Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14])=[C:5]2[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([N:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]1.[F:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]>>[CH:15]1([C:13]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([N:25]([CH3:26])[CH3:27])[CH2:21][CH2:20]2)=[CH:3][C:2]([C:33]2[CH:34]=[C:29]([F:28])[C:30]([OH:45])=[C:31]([F:44])[CH:32]=2)=[C:11]([F:12])[CH:10]=3)=[O:14])[CH2:17][CH2:16]1
Reactant: CC1(C)OB(c2cc(F)c(O)c(F)c2)OC1(C)C
Reactant: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3cc(F)c(Br)cc23)CC1
Product: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3cc(F)c(-c4cc(F)c(O)c(F)c4)cc23)CC1

Procedure:
Following general procedure F, {6-bromo-4-[trans-4-(dimethylamino)cyclohexylamino]-7-fluoroquinolin-3-yl}(cyclopropyl)methanone (43 mg, 0.099 mmol) was reacted with 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (38 mg, 0.149 mmol) to afford the desired product (14 mg, 29%) as a light yellow solid: NMR (300 MHz, CD3OD) δ 9.27 (s, 1H), 8.37 (d, J=7.8 Hz, 1H), 7.68 (d, J=11.1 Hz, 1H), 7.33 (d, J=7.8 Hz, 2H), 4.31 (s, 1H), 3.47-3.35 (m, 1H), 3.27 (s, J=6.8 Hz, 1H), 2.88 (s, 5H), 2.87-2.75 (m, 1H), 2.43 (s, 2H), 2.26 (s, 2H), 1.88-1.64 (m, 4H), 1.35-1.13 (m, 4H), ESI MS m/z 484 [C27H28F3N3O2+H]+; HPLC 98.3% (AUC), tR=8.83 min.
Reaction SMILES: [F:1][CH:2]([F:21])[CH2:3][O:4][C:5]1[CH:15]=[C:14]([NH:16][CH3:17])[C:13]([N+:18]([O-])=O)=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[O-]S([O-])(=O)=O.[Na+].[Na+]>[Ni].C1COCC1>[NH2:18][C:13]1[C:14]([NH:16][CH3:17])=[CH:15][C:5]([O:4][CH2:3][CH:2]([F:21])[F:1])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(NC)cc1OCC(F)F
Agent: [Ni]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(N)c(NC)cc1OCC(F)F
Temperature: 25 °C

Procedure:
A mixture of ethyl 2-(2,2-difluoroethoxy)-4-(methylamino)-5-nitrobenzoate (2.0 g; 6.57 mmol), Ra—Ni (1.0 g) and THF (100 mL) was stirred under H2-atmosphere (8 atm) over night at rt. Na2SO4 was added and the mixture was stirred another 30 min under H2-atmosphere. The mixture was filtered through celite and the sub-title compound was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[NH:10][C:6]=2[CH:5]=[C:4]([CH2:14][OH:15])[CH:3]=1.[H-].[Na+].[CH3:18][O:19][C:20](=[O:30])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Br)=[CH:23][C:22]=1[F:29]>CN(C=O)C>[CH3:18][O:19][C:20](=[O:30])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:10]2[C:6]3[CH:5]=[C:4]([CH2:14][OH:15])[CH:3]=[C:2]([CH3:1])[C:7]=3[N:8]=[C:9]2[CH2:11][CH2:12][CH3:13])=[CH:23][C:22]=1[F:29]
Reactant: CCCc1nc2c(C)cc(CO)cc2[nH]1
Reactant: COC(=O)c1ccc(CBr)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(CO)cc2n1Cc1ccc(C(=O)OC)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
(7-Methyl-2-propyl-3H-benzoimidazol-5-yl)methanol (3 g, 15 mmol; prepared as described in Preparation 7) was dissolved in 20 mL of dry DMF. The solution was cooled to 0° C. and sodium hydride (598 mg, 15 mmol, 60 wt % in mineral oil) was added. The mixture was stirred for 30 minutes. 4-Bromomethyl-2-fluorobenzoic acid methyl ester (3.7 g, 15 mmol; prepared as described in Preparation 3) in 50 mL of DMF was added, and the mixture was warmed to room temperature and stirred for 10 minutes. The solution was partitioned between EtOAc (300 mL) and 150 mL 10% LiCl (aqueous). The organic layer was separated, dried over MgSO4 and concentrated. The concentrate was flash chromatographed to produce Intermediate (8a) as a clear oil (2.4 g). MS m/z: [M+H+] calcd for C21H23FN2O3, 371.7. found 371.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[Cl:13].[CH3:14][O-:15].[Na+]>CO>[C:6]([C:5]1[CH:11]=[C:12]([Cl:13])[C:2]([Cl:1])=[CH:3][C:4]=1[C:9]([OH:8])=[O:10])([O:15][CH3:14])=[O:7]
Reactant: C[O-]
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Cl)c(Cl)cc1C(=O)O
Reaction time: 72 h
Yield: 92.3 %

Procedure:
To a solution of 4,5-dichlorophthalic anhydride (1.0 g, 4.61 mmol) in 15 mL of methanol was added 0.25 g (9.22 mmol, 2.0 eq) of sodium methoxide. The suspension was stirred for 3 days and the methanol was removed in vacuo. The resultant white solid was suspended in 500 mL of CH2Cl2 and washed with 1N HCl. The organic phase was dried over anhydrous Na2SO4, filtered and the volatiles removed in vacuo to yield 1.06 g (92.5%) of the titled compound as a white powder.
Reaction SMILES: [N:1]1([C:10]2[CH:23]=[CH:22][C:13]([C:14]([N:16]3[CH2:20][CH2:19][C@@H:18]([OH:21])[CH2:17]3)=[O:15])=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(N(C(C)C)CC)(C)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH3:33][S:34]([O:21][C@@H:18]1[CH2:19][CH2:20][N:16]([C:14](=[O:15])[C:13]2[CH:22]=[CH:23][C:10]([N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[CH:2]3)=[CH:11][CH:12]=2)[CH2:17]1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1ccc(-n2cnc3ccccc32)cc1)N1CC[C@@H](O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1CCN(C(=O)c2ccc(-n3cnc4ccccc43)cc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of (3R)-1-[4-(1H-benzimidazol-1-yl)benzoyl]pyrrolidin-3-ol (2.30 g, 7.48 mmol) in anhydrous dichloromethane at 0° C. is treated with diisopropylethyl amine (2.13 g, 16.46 mmol) and methanesulfonyl chloride (1.29 g, 11.22 mmol), stirred at 0° C. for 2 hours and concentrated to give a crude oil. Purification of this oil by flash column chromatography (silica, methanol:dichloromethane 5:95) provides the title product as a yellow solid, 2.3 g (81% yield), identified by NMR and mass spectral analyses. MS [386.5 m/e (M+H)].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[C:23]1[C:24]2[CH:31]=[CH:30][S:29][C:25]=2[N:26]=[CH:27][N:28]=1>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:23]2[C:24]3[CH:31]=[CH:30][S:29][C:25]=3[N:26]=[CH:27][N:28]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Clc1ncnc2sccc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ncnc3sccc23)cc1
Temperature: 130 °C
Reaction time: 30 h
Yield: 51.7 %

Procedure:
After adding 600 mg of 4-nitrophenol, 1.2 g of potassium carbonate and 2 ml of dimethylformamide to 302 mg of the 4-chlorothieno[2,3-d]pyrimidine described in Seans Acad. Sci., Ser, C (1967)264(2)207, and stirring the mixture for 30 hours at 130° C., the mixture was returned to room temperature, water was added, liquid separation and extraction were performed with an ethyl acetate-tetrahydrofuran mixed solvent, and the solid obtained by concentration to dryness was washed with ether to obtain 250 mg of the title compound.
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.Cl[CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]>C1COCC1>[CH3:28][O:29][CH2:30][CH2:31][O:32][CH2:33][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COCCOCCl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(COCCOC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (2.0 g, 7.8 mmol) in THF (70 mL) at −78° C. was added dropwise LDA over 8 minutes, maintaining the temperature below −75° C. The mixture was stirred at −78° C. for 1 hour. 1-Chloromethoxy-2-methoxy-ethane (0.97 g. 7.8 mmol) was added dropwise while maintaining the temperature below −75° C. The mixture was stirred at −78° C. for 3 hours, and then allowed to warm slowly to room temperature overnight. The mixture was quenched with sat. aq. NH4Cl and extracted 3 times with EtOAc. The organics were combined, washed with brine, dried over MgSO4, and concentrated. Silica gel chromatography (10-20% ethyl acetate:hexanes) gave the title compound in 67% yield. MS (ES+) [M+H]+=346.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[N:11]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:12]=[C:13]([CH3:25])[C:14]=2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:5][CH:4]=1)#[N:2].[OH-].[K+].CO>O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]3[N:11]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:12]=[C:13]([CH3:25])[C:14]=2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CCCCCc1c(C)nn2c(CC)ccc2c1-c1ccc(C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc2c(-c3ccc(C#N)cc3)c(CCCCCC(=O)O)c(C)nn12
Temperature: 60 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
To a solution of ethyl 6-[4-(4-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoate (1.5 g) in tetrahydrofuran (15 ml) was added 2N potassium hydroxide (7.4 ml), followed by methanol (7.4 ml). After stirring at 50° C. for 2 hours and 60° C. for 3 hours, the mixture was partitioned between 1N hydrochloric acid and ethyl acetate. The precipitates were filtered and washed with ethyl acetate. The organic layer and the washings were combined, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was triturated with ethyl acetate and the precipitates were filtered. The filtrate was purified by silica gel column chromatograpy eluting with a mixture of ethyl acetate and hexane (1:1) and triturated with isopropyl ether to give 6-[4-(4-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoic acid (650 mg) as an yellow crystals. The two precipitates were combined and recrystallized from ethyl acetate to give 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid (550 mg, 37.6%) as an yellow crystals.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[C:4]([Cl:11])[CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[CH:13]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:11][C:4]1[CH:3]=[C:2]([NH:19][CH2:18][C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=1
Reactant: NC(=O)c1cnc(Cl)cc1Cl
Reactant: NCc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: NC(=O)c1cnc(Cl)cc1NCc1cccnc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 82.6 %

Procedure:
A mixture of 4,6-Dichloronicotinamide (1, 950 mg, 5 mmoles), 3-picolylamine (756 mg, 7 mmoles) and DIEA (12 mmoles) in NMP (5 mL) was stirred at 60° C. for 20 hrs. The reaction mixture was concentrated under an oil pump. The residue was washed with water and dried under an oil pump. The desired 6-chloro-4-(pyridin-3-ylmethylamino)nicotinamide (2, 1.085 g) was obtained. MS+: 263.1, UV: λ=220.9; 260.9 nm. 1H NMR: (CDCl3) δ8.96 (s, 1H), δ8.60 (s, 1H), δ8.57 (d, J=3.2 Hz, 1H), δ8.30 (s, 1H), δ7.64 (d, J=7.6Hz, 1H), δ7.31 (dd, J1=7.6Hz, J2=3.2Hz, 1H), δ6.51 (s, 1H), δ5.80 (b, 2H), δ4.47 (s, 1H), δ4.45 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.Br[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:18][CH:19]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1
Reactant: COC(=O)CCCBr
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Product: COC(=O)CCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1

Procedure:
Methyl 4-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenoxy)butanoate was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) following the procedure described for the preparation of Example 139, but using methyl 4-bromobutanoate. 1H NMR (Acetone-d6): δ 8.74 (s, 1H), 8.67 (s, 1H), 8.24 (d, 1H), 7.39 (s, 1H), 7.09-7.19 (m, 3H), 6.82 (d, 2H), 6.53 (br, 2H), 3.97 (t, 2H), 3.60 (s, 3H), 3.19 (t, 2H), 3.04 (t, 2H), 2.48 (t, 2H), 2.44 (s, 3H), 0.84-0.91 (m, 2H). LRMS [M+H]=430.2.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].C=O.[CH3:31]CN(CC)CC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][N:20]([CH3:31])[CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNC3)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C)C3)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
To a solution of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 7) (150 mg, 0.36 mmol) in THF (3 mL) was added aqueous formaldehyde 37 Wt % (58 μL, 0.72 mmol) and Et3N (149 μL, 1.07 mmol). The reaction mixture was then stirred at room temperature (20° C.) for 1 h. After this time sodium triacetoxyborohydride (152 mg, 0.72 mmol) was added and stirring at room temperature (20° C.) continued for 18 h. The crude reaction mixture was then partitioned between water and EtOAc, the phases separated and the organic layer washed with NaHCO3 and brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by prep HPLC (low pH) to give as a light brown solid (48 mg, 33%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[C:1]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
Methoxyaryl 1i can be coupled with benzoyl chloride 2i, either commercially available or prepared in situ from the corresponding benzoic acid, using a Lewis acid, typically AlCl3 or the like, to give benzophenone product 3i. Reduction of 3i can be accomplished by triethylsilane and an appropriate protic or Lewis acid, typically trifluoroacetic acid or borontrifluoroetherate, to give arylbenzyl 4i.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].Br[CH2:10][CH2:11][O:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:13][O:12][CH2:11][CH2:10][O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: COCCBr
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COCCOc1ccccc1O

Procedure:
Catechol (10.0 g, 91 mmol), bromoethylmethylether (12.6 g, 91 mmol), and potassium carbonate (12.6 g, 91 mmol) were mixed in ethanol (100 ml) and refluxed for 15 h. The solvent was evaporated and dichioromethane (200 ml) was added. The inorganics were filtered off and the solvent was removed in vacuum. Chromatography on silica gel with 0.5% methanol in dichloromethane as the eluent gave the title compound. Yield 4.5 g, 29%.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=O)[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH:26][NH2:27])[CH2:24][CH3:25]>>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][C:14]1[C:19]([CH2:20][CH3:21])=[N:27][N:26]([CH2:23][CH2:24][CH3:25])[C:15]=1[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCNN
Reactant: CCC(=O)C(Cc1nccn1Cc1ccccc1)C(=O)CC
Product: CCCn1nc(CC)c(Cc2nccn2Cc2ccccc2)c1CC

Procedure:
4-(1-Benzyl-1H-imidazol-2-ylmethyl)-3,5-diethyl-1-propyl-1H-pyrazole was prepared from 4-(1-benzyl-1H-imidazol-2-ylmethyl)-heptane-3,5-dione and propylhydrazine in analogy to Example 190 b): light yellow viscous oil; MS (EI): 336.2 ((M+.), 100%), 245.3 ((M-PhCH2)+.).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:23]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:29]2[C:21]([CH:18]2[CH2:19][CH2:20][N:15]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=4)[N:7]=3)[CH2:16][CH2:17]2)=[CH:22]1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: c1cnc2[nH]cc(C3CCNCC3)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: FC(F)(F)c1nnc2ccc(N3CCC(c4c[nH]c5ncccc45)CC3)nn12
Temperature: 80 °C
Yield: 77.8 %

Procedure:
6-Chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (160 mg, 0.72 mmol), 3-(piperidin-4-yl)-1H-pyrrolo[2,3-b]pyridine (145 mg, 0.72 mmol) and DIPEA (0.14 mL, 0.79 mmol) in DMF (2.0 mL) were stirred and heated at 80° C. for 1 hour. The resulting mixture was then cooled to ambient temperature and quenched in water (10 mL) to give a beige solid. The solid was collected by filtration, washed sequentially with water, acetonitrile and ether, and air dried to give 6-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (217 mg, 78%) as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:18][N:19]3[CH:23]=[N:22][C:21]([NH2:24])=[N:20]3)[CH:11]=[N:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH:5]=[CH:6][CH:7]=1.C=O.[C:27](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:18][N:19]3[CH:23]=[N:22][C:21]([NH:24][CH3:27])=[N:20]3)[CH:11]=[N:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1ncn(Cc2cnc(OC(F)F)c(-c3cccc(Cl)c3)c2)n1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNc1ncn(Cc2cnc(OC(F)F)c(-c3cccc(Cl)c3)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.1 %

Procedure:
To a solution of 1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazol-3-amine (Example 219, 120 mg, 0.34 mmol) in DCM (2 mL), was added formaldehyde (26 μL of 37 wt % solution, 0.35 mmol), sodium triacetoxyborohydride (145 mg, 0.68 mmol) and a few drops of AcOH. The mixture was stirred at room temperature for 16 h. Purification by reverse-phase PREP-HPLC gave the title compound (25 mg, 20%). 1H NMR (400 MHz, CD3OD) δ 8.19-8.11 (m, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.71 (s, 1H), 7.53 (s, 1H), 7.47 (s, 1H), 7.41-7.28 (m, 3H), 5.21 (s, 2H), 2.72 (s, 3H). [M+H]=366.21.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)[CH3:2].Br[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][C:33]=1[CH:38]([OH:48])[CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:32]4[CH:37]=[CH:36][N:35]=[CH:34][C:33]=4[CH:38]([OH:48])[CH2:39][CH2:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)CC1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Reactant: OC(CCCc1ccccc1)c1cnccc1Br
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4ccncc4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: {1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropyl}-acetic acid ethyl ester and 1-(4-bromo-pyridin-3-yl)-4-phenyl-butan-1-ol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:23]=[C:22](F)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:22]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([Cl:15])[CH:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)c(Cl)c2)CC1
Temperature: 120 °C
Yield: 44.8 %

Procedure:
A mixture of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (427 mg; 2.13 mmol), 2-chloro-4-fluoro-benzonitrile (302 mg; 1.94 mmol) and potassium carbonate (1.07 g; 7.76 mmol) is diluted in dimethylsulfoxide (5 mL) and is heated to 120° C. for 7 hours. After cooling to room temperature, the mixture is diluted with dichloromethane (50 mL) and is filtered. The filtrate is washed with 1N aq. hydrochlorid acid (2×15 mL), with water (20 mL) is then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is finally purified by column chromatography on silica gel (dichloromethane:methanol 1:0 and then 98:2) to afford the desired product (290 mg; 0.87 mmol).
Reaction SMILES: [O:1]=[C:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1.[BH4-].[Na+].C(O)C.[Cl-].[Na+]>O1CCCC1>[OH:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1[nH]c2cccc3c2c1CCC3=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1[nH]c2cccc3c2c1CCC3O
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
A mixture of ethyl 1,3,4,5-tetrahydro-5-oxo-benz[cd]indole-2-carboxylate (0.40 g, 1.64 mmol), sodium borohydride (0.062 g, 1.64 mmol), ethanol (2 ml) and tetrahydrofuran (8 ml) was stirred at 0°-5° C. for 1.5 hours. The reaction mixture was poured into a 5% aqueous sodium chloride solution, followed by extraction with ethyl acetate (three times). The extract solution was washed twice with a 5% aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=15/85) to obtain ethyl 1,3,4,5-tetrahydro-5-hydroxy-benz[cd]indole-2-carboxylate (0.40 g).
Reaction SMILES: Br[CH:2]([CH3:6])[C:3]([O-:5])=[O:4].[Na+].[CH2:8]([C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1)[CH:9]([CH3:11])[CH3:10].O.S(=O)(=O)(O)O>C1COCC1>[CH2:8]([C:12]1[CH:17]=[CH:16][C:15]([CH:2]([CH3:6])[C:3]([OH:5])=[O:4])=[CH:14][CH:13]=1)[CH:9]([CH3:11])[CH3:10]
Reactant: CC(Br)C(=O)[O-]
Reactant: CC(C)Cc1ccc([Mg]Br)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reaction time: 0.21 h
Yield: 10.2 %

Procedure:
A suspension of 1.75 g of sodium α-bromopropionate in 20 ml of THF was added to 15 ml of a 0.67 M solution of p-isobutylphenyl magnesium bromide in THF. The mixture was heated under reflux for 1 hour, and then cooled. Then, 15 ml of water and then 5 ml of 20% sulfuric acid were added. The mixture was stirred for 10 to 15 minutes, and extracted with diethyl ether. The extract was washed with water, and then, extracted with a 1 N aqueous solution of potassium carbonate. The extract was washed with diethyl ether. The resulting aqueous layer was added to a mixture of 10 ml of concentrated hydrochloric acid and 20 ml of water, and the mixture was extracted with diethyl ether. The extract was washed with water, dried, concentrated and purified by silica gel column chromatography to give 0.21 g (yield 10.2%) of α-(p-isobutylphenyl)propionic acid.