Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([O:4][C:5](=[O:18])[CH2:6][NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)C.C([NH:29][C@H:30]([C:32](O)=[O:33])[CH3:31])(OCC1C=CC=CC=1)=O>>[NH2:29][C@H:30]([C:32]([N:7]([CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)[CH2:6][C:5]([OH:4])=[O:18])=[O:33])[CH3:31]
Reactant: CCOC(=O)CNC1CCc2ccccc2C1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: C[C@H](N)C(=O)N(CC(=O)O)C1CCc2ccccc2C1
Yield: 54.2 %

Procedure:
By reacting 13.5 g of N-(1,2,3,4-tetrahydronaphthalen-2-yl)glycine ethyl ester hydrochloride with 11.6 g of N-carbobenzoxy-L-alanine and treating the reaction mixture as in Reference Example 4, there is obtained 7.5 g of L-alanyl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)glycine as colorless amorphous powder.
Reaction SMILES: [K].[C:2]([C:4]([CH3:17])([C:6](=[O:16])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH3:5])#[N:3].Cl[C:19]1[CH:28]=[N:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:25]=2)[N:20]=1.O>CN(C)C=O>[C:2]([C:4]([CH3:17])([C:6](=[O:16])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:19]2[CH:28]=[N:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:29]([F:30])([F:31])[F:32])[CH:25]=3)[N:20]=2)=[CH:13][CH:14]=1)[CH3:5])#[N:3]
Reactant: FC(F)(F)c1ccc2nc(Cl)cnc2c1
Reactant: CC(C)(C#N)C(=O)COc1ccc(O)cc1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C#N)C(=O)COc1ccc(Oc2cnc3cc(C(F)(F)F)ccc3n2)cc1
Temperature: 100 °C
Yield: 47.1 %

Procedure:
2.20 Grams of a potassium salt of 2-cyano-2-methyl-4-(4-hydroxyphenoxy)-3-butanone and 1.69 g of 2-chloro-6-trifluoromethylquinoxaline were refluxed in 50 nl of N,N-dimethylformamide under heat at 100° C. for 4 hours. The reaction mixture was added to water, and after the mixture was subjected to extraction with chloroform, the extract was concentrated. The residue was separated and purified by column chromatography to give 1.67 g of a compound No. 166 which was a light yellow solid (melting point 113°-115° C.). The yield was 47.1%. The compound No. 166 was analyzed, and the results are shown in Tables 1 to 23.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15]([C:17]1[N:18]=[C:19]([N:22]2[CH2:25][CH:24](OS(C)(=O)=O)[CH2:23]2)[S:20][CH:21]=1)=[O:16])[CH:11]([CH3:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:31]([O-:34])(=[S:33])[CH3:32].[K+]>CN(C)C=O>[C:31]([S:33][CH:24]1[CH2:25][N:22]([C:19]2[S:20][CH:21]=[C:17]([C:15](=[O:16])[NH:14][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3])[CH:11]([CH3:13])[CH3:12])[N:18]=2)[CH2:23]1)(=[O:34])[CH3:32]
Reactant: CC(C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)C(C)C)cs2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
To a solution of 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-2-methylpropylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (890 mg, 1.75 mmol) (obtained as described in Reference Example 36(5)) in dimethylformamide (45 ml) was added potassium thioacetate (1.20 g, 10.5 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (3:1→1:1) as the eluant to afford 3-acetylthio-1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-2-methylpropylcarbamoyl]-1,3-thiazol-2-yl}azetidine (502 mg, yield 63%) as a pale brown oil.
Reaction SMILES: [I-:1].[Na+].[Si:3]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Cl)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>CC(C)=O>[Si:3]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][I:1])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: [I-]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCCl
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCI
Temperature: 25 °C

Procedure:
A solution of sodium iodide (13.5 g, 90 mmol) and 1-(tert-butyldimethylsilyloxy)-6-chloro-hexane (Preparation 20) (8.35 g, 22 mmol) in acetone (70 ml) was refluxed overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was worked-up (hexane) to give the desired compound as yellow oil.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH:11]=[C:12]([C:16]#[N:17])[CH2:13][C:14]#[N:15].[O-]CC.[Na+].Cl>C(O)C>[O:2]=[C:3]1[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:10]2[CH:11]=[C:12]([C:16]#[N:17])[CH:13]=[C:14]2[NH:15]1
Reactant: COC(=O)c1ccccc1NC=C(C#N)CC#N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cc2[nH]c(=O)c3ccccc3n2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
Under cooling on ice, in a solution of 2-(2,3-dicyanopropen-1-ylamino)benzoic acid methyl ester (E isomer/Z isomer mixture) (Reference Compound 2-1, 40.1 g, 0.166 mol) in ethanol (700 mL), a solution of sodium ethoxide (28.2 g, 0.414 mol) in ethanol (300 mL) was added dropwise. After stirring the reaction solution at room temperature for 2 hours, 1M hydrochloric acid (500 mL) was added under cooling on ice. The precipitated solid was collected by filtration, and washed with water. By drying under reduced pressure, the title Reference Compound (33.8 g, yield: 97%) was obtained as a colorless powder (see Z. Chem. 1961, 1, 349).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH:47]3[CH2:49][CH2:48]3)=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH:47]3[CH2:48][CH2:49]3)=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K21) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (344 mg, 72%).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[C:24]([O:28][C:29]([N:31]([CH2:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)[CH3:32])=[O:30])([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[C:24]([O:28][C:29]([N:31]([CH2:33][C:34]1[CH:40]=[CH:39][C:37]([NH:38]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:36][CH:35]=1)[CH3:32])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CN(Cc1ccc(N)cc1)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CN(Cc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1)C(=O)OC(C)(C)C

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(N-tert.butoxycarbonyl-N-methyl-amino)methyl-aniline in DMF.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([CH3:12])([CH2:8][CH2:9][CH2:10][OH:11])[CH:6]([CH3:13])[CH2:5][CH2:4][NH:3]1.[CH3:14][C:15]([CH3:17])=O.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH3:1][CH:2]1[C:7]([CH3:12])([CH2:8][CH2:9][CH2:10][OH:11])[CH:6]([CH3:13])[CH2:5][CH2:4][N:3]1[CH:15]([CH3:17])[CH3:14]
Reactant: CC1CCNC(C)C1(C)CCCO
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)N1CCC(C)C(C)(CCCO)C1C
Reaction time: 2 h
Yield: 99 %

Procedure:
A mixture of 2,3,4-trimethyl-3-piperidinepropanol (13.0 g, 70 mmol), acetone (400 mL), methanol (300 mL), sodium cyanoborohydride (4.4 g, 70 mmol), 3A molecular sieves (30 g) and acetic acid (4.0 mL, 70 mmol) was stirred under a nitrogen atmosphere for 2 hours. The pH was readjusted to a pH of 5 by the addition of 1.5 mL of additional acetic acid and the reaction mixture was stirred for 24 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in water (200 mL) and acetone (20 mL) and was acidified with concentrated hydrochloric acid. The mixture was basified with 10% NAOH and extracted with ether (4×300 mL) . The ether extracts were combined, washed with brine and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by a Kugelrohr distillation at 0.1 mm Hg and 100-110° C. to afford 15.7 g (99%) of 2,3. 4-trimethyl-l- (1-methylethyl)-3-piperidinepropanol as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[CH3:12][N:13](C=O)C>C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.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>[CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[C:12]#[N:13])[CH:7]=[CH:8][N:9]=1
Reactant: CN(C)C=O
Reactant: Brc1cccc2ccncc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: N#Cc1cccc2ccncc12
Temperature: 25 °C
Reaction time: 70.5 h

Procedure:
To a solution of 0.5035 g (2.42 mmol) 24 in 10 mL DMF was added 0.1713 g (1.45 mmol) zinc cyanide and 0.1687 g (0.15 mmol) tetrakis(triphenylphosphine)palladium(0). After 70.5 h under argon at 80° C., the reaction mixture was cooled to room temperature, diluted with 50 mL toluene and washed with 15 mL 2N NH4H. The aqueous layer was extracted with 15 mL toluene. The combined organic layers were washed with 15 mL brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (40×105 mm silica gel, linear gradient 1-4% MeOH:CH2Cl2) yielded 25. 1H NM (CDCl3, 400 MHz) δ 9.679 (s, 1H, ArH); 8.732 (d, 1H, J=5.67 Hz, ArH); 8.097 (d, 1H, J=8.41 Hz, ArH); 8.031 (d, 1H, J=7.13, ArH); 7.771 (dd, 2H, J=6.81, 10.47 Hz, ArH); MS (Electrospray): m/z 155.0 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([Cl:34])[CH:30]=4)[CH:25]=3)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:35])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:36](I)[CH3:37]>>[Cl:34][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:21]([N:18]1[CH2:19][CH2:20][N:15]([N:14]([CH2:36][CH3:37])[CH:11]3[CH2:12][CH2:13][N:8]([C:11]4[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=4)[CH2:9][CH2:10]3)[C:16](=[O:35])[CH2:17]1)(=[O:22])=[O:23])[CH:33]=[CH:32]2
Reactant: CC(C)(C)OC(=O)N1CCC(NN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CC1
Reactant: CCI
Product: CCN(C1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O
Yield: 590.5 %

Procedure:
(Method A) Similarly to Method A in Example 38 and using 1-[1-(tert-butoxycarbonyl)-4-piperidinylamino]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (1.57 g) and ethyl iodide (4.68 g) instead of methyl iodide, the title compound (4.68 g) was obtained as colorless crystals.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[F:13].[Cl-].[Cl-].[Cl-].[Al+3]>Cl>[Cl:5][C:6]1[C:7]([F:13])=[CH:2][C:1]([OH:3])=[C:10]([C:9](=[O:12])[CH3:8])[CH:11]=1
Reactant: CC(=O)Cl
Reactant: Oc1ccc(Cl)c(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc(Cl)c(F)cc1O
Temperature: 60 °C
Yield: 100 %

Procedure:
Acetyl chloride (3.6 mL, 51 mmol) was added to 4-chloro-3-fluorophenol (5.1 g, 35 mmol) and the resulting mixture was heated at 60° C. for 2 hours. Aluminum trichloride (7.0 g, 52 mmol) was added and the mixture was heated at 180° C. for 30 minutes. The mixture was cooled to room temperature. The mixture was cooled to 0° C. and 1 N HCl solution (100 mL) was added dropwise over 30 minutes. The precipitate was washed well with water and dried under vacuum to give the desired compound (6.6 g, 100%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH:30]=O)=[CH:22][CH:21]=1>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:30][C:23]4[C:24]5[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=5)[N:20]=[CH:21][CH:22]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccnc2ccccc12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccnc5ccccc45)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with quinoline-4-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]quinoline.
Reaction SMILES: FC(F)(F)[C:3]([N:5](C)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][NH:15][C:16]2[C:21](=[O:22])[N:20]([CH2:23][C:24]([NH:26][CH2:27][C:28]3[CH:29]=[C:30]4[C:34](=[CH:35][CH:36]=3)[NH:33][CH:32]=[C:31]4[CH3:37])=[O:25])[C:19]([CH3:38])=[CH:18][N:17]=2)[CH:8]=1)=O.C([O-])([O-])=O.[Na+].[Na+].O>CO>[CH3:37][C:31]1[C:30]2[C:34](=[CH:35][CH:36]=[C:28]([CH2:27][NH:26][C:24](=[O:25])[CH2:23][N:20]3[C:19]([CH3:38])=[CH:18][N:17]=[C:16]([NH:15][CH2:14][CH2:13][C:9]4[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][NH:5][CH3:3])[CH:8]=4)[C:21]3=[O:22])[CH:29]=2)[NH:33][CH:32]=1
Reactant: Cc1c[nH]c2ccc(CNC(=O)Cn3c(C)cnc(NCCc4cccc(CN(C)C(=O)C(F)(F)F)c4)c3=O)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1cccc(CCNc2ncc(C)n(CC(=O)NCc3ccc4[nH]cc(C)c4c3)c2=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.8 %

Procedure:
2,2,2-Trifluoro-N-methyl-N-[3-(2-{[5-methyl-4-(2-{[(3-methyl-1H-indol-5-yl)methyl]amino}-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}ethyl)benzyl]acetamide (preparation 38) (40 mg, 0.07 mmol) was dissolved in hot methanol (15 ml) and treated with an aq. solution of Na2CO3 (0.6 ml, 0.46 mol) followed by an additional portion of water (1.5 ml). The resultant cloudy mixture was stirred at room temperature for 18 hr, then evaporated to dryness and dried. The resultant white solid was purified by chromatography (SiO2, gradient elution with 90:10 CH2Cl2:MeOH; 90:10:1 CH2Cl2:MeOH:NH3) to give the desired product (34 mg, 100%). 1H NMR (CDCl3) δ 2.15 (s, 3H), 2.30 (s, 3H), 2.50 (s, 3H), 2.90 (t, 2H), 3.60 (t, 2H), 3.90 (s, 2H), 4.50 (s, 2H), 4.75 (s, 2H), 6.70 (s, 1H), 7.00 (s, 1H), 7.05 (d, 1H), 7.20-7.40 (m, 5H), 7.45 (s, 1H). LRMS m/z=473.4 (M+1)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[C:21]([C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:23])=[C:20]([F:30])[C:19]([F:31])=[CH:18][CH:17]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([F:31])=[C:20]([F:30])[C:21]=2[C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:23])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(F)c(F)c1C(=O)c1cccnc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(F)c(F)c2C(=O)c2cccnc2)cc1

Procedure:
The title compound was prepared by the reaction of 4-t-butylbenzenesulfonyl chloride with (6-Amino-2,3-difluoro-phenyl)-pyridin-3-yl-methanone following the general procedure. MS: m/z 431.1 (M++1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:34])([CH3:33])[CH2:13][C:14]([NH:16][C@H:17]1[C:23](=[O:24])[NH:22][C:21]2[CH:25]=[CH:26][C:27]3[C:32]([C:20]=2[CH2:19][CH2:18]1)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]([O:39][C:40]([NH:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[CH:55]=[CH:54][C:53]([CH2:56]O)=[CH:52][CH:51]=1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:34])([CH3:33])[CH2:13][C:14]([NH:16][C@H:17]1[C:23](=[O:24])[N:22]([CH2:56][C:53]2[CH:52]=[CH:51][C:50]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[CH2:43][NH:42][C:40]([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:41])=[CH:55][CH:54]=2)[C:21]2[CH:25]=[CH:26][C:27]3[C:32]([C:20]=2[CH2:19][CH2:18]1)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2c(ccc3ccccc23)NC1=O)NC(=O)OCc1ccccc1
Product: CC(C)(CC(=O)N[C@@H]1CCc2c(ccc3ccccc23)N(Cc2ccc(-c3ccccc3CNC(=O)OC(C)(C)C)cc2)C1=O)NC(=O)OCc1ccccc1

Procedure:
The product of Step B is prepared from 3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide (Step A) and 2′-[(t-butoxycarbonylamino)methyl]-1,1′-biphenyl-4-methanol, methanesulfonate ester (Example 1, Step G) according to the procedure for Example 1, Step H.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:16]I)[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].[C:31]([NH:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:33])[CH3:32].O>CN(C=O)C>[C:31]([NH:34][CH:35]1[CH2:40][CH2:39][N:38]([CH2:16][CH:15]2[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH:9]2[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:37][CH2:36]1)(=[O:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCOC(CI)C(c2ccc(Cl)c(Cl)c2)C1
Reactant: CC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NC1CCN(CC2OCCN(C(=O)OC(C)(C)C)CC2c2ccc(Cl)c(Cl)c2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a solution of tert-butyl (6SR,7RS)-6-(3,4-dichlorophenyl)-7-(iodomethyl)-1,4-oxazepane-4-carboxylate (300 mg) in DMF (5 mL) were added potassium carbonate (260 mg) and 4-acetamidopiperidine (130 mg), and the mixture was stirred at 80° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (190 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1B(O)O>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>[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1N
Reactant: OB(O)c1cc(F)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cnc(-c2cc(F)ccc2F)nc1N
Temperature: 95 °C

Procedure:
Bis(triphenylphosphine)palladium chloride (0.733 g, 1.045 mmol), 2-chloro-5-methylpyrimidin-4-amine (1.5 g, 10.45 mmol), Na2CO3 (5.22 mL, 10.45 mmol) and 2,5-difluorophenylboronic acid (2.145 g, 13.58 mmol) were combined and heated at 95° C. overnight. The reaction was filtered warm through a pad of Celite®, the solids rinsed with dioxane (3×25 mL) and the filtrate was concentrated directly onto a silica chromatography column which was then eluted with EtOAc (0-100%) in hexanes afforded 2-(2,5-difluorophenyl)-5-methylpyrimidin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.03 (d, J=0.76 Hz, 3H) 6.82 (br. s., 2H) 7.26-7.33 (m, 2H) 7.57-7.64 (m, 1H) 8.06 (d, J=0.76 Hz, 1H). MS [M+H] found 222.2.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][S:16][C:17]1[CH:22]=[CH:21][C:20]([P:23](Cl)(Cl)=[O:24])=[CH:19][CH:18]=1>>[CH3:15][S:16][C:17]1[CH:22]=[CH:21][C:20]([P:23]2(=[O:24])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:19][CH:18]=1
Reactant: CSc1ccc(P(=O)(Cl)Cl)cc1
Reactant: c1ccc(CNc2ccccc2)cc1
Product: CSc1ccc(P2(=O)c3ccccc3CN2c2ccccc2)cc1
Yield: 11 %

Procedure:
The procedure of Example 1 was employed utilizing N-benzylaniline and 4-methylthiophenyl phosphonic dichloride. The reaction of the dilithio compound and the 4-methylthiophenyl phosphonic dichloride was conducted at -76° C. to yield a beige solid. The beige solid was recrystallized from ethyl acetate to yield 1-(4-methylthiophenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (2.1 g, 11% yield) as a white solid having a melting point of 164°-167° C. and the following analysis:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:12]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=1[F:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH2:15][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[C:12]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:11]=3[N:10]=2)=[C:6]([CH:7]=1)[O:8][CH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=1[F:38]
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CCC1CCCCC1
Reactant: N#Cc1ccc(CBr)c(F)c1
Product: N#Cc1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CCC2CCCCC2)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-[1-(2-cyclohexyl-ethyl)-5,6-difluoro-1H-benzoimidazol-2-yl]-phenol and 4-bromomethyl-3-fluoro-benzonitrile (CAS Reg. No. 105942-09-4). Brown sticky solid (81%). MS (Turbo Spray): m/z=524.0 (M+H).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C(N(CC)CC)C.[CH2:24]([CH:26]([CH2:30][CH2:31][CH2:32][CH3:33])[C:27](Cl)=[O:28])[CH3:25]>C(Cl)(Cl)Cl>[CH2:24]([CH:26]([CH2:30][CH2:31][CH2:32][CH3:33])[C:27]([N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:28])[CH3:25]
Reactant: CCCCC(CC)C(=O)Cl
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)N1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCC(CC)C(=O)N1C(=O)CC[C@H]1C(=O)OCc1ccccc1

Procedure:
39.4 g (180 mmol) of benzyl (L)-pyroglutamate, prepared according to Example II(1), are dissolved in 160 ml of chloroform and 28.4 g (28 mmol) of triethylamine at ordinary temperature. A solution of 29.3 g (180 mmol) of 2-ethylhexanoyl chloride in 40 ml of chloroform is run in and the mixture is heated under reflux for 5 hours.