Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[OH-].[Na+].I[CH2:14][CH3:15]>CN(C)P(=O)(N(C)C)N(C)C.O>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:14][CH3:15])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnccc1Cl
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1cnccc1Cl
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of 4-chloronicotinic acid (7.03 g, 44.6 mmol) in 100 mL of hexamethylphosphoric triamide (HMPA) was added a solution of 5.5 N sodium hydroxide (13 mL) at 0° C. Then iodoethane (27.8 g, 179 mmol) was added into the reaction mixture at 0° C. over 1 h, and stirring was continued for a further 1 h at room temperature. The mixture was diluted with 250 mL of water, and then extracted three times with ether. The ethereal extracts were combined, washed three times with water, then dried (MgSO4), filtered, and the solvent was evaporated to give ethyl 4-chloronicotinate (6.21 g) as a brown oily residue, which was used for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH3:14])[CH2:12][N:11]([C:15](OCC2C=CC=CC=2)=O)[C@@H:10]([CH2:25][OH:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCCl>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@H:10]([CH2:25][OH:26])[N:11]([CH2:15][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:12][C@H:13]1[CH3:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=Cc1ccccc1
Reactant: C[C@@H]1CN(C(=O)OCc2ccccc2)[C@@H](CO)CN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](CO)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
A mixture of (2R,5R)-2-hydroxymethyl-5-methyl-piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester (3.48 g, 15.1 mmol), benzaldehyde (1.76 g, 16.6 mmol), sodium triacetoxyborohydride (3.84 g, 18.1 mmol) and 1,2-dichloroethane (30 mL) was stirred at 20° C. for 18 h, then partitioned between saturated aqueous NaHCO3 (150 mL) and DCM (3×50 mL). Combined organic extracts were dried (Na2SO4) then evaporated in vacuo to give an oil. Chromatography (SiO2, 0-30% EtOAc in petrol) gave the title compound (4.588 g, 74%) as a colourless solid. MS: [M+H]+=321.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:12]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:4][CH2:3]1.[N:18]#CBr.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[C:1]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:12]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:4][CH2:3]1)#[N:18]
Reactant: N#CBr
Reactant: Cc1ccc2onc(C3CCN(C)CC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc2onc(C3CCN(C#N)CC3)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 34 %

Procedure:
A suspension of 0.5 g of 3-(1-methyl-4-piperidyl)-5-methyl-1,2-benzisoxazole, 0.37 g of cyanogen bromide and 1.5 g of potassium carbonate in 50 ml of chloroform was heated under reflux for 48 hrs and stirred at room temperature for 48 hrs. The reaction was filtered, the solvent was removed and the residue was triturated with hexane to give a solid. The solid was recrystallized from hexnae (three times) to give 0.178 g (37%) of product, mp, 125°-126°.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].C(=[NH:30])(C1C=CC=CC=1)C1C=CC=CC=1.NO>C1(C)C=CC=CC=1.CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[O:10]1[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:30])[C:7]=2[CH:8]=[CH:9]1
Reactant: Clc1nccc2occc12
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: NO
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Nc1nccc2occc12
Temperature: 80 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
To 4-chlorofuro[3,2-c]pyridine (1 g, 6.5 mmol) in toluene under nitrogen was added racemic BINAP (0.243 g, 0.4 mmol), Pd2(dba)3 (0.12 g, 0.13 mmol) and sodium tert-butoxide (0.88 g, 9.1 mmol). Benzophenoneimine (1.3 mL, 7.81 mmol) was added and the mixture was heated to 80° C. for 3 h and cooled to room temperature. The reaction mixture was diluted with ether, filtered through Celite, and washed with ether. The filtrate was concentrated and the deep orange residue was taken up in methanol (90 ml) and treated with hydroxylamine (1.2 mL, 19.5 mmol). The mixture was stirred at ambient temperature for 18 h and concentrated. The residue was purified by column chromatography (95-100% ethyl acetate/hexanes) to afford furo[3,2-c]pyridin-4-amine (776 mg, 5.79 mmol, 89% yield) as a deep orange solid. MS (LC/MS) R.T.=0.51; [M+H]+=135.02.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]([C:8]1[CH:13]=[C:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])[C:11]([O:23][CH3:24])=[CH:10][C:9]=1[F:25])=[O:7])[CH3:2].CO[CH:29](OC)[N:30]([CH3:32])[CH3:31]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:26])[C:5]([C:6](=[O:7])[C:8]1[CH:13]=[C:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])[C:11]([O:23][CH3:24])=[CH:10][C:9]=1[F:25])=[CH:29][N:30]([CH3:32])[CH3:31])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1cc(Cc2cccc(Cl)c2F)c(OC)cc1F
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Cc2cccc(Cl)c2F)c(OC)cc1F
Reaction time: 3 h

Procedure:
To a solution of 3-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxyphenyl)-3-oxopropionic acid ethyl ester prepared in Step VI-2 in toluene was added dropwise at 75-85° C., N,N-dimethylformamide dimethyl acetal (5.08 g) with stirring, and the mixture was stirred for 3 hr. After cooling, a solution of 2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-dimethylaminoacrylic acid ethyl ester in toluene was obtained. This was identified as the title compound by HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4]([N:6]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=[O:5].[C:36](OC(=O)C)(=[O:38])[CH3:37]>>[C:36]([NH:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4]([N:6]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH2:19][CH2:18]1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=[O:5])(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccccc2N)c1
Product: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccccc2NC(C)=O)c1
Yield: 65.8 %

Procedure:
Using 2-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-methoxyphenyl)benzamide (238.0 mg, 0.50 mmol) and acetic anhydride (0.057 ml, 0.60 mmol), the procedure of Inventive Example 94 was repeated to obtain 170.4 mg (65.9%) of the title compound in a colorless amorphous form.
Reaction SMILES: [CH3:1][C:2]([CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(OCC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH-].[K+]>>[CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)(CCCc1ccccc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)C(C)CCCc1ccccc1
Yield: 91.1 %

Procedure:
In a similar manner to that described in Reference example 2(b), a reaction was carried out using diethyl 2-methyl-2-(3-phenylpropyl)malonate (4.63 g) and potassium hydroxide (3.55 g) and the reaction mixture was treated to afford the desired compound (3.18 g) as a syrup.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10](=[CH:11][C:12]3[NH:13][CH:14]=[N:15][C:16]=3[CH3:17])[C:9](=[O:18])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:17][C:16]1[N:15]=[CH:14][NH:13][C:12]=1[CH:11]=[C:10]1[C:3]2[C:2]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)=[N:7][CH:6]=[N:5][C:4]=2[NH:8][C:9]1=[O:18]
Reactant: Cc1nc[nH]c1C=C1C(=O)Nc2ncnc(Cl)c21
Reactant: CN1CCNCC1
Product: Cc1nc[nH]c1C=C1C(=O)Nc2ncnc(N3CCN(C)CC3)c21
Yield: 49 %

Procedure:
The title compound (49% yield) was prepared from 4-chloro-5-(5-methyl-3H-imidazol-4-ylmethylene)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one and 1-methylpiperazine according to the procedure described for Example 14. MS-EI 325 [M+].
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[C:6]2[CH2:15]Br.[OH:25][CH2:26][C:27]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.[H-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[N:3]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24])[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([C:11]([F:13])([F:12])[F:14])[CH:7]=[C:6]2[CH2:15][O:25][CH2:26][C:27]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:29][CH2:28]1
Reactant: C[Si](C)(C)CCOCn1nc2c(CBr)cc(C(F)(F)F)cc2c1Br
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3c(Br)n(COCC[Si](C)(C)C)nc23)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Bromo-7-(bromomethyl)-5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (140 mg, 0.29 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (75 mg, 0.26 mmol) were combined in dimethylformamide (2 mL) and cooled to 0° C. The reaction was treated with sodium hydride (14 mg, 0.57 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (10%→20% ethyl acetate/hexanes) gave 101 mg (50%) as an oil. 1H-NMR (CDCl3, 500 MHz) δ 7.86 (s, 1H), 7.44 (s, 1H), 7.14-7.18 (m, 5H), 5.26 (s, 2H), 4.68 (s, 2H), 3.69 (m, 2H), 3.44 (s, 2H), 3.38-3.41 (m, 2H), 2.98-3.02 (m, 2H), 2.11-2.14 (m, 2H), 1.72-1.77 (m, 2H), 1.41 (s, 9H), 0.74-0.77 (m, 2H), 0.10 (s, 9H). Mass spec.: 700.11 (MH)+.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:19]2[C:16]3=[C:17]4[C:18]5[C:9]([C:10](=[O:35])[N:11]([C:23]6[C:28]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=6[CH:32]([CH3:34])[CH3:33])[C:12](=[O:22])[C:13]=5[CH:14]=[CH:15]3)=[CH:8][CH:7]=[C:6]4[C:5]3=[CH:36][CH:37]=[CH:38][C:3]=1[C:4]=23.[NH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[SH:46].C(=O)([O-])[O-].[K+].[K+].Cl>CN1CCCC1=O>[NH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:46][C:2]1[CH:21]=[CH:20][C:19]2[C:16]3=[C:17]4[C:18]5[C:9]([C:10](=[O:35])[N:11]([C:23]6[C:28]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=6[CH:32]([CH3:34])[CH3:33])[C:12](=[O:22])[C:13]=5[CH:14]=[CH:15]3)=[CH:8][CH:7]=[C:6]4[C:5]3=[CH:36][CH:37]=[CH:38][C:3]=1[C:4]=23
Reactant: Nc1ccccc1S
Reactant: CC(C)c1cccc(C(C)C)c1N1C(=O)c2ccc3c4cccc5c(Br)ccc(c6ccc(c2c36)C1=O)c54
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)c1cccc(C(C)C)c1N1C(=O)c2ccc3c4cccc5c(Sc6ccccc6N)ccc(c6ccc(c2c36)C1=O)c54
Reaction time: 8 h
Yield: 85.6 %

Procedure:
Compound 8-bromo-2-(2,6-diisopropylphenyl)-1H-benzo[5,10]anthra[2,1,9-def]isoquinoline-1,3(2H)-dione (9.0 g), 2-aminobenzenthiol (2.19 g, 10% excess) and anhydrous potassium carbonate (1.10 g) were added to 100 mL of N-methyl-2-pyrrolidinone (NMP). The solution was heated rapidly and refluxed for 30 min. After a minute the liquor was added to 2% aqueous hydrochloride acid (750 ml) and after standing overnight, filtered and dried at 105° C. to give a red-blue solid of 8-((2-aminophenyl)thio)-2-(2,6-diisopropylphenyl)-1H-benzo[5,10]anthra[2,1,9-def]isoquinoline-1,3(2H)-dione (8.31 g) with a nominal yield of 86.3%. 8-((2-aminophenyl)thio)-2-(2,6-diisopropylphenyl)-1H-benzo[5,10]anthra[2,1,9-def]isoquinoline-1,3(2H)-dione (5.15 g) was dissolved in warm glacial acetic (31 mL) and concentration hydrochloride acid (3.1 mL) giving a fine suspension. The suspension was cooled to 0° C. and a solution of sodium nitrite (0.6 g) in water (9 mL) added and stirred continuously till clear. The prepared solution was added to a boiling solution of hydrated cupric sulphate (9.7 g) in water (150 mL) with good stirring within 1 hour. After boiling a further 1 hour, the solution was cooled, filtered and a blue solid was given. The solid was washed with a warm solution of sodium hydroxide (50 mL, 3%) three times and purified on chromatography column to eliminate by-products. The blue solid of 2-(2,6-diisopropylphenyl)-1H-thioxantheno[2′,1′,9′:10,5,6]anthra[2,1,9-def]isoquinoline-1,3(2H)-dione (1.82 g) was given with a nominal yield of 36.5%. MS: base peak 587.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1.C[C:14]([N:16](C)C)=O>O.[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>[C:14]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1)#[N:16]
Reactant: CC(=O)N(C)C
Reactant: CC(=O)Nc1ccc(Br)cc1F
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: O
Product: CC(=O)Nc1ccc(C#N)cc1F
Yield: 86 %

Procedure:
A solution of N-(4-bromo-2-fluorophenyl)acetamide (12.9 g, 55.4 mmol) in 125 mL of anhydrous dimethyl acetamide was heated in the presence of zinc cyanide (5.53 g, 47.1 mmol) and tetrakis(triphenylphosphine)palladium (0) (5.2 g, 4.5 mmol) at 100° C. for 3 hours. The mixture was diluted with 300 mL of cold water, the resulting solid was filtered, washed with water, and dried. The filtrate was extracted with three 100 mL portions of ethyl acetate and the combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was combined with the solid from the filtration. This combined material was filtered through a silica gel column (100% dichloromethane followed by 100% ethyl acetate) to give 8.5 g of N-(4-cyano-2-fluorophenyl)acetamide as a light cream solid (86% yield).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][CH:14]([F:27])[CH:15]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:16][CH2:17]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:47]1(=[O:57])[NH:51][C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12>O1CCCC1.C(OCC)(=O)C.C1CCCCC1>[F:13][CH:14]([F:27])[CH:15]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:16][CH2:17][N:51]1[C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]2[C:47]1=[O:57]
Reactant: OCCC(NCc1ccccc1)C(F)F
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: O=C1c2ccccc2C(=O)N1CCC(NCc1ccccc1)C(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A solution of diethyl azodicarboxylate (0.639 g, 3.65 mM), in anhydrous tetrahydrofuran (5 ml) is added, dropwise, over a period of 0.5 hours, at room temperature to a mixture of 4,4-difluoro-3-benzylamino-butanol (0.790 g, 3.65 mM) prepared as in Step C, triphenylphosphine (0.962 g, 3.65 mM), and phthalimide (0.540 g, 3.65 mM) in tetrahydrofuran (20 ml). After stirring for 2.5 hours at room temperature, the solvent is evaporated in vacuo. The residue is taken off in benzene and the solution filtered. The solid is washed three time with benzene. The filtrate is evaporated to dryness; the residue is taken off in diethyl ether. Filtration and evaporation of the solvent in vacuo yields a yellow oil. The expected phthalimide is isolated by column chromatography (medium pressure silica gel chromatography technique, ethyl acetate/cyclohexane 2:8): 0.800 g (yield 65%).
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.[CH3:8][O:9][C:10]1[C:11](=[O:26])[CH:12]=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH:15]=1.[C:27](#[N:29])[CH3:28]>O>[N:29]1[C:19]2[C:18](=[CH:17][CH:16]=[CH:21][CH:20]=2)[CH:22]=[CH:28][C:27]=1[CH2:8][O:9][C:10]1[C:11](=[O:26])[CH:12]=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)[CH:15]=1
Reactant: COc1cn(-c2cccc(C(F)(F)F)c2)ncc1=O
Reactant: CC#N
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: O=c1cnn(-c2cccc(C(F)(F)F)c2)cc1OCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Sodium iodide (0.2772 g) and chlorotrimethylsilane (0.235 mL) were stirred in acetonitrile (1.85 mL) at room temperature for 30 min. A solution of 5-methoxy-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.100 g) in acetonitrile (3.7 mL) was added at room temperature. The reaction mixture was heated under reflux for 3 hr. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated, purified by silica gel column chromatography (ethyl acetate/hexane-methanol/ethyl acetate), and concentrated under reduced pressure. The obtained residue, potassium carbonate (0.1125 g) and 2-(chloromethyl)quinoline hydrochloride (0.0871 g) were suspended in N,N-dimethylformamide (2 mL), and the mixture was stirred at room temperature for 14 hr, and at 60° C. for 5 hr. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The residue was purified by NH silica gel column chromatography (ethyl acetate/hexane), silica gel column chromatography (ethyl acetate/hexane) and HPLC, and recrystallized from ethyl acetate/hexane to give the title compound (0.0527 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:51][C:52]1[CH:53]=[C:54]([CH:62]=[CH:63][CH:64]=1)[O:55][CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>CN(C=O)C.O>[Cl:51][C:52]1[CH:53]=[C:54]([CH:62]=[CH:63][CH:64]=1)[O:55][CH:56]1[CH2:57][CH2:58][N:59]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]2[CH:17]=[C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:20][N:19]=2)=[O:22])[CH2:60][CH2:61]1
Reactant: Clc1cccc(OC2CCNCC2)c1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(Cl)c2)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 38.2 %

Procedure:
DIPEA (155 mg, 1.2 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (99 mg, 0.4 mmol) in DMF (2 mL) followed by HOBt (54 mg, 0.4 mmol) and EDCI.HCl (84 mg, 0.44 mmol). After 2 minutes 4-(3-chloro-phenoxy)-piperidine hydrochloride (100 mg, 0.4 mmol) (prepared by method used for the synthesis of Intermediate 15) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure The residue was purified by washing with methanol to afford 67 mg (39.4% Yield) 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(3-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 439, 92.8%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (m, 1H), 8.0 (m, 1H), 7.8 (m, 2H), 7.5 (m, 2H), 7.4 (m, 1H), 7.3 (m, 2H), 7.1 (m, 2H), 7.0 (m, 2H), 4.7 (m, 1H), 4.2 (m, 2H), 4.0 (m, 1H), 3.7 (m, 1H), 3.4 (m, 1H), 3.2 (m, 1H), 2.0 (m, 2H), 1.5 (m, 2H).
Reaction SMILES: CN(OC)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[CH2:13]([Mg]Cl)[CH2:14][CH3:15]>C1COCC1>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3](=[O:10])[CH2:13][CH2:14][CH3:15])[CH:5]=1
Reactant: CON(C)C(=O)c1cccnc1
Reactant: CCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask is charged with N-methyl-N-methoxy-nicotinamide (1.0 g, 6.02 mmol) and THF (10 mL). Propyl magnesium chloride (2M in THF, 3.31 mL, 6.62 mmol) is added and the mixture is stirred at room temperature overnight. It is quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer is dried over sodium sulfate and concentrated in vacuo to afford 1-pyridin-3-yl-butan-1-one as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.03 (t, J=7.5 Hz, 3H), 1.74-1.87 (m, 2H), 2.97 (t, J=7.3 Hz, 2H), 7.42 (dd, J=8.0, 4.9 Hz, 1H), 8.24 (dt, J=8.0, 2.0, 1.9 Hz, 1H), 8.78 (dd, J=4.9, 2.0 Hz, 1H), 9.18 (d, J=2.0 Hz, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:25])[NH:10][C@@H:11]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:12]([O:14]C)=[O:13])[N:3]=[CH:2]1.[OH-].[Li+].O1CCCC1>O>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:25])[NH:10][CH:11]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[C:12]([OH:14])=[O:13])[N:3]=[CH:2]1
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)NCCc1c[nH]cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CC(NC(=O)NCCc2c[nH]cn2)C(=O)O)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 570.4 %

Procedure:
To 500 mg (1.44 mmol) of methyl(S)-2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)propanoate are added 500 mg of lithium hydroxide, 7 mL of tetrahydrofuran and 2 mL of water. The reaction medium is placed in a microwave reactor with stirring, at 100° C. for 10 minutes. Seven other identical tests are performed. The various tests are combined and concentrated to dryness. The crude product obtained is purified by filtration on a pad of silica (eluent: 1/1 dichloromethane/methanol). 2.73 g of 2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)propanoic acid in the form of a pale yellow powder are obtained in a yield of 70%.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=2[C:17]([F:20])([F:19])[F:18])=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:52][C:53]1[CH:65]=[CH:64][C:56]2[NH:57][C:58]([C@@H:60]([NH2:63])[CH2:61][OH:62])=[N:59][C:55]=2[CH:54]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:52][C:53]1[CH:65]=[CH:64][C:56]2[NH:57][C:58]([C@@H:60]([NH:63][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][C:8]([C:6]([N:1]4[CH2:2][CH:3]=[CH:4][CH2:5]4)=[O:7])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:10]=3)[CH2:61][OH:62])=[N:59][C:55]=2[CH:54]=1
Reactant: N[C@@H](CO)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(O)c1ccc(C(=O)N2CC=CC2)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(N[C@@H](CO)c1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CC=CC2)c(C(F)(F)F)c1
Yield: 20 %

Procedure:
Prepared analogously to Example 1g from 4-(2,5-dihydropyrrol-1-ylcarbonyl)-3-trifluoromethylbenzoic acid, TBTU, diisopropylethylamine, and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-hydroxyethylamine in tetrahydrofuran. Yield: 20%; Rf value: 0.43 (silica gel: dichloromethane/ethanol=9:1); C22H18ClF3N4O3 (478.856); mass spectrum: (M+H)+=479/481 (chlorine isotope).