Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:6][N:7]=[C:8](OCC)[CH2:9][CH2:10][CH2:11][CH3:12])([O:3]CC)=O.[NH2:16][CH2:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][CH:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=1>C(O)C>[CH2:9]([C:8]1[N:16]([CH2:17][C:18]2[CH:36]=[CH:35][C:21]([O:22][CH:23]([C:24]([O:26][CH3:27])=[O:25])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])=[CH:20][CH:19]=2)[C:1](=[O:3])[NH:6][N:7]=1)[CH2:10][CH2:11][CH3:12]
Reactant: COC(=O)C(Oc1ccc(CN)cc1)c1ccccc1Cl
Reactant: CCCCC(=NNC(=O)OCC)OCC
Solvent: CCO
Product: CCCCc1n[nH]c(=O)n1Cc1ccc(OC(C(=O)OC)c2ccccc2Cl)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of approximately equimolar quantities of ethyl valerimidate carbethoxyhydrazone (from Step A) and methyl 2-[4-(aminomethyl)phenoxy]-2-(2-chlorophenyl)acetate (Step F) in ethanol is stirred at 80° C. under N2. After about 2 hours, or when TLC indicates complete reaction, the mixture is cooled and concentrated to dryness. The residue is re-concentrated from CH2Cl2 and then chromatographed on silica gel to yield the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[N:9]([CH3:11])[CH3:10].CN(CCN(C)C)C.[Li]CCCC.CN([CH:32]=[O:33])C>C1COCC1.O>[CH3:11][N:9]([CH3:10])[C:8]1[CH:12]=[CH:13][CH:14]=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:15])[CH3:1])[C:7]=1[CH:32]=[O:33]
Reactant: CN(C)C=O
Reactant: CN(C)CCOc1cccc(N(C)C)c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCOc1cccc(N(C)C)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of Compound 71 (2.8 g, 13.5 mmol) in THF (10 mL) was added TMEDA (1.88 g, 16.2 mmol) followed by n-BuLi (2.5 M solution in hexane, 6.5 mL, 16.2 mmol). The mixture was stirred for 30 min at room temperature then DMF (1.48 g, 20.25 mmol) was added and the solution stirred for 3 h at room temperature. The reaction was then diluted with water (20 mL), and the product was extracted with EtOAc (3×50 mL). The organic layers were combined and washed with brine, and dried (MgSO4), and filtered, and the solvent was removed under reduced pressure. After silica gel chromatography, the product (Compound 72) was obtained as an oil.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O-]CC.[Na+].[Br:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][CH:40]=1.O>C(O)C>[Br:38][C:39]1[CH:46]=[CH:45][C:42](/[CH:43]=[CH:14]/[C:4]2[N:5]=[C:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:7][C:3]=2[CH3:2])=[CH:41][CH:40]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Cc1oc(-c2ccccc2)nc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1/C=C/c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.2 %

Procedure:
(5-Methyl-2-phenyl-4-oxazolylmethyl)triphenyl-phosphonium chloride (25.4 g) was added to a solution of sodium ethoxide in ethanol [prepared from sodium (1.4 g) and ethanol (300 ml)] under cooling. The mixture was stirred at room temperature for 5 minutes, and then 4-bromobenzaldehyde (10.0 g) was added. After stirring at room temperature for 2 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ether-hexane (1:20, v/v) gave (E)-4-[2-(4-bromophenyl)vinyl]-5-methyl-2-phenyloxazole (13.1 g, 71%). This product was recrystallized from ethyl acetate-hexane. Colorless prisms, mp: 138-139° C.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:34])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH2:29][C:30]([F:33])([F:32])[F:31])[N:17]=2)[CH2:9]1.[CH2:35]([O:37][C:38]([CH:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)=[O:39])[CH3:36]>>[CH2:35]([O:37][C:38]([CH:40]1[CH2:45][CH2:44][CH:43]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:34])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:28])[F:26])[CH:23]=4)[N:18]([CH2:29][C:30]([F:31])([F:32])[F:33])[N:17]=3)[CH2:9]2)[CH2:42][CH2:41]1)=[O:39])[CH3:36]
Reactant: O=C(CNc1nn(CC(F)(F)F)c2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: CCOC(=O)C1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCC(N2CC(NC(=O)CNc3nn(CC(F)(F)F)c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-(azetidin-3-yl)-2-((1-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)-1H-indazol-3-yl)amino)acetamide TFA salt (as prepared in the previous step) and 4-oxo-cyclohexanecarboxylic acid ethyl ester using the procedure described in Step E of Example 1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=[O:6].CC1(C)C(C)(C)OB(/[CH:22]=[CH:23]/[CH2:24][O:25][CH3:26])O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[CH3:26][O:25][CH2:24]/[CH:23]=[CH:22]/[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(Br)cc(C(F)(F)F)c1
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC/C=C/c1cc(C=O)cc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)benzaldehyde (1 eq.) from the previous step and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1.5 eq.) in DMF (0.2 M) was added trans-bis(triphenylphosphine) palladium(II) bromide (0.05 eq.). The vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting mixture was stirred at 100° C. for 2 h. The now black suspension was cooled to RT, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:7]1[CH2:11][CH:8]1[CH:9]=[CH2:10]>C1COCC1.[Pd]>[OH:7][CH2:11][CH:8]=[CH:9][CH2:10][N:1]1[CH2:6][CH2:5][N:4]([CH2:10][CH:9]=[CH:8][CH2:11][OH:7])[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: C=CC1CO1
Agent: [Pd]
Solvent: C1CCOC1
Product: OCC=CCN1CCN(CC=CCO)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
1.23 g (14.3 mmol) of piperazine was dissolved in 20 ml of THF. 0.8 g of the polymer-bound palladium catalyst of Example 2 and 2.3 ml (28.6 mmol) 3,4-epoxy-1-butene was then added to the reaction mixture. The reaction mixture was stirred for 24 hours at room temperature. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure, resulting in a 98% yield of N,N'-di-(4-hydroxy-2-butenyl)-piperazine (1,4 adduct). None of the isomeric 1,2 adduct was detected.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([NH:11][C:12]1[C:13]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][N:27]=3)=[O:25])[CH2:20][CH2:19]2)=[N:14][CH:15]=[CH:16][CH:17]=1)([CH3:10])[CH3:9].C(Cl)(=O)C(C)(C)C.[NH2:42][C:43]1[CH:47]=[C:46]([CH3:48])[NH:45][N:44]=1>C(Cl)Cl>[CH:8]([NH:11][C:12]1[C:13]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([NH:42][C:43]4[CH:47]=[C:46]([CH3:48])[NH:45][N:44]=4)=[O:32])=[CH:28][N:27]=3)=[O:25])[CH2:20][CH2:19]2)=[N:14][CH:15]=[CH:16][CH:17]=1)([CH3:9])[CH3:10]
Reactant: Cc1cc(N)n[nH]1
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)c2ccc(C(=O)N3CCN(c4ncccc4NC(C)C)CC3)nc2)n[nH]1
Temperature: 5 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
Triethylamine (0.8 ml) was added to 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid (2 g) in methylene chloride (30 ml) for dissolution and cooled. With the slow addition of pivaloyl chloride (0.7 ml) at 0° C.˜5° C., the mixture was stirred at 5° C. for 1 hour. With the addition of triethylamine (0.9 ml) and 3-amino-5-methylpyrazole (0.56 g), the mixture was stirred at 5° C.˜10° C. for 3 hours. The solution was slowly heated and stirred at 15° C.˜20° C. for 30 minutes. The solution was washed with an aqueous sodium bicarbonate and water twice. The separated organic layer was concentrated under reduced pressure. The concentrated residue was chromatographed on column (chloroform/isopropanol=10/1, v/v). The purified solution was recovered and concentrated under reduced pressure. The residue was treated with ether for crystallization and with the addition of isopropyl ether (20 ml), and stirred for 2 hours, filtered and washed to give a desired compound of 1.77 g (yield: 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>[Cu].C(OCC)(=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)[nH]c1ccccc12
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1ccc2c3ccccc3n(-c3ccccc3)c2c1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
Next, a mixed solution of 17.7 g of 2-chloro-9H-carbazole, 22 g of iodobenzene, 20 g of a copper powder, 43 g of potassium carbonate and 200 ml of dimethylformamide was heated/stirred at 140° C. for 16 hours under a nitrogen flow. The solution was cooled to room temperature, 50 ml of ethyl acetate was added, and the mixture was filtered with Celite. To the resultant filtrate was added a saturated aqueous ammonium chloride solution, and the mixture was stirred for a while, and then extracted with ethyl acetate and hexane. The extract was dried over magnesium sulfate, and then evaporated. The concentrate was purified by silica gel column chromatography and vacuum-dried to obtain 14 g of 2-chloro-9-phenyl-9H-carbazole.
Reaction SMILES: [OH:1][N:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[C:5]([O:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[C:4]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])[C:3]1=[O:29].[O:30]1[CH:34]=[CH:33][CH2:32][CH2:31]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:13][O:12][N:9]1[CH2:10][CH2:11][C:6]2([N:2]([O:1][CH:31]3[CH2:32][CH2:33][CH2:34][O:30]3)[C:3](=[O:29])[C:4]([C:20]3[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])=[C:5]2[O:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])[CH2:7][CH2:8]1
Reactant: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)N(O)C12CCN(OC)CC2
Reactant: C1=COCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)N(OC2CCCO2)C12CCN(OC)CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of carbonic acid ethyl ester 1-hydroxy-8-methoxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester (150 mg, 0.37 mmol) in dichloromethane (3 ml) under argon atmosphere was added 2,3-dihydro-furan (56 μl, 52 mg, 0.74 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate (2 mg). The reaction mixture was stirred at room temperature for 4 hours, diluted with dichloromethane, washed twice with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/hexane 2:1). Yield: 114 mg of carbonic acid ethyl ester 8-methoxy-2-oxo-1-(tetrahydro-furan-2-yloxy)-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester (title compound P1ii.9) as a colorless gum.
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][CH2:8][CH3:9])[C:5]#[N:6])[CH2:2][CH3:3].S(=O)(=O)(O)[OH:11].N([O-])=O.[Na+].N([O-])=O>>[CH2:1]([CH:4]([CH2:7][CH2:8][CH3:9])[C:5]([NH2:6])=[O:11])[CH2:2][CH3:3]
Reactant: CCCC(C#N)CCC
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Product: CCCC(CCC)C(N)=O

Procedure:
As regards the hydrolysis of the di-n-propyl acetonitrile, this will advantageously be carried out by means of 80% by weight sulphuric acid in the proportion of 3 to 5 g of dilute acid/g of nitrile, for example, 3.75 g of dilute acid/g of nitrile over a period of 90 minutes at 80°-85° C. and adding to the resulting amide an aqueous solution of sodium nitrite in the proportion of 1.4 mol of nitrite/mol of di-n-propyl acetonitrile, the reaction taking place for 2 hours at 40°-50° C. It will also be just as advantageous to use a 75% by weight sulphuric acid aqueous solution in the proportion of 1.7 g of dilute acid/g of nitrile for 30 minutes at 140° C., to obtain the intermediate di-n-propyl acetamide, which is hydrolysed in the same sulphuric acid medium in the presence of sodium nitrite in the proportion of 1.4 to 1.5 mol of nitrite/mol of di-n-propyl acetonitrile for one hour at 50°-60° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([N:18]=[C:19]=S)[CH:15]=[CH:16][CH:17]=1>>[N:1]1[C:2]2[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:5][C:19]=1[NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[CH:13]=1
Reactant: NCc1ccccc1N
Reactant: COc1cccc(N=C=S)c1
Product: COc1cccc(NC2=Nc3ccccc3CN2)c1

Procedure:
The title compound (MS: m/e=254.1 [M+H+]) was prepared in analogy to example 1 from 2-aminobenzylamine and 3-methoxyphenylisothiocyanate.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:26])[CH3:25])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.[CH3:27][O:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:30]=1[CH:31]=[C:32]([C:39]([NH:41][C:42]1[CH:47]=[CH:46][C:45](B3OC(C)(C)C(C)(C)O3)=[CH:44][C:43]=1[O:57][CH3:58])=[O:40])[N:33]2[CH3:38]>>[C:24]([N:21]1[CH2:22][CH2:23][N:18]([C@H:15]2[CH2:16][CH2:17][C@H:12]([C:4]3[N:5]4[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]4=[C:2]([C:45]4[CH:46]=[CH:47][C:42]([NH:41][C:39]([C:32]5[N:33]([CH3:38])[C:34]6[C:30]([CH:31]=5)=[C:29]([O:28][CH3:27])[CH:37]=[CH:36][CH:35]=6)=[O:40])=[C:43]([O:57][CH3:58])[CH:44]=4)[N:3]=3)[CH2:13][CH2:14]2)[CH2:19][CH2:20]1)(=[O:26])[CH3:25]
Reactant: CC(=O)N1CCN([C@H]2CC[C@H](c3nc(Br)c4c(C)nccn43)CC2)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2c(OC)cccc2n1C
Product: COc1cc(-c2nc([C@H]3CC[C@H](N4CCN(C(C)=O)CC4)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc2c(OC)cccc2n1C

Procedure:
Using the procedure described in example 1 step 1f 1-(4-((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)piperazin-1-yl)ethanone (0.059 mmol, 25 mg) and 4-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-indole-2-carboxamide (0.059 mmol, 26 mg) gave after purification on prep-HPLC (column Luna C18(2); gradient acetonitrile/water with constant 0.003M trifluoroacetic acid) 11 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:20]2[O:19][CH:23]=[CH:22][CH:21]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccco1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccco2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and furan-2-boronic acid according to the general procedure B. Obtained as an orange solid (282 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:32])[CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21](C(C)=C)[C:20]3=[O:31])[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.Cl.C(O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:32])[CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[NH:21][C:20]3=[O:31])[CH2:14][CH2:15]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)n1c(=O)n(CCCN2CCC(CC(=O)c3cccc(Cl)c3)CC2)c2ccccc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(CC1CCN(CCCn2c(=O)[nH]c3ccccc32)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A mixture of 9 parts of 1-[3-[4-[2-(3-chlorophenyl)-2-oxoethyl]-1-piperidinyl]propyl]-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, 18 parts of a concentrated hydrochloric acid, 80 parts of ethanol and 50 parts of water is stirred for 30 minutes at room temperature. The reaction mixture is evaporated and water is added to the residue. The free base is liberated in the conventional manner with ammonium hydroxide and extracted with trichloromethane. The extract is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 6.4 parts (78%) of 1 -[3-[4-[2-(3-chlorophenyl)-2-oxoethyl]-1-piperidinyl]propyl]-1,3-dihydro-2H-benzimidazol-2-one; mp. 160.3° C.
Reaction SMILES: [FH:1].N[C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.N([O-])=O.[Na+]>>[Cl:10][C:4]1[C:3]([F:1])=[CH:8][C:7]([Cl:9])=[CH:6][N:5]=1
Reactant: Nc1cc(Cl)cnc1Cl
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Product: Fc1cc(Cl)cnc1Cl
Reaction time: 2 h
Yield: 85.3 %

Procedure:
A Monel autoclave is charged with 450 ml (22.5 mol) of hydrogen fluoride and then 163 g (1.0 mol) of 3-amino-2,5-dichloropyridine are added at a temperature in the range from -5° to -1° C. Over 11/2 hours, 82.8 g (1.2 mol) of sodium nitrite are introduced into this solution. After the reaction mixture has been stirred at the same temperature for 11/2 hours, the temperature is raised stepwise to +60° C. When the evolution of gas ceases, the hydrogen fluoride is evaporated off and the residue is taken up in methylene chloride and the resultant solution is poured into ice water. The two-phase mixture is neutralised with concentrated ammonia solution. The organic phase is separated and the aqueous phase is extracted three times with methylene chloride. The combined organic phases are washed with water, dried over magnesium sulfate, treated with active carbon, filtered through silica gel and concentrated by evaporation, affording 141.5 g (85% of theory) of 2,5-dichloro-3 -fluoropyridine, m.p. 38°-39° C.
Reaction SMILES: [F:1][C:2]([F:15])([CH:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=CN=1)[C:3]([NH:5][NH2:6])=[O:4].FC(F)(C(O)C1[S:25]C=CC=1)C(OCC)=O.NN>>[F:1][C:2]([F:15])([CH:7]([OH:14])[C:8]1[S:25][CH:11]=[CH:12][CH:13]=1)[C:3]([NH:5][NH2:6])=[O:4]
Reactant: CCOC(=O)C(F)(F)C(O)c1cccs1
Reactant: NNC(=O)C(F)(F)C(O)c1ccccn1
Agent: NN
Product: NNC(=O)C(F)(F)C(O)c1cccs1

Procedure:
α,α-difluoro-β-hydroxy-2-thiophenepropanoic acid, hydrazide (26) was prepared in the same manner as α,α-difluoro-β-hydroxy-3-(2-pyridinyl)-propanoic acid, hydrazide (10), as described above in Example10, on a 1.4 mmol scale from ethyl α,α-difluoro-β-hydroxy-2-thiophenepropanoate and hydrazine to yield 0.23 g (74%) of product. Analysis calculated for C7H8N2O2F2S (M.W. 222.21): C, 37.84; H, 3.63; N, 12.61. Found: C, 37.72; H, 3.51; N, 12.42.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][NH:6][C:7]([C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]4[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=4[F:38])=[O:29])=[C:23]([F:39])[CH:22]=3)[CH:17]=[CH:16][N:15]=2)[NH:11][CH:10]=1)=[O:8])C.Cl.O.C([O-])(O)=O.[Na+]>C1COCC1>[F:39][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[NH:27][C:28]([NH:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1[F:38])=[O:29])[O:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:12]2[NH:11][CH:10]=[C:9]([C:7]([NH:6][CH2:5][CH:4]=[O:3])=[O:8])[CH:13]=2)[CH:19]=1
Reactant: CCOC(CNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)ccn2)c1)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCC=O)c[nH]4)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-(2,2-diethoxyethyl)-5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide (550 mg, 0.95 mmol) in 10 ml of THF was added 2 ml of 2M HCl. The mixture was stirred at room temperature under nitrogen for overnight, and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=8. The precipitates were filtered, washed with water, and dried to give 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(2-oxoethyl)-1H-pyrrole-3-carboxamide as off-white solid. Yield: 475 mg, 99%.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH:7]([N:10]([CH:29]([CH3:31])[CH3:30])[CH2:11][CH2:12][C@@H:13]([C:20]1[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[CH:22][C:21]=1[OH:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:9])[CH3:8]>ClCCl>[CH3:3][CH:2]([C:1]([O:28][C:21]1[CH:22]=[CH:23][C:24]([CH2:26][OH:27])=[CH:25][C:20]=1[C@@H:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12][CH2:11][N:10]([CH:7]([CH3:9])[CH3:8])[CH:29]([CH3:31])[CH3:30])=[O:5])[CH3:4]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CO)ccc1O)C(C)C
Solvent: ClCCl
Product: CC(C)C(=O)Oc1ccc(CO)cc1[C@H](CCN(C(C)C)C(C)C)c1ccccc1
Temperature: -3 °C

Procedure:
Drops of a solution of 18.6 g isobutyric acid chloride in 250 ml dichloromethane were added in approximately 10 minutes to a solution of 59.8 g (175.1 mol) (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol cooled to −3° C. (A, see FIG. 1) dissolved in 750 ml dichloromethane with agitation and cooling by ice bath. A white substance precipitated after approximately 5 minutes. For this purpose, drops of a solution of 17.7 g triethylamine in 250 ml dichloromethane were added in 5 minutes under agitation and ice bath cooling. The batch was washed once with each of 250 ml water, 250 ml approximate 5% aqueous NaHCO3 solution and 250 ml water. The dichloromethane extract dried over Na2SO4 was evaporated to a low small bulk on a rotary evaporator to constant weight, whereby a sallow, high viscosity oil was left. Raw yield: 63.7 g (88.5% of the theory).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[C@H:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].O.C(=O)([O-])[O-].[K+].[K+].[C:32]([O:36][C:37](=[O:40])[CH2:38]Br)([CH3:35])([CH3:34])[CH3:33]>O1CCCC1>[C:1]([O:5][C:6](=[O:24])[CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:38][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:40])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN(Cc1ccccc1)C(Cc1ccc(O)cc1)C(=O)OC(C)(C)C

Procedure:
15.1 g (46.1 mmol) of N-benzyl-tyrosine-tert-butyl ester (Example i) is dissolved in 50 ml of tetrahydrofuran and mixed with 5 ml of water and 9.54 g (69 mmol) of potassium carbonate. After instillation of 9.89 g (51 mmol) of bromoacetic acid-tert-butyl ester, it is stirred for two days at 65° C. After cooling, it is filtered, concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel with diethyl ether/hexane/triethylamine. The product fractions are concentrated by evaporation in a vacuum and dried.