Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:46]=[CH:45][C:28]([C:29]([NH:31][CH2:32][C:33]([CH3:44])([CH3:43])[CH2:34][NH:35]C(=O)OC(C)(C)C)=[O:30])=[CH:27][C:26]=4[F:47])[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>Cl.O1CCOCC1>[NH2:35][CH2:34][C:33]([CH3:44])([CH3:43])[CH2:32][NH:31][C:29](=[O:30])[C:28]1[CH:45]=[CH:46][C:25]([NH:24][C:14]2[N:13]=[C:12]([NH:11][C:8]3([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)[N:17]=[C:16]([O:18][CH2:19][C:20]([F:22])([F:23])[F:21])[N:15]=2)=[C:26]([F:47])[CH:27]=1
Reactant: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(CN)CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-butyl 3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzamido)-2,2-dimethylpropylcarbamate (270 mg, 0.40 mmol) was dissolved in 4 M HCl in dioxane (5 mL) solution. After being stirred at room temperature for 3 hours, the mixture was concentrated to give N-(3-amino-2,2-dimethylpropyl)-4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzamide as crude product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][CH:3]=1.C([Li])CCC.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C>>[CH2:9]([N:8]([CH2:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([B:18]([OH:23])[OH:19])=[CH:3][CH:4]=1)[CH3:10]
Reactant: CCN(CC)c1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Product: CCN(CC)c1ccc(B(O)O)cc1
Yield: 94.6 %

Procedure:
In a manner similar to that of Example 1c, by reacting 5 g of (4-bromo-phenyl)diethylamine (21.9 mmol) with 13 mL of 2.0 M n-butyllithium solution and 6 mL (26 mmol) of triisopropyl borate. 4 g of 4-diethylaminophenylboronic acid (yield=94%) are obtained in the form of a white solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:34][O:33][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:17]5[CH2:18][CH2:19][C@H:20]6[CH2:25][C@@H:24]([O:26]C(C)=O)[CH2:23][CH2:22][C@:21]6([CH3:30])[C@H:16]5[CH2:15][C:13](=[O:14])[C@:12]4([CH3:31])[C@H:7]3[C@@H:6]2[CH3:32])[CH2:4][CH2:3]1.[CH3:35][C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@@H](O)CC[C@]6(C)[C@H]5CC[C@]4(C)[C@H]3[C@@H]2C)CC1.C([O-])(=O)C>>[CH3:1][C@H:2]1[CH2:34][O:33][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:17]5[CH2:18][CH2:19][C@@:20]6([CH3:35])[CH2:25][C@@H:24]([OH:26])[CH2:23][CH2:22][C@:21]6([CH3:30])[C@H:16]5[CH2:15][C:13](=[O:14])[C@:12]4([CH3:31])[C@H:7]3[C@@H:6]2[CH3:32])[CH2:4][CH2:3]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC(=O)[C@]2(C)[C@@H]4[C@H](C[C@@H]32)O[C@]2(CC[C@@H](C)CO2)[C@H]4C)C1
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: CC(=O)[O-]
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@]5(C)C[C@@H](O)CC[C@]5(C)[C@H]4CC(=O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
This material was recrystallized by dissolving in 300ml of heptane at reflux temperature. The clear solution was concentrated to 65ml, cooled to ambient temperature, and the crystallization product filtered. Washing with a little heptane, collection and drying gave 1.9g of material in well developed prismatic crystals of slightly green color (chlorophyll), and which on TLC (80% benzene, 20% ethyl acetate) analyzed as essentially hecogenin acetate with only a shade of the tigogenin acetate (corresponding to 0.95H and 0.05% approximately). M.p: 243°-244°C., Saponification gave hecogenin m.p. 262°-263°.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([CH:8]([CH3:28])[CH2:9][C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:4][C@H:3]1[OH:29].[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36].C(=O)([O-])[O-].[Na+].[Na+]>O.ClC(Cl)Cl.C(N(CC)CC)C>[OH:29][C@H:3]1[C@H:2]([NH:1][C:35](=[O:36])[C:34]2[CH:38]=[CH:39][CH:40]=[C:32]([C:31]([F:30])([F:41])[F:42])[CH:33]=2)[CH2:7][CH2:6][N:5]([CH:8]([CH3:28])[CH2:9][C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:4]1
Reactant: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](N)[C@H](O)C1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](NC(=O)c2cccc(C(F)(F)F)c2)[C@H](O)C1
Yield: 86.3 %

Procedure:
To a stirred and cooled solution of 4 parts of trans-4-amino-3-hydroxy-N,N,γ-trimethyl-α,αdiphenyl-1-piperidinebutanamide in 120 parts of trichloromethane were added 1.26 parts of N,N-diethylethanamine. A solution of 2.3 parts of 3-(trifluoromethyl)benzoyl chloride in 75 parts of trichloromethane was added dropwise. Upon completion, the reaction mixture was stirred overnight at room temperature. A solution of sodium carbonate in water was added. The separated organic layer was washed with water, dried, filtered and evaporated. The residue was taken up in 2,2'-oxybispropane. The precipitated product was filtered off and dried in vacuo at 60° C., yielding 4.9 parts (86.3%) of trans-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-4-[[3-(trifluoromethyl)benzoyl]amino]-1-piperidinebutanamide; mp. 140.7° C. (compound 1).
Reaction SMILES: [C:1]([N:8]([CH3:20])[C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:22][O:23][C:24](=[O:31])[C@@H:25]([C:27]([SH:30])([CH3:29])[CH3:28])[NH2:26]>>[CH3:7][C:4]([CH3:5])([O:3][C:1]([N:8]([CH3:20])[C@H:9]([C:17]([NH:26][C@@H:25]([C:24]([O:23][CH3:22])=[O:31])[C:27]([SH:30])([CH3:29])[CH3:28])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:2])[CH3:6]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](N)C(C)(C)S
Agent: Cl
Product: COC(=O)[C@H](NC(=O)[C@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C)C(C)(C)S

Procedure:
The title compound was synthesized by coupling Nα -Boc-(N-methyl) phenylalanine (19.0 g, 68.0 mmol) to 13.8 g (69.0 mmol) of D-penicillamine methylester hydrochloride using the procedure described above in Example 19. The title compound was obtained as a white solid (29.6 g, 99.3%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([O:6][C:7]([O:9]N2C(=O)CCC2=O)=O)[CH2:2]1.Cl.Cl.[CH3:19][C:20]1[N:24]([CH:25]2[CH2:31][CH:30]3[N:32]([CH2:33][CH2:34][C:35]4([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH:27]([CH2:28][CH2:29]3)[CH2:26]2)[C:23]2[CH:47]=[CH:48][CH:49]=[CH:50][C:22]=2[N:21]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:19][C:20]1[N:24]([CH:25]2[CH2:31][C@H:30]3[N:32]([CH2:33][CH2:34][C:35]4([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[CH2:36][CH2:37][N:38]([C:7]([O:6][C@H:3]5[CH2:4][CH2:5][O:1][CH2:2]5)=[O:9])[CH2:39][CH2:40]4)[C@H:27]([CH2:28][CH2:29]3)[CH2:26]2)[C:23]2[CH:47]=[CH:48][CH:49]=[CH:50][C:22]=2[N:21]=1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: O=C(O[C@H]1CCOC1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCN(C(=O)O[C@H]2CCOC2)CC1

Procedure:
A solution of 1-({[(3S)-tetrahydrofuran-3-yloxy]carbonyl}oxy)pyrrolidine-2,5-dione (U.S. Pat. No. 6,344,465) (55 mg, 0.24 mmol), amine dihydrochloride II (100 mg, 0.199 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.80 mmol) in acetonitrile (3 mL) was stirred overnight at rt. The solvent was removed at reduced pressure and the remaining material was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution and dried over magnesium sulfate. Filtration and evaporation of the dichloromethane solution provided the crude product which was purified by chromatography on silica gel eluting with 5% methanol/dichloromethane. Title compound in example 692 was obtained as a white hygroscopic powder (70 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 7.66 (d, 1H, J=8 Hz), 7.37 (m, 2H), 7.30-7.20 (m, 4H), 7.16 (m, 2H), 5.25 (m, 1H), 4.61 (m, 1H), 3.85 (m, 4H), 3.73 (m, 2H), 3.22 (m, 4H), 2.58 (br s, 3H), 2.36 (m, 2H), 2.17 (m, 3H), 2.05-1.70 (m, 13H). HRMS C33H42N4O3 m/z 543.3335 (M+H)Cal., 543.3331 (M+H)Obs..
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[O:20][C:19]([C:21]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH2:35][CH2:34][CH:33]([C:36]([O:38]C(C)(C)C)=[O:37])[CH2:32][CH2:31]3)=[N:28][CH:29]=2)=[O:22])=[N:18][N:17]=1.[ClH:43]>C(Cl)Cl.O1CCOCC1>[ClH:43].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[O:20][C:19]([C:21]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH2:31][CH2:32][CH:33]([C:36]([OH:38])=[O:37])[CH2:34][CH2:35]3)=[N:28][CH:29]=2)=[O:22])=[N:18][N:17]=1
Reactant: CC(C)(C)OC(=O)C1CCN(c2ccc(NC(=O)c3nnc(Nc4ccccc4F)o3)cn2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: O=C(Nc1ccc(N2CCC(C(=O)O)CC2)nc1)c1nnc(Nc2ccccc2F)o1
Yield: 42 %

Procedure:
TFA (0.307 mL; 4.0 mmol) was added to a suspension of tert-Butyl 1-{5-[({5-[(2-fluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]pyridin-2-yl}piperidine-4-carboxylate (483 mg; 1.0 mmol) in DCM (5 mL). After 3 days more TFA was added in aliquots (0.31 mL) over 2 days then HCl (1 mL of a 4M solution in 1,4-dioxan) was added. After 24 h the mixture was filtered and the solid was washed with ether and dried under vacuum at 60° C. to give the title compound (193 mg, 42%) as a solid; 1H NMR δ1.55-1.74 (m, 2H), 1.88-2.06 (m, 2H), 2.56-2.69 (m, 1H), 2.69-2.81 (m, 1H), 3.18-3.35 (m, 2H), 4.17 (d, 2H), 7.13-7.22 (m, 1H), 7.24-7.31 (m, 1H), 7.31-7.37 (m, 1H), 7.44 (d, 1H), 7.98-8.09 (m, 1H), 8.19-8.28 (m, 1H), 8.51-8.59 (m, 1H), 10.87 (s, 1H), 11.37 (s, 1H); MS m/e MH+ 427.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][C:9]([NH2:11])=[S:10])=[CH:6][CH:5]=[CH:4][N:3]=1.Br.Br[CH2:14][C:15]([C:17]1[S:21][C:20]([NH:22][C:23](=[O:25])[CH3:24])=[N:19][C:18]=1[CH3:26])=O.O>CCO>[F:1][C:2]1[C:7]([NH:8][C:9]2[S:10][CH:14]=[C:15]([C:17]3[S:21][C:20]([NH:22][C:23](=[O:25])[CH3:24])=[N:19][C:18]=3[CH3:26])[N:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)Nc1nc(C)c(C(=O)CBr)s1
Reactant: NC(=S)Nc1cccnc1F
Agent: Br
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1nc(C)c(-c2csc(Nc3cccnc3F)n2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
According to the general procedure 1, N-(2-fluoropyridin-3-yl)thiourea (prepared from 3-amino-2-fluoropyridine (Asymchem), following procedure D) is added to a solution of N-[5-(bromoacetyl)-4-methyl-1,3-thiazol-2-yl]acetamide, hydrobromide salt (Intermediate 1) and TEA (3 eq) in EtOH. The mixture is stirred for 2 h at RT. After addition of water, the desired product is filtrated off and washed with water. N-{2-[(2-fluoropyridin-3-yl)amino]-4′-methyl-4,5′-bi-1,3-thiazol-2′-yl}acetamide is isolated as a pale yellow solid (57%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8].Cl.[O:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:10]1[CH2:14][CH2:13][N:12]=[C:11]1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8])=[CH:17][CH:16]=1
Reactant: Oc1ccc(-c2ncco2)cc1
Reactant: N#CCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCCCCOc1ccc(C2=NCCO2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
A mixture of 6-bromohexanenitrile, 12 parts of 4-(2-oxazolyl)phenol monohydrochloride, 16.6 parts of potassium carbonate and 282 parts of N,N-dimethylformamide was stirred overnight at 60° C. After cooling, the reaction mixture was poured into water and the product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.2 parts (20.6%) of 6-[4-(4,5-dihydro-2-oxazolyl)phenoxy]hexanenitrile (int. 107).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[N:4][C:5]([C:8]2[NH:12][CH:11]=[N:10][N:9]=2)=[CH:6][CH:7]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.CS(O)(=O)=O.C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[C:3]([CH3:13])=[N:4][C:5]([C:8]2[N:12]=[CH:11][N:10]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][O:14]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2nnc[nH]2)ccc1Br
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(-c2ncn(C3CCCCO3)n2)ccc1Br
Temperature: 68 °C
Yield: 80 %

Procedure:
3-Bromo-2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridine (1 equiv), 3,4-dihydro-2H-pyran (2 equiv) and methanesulfonic acid (0.1 equiv) were combined in tetrahydrofuran, while stirring under nitrogen. The reaction was heated to 68° C. for 3.5 h. After cooling to room temperature over 1 h, triethylamine (0.4 equiv) was added and the resulting solution was stirred 10 min and then concentrated under reduced pressure. Acetonitrile was added and excess tetrahydrofuran was removed by codistillation under reduced pressure, with heating to 35° C. (twice). The resulting residue was dissolved in acetonitrile (1 volume) and water (2.25 volumes) was added. The resultant suspension was stirred 30 min. Solids were collected by filtration, washed with a solution of 20% acetonitrile in water and dried under reduced pressure. The crude product was triturated with hexanes, filtered, further washed with hexanes and dried in a vacuum oven at 35° C. to provide the desired product in 80% yield, as an off white solid. MS (ESI) m/z 324.9 [M+2]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=O)[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].CC1C=C(C=C(C)C=1)C(O)=O.[Br:24]Br.N(C(C)(C)C#N)=NC(C)(C)C#N>>[Br:24][CH2:11][C:4]1[CH:5]=[C:6]([CH:10]=[C:2]([CH3:1])[CH:3]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1cc(C=O)cc(C(=O)O)c1
Reactant: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cc1cc(C)cc(C(=O)O)c1
Product: Cc1cc(CBr)cc(C(=O)O)c1

Procedure:
In general, 5-alkyl-3-formyl-benzoic acids may be prepared from 5-bromo-3-formyl-benzoic acid which in turn is prepared from 3-formyl-benzoid acid according to literature procedures (e.g. D. Zhao, J. S. Moore, J. Org. Chem. (2002), 67, 3548-3554). Thus, a 5-bromo-3-formyl-benzoic acid ester is reacted with the appropriate alkenyl boron derivative (e.g. 2,4,6-trivinyl-cyclotriboroxane) under Suzuki conditions (Lit.: e.g. F. Kerins, D. F. O'Shea, J. Org. Chem. (2002), 67, 4968-4971) followed by catalytic hydrogenation and subsequent ester cleavage to give the desired 5-alkyl-3-formyl-benzoic acid. Alternatively, the alkyl group may also be introduced using the appropriate alkyl-Zn reagents under Negishi conditions (e.g. H. Matsushita, E. Negishi, J. Org. Chem. (1982), 47, 4161-4165). The 3-formyl-group may require protection e.g. as an acetal during these transformations. More specifically, 5-methyl-3-formyl-benzoic acid may be prepared by brominating 3,5-dimethylbenzoic acid using Br2 in the presence of 2,2′-azo-bis-isobutyronitrile (Lit. e.g. Y. Sawada, et al. J. Pesticide Sci. (2002), 27, 365-373) to give 3-bromomethyl-5-methyl-benzoic acid which is then oxidised with MnO2 (Lit. e.g. S. Goswami, et al. Chem. Letters 34 (2005), 194-195) to give the desired 5-methyl-3-formyl-benzoic acid.
Reaction SMILES: [CH:1]([CH:4]([C:10](OCC)=O)[C:5]([O:7]CC)=O)([CH3:3])[CH3:2].[H-].[Na+].[Br:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1CBr.O=S(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C1COCC1.ClCCl>[Br:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:19]=1[CH2:10][CH:4]([CH:1]([CH3:2])[CH3:3])[C:5]2=[O:7]
Reactant: CCOC(=O)C(C(=O)OCC)C(C)C
Reactant: BrCc1ccccc1Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)C1Cc2c(Br)cccc2C1=O
Temperature: 25 °C

Procedure:
To a solution of 99.1 g (0.49 mol) of diethyl isopropylmalonate in 500 ml of THF, 11.7 g (0.49 mol) of sodium hydride was added. This mixture was refluxed for 1 h and then cooled to room temperature. Next, 120 g (0.49 mol) of 2-bromobenzylbromide was added, and the resulting mixture was refluxed for 3 h. This mixture was cooled to ambient temperature and filtered through a glass frit (G2). The precipitate (NaBr) was additionally washed with 3×100 ml of THF. The combined filtrate was evaporated to dryness. The residue was dissolved in 400 ml of ethanol and 160 g of potassium hydroxide and 50 ml of water were added. The resulting mixture was refluxed for 4 h, and then 200 ml of water was added. Ethanol was distilled off at atmospheric pressure. The resulting aqueous solution was acidified with 5 M HCl to pH 1. The precipitate obtained at −30° C. was filtered off, washed with 100 ml of water, and dried in air. The dibasic acid was decarboxylated by heating for 2 h at 160° C. The product obtained was dissolved in 600 ml of dichloromethane, and 600 ml of SOCl2 was added. The mixture was refluxed for 3 h and then evaporated to dryness. The residue was dissolved in 270 ml of dry dichloromethane, and the solution obtained was added dropwise to a suspension of 136 g (1.02 mol) of AlCl3 in 1350 ml of dichloromethane for 1 h at 0° C., while vigorously stirring. Next, the reaction mixture was refluxed for 3 h, cooled to ambient temperature, poured on 500 cm3 of ice, and, finally, acidified with 8M HCl to pH 3. The organic layer was separated, the aqueous layer was washed with 3×300 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The product was isolated by vacuum distillation (bp 154-157° C./3 mm Hg). Yield 73.4 g (60%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH:2]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C(OC(=O)C)(=O)C.C(N(CC)CC)C>[F:13][C:14]1[CH:15]=[C:16](/[CH:17]=[C:7](\[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1cccc(F)c1
Reactant: CCOC(=O)Cc1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)/C(=C/c1cccc(F)c1)c1ccncc1
Yield: 62.2 %

Procedure:
A solution of ethyl 4-pyridylacetate (25.0 g, 0.151 mol) and 3-fluorobenzaldehyde (20.7 g, 0.167 mol) in a mixture of acetic anhydride (100 mL) and triethylamine (20 mL) was heated under reflux for 5.5 hours. After standing to cool, the reaction mixture was concentrated. The residue was diluted with ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium hydrogencarbonate solution twice and brine, dried over anhydrous sodium sulfate and then concentrated. The residue was subjected to silica gel column chromatography (eluent; hexane, hexane:ethyl acetate=9:1), to give the title compound (25.5 g, 62%) as a red-orange oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: NCCCCCC(=O)O
Product: O=C(O)CCCCCN1C(=O)c2ccc(C(=O)O)cc2C1=O
Yield: 85 %

Procedure:
4-carboxyphthalic anhydride (1.0 g, 0.0052 mol) and 6-aminohexanoic acid (0.68 g, 0.0052 mol) were refluxed as above overnight. Crystallisation of the product from EtOH yielded 1.35 g (85%) of 104 as a white solid: mp=202-204° C.; Rf0.80 (A): Rf0.84 (B): Rf0.47 (D): IR (cm−1): 2800-3250 (OH), 3103 (C═CH), 2675 (C—H), 1769 (C═O), 1709 (bs, C═O), 1625 (C═C), 1485 (C═C), 1403(C—O), 1303 (C—O), 730 (C═CH); MS m/z (rel intensity) 305 (16), 304 (100).
Reaction SMILES: [C:1]1(=[O:11])[CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][N:4]2[C:3](=[O:10])[NH:2]1.N(CCCCCC)=[C:13]=O>O1CCOCC1>[O:11]=[C:1]1[CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][N:4]2[C:3](=[O:10])[NH:2]1.[CH3:13][CH:5]([C:1]([NH2:2])=[O:11])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCN=C=O
Agent: O=C1NC(=O)N2CCCCC12
Solvent: C1COCCO1
Product: CCCCC(C)C(N)=O

Procedure:
Tetrahydroimidazo[1,5-a]pyridine-1,3-dione (690 mg, 4.476 mmol) and isocyanato-hexane (1.5 ml, 10.3 mmol, addition in several portions) were stirred in 30 ml of dioxane at 80° C. for 3 h and at 110° C. for 5 h. Concentration was followed by purification by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 23 mg (2%), M+H+:282.20.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[O:12][CH:13]1[CH2:18][CH2:17][N:16](CC)[CH2:15][CH2:14]1.C1C2C(=CC=CC=2)C=CC=1OC1CCN(CC2C=CC=CC=2)CC1>>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[O:12][CH:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1
Reactant: CCN1CCC(Oc2cccc3c(F)cccc23)CC1
Agent: c1ccc(CN2CCC(Oc3ccc4ccccc4c3)CC2)cc1
Product: Fc1cccc2c(OC3CCNCC3)cccc12

Procedure:
When in the procedure of Example 7, 4-(5-fluoro-1-naphthalenyloxy)-1-ethylpiperidine is substituted for 4-(2-naphthalenyloxy)-1-(phenylmethyl)piperidine, 4-(5-fluoro-1-naphthalenyloxy)piperidine is produced.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]1[C:29]([C:38](O)=[O:39])=[CH:30][C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:38]([C:29]4[C:28]([O:27][CH3:26])=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=4)=[O:39])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1cc2ccccc2cc1C(=O)O
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc5ccccc5cc4OC)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 3-methoxynaphthalene-2-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from diethyl ether to yield the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[CH:13]=[C:14]([CH:35]=[CH:36][CH:37]=3)[CH2:15][NH:16][C:17]([C:19]3[C:20](=[O:34])[N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=4)[CH:22]=[CH:23][CH:24]=3)=[O:18])=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1)#N.FC1C=C(C=CC=1F)CN1C=CC=C(C(NCC2C=C(B(O)O)C=CC=2)=[O:50])C1=O.[B].N1C2=NC=C(CO)C=C2C=C1>>[OH:50][CH2:1][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[CH:13]=[C:14]([CH:35]=[CH:36][CH:37]=3)[CH2:15][NH:16][C:17]([C:19]3[C:20](=[O:34])[N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=4)[CH:22]=[CH:23][CH:24]=3)=[O:18])=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: N#Cc1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Reactant: O=C(NCc1cccc(B(O)O)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Agent: OCc1cnc2[nH]ccc2c1
Agent: [B]
Product: O=C(NCc1cccc(-c2c[nH]c3ncc(CO)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
Except where indicated, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-hydroxymethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide was synthesized as per Example 68, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide using 3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenylboronic acid as activated boron species and (1H-Pyrrolo[2,3-b]pyridin-5-yl)-methanol as substituted bicyclic heterocycle, to yield the title compound. 1H NMR (400 MHz, DMSO-d6) d ppm 11.935 (s, 1H) 10.072 (t, J=5.9 Hz, 1H) 8.402 (dd, J=7.4, 2.0 Hz, 1H) 8.269-8.228 (m, 2H) 8.221 (dd, J=6.7, 2.0 Hz, 1H) 7.848 (d, J=2.6 Hz, 1H) 7.679 (s, 1H) 7.594 (d, J=7.4 Hz, 1H) 7.464-7.332 (m, 3H) 7.193 (d, J=7.7 Hz, 1H) 7.175-7.120 (m, 1H) 6.589 (t, J=6.9 Hz, 1H) 5.198 (s, 2H) 4.610-4.549 (m, 4H); MS m/z=501.21 M+H.