Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:44])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:40])[NH:32][C:33]5[CH:34]=[N:35][CH:36]=[C:37]([F:39])[CH:38]=5)=[CH:27][C:26]=4[N+:41]([O-])=O)=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+].C(O)C.O1CCCC1>O.C(OCC)(=O)C.[Fe]>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:44])[NH:17][C:18]3[CH:19]=[CH:20][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:40])[NH:32][C:33]5[CH:34]=[N:35][CH:36]=[C:37]([F:39])[CH:38]=5)=[CH:27][C:26]=4[NH2:41])=[CH:22][CH:23]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Nc3cncc(F)c3)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(C(=O)Nc2cncc(F)c2)ccc1Sc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 80 °C
Yield: 96.7 %

Procedure:
The product of Example 224D (174 mg, 0.2868 mmol), ammonium chloride (100.5 mg, 1.879 mmol), and iron powder (98.5 mg, 1.764 mmol) in a mixture of water (3 mL), ethanol (6 mL) and tetrahydrofuran (6 mL) was heated at 80° C. under a nitrogen atmosphere for 1 hour. The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with water (2×25 mL) and brine (25 mL). The organic was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to give the product as a yellow solid (160 mg, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[CH2:16]([NH:23][C:6](=[O:7])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: ClCCl
Product: COc1cc(C(=O)NCc2ccccc2)cc(OC)c1OC

Procedure:
3,4,5-Trimethoxybenzoyl chloride (5.0 g, 21.7 mmol) was dissolved in dichloromethane (50 ml). The reaction mixture was cooled with an ice-bath and benzylamine (4.74 ml, 43.4 mmol) was added slowly. The solid material was removed by filteration. The filtrate was poured into 30 ml of water. The organic phase was washed several times with water. The crude product was recrystallized from i-propanol.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1.[Si:15]([O:22][C@H:23]1[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]2[N:28]=[C:27]([CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[C:26]([CH:40]=[O:41])=[C:25]([I:42])[C:24]1=2)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>O1CCCC1>[Si:15]([O:22][C@H:23]1[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]2[N:28]=[C:27]([CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39]3)[C:26]([C@H:40]([C:5]3[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=3)[OH:41])=[C:25]([I:42])[C:24]1=2)([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: CC1(C)Cc2nc(C3CCCC3)c(C=O)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(C3CCCC3)c([C@@H](O)c3ccc(C(F)(F)F)cc3)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
To 300 mg magnesium turnings and 2 crystals of iodine were added 1 ml tetrahydrofurane. Afterwards a few drops of a solution of 2 ml 4-bromobenzotrifluoride in 15 ml tetrahydrofurane were added and the mixture was gently heated to start the reaction. Then the rest of the 4-bromobenzotrifluoride solution is added dropwise. After complete formation the Grignard reagent is added dropwise via syringe to a solution of 880 mg (S)-5-(tert-butyldimethylsilyloxy)-2-cyclopentyl-4-iodo-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde in 10 ml tetrahydrofurane at −50° C. The reaction is stirred for 1 hour at −50° C. and then quenched by dropwise addition of 10 ml methanol. The mixture is partitioned between dichloromethane and saturated ammonium chloride. The organic phase is washed with brine and dried with sodium sulphate. The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 100:0 to 95:5).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21](Cl)=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[N:24]2)=[CH:19][CH:18]=1.O>CN(C=O)C>[CH2:8]([NH:15][C:21]1[C:20]2[C:25](=[CH:26][C:17]([Br:16])=[CH:18][CH:19]=2)[N:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Reactant: NCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Triethylamine (5.24 g, 51.8 mmol) and benzylamine (4.15 mL, 38.0 mmol) were sequentially added to a solution of 7-bromo-4-chloro-3-nitroquinoline (10.0 g, 34.5 mmol, see U.S. Patent Publication Application No. US 2004/0147543 (Hays et al.), Example 1 Parts A through D) in DMF (100 mL). The reaction was stirred at room temperature for three days, poured into water (800 mL), and stirred vigorously for 20 minutes. A precipitate formed and was isolated by filtration, washed with diethyl ether (800 mL), and dried under vacuum for four hours to provide 10.98 g of N-benzyl-7-bromo-3-nitroquinolin-4-amine as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([O:9][CH:10]2[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]2)=[CH:5][CH:4]=1.[H-].[Na+].CI.[C:25](O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)(Cl)Cl.ClCCCl.O.CCOC(C)=O.C1COCC1>[NH:12]1[CH2:13][CH:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][O:1][CH3:25])=[N:8][CH:7]=2)[CH2:11]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(CO)nc2)C1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1ccc(OC2CNC2)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 3-{[6-(hydroxymethyl)pyridin-3-yl]oxy}azetidine-1-carboxylate (198 mg) was mixed with THF (3 ml), and sodium hydride (55% suspended in oil) (50 mg) was added thereto at 0° C., followed by stirring at 0° C. for 30 minutes. Methyl iodide (0.4 ml) was added to the reaction mixture, followed by stirring at room temperature for 3 hours. EtOAc and water were added to the reaction mixture, and the organic layer was dried over Na2SO4, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH). The purified product thus obtained was mixed with DCE (2.8 ml), and TFA (902 mg) was added thereto, followed by stirring at room temperature for 5 hours. CHCl3 and a 1 M aqueous NaOH solution were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (CHCl3/MeOH) to obtain 5-(azetidin-3-yloxy)-2-(methoxymethyl)pyridine.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][O:13][CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:7]1[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5])[CH3:2].C([Li])CCC.Cl>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@@H:8]([CH2:11][CH2:12][O:13][CH2:14][O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:7]1[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H](CCOCOCc2ccccc2)CCN1C(=O)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCO
Product: CCOC(=O)[C@H]1[C@H](CCOCOCc2ccccc2)CCN1C(=O)OCC

Procedure:
A solution of 6.2 g of cis ethyl 1-ethoxycarbonyl-3-[2-(benzyloxymethoxy)-ethyl]-pyrrolidine-2-carboxylate in 75 ml of anhydrous ethanol containing 1 ml of butyllithium (1.6 M) is refluxed under nitrogen for 6 days. After cooling, 1.7 ml of 1N hydrochloric acid is added, the solution is concentrated in vacuo, cold water added and mixture extracted with methylene chloride. The extract is dried over sodium sulfate, filtered, concentrated and purified by high pressure liquid chromatography using ethyl acetate/hexane (15:85) to yield trans ethyl 1-ethoxycarbonyl-3-[2-(benzyloxymethoxy)-ethyl]-pyrrolidine-2-carboxylate.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([CH2:8][Br:17])[CH:7]=1
Reactant: Cc1cnc(Cl)c(Br)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ncc(CBr)cc1Br

Procedure:
Synthesized from 3-bromo-2-chloro-5-methylpyridine (4.00 g, 19.3 mmol), NBS (3.79 g, 21.3 mmol) and DBPO (233 mg, 0.97 mmol) in CCl4 according to Method A. Yield: 2.38 g, 8.34 mmol, 43%. This compound was directly used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=3[C:14](=[O:22])[N:13]3[CH2:23][CH2:24][CH2:25][C@H:12]3[C:11]=12)=[O:6])[C:2]#[CH:3].IN1C(=O)CCC1=O.[CH2:34]([NH:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36]>C(O)(=O)C>[Cl:21][C:20]1[C:15]2[C:14](=[O:22])[N:13]3[CH2:23][CH2:24][CH2:25][C@H:12]3[C:11]3[N:10]([CH:9]=[N:8][C:7]=3[C:5]3[O:6][C:2]([CH2:3][N:37]([CH2:38][CH2:39][CH3:40])[CH2:34][CH2:35][CH3:36])=[CH:1][N:4]=3)[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: C#CCNC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: CCCNCCC
Agent: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1cnc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.7 %

Procedure:
A solution of 1.07 g (0.003 mol) of (S)-8-chloro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]-benzodiazepine-1-carboxylic acid prop-2-ynylamide in 10 ml of acetic acid was treated with 1.01 g (0.0045 mol) of N-iodosuccinimide. After stirring at room temperature for 12 hrs. the mixture was heated to 50° for a further 4 hrs. The dark suspension obtained was completely freed from solvent in a vacuum and dried azeotropically several times with toluene. The brown residue was dissolved in 10 ml of THF, treated at room temperature with 10 ml (0.073 mol) of dipropylamine and stirred at 50° for 2 hrs. The suspension obtained was completely freed from the solvents and the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated, the pale brown product was chromatographed over silica gel with dichloromethane/methanol 95:5 as the eluent and digested with diethyl ether. There was obtained 0.65 g (48%) of (S)-8-chloro-1-(5-dipropylaminomethyl-oxazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]-benzodiazepin-9-one; [α]D20 =+11.5° (MeOH, c=1%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8]/[C:9](/[CH3:15])=[CH:10]\[C:11]([O:13][CH3:14])=[O:12].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1>[CH3:15][C:9]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:9]([CH3:15])=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)/C=C(/C)Nc1ccccc1C
Reactant: O=Cc1ccccc1
Solvent: c1ccccc1
Product: COC(=O)C1=C(C)N(c2ccccc2C)C(C)=C(C(=O)OC)C1c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 4.1 grams (20 millimoles) of methyl 3-(2-methylphenyl)aminocrotonate in 5 milliliters of dry benzene is added to the titanamine complex followed by 1.1 grams (10 millimoles) of benzaldehyde and the mixture stirred at ambient temperature for several hours to obtain the desired dimethyl 2,6-dimethyl-4-phenyl-1-(2-methylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate which may be recovered in a manner similar to that previously described.
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][N:13]([C:16]2[C:20]([NH:21][C:22]([C:24]3[N:25]=[C:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([N:35]([CH2:43][C:44]([F:47])([F:46])[F:45])C(=O)OC(C)(C)C)[CH:30]=4)[O:27][CH:28]=3)=[O:23])=[CH:19][N:18]([CH3:48])[N:17]=2)[C:12]1=[O:49])C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[OH:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][N:13]([C:16]2[C:20]([NH:21][C:22]([C:24]3[N:25]=[C:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([NH:35][CH2:43][C:44]([F:45])([F:47])[F:46])[CH:30]=4)[O:27][CH:28]=3)=[O:23])=[CH:19][N:18]([CH3:48])[N:17]=2)[C:12]1=[O:49]
Reactant: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2CCN(CCOCc3ccccc3)C2=O)n1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(NC(=O)c2coc(-c3ccnc(NCC(F)(F)F)c3)n2)c(N2CCN(CCO)C2=O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.6 %

Procedure:
A solution of tert-butyl (4-(4-((3-(3-(2-(benzyloxy)ethyl)-2-oxoimidazolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamoyl)-1,3-oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate (400 mg) in TFA (4.0 mL) was stirred at room temperature for 3 hr, and the reaction mixture was concentrated under reduced pressure. A solution of the obtained residue and 20% palladium hydroxide-carbon (80 mg) in acetic acid (10 mL) was stirred at room temperature for 5 hr under hydrogen atmosphere (3 atm). The reaction mixture was filtered through a membrane filter, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) and then silica gel column chromatography (methanol/ethyl acetate). The obtained solid was washed with a mixed solvent of ethyl acetate/hexane (1:1), and dried under reduced pressure to give the title compound (100 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]1[C:14]2[C:15](=[O:29])[N:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[N:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:13]=2[NH:12][N:11]=1.C(O)(=O)C.[O-:34][C:35]#[N:36].[K+]>O>[C:23]1([N:16]2[C:17]3[N:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:13]3[NH:12][N:11]=[C:10]([CH2:9][CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[NH:1][C:35]([NH2:36])=[O:34])[C:14]=3[C:15]2=[O:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccccc1CCc1n[nH]c2c1c(=O)n(-c1ccccc1)c1ncccc21
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1ccccc1CCc1n[nH]c2c1c(=O)n(-c1ccccc1)c1ncccc21
Temperature: 35 °C
Reaction time: 8 h
Yield: 104.7 %

Procedure:
To a suspension of 3-[2-(2-aminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (38 mg, 0.09 mmol, prepared in Example 36) in a mixture solvent of acetic acid (1 mL) and water (1 mL) was added potassium cyanate (12 mg, 0.15 mmol, 1.7 eq) at room temperature. The mixture was stirred overnight at 35° C., and filtered to give precipitates which were washed with water and then dried to afford 5-phenyl-3-[2-(2-ureidophenyl)ethyl]-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (40 mg, 94%).
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:31]1([C:37]2[NH:41][N:40]=[C:39]([C:42]([NH:44][CH2:45][C:46]([OH:48])=O)=[O:43])[CH:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.[F:50][C:51]1[CH:52]=[C:53]([CH:59]=[C:60]([C:62]([F:65])([F:64])[F:63])[CH:61]=1)[O:54][CH:55]1[CH2:58][NH:57][CH2:56]1>CN(C=O)C>[F:50][C:51]1[CH:52]=[C:53]([CH:59]=[C:60]([C:62]([F:64])([F:63])[F:65])[CH:61]=1)[O:54][CH:55]1[CH2:58][N:57]([C:46](=[O:48])[CH2:45][NH:44][C:42]([C:39]2[CH:38]=[C:37]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:41][N:40]=2)=[O:43])[CH2:56]1
Reactant: Fc1cc(OC2CNC2)cc(C(F)(F)F)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: CN(C)C=O
Product: O=C(NCC(=O)N1CC(Oc2cc(F)cc(C(F)(F)F)c2)C1)c1cc(-c2ccccc2)[nH]n1
Yield: 24.4 %

Procedure:
DIPEA (143 mg, 1.1 mmol) followed by HOBt (39 mg, 0.29 mmol) and EDCI (56 mg, 0.29 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (68 mg, 0.27 mmol) in DMF (2 mL) After 2 minutes of stirring, 3-(3-fluoro-5-trifluoromethyl-phenoxy)-azetidine hydrochloride (prepared by the method used for the synthesis of Intermediate 71) (75 mg, 0.27 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between cold water and ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by preparative HPLC afforded 31 mg (24.4% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[3-(3-fluoro-5-trifluoromethyl-phenoxy)-azetidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 463, 81.67%. 1H NMR (300 MHz, DMSO-d6): δ 13.75 (s, 1H), 7.8 (d, 2H), 7.42 (t, 2H), 7.26 (m, 2H), 7.1 (d, 1H), 7.04 (s, 1H), 5.2 (m, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 4.2 (m, 2H), 3.7 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13])=[C:4]([O:15][CH3:16])[C:3]=1[N+:17]([O-])=O.C(O)(=O)C.C(O)C.Cl>C(Cl)Cl.[Fe]>[NH2:17][C:3]1[C:4]([O:15][CH3:16])=[C:5]([NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13])[C:6]([F:8])=[CH:7][C:2]=1[Cl:1]
Reactant: CCOC(=O)Nc1c(F)cc(Cl)c([N+](=O)[O-])c1OC
Agent: [Fe]
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)Nc1c(F)cc(Cl)c(N)c1OC
Reaction time: 2 h
Yield: 79.3 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 21.3 grams (0.072 mole) of ethyl N-(4-chloro-6-fluoro-2-methoxy-3-nitrophenyl)-carbamate, 18.3 grams (0.328 mole) of iron powder, 50 mL of acetic acid, and 250 mL of ethanol was heated to 65° C. where it stirred for two hours. At the conclusion of this time, 3 mL (0.036 mole) of 12M hydrochloric acid was added. Upon completion of addition, the reaction mixture was stirred for an additional two hours. After this time, the reaction mixture was concentrated under reduced pressure to yield a brown oil. The oil was then taken up in methylene chloride. The mixture was filtered through diatomaceous earth, and the filter cake was washed with water and an aqueous saturated sodium bicarbonate solution. The filtrate was stored over sodium sulfate for about 18 hours and then filtered. The solvent was removed under reduced pressure to yield a black oil. This oil was filtered through a silica gel pad, yielding 15.0 grams of ethyl N-(3-amino4-chloro-6-fluoro-2-methoxyphenyl)carbamate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[C:17]1([N:23]2[C:27](=[O:28])[CH:26]([C:29](=O)[CH2:30][C:31](=O)[CH3:32])[C:25]([CH3:35])=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:29]([C:26]3[C:25]([CH3:35])=[N:24][N:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:27]=3[OH:28])=[CH:30][C:31]([CH3:32])=[N:11]2)=[CH:6][CH:5]=1
Reactant: CC(=O)CC(=O)C1C(=O)N(c2ccccc2)N=C1C
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-n2nc(C)cc2-c2c(C)nn(-c3ccccc3)c2O)cc1
Reaction time: 0.17 h

Procedure:
To (4-methoxyphenyl)-hydrazine hydrochloride (0.083 g, 0.48 mmol) in ethanol (5 ml) add sodium bicarbonate (0.067 g, 0.80 mmol) after which stir the mixture for 10 min. Add 1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione (0.103 g, 0.40 mmol. The mixture was heated at reflux for 1.5 hours after which it was evaporated to dryness. Chromatography on silica gel, eluting with 50 to 100% ethyl acetate/heptane provided 0.071 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:15]O>>[CH3:15][O:9][C:8](=[O:10])[CH:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:13][CH:12]=1)[CH3:11]
Reactant: CC(Oc1ccc(N)cc1)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)C(C)Oc1ccc(N)cc1
Yield: 37.2 %

Procedure:
To a mixture of 2-(4-Amino-phenoxy)-propionic acid 17 (240 g, 1.103 mol), in methanol (4.8 liters) was passed dry HCl gas at 10° C. for 1 hour and refluxed for 48 hours. Methanol (2.5 liter) was distilled off, ice water (1 liter) was added and the pH was adjusted to 7.5 with K2CO3. Crude 18 was extracted into chloroform, washed with 5% NaHCO3 solution, water, dried over Na2SO4 and distilled to give 18 (80 g, 37.2%) as a brown syrup. The structure was confirmed with NMR.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>O1CCOCC1.O>[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:24][CH2:23]1
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Reactant: OCCN1CCNCC1
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1c(N2CCN(CCO)CC2)n(-c2ccccc2)c2ccccc12

Procedure:
2-Chloro-1-phenyl-1H-indole-3-carboxaldehyde (2.55 g, 19.6 mmol), 4-(2-hydroxyethyl)-piperazine (1.00 g, 3.92 mmol) in dioxane (13 mL) is heated overnight at reflux. The cooled reaction is diluted with water and extracted with dichloromethane. The organic layer is dried, filtered and evaporated to a semi-solid that is triturated with ether to give the 2-[4-(2-hydroxyethyl)piperazin-1-yl]-1-phenyl-1H-indole-3-carboxaldehyde as a brownish solid. MS 350 (M+H).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([O:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH3:27].[CH:28]([O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([CH3:30])[CH3:29]>C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:25]([O:24][C:5]1[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]([C:35]2[CH:36]=[CH:37][C:32]([O:31][CH:28]([CH3:30])[CH3:29])=[CH:33][CH:34]=2)=[C:3]([CH3:27])[N:4]=1)[CH3:26]
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: CCOc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOc1nc(C)c(-c2ccc(OC(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 93.8 %

Procedure:
4′-[(5-Bromo-2-ethoxy-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.50 g), 4-isopropoxyphenylboronic acid (0.32 g) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.050 g) were dissolved in 2 M aqueous cesium carbonate solution (2 mL) and 1,4-dioxane (10 mL), and the mixture was stirred at 90° C. overnight under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.53 g, 94%) as a colorless solid.