Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.Br[CH2:11][C:12]([C:14]1[CH:23]=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Br:24])[CH:20]=2)[N:15]=1)=[O:13].[C:25]([O:29][C:30]([N:32]1[C@H:37]([C:38]([OH:40])=[O:39])[CH2:36][C@@H:35]2[C@H:33]1[CH2:34]2)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(#N)C>[C@@H:33]12[CH2:34][C@@H:35]1[CH2:36][C@@H:37]([C:38]([O:40][CH2:11][C:12]([C:14]1[CH:23]=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Br:24])[CH:20]=3)[N:15]=1)=[O:13])=[O:39])[N:32]2[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Reactant: O=C(CBr)c1cnc2cc(Br)ccc2n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)OCC(=O)c1cnc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
DIPEA (0.040 mL, 0.227 mmol) was added to a solution of 2-bromo-1-(6-bromoquinoxalin-2-yl)ethanone (50 mg, 0.152 mmol) and (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (37.9 mg, 0.167 mmol) in acetonitrile (1.5 mL) and the mixture was stirred at rt for 16 h. The solvent was evaporated and the residue was partitioned between EtOAc (20 mL)/aq. sat. NaHCO3 (5 mL). The organic layer was dried (MgSO4), filtered and concentrated to yield crude (1R,3S,5R)-3-(2-(6-bromoquinoxalin-2-yl)-2-oxoethyl) 2-tert-butyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (63 mg) as orange solid. LC-MS retention time 2.74 min; m/z 476 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm 510. Solvent A=90% water: 10% methanol: 0.1% TFA. Solvent B=10% water: 90% methanol: 0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH:8]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([CH3:15])[CH:9]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:14][C:13]1[CH:12]=[CH:11][C:10]([CH3:15])=[CH:9][CH:8]=1)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Cc1ccc(O)cc1
Reactant: CCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)Oc1ccc(C)cc1

Procedure:
Pentanoyl chloride (39.8 g) in dichloromethane (50 ml) was added slowly to a solution of p-cresol (32.4 g) and triethylamine (36.4 g) in dichloromethane (250 ml) with ice cooling. After 1 hour the reaction mixture was washed with brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 4-methylphenyl pentanoate.
Reaction SMILES: P([O-])([O-])([O-])=[O:2].[K+].[K+].[K+].[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][C:19]#[N:20])=[CH:10]1>>[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:18][C:19]([NH2:20])=[O:2])=[CH:10]1
Reactant: O=P([O-])([O-])[O-]
Reactant: N#CCc1c[nH]c2ccccc12
Agent: [K+]
Product: NC(=O)Cc1c[nH]c2ccccc12

Procedure:
The suspension of the bacterial cells (corresponding t 25 to 5.92 mg of the dry cells) obtained in Example 8 was added to 4 ml of the reaction solution containing 10 mM of a potassium phosphate buffer (pH 8.0) and 4 M of 3-indoleacetonitrile, and the reaction was conducted at 25° C. After 24 hours from the initiation of the reaction, 4 M (697 g/lit.) of 3-indoleacetamide was produced with a 100% conversion.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[C:41]([CH3:43])[N:40]=[C:39]([O:44][CH2:45][CH3:46])[CH:38]=1>>[CH2:45]([O:44][C:39]1[CH:38]=[C:37]([C:16]2[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:34])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:14][CH:15]=2)[CH:42]=[C:41]([CH3:43])[N:40]=1)[CH3:46]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CCOc1cc(Br)cc(C)n1
Product: CCOc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc(C)n1

Procedure:
The title compound was prepared from (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 and 4-bromo-2-ethoxy-6-methylpyridine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.259 min, m/z=489.2; 1H NMR (CDCl3) 1.10 (s, 3H), 1.15 (s, 3H), 1.34 (m, 3H), 1.49 (m, 3H), 2.16 (m, 3H), 2.19 (m, 1H), 2.32 (m, 1H), 2.42 (m, 3H), 2.79 (m, 1H), 4.32 (m, 2H), 5.66 (m, 1H), 6.55 (s, 1H), 6.76 (s, 1H), 6.98 (m, 2H), 7.19-7.29 (m, 7H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6]C=CC=1.[CH3:18][O:19][C:20](=[O:41])[CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[C:20]([CH:21]=[CH:13][C:12]1[CH:15]=[CH:16][C:9]([O:8][CH2:1][CH2:2][CH2:7][CH3:6])=[CH:10][C:11]=1[OH:17])([O:19][CH3:18])=[O:41]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCCOc1ccc(C=CC(=O)OC)c(O)c1

Procedure:
A solution of 4-benzyloxy-2-hydroxybenzaldehyde (1.14 g, 5 mmol) and methyl(triphenylphosphoranylidene)acetate (3.51 g, 10 mmol) in THF (40 ml) is stirred at room temperature for 18 hours. The reaction mixture is then concentrated in vacuo and the residue purified by dry column chromatography using 25% EtOAc in hexane to 2:1/hexane:EtOAc. The concentrated residue is triturated with EtOAc/ether to obtain 2-carbomethoxyvinyl-5-butoxyphenol which is confirmed by NMR and used directly in the next step.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5][O:6][CH2:7][C:8]([OH:10])=O)[CH3:2].[NH2:12][C@@H:13]([CH2:36][C:37]([NH:39][C:40]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[C:14]([N:16]([CH2:26][C:27]1[C:28]2[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=2[S:30][CH:31]=1)[C@@H:17]([CH3:25])[CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[O:15]>>[S:30]1[CH:31]=[C:27]([CH2:26][N:16]([C@@H:17]([CH3:25])[CH:18]([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])[C:14](=[O:15])[C@@H:13]([NH:12][C:8](=[O:10])[CH2:7][O:6][NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[CH2:36][C:37](=[O:38])[NH:39][C:40]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:28]2[CH:35]=[CH:34][CH:33]=[CH:32][C:29]1=2
Reactant: CCNC(=O)NOCC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCNC(=O)NOCC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N(Cc1csc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 37 mg (0.23 mmol) was coupled with (S)-2-amino-N1-(benzo[b]thiophen-3-ylmethyl)-N1—((S)-1,1-diethoxypropan-2-yl)-N4-tritylsuccinamide (Compound IV-21) 100 mg (0.15 mmol) to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:21][CH:22]=1)([O-:16])=[O:15].C(N(C(C)C)CC)(C)C>ClCCl>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:24][CH2:25][N:26]([C:5]([C:4]3[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=3[C:2]([F:13])([F:12])[F:1])=[O:6])[CH2:27][CH2:28]2)=[N:21][CH:22]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)nc1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
2-(Trifluoromethyl)benzoyl chloride (2.0 mL, 11.0 mmol) was added slowly to a solution of 1-(5-nitropyridin-2-yl)piperazine (2.0 g, 10 mmol) and diisopropylethylamine (3.5 mL, 20 mmol) in dichloromethane (15 mL) at 0° C. under argon. The mixture was then stirred at 25° C. for 2 h. The reaction was quenched with H2O. The aqueous phase was extracted with ethyl acetate. The organic phase was washed with saturated NaCl and dried over anhydrous MgSO4. The organic phase was concentrated and then purified by column chromatography to yield [4-(5-nitropyridin-2-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone as a yellow solid (1.55 g, 41% yield). MS (ES+) m/z 381.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:19][CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccccc1CBr
Temperature: 25 °C
Yield: 623.6 %

Procedure:
To a solution of methyl 2-(methyl)benzoate 3a (9.46 g, 6.3 mmol) in chloroform (200 mL) were added NBS (13.8 g, 7.6 mmol) and benzoyl peroxide (760 mg, 0.32 mmol). The reaction mixture was stirred at reflux overnight. When the mixture was cooled to rt, filtered and concentrated. The residue was purified by CC, eluted with PE to give 3b as a colorless oil (9 g, 62% yield).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH2:7]([OH:13])[CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH3:12].OS(O)(=O)=O>N1C=CC=CC=1>[CH2:7]([O:13][C:1](=[O:5])[C:2]([O:13][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH3:12])=[O:3])[CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH3:12]
Reactant: CC/C=C\CCO
Reactant: O=C(Cl)C(=O)Cl
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Product: CC/C=C\CCOC(=O)C(=O)OCC/C=C\CC
Temperature: 25 °C

Procedure:
Oxalyl chloride (12.7 g, 100.0 mmol) was added dropwise during 20 min to a stirred solution of (Z)-3-hexenol (20.0 g, 200.0 mmol) in pyridine (240 mL) at 0° C. The reaction mixture was allowed to warm up to room temperature during the week-end, then added to H2SO4 (50%, containing ice, 400 mL), extracted with ether (400 mL and 200 mL), treated again with H2SO4 (50%, containing ice, 400 mL), washed with a saturated solution of NaCl (200 mL) and a saturated solution of NaHCO3 (200 mL, 2×). The organic layer was dried (Na2SO4) and concentrated. Column chromatography (SiO2, heptane/diethyl ether 9:1) gave, after drying under vacuum (0.5 mbar, 1 h), 20.9 g (82%) of an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].N1C=CN=C1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16].O>CN(C)C=O>[C:15]([Si:19]([CH3:21])([CH3:20])[O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A mixture of 3-hydroxy-benzonitrile (5.0 g, 42.0 mmol) and imidazole (7.15 g, 105 mmol) in N,N-dimethylformamide (100 mL) was treated with tert-butyl-chloro-dimethyl-silane (7.6 g, 50.4 mmol) in N,N-dimethylformamide (50 mL) over 10 min. The reaction was stirred at rt overnight. The reaction mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographered using hexane/ethyl acetate (10:1) to give the title compound (9.27 g, 95%). MS (DCI/NH3) m/z 234 (M+1)+. 1HNMR (500 MHz, DMSO-d6) δ ppm 0.26 (s, 6H) 1.00 (s, 9H) 7.26 (dq, J=7.93, 1.22 Hz, 1H) 7.35 (t, J=2.44 Hz, 1H) 7.50 (m, 2H).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([NH:10][C:11]2[N:16]=[C:15]([NH:17][CH3:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[CH:13][N:12]=2)=[C:4]([Cl:23])[CH:3]=1.[CH3:24][N:25]1[C:29]([Sn](CCCC)(CCCC)CCCC)=[CH:28][N:27]=[N:26]1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:23][C:4]1[CH:3]=[C:2]([C:29]2[N:25]([CH3:24])[N:26]=[N:27][CH:28]=2)[C:7]([O:8][CH3:9])=[CH:6][C:5]=1[NH:10][C:11]1[N:16]=[C:15]([NH:17][CH3:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[CH:13][N:12]=1
Reactant: CNc1nc(Nc2cc(OC)c(Br)cc2Cl)ncc1C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnnn1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CNc1nc(Nc2cc(OC)c(-c3cnnn3C)cc2Cl)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 44.3 %

Procedure:
A mixture of N2-(4-bromo-2-chloro-5-methoxyphenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (50 mg, 0.12 mmol), 1-methyl-5-(tributylstannyl)-1H-1,2,3-triazole (68 mg, 0.18 mmol) and Pd(dppf)2Cl2 (10 mg, 0.012 mmol) in dioxane (4 mL) was degassed under a stream of nitrogen for 10 min. The reaction mixture was heated to 100° C. for 18 h. Further amounts of 1-methyl-5-(tributylstannyl)-1H-1,2,3-triazole (68 mg, 0.18 mmol) and Pd(dppf)2Cl2 (10 mg, 0.012 mmol) were added and the mixture maintained at 100° C. for another 24 h, after which further amounts of 1-methyl-5-(tributylstannyl)-1H-1,2,3-triazole (68 mg, 0.18 mmol) and Pd(dppf)2Cl2 (10 mg, 0.012 mmol) were added. The mixture was maintained at 100° C. for another 48 h. The mixture was cooled and concentrated to dryness under vacuum, and the residue partitioned between DCM and water. The separated organic phase was concentrated to dryness under vacuum and the residue purified by RP-HPLC; the product was isolated as a cream solid (22 mg, 44%). LCMS (ESCI_Formic_MeCN): [MH+]=414 at 3.45 min. 1H NMR δ (DMSO-d6): 8.58 (s, 1H); 8.16 (s, 1H); 7.98 (s, 1H); 7.71 (s, 1H); 7.42 (s, 1H); 7.24 (d, J=5.1, 1H); 3.82 (s, 3H); 3.76 (s, 3H); 2.87 (d, J=4.4, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[N:8]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1.[CH2:21]1[N:26]([C:27]2[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=2)[CH2:25][CH2:24][N:23]2[CH2:34][CH2:35][CH2:36][CH:22]12>>[CH:16]1([N:8]2[C:6]3[N:7]=[C:2]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([N:26]5[CH2:25][CH2:24][N:23]6[CH2:34][CH2:35][CH2:36][CH:22]6[CH2:21]5)=[CH:32][N:31]=4)[N:3]=[CH:4][C:5]=3[CH:10]=[C:9]2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: Nc1ccc(N2CCN3CCCC3C2)cn1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN5CCCC5C4)cn3)nc2n1C1CCCC1
Yield: 37.2 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (100 mg, 0.34 mmole) was combined with 5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-2-amine (74.6 mg, 0.34 mmole) which gave 7-cyclopentyl-2-(5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (60 mg) in 37% yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=3[C:13]([O:15]C)=[O:14])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+].Cl>O1CCCC1.CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=3[C:13]([OH:15])=[O:14])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1ccccc1Oc1ccc2[nH]ncc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1Oc1ccc2[nH]ncc2c1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 86.8 %

Procedure:
The methyl 2-(1H-indazol-5-yloxy)benzoate (960 mg, 3.58 mmol) synthesized in Example 478 was dissolved in a mixture of tetrahydrofuran (10 ml) and methanol (5 ml), and a 1N-aqueous sodium hydroxide solution (7 ml) was added thereto at room temperature and then stirred at 60° C. for 40 minutes. After the reaction, the reaction solution was cooled to 0° C., adjusted to pH 4 with a 2N-aqueous hydrochloric acid solution, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated to obtain 2-(1H-indazol-5-yloxy)benzoic acid (790 mg, 86%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a solution of 1-benzyl-4-(4-methoxyphenyl)piperidin-4-ol (7 g, 23.5 mmol) in DCM (150 mL) was added trifluoroacetic acid (2.68 g, 23.5 mmol) and the reaction mixture was stirred at rt overnight. The mixture was then evaporated under reduced pressure and partitioned between 500 mL saturated aqueous sodium bicarbonate and 500 mL of ethyl acetate. The organic layer was separated, dried over Na2SO4, filtered, and evaporated under reduced pressure to yield 1-benzyl-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (5.9 g, 88% yield). LCMS (method F) RT 2.84 min, 100% AP, m/z 280.4 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([NH:11][CH:12]2[CH2:14][CH2:13]2)[N:3]=1.[NH:15]1[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[CH:8]1([C:6]2[N:5]=[C:4]([NH:11][CH:12]3[CH2:14][CH2:13]3)[N:3]=[C:2]([N:15]3[CH2:20][CH2:19][S:18][CH2:17][CH2:16]3)[N:7]=2)[CH2:10][CH2:9]1
Reactant: Clc1nc(NC2CC2)nc(C2CC2)n1
Reactant: C1CSCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: C1CN(c2nc(NC3CC3)nc(C3CC3)n2)CCS1
Yield: 83.4 %

Procedure:
12.2 g of 2-chloro-4-cyclopropyl-6-cyclopropylamino-1,3,5-triazine (0.057 mole), 5.97 g of thiomorpholine (0.057 mole) and 8 g of potassium carbonate (0.057 mole) are mixed in 100 ml of isopropyl alcohol and the mixture is heated at 75°-80° C. for 2 hours. It is cooled, the salts are filtered off and the filtrate is evaporated to dryness. The residue is taken up in 200 ml of dichloromethane, the solution is washed with water and dried over sodium sulfate and the solvent is evaporated. The product obtained is crystallized from a 1:2 (v/v) mixture of ethyl acetate-hexane to give 13.18 g of 2-cyclopropyl-4-cyclopropylamino-6-thiomorpholino-1,3,5-triazine. Yield: 83.5%. M.P.: 133°-134° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].Br[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:24][C:25]([F:28])([F:27])[F:26])[C:19]=2[F:23])[CH:14]=1.C1(C)C=CC=CC=1>CN(C)C=O.[Cu](I)I.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>[F:23][C:19]1[C:20]2[C:15](=[CH:14][C:13]([C:11]#[C:10][C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)=[CH:22][CH:21]=2)[CH:16]=[CH:17][C:18]=1[O:24][C:25]([F:28])([F:27])[F:26]
Reactant: C#Cc1ccc(CCC)cc1
Reactant: Fc1c(OC(F)(F)F)ccc2cc(Br)ccc12
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCc1ccc(C#Cc2ccc3c(F)c(OC(F)(F)F)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.6 %

Procedure:
10 g of 4-propyl-1-ethynylbenzene and 19.5 g of 2-bromo-5-fluoro-6-trifluoromethoxynaphthalene were dissolved in 50 ml of N,N-dimethylformamide (DMF). To the solution wore then added 50 mg of copper iodide (I) and 100 mg of tetrakis(triphenylphosphine)palladium (0). The reaction mixture was then stirred at room temperature for 5 hours. To the reaction solution was then added toluene. Insoluble matters were removed by filtration. The residue was then washed with water and saturated brine. The solvent was then distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate 9/1), and then recrystallized from ethanol to obtain 8.6 g of 1-fluoro-2-trifluoromethoxy-6-[(4-propylphenyl)ethynyl]naphthalene.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[NH:33]N>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[N:33]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1cc(F)ccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1cc(F)ccc1F
Yield: 32 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-3) and 2,5-difluorophenylhydrazine according to the method described for Example 1 in 32% yield. MS: M=419.1 (M+H)+
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]([C:7]1[N:27]=[CH:26][C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]=1[CH3:28])=[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:15]=[CH:14][CH:13]=3)=[O:6])[CH3:3].[H-].[Na+].[CH3:31][N:32]([CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33](=[O:36])[CH2:34]Br>O1CCCC1>[CH3:3][CH:2]([O:4][C:5]([C:7]1[N:27]=[CH:26][C:10]2[N:11]([CH2:34][C:33]([N:32]([CH3:31])[CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[C:12]3[C:17]([C:9]=2[C:8]=1[CH3:28])=[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:15]=[CH:14][CH:13]=3)=[O:6])[CH3:1]
Reactant: Cc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(OCc4ccccc4)c3c12
Reactant: CN(CCc1ccccc1)C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C(=O)OC(C)C)ncc2c1c1c(OCc3ccccc3)cccc1n2CC(=O)N(C)CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
A solution of 1.096 g of 5-benzyloxy-4-methyl-9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methylethyl)-ester (2.93 mmol) in 2.9 ml of tetrahydrofuran is added to a suspension of 92.2 mg of sodium hydride (3.03 mmol; 80% in mineral oil) at 0° C. under nitrogen, and it is stirred for 10 minutes at 0° C. Then, 750 mg (2.93 mmol) of N-methyl-N-phenylethyl-2-bromoacetamide is added, and it is then stirred for 18 hours at 24° C. It is filtered off on Celite, the filtrate is concentrated by evaporation in a vacuum, and the crude product that is thus obtained is purified on a silica gel column with hexane/0-100% ethyl acetate. In this way, 1.24 g of 5-benzyloxy-4-methyl-9-(2-[N-methyl-N-(2-phenylethyl)-amino]-2-oxoethyl)-9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methylethyl)-ester is obtained as an amorphous, yellowish-colored solid with a melting point of 69°-74° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cncn2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J15) (290 mg, 1.0 mmol) and 3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionic acid tert-butyl ester (Example K15) (287 mg, 1.0 mmol) according to the general procedure M. Obtained as a white foam (420 mg, 83%).