Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:27])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:20]=2)[C:16]=1Cl)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH2:28]1[C:32]2([CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:31][CH2:30][NH:29]1.C(N(CC)C(C)C)(C)C.[OH-].[Li+]>CN1C(=O)CCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:27])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:20]=2)[C:16]=1[N:29]1[CH2:30][CH2:31][C:32]2([CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:28]1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3ccccc3)nn2c1Cl
Reactant: C1CCC2(C1)CCNC2
Agent: [Li+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(-c3ccccc3)nn2c(N2CCC3(CCCC3)C2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
(S)-methyl 2-(tert-butoxy)-2-(7-chloro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)acetate was dissolved in NMP (1 mL) and combined with 2-azaspiro[4.4]nonane (8.72 mg, 0.070 mmol) and N,N-diisopropylethylamine (27 mg, 0.21 mmol). This mixture was stirred at rt for 24 h. A 1M lithium hydroxide solution (0.348 mL, 0.348 mmol) was added to the reaction mixture and it was heated at 50° C. for 4 h to complete the ester hydrolysis. The reaction mixture was concentrated in vacuo and purified by Biotage (4 g column, 0-10% MeOH/CH2Cl2 ramp) to give 11.1 mg (27% yield) of S)-2-(tert-butoxy)-2-(5-methyl-2-phenyl-7-(2-azaspiro[4.4]nonan-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetic (1:1 solvate with NMP) as a yellow waxy solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:22])([CH3:21])[CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][C:12]1=[O:20])(C)(C)C.O1C2C=CC=CC=2NC1=O.[H-].[Na+].NCCC(NC(=O)OC(C)(C)C)(C)C.C(=O)([O-])O.[Na+]>CN1C(=O)N(C)CCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[NH2:7][C:8]([CH3:22])([CH3:21])[CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][C:12]1=[O:20]
Reactant: CC(C)(CCn1c(=O)oc2ccccc21)NC(=O)OC(C)(C)C
Agent: CC(C)(CCN)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN1CCCN(C)C1=O
Product: CC(C)(N)CCn1c(=O)oc2ccccc21
Temperature: 25 °C

Procedure:
tert-butyl[1,1-dimethyl-3-(2-oxo-benzoxazol-3-yl)-propyl]-carbamate: 4.0 g (29.6 mmol) benzoxazol-2-one are dissolved in 40 mL DMPU and cooled with an ice bath. Under protective gas 897 mg (95%; 35.5 mmol) sodium hydride is added batchwise to this solution. The reaction mixture is heated to ambient temperature and then stirred for another hour. 9.85 g (44.4 mmol) tert-butyl (3-amino-1,1-dimethyl-propyl)-carbamate and 1.97 g (5.3 mmol) tetrabutylammonium iodide are added and the mixture is stirred overnight. The reaction is stopped by the careful addition of sodium hydrogen carbonate solution. Ethyl acetate is added, the aqueous phase is separated off and extracted repeatedly with ethyl acetate. The combined organic phases are washed with sodium chloride solution, dried with sodium sulphate and evaporated down. Purification of the residue by column chromatography (silica gel; petroleum ether/ethyl acetate=7:3) yields the desired product. Yield 4.1 g (43%); mass spectroscopy: [M+H]+=321.
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]1[C:14]([O:16][C:17](=[O:18])[C:8]1=[CH:7]2)=[O:15].[NH2:20][C:21]([CH3:28])([CH:25]([CH3:27])[CH3:26])[C:22]([NH2:24])=[O:23]>C1COCC1>[F:1][CH:2]([F:19])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14](=[O:15])[NH:20][C:21]([C:22](=[O:23])[NH2:24])([CH3:28])[CH:25]([CH3:27])[CH3:26])[C:8]([C:17]([OH:16])=[O:18])=[CH:7]2
Reactant: O=C1OC(=O)c2nc3ccc(OC(F)F)cc3cc21
Reactant: CC(C)C(C)(N)C(N)=O
Solvent: C1CCOC1
Product: CC(C)C(C)(NC(=O)c1nc2ccc(OC(F)F)cc2cc1C(=O)O)C(N)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 6-difluoromethoxyquinoline-2,3-dicarboxylic acid anhydride (0.037 mol) in 250 mL THF is stirred at 5° C. under nitrogen and a solution containing 2-amino-2,3-dimethylbutyramide (0.037 mol) in 50 mL THF added dropwise. After stirring at room temperature for 17 hours, the solvent is removed in vacuo to give the desired 6-difluoromethoxy-2-[(1-carbamoyl-1,2-dimethylpropyl)-carbamoyl]-3-quinolinecarboxylic acid mp 194°-196° C.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6](O)=[O:7].C(Cl)(=O)C([Cl:16])=O.CN(C)C=O>C(Cl)Cl>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6]([Cl:16])=[O:7]
Reactant: Cc1ccccc1CCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1CCC(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-methylhydrocinnamic acid (3.0 g, 18.3 mmole), oxalyl chloride (3.19 ml, 36.6 mmole) and methylene chloride (30 ml) was cooled in an ice bath and N,N-dimethylformamide (0.14 ml, 1.81 mmole) was added dropwise. The mixture was stirred at room temperature overnight. Concentration in vacuo gave 3-(2-methylphenyl)propanoyl chloride which was taken up in methylene chloride and used in the next step as a crude.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9](=[C:10]3[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:8][CH2:7][CH2:6][CH2:5]2.C([Li])CCC.C[Si]([N:25]=[C:26]=[S:27])(C)C>>[CH3:1][C:2]1[N:3]=[C:4]2[C:9](=[C:10]3[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:8][CH2:7][CH2:6][CH:5]2[C:26](=[S:27])[NH2:25]
Reactant: Cc1nc2c(c3c1CCCC3)CCCC2
Reactant: C[Si](C)(C)N=C=S
Agent: [Li]CCCC
Product: Cc1nc2c(c3c1CCCC3)CCCC2C(N)=S

Procedure:
By the method of Example 2, 1,2,3,4,7,8,9,10-octahydro-6-methyl-phenanthridine is reacted with n-butyl-lithium solution and the resulting anion is reacted with trimethylsilyl isothiocyanate to give 1,2,3,4,7,8,9,10-octahydro-6-methylphenanthridine-4-thiocarboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=O)[CH2:11][C:10]([CH3:15])([CH3:14])[C:9]2=O)[CH:5]=[CH:6][CH:7]=1.B.CO.O>C1COCC1.CSC.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][C:10]([CH3:15])([CH3:14])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)N(c2cccc(Br)c2)C1=O
Agent: B
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)CCN(c2cccc(Br)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
1-(3-Bromo-phenyl)-3,3-dimethyl-pyrrolidine-2,5-dione (2.5 g, 8.9 mmol) was suspended in 45 ml of THF. Borane (7.9 ml of a 10.1M solution in methyl sulfide) was added and the reaction was stirred at room temperature for 3 hours. The reaction was cooled to 0° C. in an ice bath and 20 ml of methanol was added dropwise, then 60 ml of water. The mixture was transferred to a separatory funnel and methylene chloride was added. The organic phase was washed with water and brine, filtered through celite and concentrated. The crude product was purified by flash chromatography using a gradient of 0% to 5% ethyl acetate in hexanes to give 1.7 g (75%) of 1-(3-bromo-phenyl)-3,3-dimethyl-pyrrolidine.
Reaction SMILES: [CH2:1]([C:4]1[S:8][C:7]([C:9]2[S:10][C:11]([C:14]3[S:15][C:16](Br)=[CH:17][CH:18]=3)=[CH:12][CH:13]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].B([O-])([O-])O[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].CCCCCC>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([C:4]1[S:8][C:7]([C:9]2[S:10][C:11]([C:14]3[S:15][C:16]([C:22]4[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:26][CH:27]=4)=[CH:17][CH:18]=3)=[CH:12][CH:13]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCCCc1ccc(OB([O-])[O-])cc1
Reactant: CCCc1ccc(-c2ccc(-c3ccc(Br)s3)s2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: COCCOC
Product: CCCCCc1ccc(-c2ccc(-c3ccc(-c4ccc(CCC)s4)s3)s2)cc1
Temperature: 25 °C

Procedure:
5-propyl-5″-bromo-2,2′:5′,2″-terthiophene (2) (0.51 g; 1.38 mmol), 4-pentylphenyl borate (50.48 g; 1.85 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.037 g; 0.03 mmol) were dissolved in dimethoxyethane (50 ml) and a 10 wt % sodium carbonate aqueous solution (50 ml) was added thereto, followed by reflux for 1 hour. After cooling to room temperature, a precipitate generated as a result of addition of water was separated by filtration, followed by purification with silica gel column chromatography (developing solvent: cyclohexane). Then, the resultant was recrystallized with n-hexane (yield: 0.47 g (1.08 mmol; yield percentage: 78%)).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[F:26])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:27]=1.BrC1C=CC2OCCN3C(CN4C=CN=C4C)=C(C(N)=O)N=C3C=2C=1.FC1C=CC=CC=1O.[CH3:61][C:62]([OH:66])([C:64]#[CH:65])[CH3:63]>>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][CH2:18][C:12]1[N:8]2[CH2:9][CH2:10][O:11][C:5]3[CH:4]=[CH:3][C:2]([C:65]#[C:64][C:62]([OH:66])([CH3:63])[CH3:61])=[CH:27][C:6]=3[C:7]2=[N:14][C:13]=1[C:15]([NH2:17])=[O:16]
Reactant: NC(=O)c1nc2n(c1COc1ccccc1F)CCOc1ccc(Br)cc1-2
Reactant: C#CC(C)(C)O
Agent: Cc1nccn1Cc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Agent: Oc1ccccc1F
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(COc3ccccc3F)n1CCO2
Yield: 6 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-3((2-fluorophenoxy)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3-((2-methyl-1H-imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing 2-methylimidazole with 2-fluorophenol) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as an off-white solid (7 mg, 6%).
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[CH:6][N:7]=1)[CH3:2].[O:8]1[C:12]2([CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1>>[CH2:1]([C:3]1[S:4][C:5]([C:15]2([OH:18])[CH2:16][CH2:17][C:12]3([O:11][CH2:10][CH2:9][O:8]3)[CH2:13][CH2:14]2)=[CH:6][N:7]=1)[CH3:2]
Reactant: CCc1nccs1
Reactant: O=C1CCC2(CC1)OCCO2
Product: CCc1ncc(C2(O)CCC3(CC2)OCCO3)s1

Procedure:
The title compound was prepared as a white solid from 2-ethyl-thiazole (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 33.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[CH2:9]([O:11][C:12]([CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[C:15]1=[O:20])=[O:13])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>C(O)(=O)C>[CH2:9]([O:11][C:12]([C:14]1([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:18][CH2:17][N:16]([CH3:19])[C:15]1=[O:20])=[O:13])[CH3:10]
Reactant: CCOC(=O)C1CCN(C)C1=O
Reactant: Fc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCOC(=O)C1(c2ccc(Br)cn2)CCN(C)C1=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-2-fluoro-pyridine (3.45 g), 1-methyl-2-oxo-pyrrolidine-3-carboxylic acid ethyl ester (5.00 g), cesium carbonate (12.77 g), and dimethyl sulfoxide (10 mL) was stirred at 100° C. overnight. After cooling to room temperature, acetic acid (4.5 mL) was added and the resulting solution was extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4), and concentrated. The residue was chromatographed on silica gel (dichloromethane/ethyl acetate 1:0→1:1) to give the title compound as an oil. Yield: 3.92 g (61% of theory); Mass spectrum (ESI+): m/z=327/329 (Br) [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:14][C@H:13]2[CH2:15][C@@H:10]1[CH2:11][C@@H:12]2[OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH2:1]([O:8][C@H:9]1[CH2:14][C@H:13]2[CH2:15][C@@H:10]1[CH2:11][C:12]2=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1C[C@H]2C[C@@H]1C[C@@H]2OCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1C[C@H]2C[C@@H]1C[C@@H]2OCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Silica gel 60 (particle size, 0.040-0.063 mm, CAS # 63231-67-4, from EMD Chemical Inc. 9.0 g) was added to a solution of (1R,2S,4R,5S)-5-(benzyloxy)bicyclo[2.2.1]heptan-2-ol (2.79 g, 12.8 mmol) in anhydrous dichloromethane (60.0 ml). The mixture was cooled to 0° C., and pyridinium chlorochromate (4.40 g, 20.4 mmol) was added. The reaction mixture was warmed to ambient temperature and stirred at this temperature for 5 h. After this time, the mixture was diluted with dichloromethane (60 mL) and then filtered through a pad of Celite. The solvent was removed in vacuo, and the residue was purified by flash column chromatography (0 to 25% of ethyl acetate in hexanes) to give the title compound as a colorless oil.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH3:12]>[Ni]>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([NH2:12])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: [Ni]
Product: CC(C)(C)C1CCC(N)CC1

Procedure:
312 g of 4-tert-butylcyclohexanone in 500 ml of ammonia-saturated methanol were hydrogenated at 100° C. and 100 bar in the presence of 10 g of Raney nickel. The catalyst was filtered off, the mixture was concentrated, and the crude product was purified on a thin-layer evaporator (105°/0.5 mm). 303 g of colorless liquid were obtained. The product is an isomer mixture in which the cis-cyclohexylamine derivative prevails. ##STR11##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([F:11])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1.[CH3:13][N:14]([CH2:19][C:20](O)=[O:21])[CH2:15][C:16](O)=[O:17].C1(C)C=CC=CC=1.CS(C)=O>O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([F:11])=[C:6]([B:8]2[O:10][C:20](=[O:21])[CH2:19][N:14]([CH3:13])[CH2:15][C:16](=[O:17])[O:9]2)[CH:7]=1
Reactant: CN(CC(=O)O)CC(=O)O
Reactant: Cc1cc(Br)cc(B(O)O)c1F
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Br)cc(B2OC(=O)CN(C)CC(=O)O2)c1F
Yield: 85.2 %

Procedure:
To a 50 mL round bottom flask equipped with a stir bar was added 5-bromo-2-fluoro-3-methylphenylboronic acid (1.0 g, 4.3 mmol), N-methyliminodiacetic acid (0.76 g, 5.2 mmol), toluene (8 mL) and DMSO (2 mL). The flask was fitted with a Dean-Stark trap and the Dean-Stark trap was fitted with a reflux condenser. The mixture was heated to reflux with azeotropic removal of water for 4.5 h. The solution was concentrated in vacuo. The residue was absorbed on Celite in vacuo from an acetone suspension and the resulting powder was subjected to Isco flash chromatography eluted with 0 to 70% acetonitrile in ether to give 2-(5-bromo-2-fluoro-3-methylphenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (1.26 g, 86%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH2:10][CH:11]([CH3:15])[C:12]([NH2:14])=O)=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22])#[N:2].C(Cl)(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCCl>[C:12]([CH:11]([CH3:15])[CH2:10][N:9]([CH2:16][C:17]([F:18])([F:19])[F:20])[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:21]([F:22])([F:24])[F:23])[CH:5]=1)#[N:14]
Reactant: CC(CN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1)C(N)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C#N)CN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 87 °C
Yield: 52.2 %

Procedure:
A mixture of 3-[[4-cyano-3-(trifluoromethyl)phenyl](2,2,2-trifluoroethyl)amino]-2-methylpropanamide (0.044 mg, 0.12 mmol), CCl4 (1.5 mL), DCE (1.5 mL) and polymer-supported triphenyl phosphine (3 mmol/g, 0.089 g, 0.27 mmol) was heated at 87° C. for 2 h. Upon cooling, the resin was filtered off, washed thoroughly with CHCl3 and the filtrate concentrated in vacuo. The residue was purified by silica gel chromatography (5-40% EtOAc-hexane gradient) and the product crystallized from CH2Cl2-hexanes to give the title compound as a white solid (0.021 g, 52% yield): 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=8.8 Hz, 1H), 7.03 (d, J=2.6 Hz, 1H), 6.94 (dd, J=8.8, 2.6 Hz, 1H), 4.31-4.10 (m, 2H), 3.79-3.68 (m, 2H), 3.10-3.01 (m, 1H), 1.41 (d, J=7.2 Hz, 3H); MS (ES) m/z 336 (M+1).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:11][CH2:12][CH2:13][C:14]1[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=1.[C:24]([C:32](O)=[O:33])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[O:31]=[C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:32]([N:11]([C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:1]=1)[CH2:12][CH2:13][C:14]1[CH:15]=[N:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=1)=[O:33]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: FC(F)(F)c1ccc(CCNc2ccc3c(c2)CCCC3)cn1
Product: O=C(C(=O)N(CCc1ccc(C(F)(F)F)nc1)c1ccc2c(c1)CCCC2)c1ccccc1
Yield: 100.6 %

Procedure:
In analogy to example 7, step 1, (5,6,7,8-tetrahydro-naphthalen-2-yl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (250 mg, 0.78 mmol, prepared as described in example 9, step 1) and benzoylformic acid (141 mg, 0.939 mmol) were coupled to provide the title compound (355 mg, 100%) as a yellow oil which was used without further purification in the next step.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1)[NH2:3].CN(C)/[CH:14]=[CH:15]/[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)=O>>[F:24][C:20]1[CH:19]=[C:18]([C:16]2[N:2]([C:4]3[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=3)[N:3]=[CH:14][CH:15]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CN(C)/C=C/C(=O)c1cccc(F)c1
Reactant: N#Cc1ccnc(NN)c1
Agent: Cl
Product: N#Cc1ccnc(-n2nccc2-c2cccc(F)c2)c1
Yield: 98 %

Procedure:
The title compound was prepared in 98% yield from 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3) and (2E)-3-(dimethylamino)-1-(3-fluorophenyl)prop-2-en-1-one according to the procedure for the preparation of Example 12, part B. 1H NMR (400 MHz, CDCl3): δ 6.53 (1H, d, J=1.6 Hz), 6.99-7.10 (3H, m), 7.29-7.35 (1H, m), 7.38-7.40 (1H, m), 7.78 (1H, d, J=2.0 Hz), 8.05 (1H, s), 8.38 (1H, d, J=4.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([NH:6][C:7]2[CH:19]=[C:18]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[N:25]([CH3:29])[CH:24]=[CH:23]4)[CH:17]=[CH:16][C:8]=2[C:9]([O:11]C(C)(C)C)=[O:10])=[CH:4][CH:3]=1.O1CCOCC1.CO.[OH-].[Na+]>O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:31]=[CH:30][C:5]([NH:6][C:7]2[CH:19]=[C:18]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[N:25]([CH3:29])[CH:24]=[CH:23]4)[CH:17]=[CH:16][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1
Reactant: Cn1ccc2cc(-c3ccc(C(=O)OC(C)(C)C)c(Nc4ccc(F)cc4)c3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: Cn1ccc2cc(-c3ccc(C(=O)O)c(Nc4ccc(F)cc4)c3)ccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To the obtained tert-butyl 2-(4-fluoroanilino)-4-(1-methyl-1H-indol-5-yl)benzoate were added dioxane 1.5 mL, methanol 1.5 mL and 2.0 mol/L sodium hydroxide aqueous solution 0.29 mL, and it was stirred at 50° C. for 2 hours. After the reaction mixture was cooled to room temperature, 2.0 mol/L sodium hydroxide aqueous solution 0.20 mL was added to it, and it was stirred at 55° C. for 1 hour and 30 minutes. Subsequently, 2.0 mol/L sodium hydroxide aqueous solution 0.29 mL was added, it was stirred at 55° C. for 1 hour and 20 minutes, 2.0 mol/L sodium hydroxide aqueous solution 0.29 mL was added, it was stirred at 55° C. for 1 hour, 2.0 mol/L sodium hydroxide aqueous solution 0.29 mL was added, and it was stirred at 55° C. for 1 hour. After the reaction mixture was cooled to room temperature, toluene and water were added to it. The water layer was separated and collected, it was adjusted to pH3.4 with 1.0 mol/L hydrochloric acid after washing with toluene, and ethyl acetate was added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Diisopropyl ether was added to the obtained residue, solid matter was filtrated to give 2-(4-fluoroanilino)-4-(1-methyl-1H-indol-5-yl)benzoic acid 37 mg of a pale yellow solid.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:27])[CH2:23][N:24]([CH3:26])[CH3:25])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:26][N:24]([CH2:23][C:22]([NH:21][NH:20][C:18]([C@H:13]1[CH2:12][CH2:11][C@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[OH:8])=[O:19])=[O:27])[CH3:25]
Reactant: [H][H]
Reactant: CN(C)CC(=O)NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN(C)CC(=O)NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2O
Yield: 87.7 %

Procedure:
To a solution of (2R,5S)-6-(benzyloxy)-N′-[(dimethylamino)acetyl]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 241 (0.15 g, 0.40 mml) in methanol (20 mL) was added 5% Pd/C (0.20 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite and the filtrate was evaporated to give (2R,5S)—N′-[(dimethylamino)acetyl]-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 242 (0.10 g, 88%) as a white foam.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:10][O:11]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([OH:9])[C:3]=1[CH:10]=[O:11]
Reactant: Cc1cc(C)cc(O)c1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(C)c(C=O)c(O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
3,5-Dimethylphenol (40.0 g; 330 mmole) was dissolved in dichloromethane (210 ml) and the solution was cooled to a temperature of 0° C. Titanium tetrachloride (105 g; 553 mmole) was added dropwise over a period of 5 minutes to the stirred solution and then the temperature of the solution was maintained at 0° C. for a period of 30 minutes while dichloromethyl methyl ether (31.6 g) was added dropwise. The solution was warmed to room temperature and stirred for a period of 30 minutes and then warmed to 35° C. and stirred for a further 15 minutes. The reaction mixture was poured onto ice (ca 300 g) and the aqueous mixture was extracted with dichloromethane. The organic phase was washed three times with water and the solvent was removed by evaporation under reduced pressure. The residue was steam distilled and the distillate was extracted with dichloromethane and the organic phase was separated, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2,4-dimethyl-6-hydroxybenzaldehyde (31.0 g; 63.0%) as a yellow solid mp <50° C. Proton magnetic resonance spectrum (CDC13 ; δ in ppm): 2.19 (3H, s); 2.42 (3H, s); 6.41-6.52 (2H, m); 10.05 (1H, s); 11.90 (1H, s).
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[CH:7][C:8]([NH2:20])=[C:9]([CH:19]=1)[CH:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])C(C)=O.[SH:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]>Cl>[ClH:17].[ClH:17].[NH2:20][C:8]1[CH:7]=[CH:6][C:5]([NH2:1])=[CH:19][C:9]=1[CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])[S:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: CC(=O)Nc1ccc(N)c(C(O)c2ccccc2Cl)c1
Reactant: O=C(O)CCS
Agent: Cl
Product: Nc1ccc(N)c(C(SCCC(=O)O)c2ccccc2Cl)c1

Procedure:
107.3 g of 5-acetamino-2-amino-2'-chlorobenzhydrol are heated to 90° for 1 hour together with 36.8 g of 3-mercaptopropionic acid in 290 ml of 6N hydrochloric acid. After cooling, the crystals are filtered off. There is obtained 3-[(2,5-diaminophenyl)(2-chlorophenyl)methylthio]propionic acid dihydrochloride of melting point 234°-235° (decomposition).