Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:11]1>>[CH:10]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use benzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (92% yield). 1H NMR (300 MHz, CDCl3) δ 8.04, 7.97, 7.44, 6.98, 3.99-3.62, 3.55, 1.50, 0.80-0.66, 0.48-0.42, 0.11-0.06. MS (ES+) m/z 380.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:24])([F:23])[C:14](=O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O>[Br:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:14]([C:13]([F:23])([F:24])[F:12])[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:4]2[OH:6]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: O=C(Cc1ccccc1)C(F)(F)F
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: Oc1c(-c2ccccc2)c(C(F)(F)F)nc2ccc(Br)cc12
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-amino-5-bromobenzoic acid (3.01 g, 13.9 mmol), 1,1,1-trifluoro-3-phenylpropan-2-one (3.11 g, 16.5 mmol), and Eaton's reagent (9.3 mL) in a sealed tube was heated at 100° C. for 4 hours. The reaction mixture was then allowed to cool to room temperature, water was added slowly, and the mixture was stirred vigorously for about 15 minutes. The precipitated solid was collected by filtration, washed with water, and dried to provide the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[Cl:18][C:19]1[C:25]([CH3:26])=[CH:24][C:22]([NH2:23])=[C:21]([O:27][CH3:28])[CH:20]=1>>[Cl:18][C:19]1[C:25]([CH3:26])=[CH:24][C:22]([NH:23][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)=[C:21]([O:27][CH3:28])[CH:20]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1cc(Cl)c(C)cc1N
Product: COc1cc(Cl)c(C)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 4-chloro-2-methoxy-5-methylaniline (50 mg, 0.289 mmol) similar to Example 117 and isolated as a tan solid (26 mg, 34%). 1H NMR (CDCl3): 9.65–9.63 (m, 1H), 8.75–8.70 (m, 2H), 8.18 (s, 1H), 7.46–7.41 (m, 1H), 7.36 (s, 1H), 6.97 (s, 1H), 6.87 (s, 1H), 3.91 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:15]([NH:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1)(=[O:17])[CH3:16].O>O1CCCC1>[CH3:3][C:4]([CH2:23][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:15](=[O:17])[CH3:16])=[CH:26][CH:25]=1)([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CC(=O)Nc1ccc(CCl)cc1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)(Cc1ccc(NC(C)=O)cc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Suspend sodium hydride (10.1 g, 0.21 mol) in tetrahydrofuran (300 mL), place under a nitrogen atmosphere and cool to 0° C. Add, by dropwise addition, diethyl methylmalonate (34.8 g, 0.2 mol). Stir for 30 minutes at 0° C. and add 4-acetamidobenzyl chloride (38.6 g, 0.21 mol). Heat at reflux for 5 hours, cool and pour into water (400 mL). Extract with ethyl acetate (3×600 mL), dry (MgSO4) and evaporate the solvent in vacuo to give diethyl methyl-(4-acetamido)benzylmalonate.
Reaction SMILES: [C:1]([N:8]([CH3:42])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:44]1[CH:49]=[CH:48][N:47]=[C:46]([N:50]([CH3:58])[C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH:45]=1>>[C:1]([N:8]([CH3:42])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33]([C:44]3[CH:49]=[CH:48][N:47]=[C:46]([N:50]([CH3:58])[C:51](=[O:57])[O:52][C:53]([CH3:54])([CH3:55])[CH3:56])[CH:45]=3)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Br)ccn1
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccnc(N(C)C(=O)OC(C)(C)C)c2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 9 (520 mg, 0.83 mmol) is coupled to pyridyl bromide 160 (240 mg, 0.83 mmol) using Method A to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[O:20]=[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][NH2:23]>>[O:20]=[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][NH:23][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19]
Reactant: NCC(=O)c1ccccc1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCC(=O)c3ccccc3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 2-oxo-2-phenyl-ethyl-amine to afford the title compound. MS: m/e=376 (M+H). 1H NMR (δ ppm): 11.74 (s, 1H); 9.13 (t, 1H, J=5.5 Hz); 8.99 (d, 1H, J=2.2 Hz); 8.72 (d, 1H, J=2.2 Hz); 8.19 (t, 1H, J=2.2 Hz); 8.05 (m, 2H); 7.70 (m, 1H); 7.58 (m, 2H); 7.32 (s, 1H); 4.85 (d, 2H, J=5.5 Hz); 2.42 (q, 2H, J=7.4 Hz); 2.20 (s, 3H); 1.12 (t, 3H, J=7.4 Hz).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][C:25]2[NH:29][N:28]=[N:27][N:26]=2)=[CH:17][CH:16]=1)C1C=CC=CC=1>CO.ClCCl.[Pd]>[NH:29]1[C:25]([CH2:24][CH2:23][CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH2:10])=[CH:16][CH:17]=2)=[N:26][N:27]=[N:28]1
Reactant: O=C(NCCCCc1ccc(OCCCc2nnn[nH]2)cc1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: NCCCCc1ccc(OCCCc2nnn[nH]2)cc1
Yield: 99.5 %

Procedure:
A solution of (4-{4-[3-(1H-tetrazol-5-yl)propoxy]phenyl}butyl)carbamic acid benzyl ester 3 (0.30 g, 0.73 mmol) in methanol (20 mL) and dichloromethane (5 mL) was stirred at room temperature overnight under hydrogen atmosphere in the presence of 10% palladium- on-carbon catalyst (0.1 g, 50% wet). The catalyst was removed by suction filtration, and the filtrate was concentrated in vacuo to give the desired product 4 as a white solid (200 mg, 99% yield) which was used for the next step without further purification. m/z (ESI): 276 [C14H21N5O+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:11][CH2:12][OH:13])[CH2:5][CH2:6][S:7]([OH:10])(=[O:9])=[O:8].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:19](Cl)=[O:20]>N1C=CC=CC=1.C(O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:19]([O:1][CH2:2][CH2:3][N:4]([CH2:11][CH2:12][O:13][C:19](=[O:20])[C:18]1[CH:17]=[C:16]([O:15][CH3:14])[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[CH:22]=1)[CH2:5][CH2:6][S:7]([OH:10])(=[O:8])=[O:9])=[O:20]
Reactant: O=S(=O)(O)CCN(CCO)CCO
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: CCO
Solvent: c1ccncc1
Product: COc1cc(C(=O)OCCN(CCOC(=O)c2cc(OC)c(OC)c(OC)c2)CCS(=O)(=O)O)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
8.5 G of the product obtained in Example 2 (a) was suspended in 25 ml of anhydrous pyridine, and 18.4 g of 3,4,5-trimethoxybenzoyl chloride added slowly under agitation. After being left for one hour at ambient temperature the mixture was heated to 80° C. for a further hour. It was then cooled to ambient temperature, diluted with 50 ml of ethanol and left to stand in a refrigerator. A colourless crystalline compound precipitated which milted at 174°-178° C. After recrystallisation from methanol, the melting point was 180°-183° C. The yield was 11.5 g of pure product.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])C1C=CC=CC=1.C1CCCCC=1>[Pd].C(O)C>[OH:8][CH2:9][CH2:10][O:11][CH2:12][P:13](=[O:20])([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19]
Reactant: CCOP(=O)(COCCOCc1ccccc1)OCC
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCOP(=O)(COCCO)OCC

Procedure:
Palladium on carbon (10%, 100 mg) was added to a solution of diethyl 2-(benzyloxy)ethoxymethylphosphonate prepared in this manner (0.9 g,2.8 mmol) and cyclohexene (2.0 ml, 20 mmol) in 20 ml ethanol under a nitrogen atmosphere. The resulting slurry was heated to reflux overnight. The catalyst was filtered off and the solution concentrated under vacuum to yield 0.5 g of diethyl 2-hydroxyethoxymethylphosphonate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22]C)=[O:21])(=[O:13])=[O:12])=[C:7]([O:24]C)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([OH:22])=[O:21])(=[O:13])=[O:12])=[C:7]([OH:24])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccsc2C(=O)O)c(O)c1
Temperature: 0 °C
Yield: 36.4 %

Procedure:
To a cooled (0° C.) solution of 32 (300.0 mg; 0.78 mmol) in dichloromethane (3.9 mL) was added boron tribromide (0.52 mL; 5.47 mL) dropwise. The reaction mixture was stirred at 0° C. then allowed to gradually warm to room temperature. After stirring 4 hours at room temperature, the reaction mixture was cooled to 0° C. again, slowly quenched with methanol; and then diluted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was re-dissolved in diethyl ether and washed with aqueous sodium hydroxide (2N). The aqueous layer was acidified to pH˜2 with concentrated hydrochloric acid and extracted with chloroform (3×). The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes and then by preparative HPLC to afford the title compound as a white solid (101 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:16][C:17](O)([CH3:19])[CH3:18].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:17]([O:14][C:13]([C:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9][S:10][CH:11]=1)=[O:15])([CH3:19])([CH3:18])[CH3:16]
Reactant: O=C(O)c1csnc1-c1ccc(Cl)cc1
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1csnc1-c1ccc(Cl)cc1

Procedure:
To a mixture of 7 (3.35 g), DMAP (1.7 g) and tBuOH (5.2 g) in CH2Cl2 (50 ml) is added 3.2 g of EDCI and the clear solution is stirred over the weekend. Additional CH2Cl2 (100 ml) is added and the mixture is washed with 1N HCl (2×150 ml), sat. NaHCO3 (150 ml), brine (150 ml), dried and concentrated. This afforded 3.75 g of 8 as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[C:18]([Cl:24])[CH:17]=2)[N:13]([CH3:25])[N:12]=1.Cl[C:27]1[C:32]([Cl:33])=[CH:31][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][N:28]=1.O>COCCOC>[Cl:24][C:18]1[CH:17]=[C:16]([C:14]2[N:13]([CH3:25])[N:12]=[C:11]([C:5]3[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:4]=3[Cl:3])[N:15]=2)[CH:21]=[CH:20][C:19]=1[CH2:22][O:23][C:27]1[C:32]([Cl:33])=[CH:31][C:30]([C:34]([F:37])([F:35])[F:36])=[CH:29][N:28]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CO)c(Cl)c1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Temperature: -5 °C
Yield: 60.7 %

Procedure:
Sodium hydride (60%, 0.16 g) is added to 1,2-dimethoxyethane (50 ml) and a solution of 3-(2-chloro-6-fluorophenyl)-5-(3-chloro 4-hydroxymethylphenyl)-1-methyl-1H-1,2,4-triazole (1.20 g) in 1,2-dimethoxyethane (20 ml) is added dropwise thereto at -5° C. with stirring. To the reaction solution is added dropwise a solution of 2,3-dichloro-5-trifluoromethyl pyridine (0.80 g) in 1,2-dimethoxyethane (20 ml) at -5° C. for 10 minutes, which is further stirred for 15 minutes. On completion of the reaction, the reaction solution is warmed to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 1.10 g of desired compound (melting point: 47.0°-49.0° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:28][O:29][CH2:30][C:31](Cl)=[O:32].N>C1COCC1.CO>[CH3:28][O:29][CH2:30][C:31]([NH:12][C:8]1[CH:7]=[C:6]([O:5][C:4]2[CH:13]=[CH:14][C:15]([N+:16]([O-:18])=[O:17])=[C:2]([CH3:1])[CH:3]=2)[CH:11]=[CH:10][N:9]=1)=[O:32]
Reactant: Cc1cc(Oc2ccnc(N)c2)ccc1[N+](=O)[O-]
Reactant: COCC(=O)Cl
Agent: N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c(C)c2)ccn1
Temperature: 25 °C
Yield: 54.2 %

Procedure:
To a suspension of 4-(3-methyl-4-nitrophenoxy)pyridin-2-amine (300 mg, 1.22 mmol) in THF (5.0 mL) and DIPEA (1.7 mL, 6.12 mmol) at 0° C. was added 2-methoxyacetyl chloride (447 μL, 4.89 mmol) in a single portion and the reaction mixture warmed to RT for 30 min. A solution of NH3 in MeOH (7M, 3.0 mL) was added and after 30 min at RT the mixture was evaporated in vacuo. The residue was partitioned between DCM (50 mL) and water (40 mL) and the organic phase was separated and dried (MgSO4) and was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, 5% MeOH in DCM, isocratic elution) to afford 2-methoxy-N-(4-(3-methyl-4-nitrophenoxy)pyridin-2-yl)acetamide (210 mg, 53%) as a yellow oil; Rt 2.06 min (Method 2); m/z 318 (M+H)+ (ES+).
Reaction SMILES: FC(F)(F)C([O-])=O.[Cl:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([C:24]3[CH:29]=[CH:28][CH:27]=C[CH:25]=3)[CH2:19][C:20]([NH:22][CH3:23])=O)[CH:16]=2)[NH:11][N:10]=1.[NH:30]1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[Cl:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([C:24]3[CH:25]=[N:30][CH:27]=[CH:28][CH:29]=3)[CH2:19][CH2:20][NH:22][CH3:23])[CH:16]=2)[NH:11][N:10]=1
Reactant: CNC(=O)CC(c1ccccc1)c1ccc2[nH]nc(Cl)c2c1
Reactant: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Agent: O=C([O-])C(F)(F)F
Product: CNCCC(c1cccnc1)c1ccc2[nH]nc(Cl)c2c1

Procedure:
[3-(3-Chloro-1H-indazol-5-yl)-3-pyridin-3-yl-propyl]-methyl-amine CCXXVI was prepared as a trifluoracetate from 3-(3-chloro-1H-indazol-5-yl)-N-methyl-3-phenyl-propionamide using the procedure described for preparation of [3-(1H-Indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (Example 4). MS (M+H)=301.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([CH2:14]Br)[CH:13]=1)[C:9]#[N:10]>CN(C=O)C>[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([CH2:14][O:2][CH3:1])[CH:13]=1)[C:9]#[N:10]
Reactant: CO
Reactant: N#Cc1cc(Br)cc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc(Br)cc(C#N)c1

Procedure:
MeOH (0.088 mL, 2.18 mmol) was added to a slurry of NaH (45 mg, 1.13 mmol) in DMF (2 mL). When gas evolution ceased, a solution of 3-bromo-5-(bromomethyl)benzonitrile (see WO2009/100169; 240 mg, 0.87 mmol) in DMF (1 mL) was added. The reaction was quenched by adding aq. sat NH4Cl solution. The mixture was partitioned between toluene (5 mL) and water (3 mL). The toluene layer was collected, washed with water, dried over Na2SO4, and concentrated in vacuo. The crude product was dried at reduced pressure and used in the next step: GCMS (CI) m/z 226 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[O:5].[C:12]([O:19][CH3:20])(=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[CH3:17][O:16][C:14](=[O:15])[CH:13]([CH:4]([OH:5])[C:3]1[C:6]([F:11])=[CH:7][CH:8]=[C:9]([F:10])[C:2]=1[F:1])[C:12]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CC(=O)OC
Reactant: O=Cc1c(F)ccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C(=O)OC)C(O)c1c(F)ccc(F)c1F
Temperature: 80 °C

Procedure:
2,3,6-trifluorobenzoaldehyde (10.2 g, 63.8 mmol) and dimethyl malonate (8.41 g, 63.8 mmol) were dissolved in 50 mL of DMF. 3 g of K2CO3 was added and the reaction mixture was heated to 80° C. for three hours. 500 mL of EtOAc and 500 mL of water were added. The organic layer was washed with saturated NH4Cl solution (200 mL), dried over Na2SO4 and concentrated. The product was purified by column chromatography using EtOAc/hex as the eluent (gradient from 0/100 to 40/60 in 40 min, 13 g, 70%). 1H NMR (CDCl3 400 MHz) δ 7.12 (m, 1H), 6.85 (m, 1H), 5.72 (d, J=9.5 Hz, 1H), 4.17 (d, J=9.5 Hz, 1H), 3.84 (s, 3H), 3.61 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][NH:15][C:16]([C@@H:18]2[CH2:24][CH2:23][C@@H:22]3[CH2:25][N:19]2[C:20](=[O:31])[N:21]3[O:26][S:27]([O-:30])(=[O:29])=[O:28])=[O:17])[CH2:9]1)=O)(C)(C)C.C([N+](CCCC)(CCCC)CCCC)CCC.FC(F)(F)C(O)=O>C(Cl)Cl>[O:31]=[C:20]1[N:19]2[CH2:25][C@@H:22]([CH2:23][CH2:24][C@H:18]2[C:16]([NH:15][O:14][C@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[O:17])[N:21]1[O:26][S:27]([OH:30])(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)[O-])C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NO[C@H]1CCCNC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a solution of N,N,N-tributylbutan-1-aminium({[(2S,5R)-2-({[(3S)-1-(tert-butoxycarbonyl)piperidin-3-yl]oxy}carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)oxidanide 20 (0.23 g, 0.32 mmol) in DCM (15 mL) was added trifluoroacetic acid (0.64 mL, 8.32 mmol) dropwise at 0° C. The reaction mixture was stirred for 1 h, then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with acetonitrile (2×) and the white solid was collected by centrifugation. The white solid was purified by HPLC and freeze-dried to give (2S,5R)-7-oxo-N-[(3S)-piperidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide Compound 4 (Table 1) (0.008 g, 6.8%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28](O)=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[CH3:32][N:33]1[CH2:37][CH2:36][C@@H:35]([NH2:38])[CH2:34]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([NH:38][C@@H:35]5[CH2:36][CH2:37][N:33]([CH3:32])[CH2:34]5)=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Reactant: CN1CC[C@@H](N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CC[C@@H](NC(=O)c2ccc3c(n2)CCC2C3=NN(c3ccc(C#N)c(Cl)c3)C2C2CCCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
In a dried reaction flask, 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (0.421 g, 1.0 mmol), the crude (R)-1-methylpyrrolidine-3-amine hydrochloride (0.252 g), DIEA (0.26 mL, 1.5 mmol), and HATU (0.418 g, 1.1 mmol) were added to a mixed solvent of DMF (4 mL) and dichloromethane (8 mL). The mixture was stirred at room temperature for 2 hr and was concentrated under reduced pressure. Water was added to the residue. The mixture was filtered to obtain a crude yellow solid, which was washed with methanol to produce a purified product (0.28 g) in 55.7% yield.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH3:7][O:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]Br)[CH:11]=1>>[CH3:7][O:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:4]2[CH:5]=[N:6][C:2]([NH2:1])=[N:3]2)[CH:11]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Nc1nc[nH]n1
Product: COC(=O)c1cccc(Cn2cnc(N)n2)c1

Procedure:
Prepared in analogy to example 3a) starting with 3-amino-1,2,4-triazole and methyl-3-(bromomethyl)benzoate. The title compound was obtained as a colorless solid (Yield=8%). MS ISP (m/e): 233.1 (100) [(M+H)+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:16]I>C1(C)C=CC=CC=1.FC(F)(F)C([O-])=O.[Ag+]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([I:16])=[C:11]([OH:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(OCc2ccccc2)c1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: Cc1ccccc1
Product: Oc1cc(OCc2ccccc2)ccc1I
Yield: 89.1 %

Procedure:
To a suspension of 3-(benzyloxy)phenol (5.00 g) and silver trifluoroacetate (5.52 g) in toluene (25 mL) was added dropwise a solution of iodine (6.35 g) in toluene (75 mL) over 30 min under ice-cooling. The reaction mixture was filtered, and to the organic layer were added saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (7.26 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:28][CH:29]=2)=[CH:4][CH:5]=1
Reactant: CCOC(=O)CCc1ccc(O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.50 g), ethyl 3-(4-hydroxyphenyl)propionate (0.31 g), anhydrous potassium carbonate (0.22 g) and N,N-dimethylformamide (15 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (0.38 g, 51%) of ethyl 3-[4-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 105-106° C.