Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([Cl:20])[C:17]([CH2:21][C@@H:22]3[CH2:26][CH2:25][N:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[C:23]3=[O:33])=[C:16]([Cl:34])[CH:15]=2)=[CH:10][CH:9]=1)=[O:7])(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>ClCCl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[Cl:34][C:16]1[CH:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[CH:9][CH:10]=2)[CH:19]=[C:18]([Cl:20])[C:17]=1[CH2:21][C@@H:22]1[CH2:26][CH2:25][N:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:23]1=[O:33]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCOCC4)C3=O)c(Cl)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCOCC4)C3=O)c(Cl)c2)cc1
Yield: 98 %

Procedure:
Treat a solution of (R)-3′,5′-dichloro-4′-(1-morpholin-4-yl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carboxylic acid tert-butyl ester (0.15 g) in dichloromethane (5 mL) with TFA (1 mL) and stir the reaction at room temperature for 12 hours. Remove the solvent and excess TFA in vacuo to afford 0.165 g (98%) of the title compound. MS (m/z): 449 (M+).
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5].[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21](O)[CH2:20]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[CH3:1][N:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([O:6][C@@H:21]1[CH:22]2[CH2:25][CH2:26][N:19]([CH2:24][CH2:23]2)[CH2:20]1)=[O:5]
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CN(c1ccccc1)C(C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN(c1ccccc1)C(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.8 %

Procedure:
2-(Methyl(phenyl)amino)-2-phenylacetic acid (I35) (2.20 g, 9.12 mmol) was dissolved in THF (25 ml), and (R)-quinuclidin-3-ol (1.28 g, 10.0 mmol) was added. To the resulting solution, HOBt (1.23 g, 9.12 mmol) and DCC (1.88 g, 9.12 mmol) were added, and the mixture was stirred at room temperature for three days. THF was removed under vacuum and the residue was portioned between H2O and EtOAc. The organic phase was washed with a saturated aqueous Na2CO3 solution, dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography (EtOAc to EtOAc/MeOH=75/25) to afford (R)-quinuclidin-3-yl 2-(methyl(phenyl)amino)-2-phenylacetate (2.2 g, 68.8% yield, mixture of diastereomers).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:24]=[CH:23][C:12]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=3)=[CH:11][CH:10]=2)O1.Br[C:27]1[N:32]2[N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=[C:31]2[CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:21]([C:18]1[N:19]=[CH:20][C:15]([CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]([C:27]3[N:32]4[N:33]=[C:34]([NH:36][C:37]([CH:39]5[CH2:40][CH2:41]5)=[O:38])[N:35]=[C:31]4[CH:30]=[CH:29][CH:28]=3)=[CH:24][CH:23]=2)=[CH:16][CH:17]=1)#[N:22]
Reactant: CC1(C)OB(c2ccc(OCc3ccc(C#N)nc3)cc2)OC1(C)C
Reactant: O=C(Nc1nc2cccc(Br)n2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(COc2ccc(-c3cccc4nc(NC(=O)C5CC5)nn34)cc2)cn1
Temperature: 90 °C

Procedure:
5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-pyridine-2-carbonitrile (10 g, 0.03 mol, 1.1 equiv.) was added to a solution of cyclopropanecarboxylic acid(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide (7.6 g, 0.027 mol) in 1,4-dioxane/water (4:1; 70 mL). K2CO3 (7.45, 0.054 mol, 2 eq.) and PdCl2dppf (5%) were added to the solution. The resulting mixture was then heated in an oil bath at 90° C. for 4 to 16 h under N2 until completion (monitored by LCMS). 1,4-Dioxane was removed under vacuum, and water/EtOAc were added and the solid was filtered. The obtained solid was dissolved in methanol/DCM, dried over MgSO4 and the final compound was obtained after purification by flash chromatography, eluted with neat EtOAc
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[F:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([S:21](Cl)(=[O:23])=[O:22])=[C:16]([N+:25]([O-:27])=[O:26])[CH:15]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:21]([C:17]2[CH:18]=[C:19]([F:20])[C:14]([F:13])=[CH:15][C:16]=2[N+:25]([O-:27])=[O:26])(=[O:22])=[O:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1S(=O)(=O)Cl
Reactant: Nc1ccc(Cl)c2cccnc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(F)c(F)cc1S(=O)(=O)Nc1ccc(Cl)c2cccnc12
Yield: 14.2 %

Procedure:
In the similar fashion using route 14 general procedure 27, 5-chloro-quinolin-8-ylamine (Intermediate 27) (400 mg, 2.2 mmol), 4,5-difluoro-2-nitro-benzenesulfonyl chloride (Intermediate 219) (750 mg, 2.9 mmol), DMAP (cat.) and pyridine (5 ml) and DCM (5 ml) gave the title compound (125 mg, 14%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:32]([OH:35])[C:33]#[CH:34]>N(CC)CC.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.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:34]#[C:33][CH2:32][OH:35])[CH:15]=[C:16]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CC3CCOCC3)cc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: ClCCl
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CC3CCOCC3)cc(C#CCO)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-quinolinecarboxamide (0.200 g), PdCl2(PPh3)2 (0.012 g) and CuI (0.029 g) in 10 mL Et2NH and 5 mL CH2Cl2 is added propargyl alcohol (0.021 g). The mixture is allowed to stir overnight at room temperature. The solvents are evaporated and the residue is partitioned between CH2Cl2 and water. The aqueous layer is extracted with CH2Cl2 (3×). The combined organic layers are washed with brine, dried and condensed. The crude product is chromatographed (Biotage flash 40S, eluent 1% MeOH/CH2Cl2 then 2% MeOH/CH2Cl2). Fractions homogeneous by TLC are combined and concentrated. The resulting solid is recrystallized from CH2Cl2/Et20 to yield 0.114 g (66%) of the desired product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[OH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([C:9]#[N:10])=[C:6]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:7]=1
Reactant: OCc1ccccn1
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OCc2ccccn2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. EI-MS m/e (%): 303 (M+, 52), 302 ([M—H]+, 74), 286 (30), 108 (100), 92 (63), 65 (52).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10]C)=[C:2]=[O:3].[CH2:12]([NH2:14])[CH3:13].B(Br)(Br)Br>ClCCl>[CH2:12]([NH:14][C:2]([NH:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])=[O:3])[CH3:13]
Reactant: CCN
Reactant: COc1ccccc1N=C=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCNC(=O)Nc1ccccc1O
Reaction time: 1 h

Procedure:
A solution of 1-isocyanato-2-methoxybenzene (0.32 g, 2.15 mmol) and ethylamine (1 mL) in dichloromethane (15 mL) was stirred at room temperature for 2 days. Then the volatiles were removed in vacuo. The residue was redissolved in dichloromethane (15 mL), and boron tribromide (BBr3) (1 M in dichloromethane (CH2Cl2), 6.5 ml, 6.5 mmol) was added dropwise via syringe under nitrogen. After stirring for 1 h the reaction mixture was diluted with dichloromethane and washed 3 times with water. The product was purified by HPLC (Kromasil column; eluant:acetonitrile+0.1% trifluoroacetic acid (TFA)/water+0.1% TFA) to give subtitle compound (167 mg).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[F:28][C:29]([F:35])([F:34])[CH2:30][C:31](O)=[O:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][C:29]([F:35])([F:34])[F:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)CC(F)(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(CC(F)(F)F)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (89 mg, 81%), MS (ISP) m/z=441.3 [(M+H)+], mp 195.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 3,3,3-trifluoro-propionic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[NH:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][C:15]1=[O:21].C(N(CC)CC)C.CC(C)(O)C#N>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH:16]2[C:17](=[O:20])[CH2:18][CH2:19][NH:14][C:15]2=[O:21])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C1CCNC(=O)C1
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: CC(C)(O)C#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCNC(=O)C1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.5 %

Procedure:
A solution of 4-chloro-2-nitrobenzoyl chloride (5.8 g) in dry dichloromethane (10 ml) was added over 5 minutes to a stirred solution of piperidine-2,4-dione (3.0 g) and triethylamine (5.5 ml) in dry dichloromethane (100 ml) and the mixture was stirred at ambient temperature for 3 hours. Acetone cyanohydrin (0.5 ml) was added and the mixture was stirred at ambient temperature for 18 hours. The solution was washed successively with 2N hydrochloric acid (50 ml) and water (2×100 ml), dried over sodium sulphate and evaporated under reduced pressure to give a solid residue which was recrystallised from ethyl acetate (70 ml) to give 3-(4-chloro-2-nitrobenzoyl)piperidine-2,4-dione (1.6 g), mp 161°-164° C., as a light brown crystalline solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12].FC1C(F)=CC([B:24]2[O:31][C:30](=[O:32])[CH2:29][N:28]([CH3:33])[CH2:27][C:26](=[O:34])[O:25]2)=C(O[C@H](CC=C)C)C=1>>[F:9][C:4]1[C:3]([O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])=[C:2]([B:24]2[O:31][C:30](=[O:32])[CH2:29][N:28]([CH3:33])[CH2:27][C:26](=[O:34])[O:25]2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: C=CC[C@H](C)Oc1c(F)cc(F)cc1Br
Reactant: C=CC[C@H](C)Oc1cc(F)c(F)cc1B1OC(=O)CN(C)CC(=O)O1
Product: C=CC[C@H](C)Oc1c(F)cc(F)cc1B1OC(=O)CN(C)CC(=O)O1
Yield: 40 %

Procedure:
Prepared from (S)-1-bromo-3,5-difluoro-2-(pent-4-en-2-yloxy)benzene in 40% yield following the procedure for (S)-2-(4,5-difluoro-2-(pent-4-en-2-yloxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione. 1H NMR (400 MHz, CDCl3) δ 7.21 (dd, J=8.5, 1.8 Hz, 1H), 6.89 (ddd, J=12.5, 7.8, 3.3 Hz, 1H), 5.91-5.73 (m, 1H), 5.17-5.03 (m, 2H), 4.88-4.75 (m, 1H), 4.10-3.95 (m, 1H), 3.92-3.83 (m, 3H), 2.66 (s, 3H), 2.53-2.41 (m, 1H), 2.39-2.28 (m, 1H), 1.24 (d, J=6.3 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −117.18 (d, J=5.2 Hz, 1F), −122.14 (d, J=5.2 Hz, 1F).
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.C([Li])CCC.[CH3:15][O:16][C:17]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:18]=1[C:19]#[N:20].Cl>CCOCC.CCCCCC>[CH3:15][O:16][C:17]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:18]=1[C:19]([NH2:3])=[NH:20]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: COc1cccc(C#N)c1OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cccc(C(=N)N)c1OC
Reaction time: 0.17 h

Procedure:
To a solution of 20 g 1,1,1,3,3,3-hexamethyldisilazane in 150 mL dry ether was added 5 mL 2.4 M n-butyllithium in hexane. After 10 min at room temperature, 16.3 g 2,3-dimethoxybenzonitrile was added in one portion and the mixture was kept at room temperature for 16 h. The reaction mixture was then poured onto excess 3N HCl. The aqueous layer was separated, basified with 50% NaOH and the product was extracted three times with 10% methanol in methylene chloride. The combined organic extracts were dried over potassium carbonate and the solvents removed in vacuo to afford 2,3-dimethoxybenzamidine as a glassy solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11]Br)[C:5]([OH:7])=[O:6].Cl.[OH2:14]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][OH:14])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(CBr)c(Br)c1
Reactant: O
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(CO)c(Br)c1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
To a solution of yield 3-bromo-4-(bromomethyl)benzoic acid (1.0 equiv.) in Water (0.56 M) at 95° C. was added potassium carbonate K2CO3 (5.0 equiv.). The homogenous reaction mixture was stirred at 95° C. in an oil bath for 1 hr. The reaction mixture was COOLED OFF TO RT, neutralized with 6 M HCl. diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude was used in next step. LC/MS (m/z)=294.8 (MH+), Rt=0.80 min.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]1[C:31]2[CH:30]=[C:29]([CH:32]=O)[N:28]=[CH:27][C:26]=2[O:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:22]1[C:31]2[CH:30]=[C:29]([CH2:32][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=5)[N:13]=[CH:12][C:11]4=[O:21])[CH2:6][CH2:7]3)[N:28]=[CH:27][C:26]=2[O:25][CH2:24][CH2:23]1
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=c1cnc2ccc(F)cc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To 10 mL of a chloroform solution containing 327 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one and 230 mg of 2,3-dihydro-1,4-dioxino[2,3-c]pyridine-7-carbaldehyde, 65 μL of acetic acid were added, and stirred at room temperature for 1 hour. To the reaction mixture, 364 mg of sodium triacetoxyborohydride was added, and stirred overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; chloroform], to give 311 mg of 1-(2-(4-((2,3-dihydro-1,4-dioxino[2,3-c]pyridin-7-yl)methylamino)piperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one as a pale yellow solid.
Reaction SMILES: [C:1]([C:3](=[N:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4]([NH:6][C:7](OCC)=[O:8])=[O:5])#[N:2].C([O-])(=O)C.[Na+].C(O)(=O)C>O>[C:14]1([N:13]2[C:7](=[O:8])[NH:6][C:4](=[O:5])[C:3]([C:1]#[N:2])=[N:12]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)NC(=O)C(C#N)=NNc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1nn(-c2ccccc2)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Intermediate b (21 g, 0.08 mol) and anhydrous sodium acetate (29 g, 0.35 mol) were added to glacial acetic acid (20 v/w, 420 mL). The mixture was warmed up to react under reflux for 2 h. After completion of the reaction, the reaction solution was cooled to 0° C. and poured into water (1200 mL). The mixture was stirred for 30 min and filtered by suction. The filtered cake was washed with water and petroleum ether, and dried to produce an orange red solid (12 g) in a yield of 67.8%.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[F:22][C:23]([F:27])([F:26])[CH2:24][NH2:25]>>[F:22][C:23]([F:27])([F:26])[CH2:24][NH:25][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: NCC(F)(F)F
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)[nH]n1
Product: CCCCc1noc(C)c1COc1cc(C(=O)NCC(F)(F)F)[nH]n1
Yield: 98 %

Procedure:
As described for example 26d, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.34 mmol) was converted, using 2,2,2-trifluoroethylamine instead of 4-aminotetrahydropyran, to the title compound (120 mg, 98%) which was obtained as a colorless oil. MS: m/e=361.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1)#[N:2].[NH2:14][CH2:15][CH2:16][C:17]1[NH:18][C:19]2[CH:25]=[C:24]([C:26]3[CH:27]=[CH:28][C:29](=[O:32])[NH:30][N:31]=3)[CH:23]=[CH:22][C:20]=2[N:21]=1>>[C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][NH:14][CH2:15][CH2:16][C:17]1[NH:18][C:19]2[CH:25]=[C:24]([C:26]3[CH:27]=[CH:28][C:29](=[O:32])[NH:30][N:31]=3)[CH:23]=[CH:22][C:20]=2[N:21]=1)#[N:2]
Reactant: NCCc1nc2ccc(-c3ccc(=O)[nH]n3)cc2[nH]1
Reactant: N#Cc1ccccc1OCC1CO1
Product: N#Cc1ccccc1OCC(O)CNCCc1nc2ccc(-c3ccc(=O)[nH]n3)cc2[nH]1

Procedure:
Prepared analogously to Example 1 from 1-(2-cyanophenoxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-3(2H)-pyridazinone.
Reaction SMILES: C([O:8][C:9](=[O:22])[CH:10]=[CH:11][C:12]1[CH:13]=[N:14][C:15]([C:18](=[O:21])[NH:19][CH3:20])=N[CH:17]=1)C1C=CC=CC=1.[CH2:23](O)C>[Pd]>[CH3:20][NH:19][C:18]([C:15]1[CH:23]=[CH:17][C:12]([CH2:11][CH2:10][C:9]([OH:8])=[O:22])=[CH:13][N:14]=1)=[O:21]
Reactant: CCO
Reactant: CNC(=O)c1ncc(C=CC(=O)OCc2ccccc2)cn1
Agent: [Pd]
Product: CNC(=O)c1ccc(CCC(=O)O)cn1
Reaction time: 8 h

Procedure:
3-(2-methylcarbamoyl-pyrimidin 5-yl)acrylic acid benzyl ester was dissolved in ethanol (20 mL) in presence of 15 mg of Pd/C, 10% and HClc (2 mL). The mixture was stirred under hydrogen balloon overnight to give 3-(2-methylcarbamoyl-pyridine-5-yl)-propionic acid which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([C@@H:14]3[CH2:16][C@H:15]3[C:17](O)=O)[CH:11]=[C:10]([CH3:20])[N:9]=2)[N:3]=1.[CH3:21][NH:22][C:23]1[C:24]([NH2:29])=[CH:25][CH:26]=[CH:27][CH:28]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([C@@H:14]3[CH2:16][C@H:15]3[C:17]3[N:22]([CH3:21])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[N:29]=3)[CH:11]=[C:10]([CH3:20])[N:9]=2)[N:3]=1
Reactant: CNc1ccccc1N
Reactant: Cc1cc([C@@H]2C[C@H]2C(=O)O)cc(-n2nc(C)nc2C)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([C@@H]2C[C@H]2c2nc3ccccc3n2C)cc(-n2nc(C)nc2C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of trans-2-(2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-methylpyridin-4-yl)cyclopropanecarboxylic acid (25-3) (45 mg, 0.165 mmol), N1-methylbenzene-1,2-diamine (28 mg, 0.231 mmol), EDC.HCl (47 mg, 0.248 mmol), HOBt (38 mg, 0.248 mmol), diisopropylethylamine (85 mg, 0.660 mmol), and tetrahydrofuran (3 mL) was stirred at room temperature overnight and evaporated. Acetic acid (3 mL) was added and the mixture was heated at 95° C. for 1 hour, cooled to room temperature, and evaporated. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The extract was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (5-10% methanol in DCM) and reverse phase (10-100% acetonitrile in water) to give trans-2-(2-(2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-methylpyridin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (25-4) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 7.74-7.65 (m, 1H), 7.38 (br s, 1H), 7.34-7.20 (m, 3H), 6.98 (br s, 1H), 3.81 (s, 3H), 2.83 (s, 3H), 2.78-2.67 (m, 1H), 2.54 (s, 3H), 2.46-2.36 (m, 1H), 2.41 (s, 3H), 2.12-2.02 (m, 1H), 1.80-1.69 (m, 1H). LRMS m/z (M+H) 359 found, 359 required. m.p. 157-159° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.O.[C:11]1([C:17]23[CH2:25][CH:21]4[CH2:22][CH:23]([CH2:24]2)[C:19]([C:26](=[O:28])[CH3:27])([CH2:20]4)[CH2:18]3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[N+](C)([O-])=O>[N+:1]([C:14]1[CH:15]=[CH:16][C:11]([C:17]23[CH2:25][CH:21]4[CH2:22][CH:23]([CH2:24]2)[C:19]([C:26](=[O:28])[CH3:27])([CH2:20]4)[CH2:18]3)=[CH:12][CH:13]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)C12CC3CC1CC(c1ccccc1)(C3)C2
Agent: O=S(=O)(O)O
Solvent: C[N+](=O)[O-]
Solvent: O
Product: CC(=O)C12CC3CC1CC(c1ccc([N+](=O)[O-])cc1)(C3)C2
Reaction time: 2 h
Yield: 87.6 %

Procedure:
Nitration mixture (1 mL) [the nitration mixture was prepared by mixing of 10.5 g of nitric acid (d 1.375 at 22° C.), 180.0 g of conc. sulphuric acid (d 1.84 at 22° C.), and 16 g of H2O) was added drop wise to a stirred solution of 1-(1-phenyltricyclo[3.3.1.03,7]non-3-yl)ethanone (240 mg, 1.0 mmol) obtained in preparation 1, in nitromethane (4 mL) at 0° C. After stirring for 2 h, the reaction mixture was poured into ice cold water and extracted with EtOAc, the combined organic layers were washed with brine and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography to obtain 1-[1-(4-nitrophenyl)tricyclo[3.3.1.03,7]non-3-yl]ethanone as an off-white solid (250 mg) in 88% yield. M.R: 61.3-66.6° C. m/z (M+1) 286; IR cm−1 2953, 1697, 1598, 1519, 1217, 1110, 852, 768. 1H NMR (CDCl3) 300 MHz δ 8.17 (d, J=8.7 Hz, 2H), 7.43 (d, J=8.7 Hz, 2H), 2.87-2.80 (m, 1H), 2.61-2.55 (m, 1H), 2.34-2.26 (m, 1H), 2.23 (s, 3H), 2.13-1.98 (m, 4H), 1.90-1.71 (m, 5H).