]4[CH2:30][O:29]C(C)(C)[O:27]4)[C:16]=3[CH2:15][CH2:14][C:13]=2[CH:33]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:10]=[CH:11][C:12]2[C:18](=[O:19])[C:17]3[CH:20]=[CH:21][CH:22]=[C:23]([O:24][CH2:25][C@H:26]([OH:27])[CH2:30][OH:29])[C:16]=3[CH2:15][CH2:14][C:13]=2[CH:33]=1
Reactant: CC1(C)OC[C@H](COc2cccc3c2CCc2cc(Nc4ccccc4N)ccc2C3=O)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: Nc1ccccc1Nc1ccc2c(c1)CCc1c(OC[C@H](O)CO)cccc1C2=O
Yield: 40 %

Procedure:
For the synthesis of the title compound, 0.10 g (0.225 mmol) of (S)-8-(2-aminophenylamino)-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one and 0.0537 g (0.282 mmol) of p-toluenesulfonic acid monohydrate in 6 ml of methanol and 1.5 ml of water are reacted by method N. C24H24N2O4 (Mr=404.47); yield: 40%
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]#[C:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[O:29][CH3:30])C1C=CC=CC=1>C(O)C.[C].[Pd]>[CH3:30][O:29][C:22]1[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8]
Reactant: COc1ccc(OC)c(C#CCCCCCCCCCCOCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(OC)c(CCCCCCCCCCCCO)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
554.1 mg of 2-(12(benzyloxy)dodec-1-ynyl)-1,4-dimethoxybenzene was dissolved in 3 ml of ethanol, 5% palladium-carbon (60 mg) was added to this solution, and this was placed under hydrogen atmosphere. The reaction mixture was stirred for one day at room temperature. The reaction solution was filtered through Celite, and the solvent was distilled off at reduced pressure. Purification of the residue by silica gel chromatography (hexane:ethyl acetate=6:4) gave 12-(2,5-dimethoxyphenyl)dodecan-1-ol as a colorless oil at a 92% yield.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl>[CH2:24]([O:23][C:21]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:22])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(R)-Pyrrolidine-2-carboxylic acid tert-butyl ester (16.11 g, 94.1 mmol) in DCM (250 ml) under an inert atmosphere of argon is treated with triethyl amine (26 ml, 188 mmol) and then cooled to 0° C. with a ice bath. To this cooled solution is added dropwise ethyl chloroformate (8.99 ml, 94.1 mmol) and the reaction mixture is left to stir at 0° C. for 3 hours. The reaction mixture is washed with 1M HCl (2×100 ml), water, brine, dried over MgSO4 and concentrated in vacuo to yield the titled compound as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[O:16][CH3:17].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[CH:28][C:27]=2[O:39][CH3:40])[C:22]([Cl:41])=[CH:21][N:20]=1>>[Cl:41][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[CH:28][C:27]=2[O:39][CH3:40])=[N:24][C:19]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[O:16][CH3:17])=[N:20][CH:21]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCCc2c1ccc(N)c2OC
Product: CCN1C(=O)CCCc2c1ccc(Nc1ncc(Cl)c(Nc3ccc(N4CCN(C)CC4)cc3OC)n1)c2OC
Yield: 31.4 %

Procedure:
Following a procedure analogous to 101b, 7-Amino-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (46 mg) and (2,5-Dichloro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine (60 mg) were reacted to give 7-{5-Chloro-4-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-2-ylamino}-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (29 mgs, 26%) as an off-white solid. 1H-NMR (CDCl3, 400 MHz): δ 8.27 (d, J=8.8 Hz, 1H), 8.19 (d, J=8.6 Hz, 1H), 8.06 (s, 1H), 7.55 (s, 1H), 7.40 (s, 1H), 6.94 (d, J=8.9 Hz, 1H), 6.59-6.55 (m, 2H), 3.93 (s, 3H), 3.85-3.81 (broad m, 2H) 3.80 (s, 3H), 3.26-3.23 (m, 4H), 2.65-2.63 (M, 4H), 2.39 (s, 3H), 2.32 (broad s, 2H), 1.74 (broad s, 4H), 1.22 (t, J=6.1 Hz, 3H); LC/MS Found (M+H)+=565.98; MP:186-187° C.