Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]1[C:13]([C:14]2[CH:15]=[C:16]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=5)=[C:25]([C:35]([NH:37][CH3:38])=[O:36])[C:24]=4[CH:39]=3)[CH:17]=[CH:18][CH:19]=2)=[N:12][N:11]=[N:10]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH2:1]([N:10]1[N:11]=[N:12][C:13]([C:14]2[CH:15]=[C:16]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=5)=[C:25]([C:35]([NH:37][CH3:38])=[O:36])[C:24]=4[CH:39]=3)[CH:17]=[CH:18][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn[nH]4)c3)cc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn(Cc5ccccc5)n4)c3)cc12
Reaction time: 8 h
Yield: 19.7 %

Procedure:
Benzyl bromide (29 μL, 0.242 mmol) was added to a stirring solution of 5-(3-(1H-tetrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (50 mg, 0.121 mmol) and Na2CO3 (26 mg, 0.242 mmol) in DMF (1.2 mL) at 100° C. It was allowed to stir overnight. The mixture was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (12 mg, 19%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.48-8.56 (1H, m), 8.30-8.35 (1H, m), 8.06 (1H, d, J=7.63 Hz), 7.98-8.03 (2H, m), 7.90-7.93 (2H, m), 7.78-7.83 (1H, m), 7.72-7.77 (1H, m), 7.69 (1H, t, J=7.78 Hz), 7.36-7.46 (7H, m), 6.04 (2H, s), 2.86 (3H, d, J=4.58 Hz). LC-MS retention time: 1.78 min; m/z (MH+): 504. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=15.69 min, purity=97%; Column: Waters XBridge phenyl column 4.6×150 mm, 3.5 μm, Rt=13.95 min, purity=98%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Li]CCCC.CN(C)[CH:24]=[O:25]>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][C:9]([CH:24]=[O:25])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (1.75 g, 6.85 mmol) in dry tetrahydrofuran (40 mL) at −78° C. was added nBuLi (3.3 mL, 1.2 equivalents, 2.5 M solution in hexanes). After stirring for 1 hour, dry N,N-dimethylformamide (796 μL, 1.5 equivalents) was added. The reaction mixture was stirred for 1 hour at −78° C. and then warmed slowly to room temperature. After a further 2 hours at room temperature the reaction mixture was poured onto ice-water yielding a yellow precipitate. This was collected by filtration and air-dried to yield the title compound (1.50 g, 77%).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][S:12][CH:11]2[C:15](O)=[O:16])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:24][CH:25]([C:29]1[CH:37]=[CH:36][C:32]2[O:33][CH2:34][O:35][C:31]=2[CH:30]=1)[CH2:26][CH2:27][OH:28]>>[O:33]1[C:32]2[CH:36]=[CH:37][C:29]([CH:25]([NH:24][C:15]([CH:11]3[N:10]([S:7]([C:4]4[CH:5]=[CH:6][C:1]([C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)=[CH:2][CH:3]=4)(=[O:8])=[O:9])[CH2:14][CH2:13][S:12]3)=[O:16])[CH2:26][CH2:27][OH:28])=[CH:30][C:31]=2[O:35][CH2:34]1
Reactant: NC(CCO)c1ccc2c(c1)OCO2
Reactant: O=C(O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Product: O=C(NC(CCO)c1ccc2c(c1)OCO2)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general strategies and protocols outlined in Example 1, starting from 3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidine-2-carboxylic acid (Intermediate 8) and 3-amino-3-(1,3-benzodioxol-5-yl)-1-propanol (Intermediate 2), the title compound was obtained in 92% purity by HPLC.
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([NH2:18])[CH2:14][CH2:15][CH2:16][NH2:17]>>[CH2:13]([NH:18][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:14][CH2:15][CH2:16][NH:17][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC1CO1
Reactant: NCCCCN
Product: CCCCCCCCCC(O)CNCCCCNCC(O)CCCCCCCCC

Procedure:
Condensation of 1-undecene oxide and 1,4-butanediamine affords N,N'-(1,4-butylene)-bis[2-hydroxyundecylamine] (I: R= CH3 (CH2)8, R' = H, X= (CH2)4, Z= H).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C:7](C)([C:13](OCC)=O)[C:8]([O:10]CC)=[O:9])=[CH:4][CH:3]=1.C>O.C(O)C.[OH-].[Na+]>[CH3:13][CH:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:20][CH:19]=1)[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C(C)(Cc1ccc(Br)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(Cc1ccc(Br)cc1)C(=O)O
Temperature: 205 °C
Yield: 88 %

Procedure:
A solution of sodium hydroxide (34.0 g) in water (155 ml) was added to a solution of diethyl 2-(4-bromobenzyl)-2-methylmalonate (29.2 g) in ethanol (165 ml), and then heated under reflux for 9 hours. The reaction mixture was cooled, the solvent was evaporated and the residue taken up in water (150 ml). Sodium hydroxide pellets were added (25.4 g) and the reaction mixture was heated under reflux for 2 hours. The reaction mixture was then cooled and acidified to pH<1 with concentrated hydrochloric acid, which caused precipitation of a solid. The reaction mixture was extracted with diethyl ether (3×150 ml), the combined organic layers were dried (MgSO4) and then the solvent was evaporated to give a white solid. This solid was heated at 205° C. for 20 minutes, cooled to ambient temperature, dissolved in 1.0M sodium hydroxide solution (150 ml), treated with activated charcoal and then filtered through diatomaceous earth. The resulting clear solution was re-acidified and then extracted with diethyl ether (3×150 ml). The combined organic layers were dried (MgSO4) and evaporated to give a yellow oil which crystallised on standing to give 2-methyl-3-(4-bromophenyl)propanoic acid as a white solid (18.2 g), m.p. 69°-70° C.; mass spectrum (+ve CI): 243 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]([CH3:40])[C:7]2[CH:8]=[C:9]([N:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)[CH:10]=[C:11]([C:14](=[O:26])[NH:15][CH2:16][C:17]3[C:18](=[O:25])[NH:19][C:20]([CH3:24])=[CH:21][C:22]=3[CH3:23])[C:12]=2[CH3:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C(Cl)Cl>[CH:1]1([N:6]([CH3:40])[C:7]2[C:12]([CH3:13])=[C:11]([CH:10]=[C:9]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:8]=2)[C:14]([NH:15][CH2:16][C:17]2[C:18](=[O:25])[NH:19][C:20]([CH3:24])=[CH:21][C:22]=2[CH3:23])=[O:26])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(N3CCNCC3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of tert-butyl 4-(3-(cyclopentyl(methyl)amino)-5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-4-methylphenyl)piperazine-1-carboxylate (0.30, 0.54 mmol) in DCM (10 mL) was cooled to 0° C. and TFA (3 mL) was added to it. The reaction mixture was stirred at room temperature for 1 h. Upon completion, the mixture was concentrated to dryness. Half crude was purified by solvent washing giving the title compound as TFA salt (0.01 g, 8.33%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[NH:14][CH:15]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)[C:16]([N:18]1[CH2:21][C:20]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:19]1)=[O:17])(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:14][CH:15]([CH2:34][C:35]1[CH:36]=[CH:37][C:38]([OH:41])=[CH:39][CH:40]=1)[C:16]([N:18]1[CH2:19][C:20]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:21]1)=[O:17]
Reactant: CCCCOC1(c2ccccc2C)CN(C(=O)C(Cc2ccc(O)cc2)NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC1(c2ccccc2C)CN(C(=O)C(N)Cc2ccc(O)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 ml of trifluoroacetic acid are added to a solution of 410 mg (0.8 mmol) of tert-butyl[2-(3-butoxy-3-o-tolyl-azetidin-1-yl)-1-(4-hydroxybenzyl)-2-oxoethyl]carbamate in 5 ml of dichloromethane. After stirring for 1 hour at ambient temperature, the solvent is evaporated off. 440 mg of 2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-hydroxyphenyl)propan-1-one trifluoroacetate are obtained with a quantitative yield.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1.CO[CH:20]1[CH2:24][CH2:23][CH:22](OC)O1.O.[OH-].[Na+]>C(O)(=O)C>[N:17]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[N:9]1[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]2[CH:20]=[CH:24][CH:23]=[CH:22]2)[CH2:11][CH2:10]1
Reactant: COC1CCC(OC)O1
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: c1cnc(N2CCN(CCCCn3cccc3)CC2)nc1
Yield: 45.3 %

Procedure:
A mixture of 4 g (17 mmol) of 2-[4(4-aminobutyl)-1-piperazinyl]pyrimidine and 3.3 g of 2.5-dimethoxytetrahydrofuran in 10 ml of acetic acid is refluxed for 1 hour. The reaction mixture is poured into cold water, neutralised with 10% sodium hydroxide solution and extracted with chloroform, the extract is dried and evaporated and 2.2 g of 1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl}pyrrole are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:14][N:13]([C:15]([O:17][C:18](C)(C)[CH3:19])=[O:16])[CH2:12]1)[CH2:10][C:9]2=[O:26].ClC(OCC)=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:14][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12]1)[CH2:10][C:9]2=[O:26]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)OC(C)(C)C)C1)O2
Agent: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)OC)ccc3O2)C1
Yield: 99.7 %

Procedure:
A suspension of Intermediate 4 (280 mg, 0.90 mmol) in DCM (7.5 ml) was treated with ethyl chloroformate (0.13 ml, 1.4 mmol) and DIPEA (0.32 ml, 1.8 mmol) as described in Example 36, Step A, giving (E)-3-[1′-ethyloxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid methyl ester as a light brown solid (310 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:19])[CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH2:11][N:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([C:21]([F:20])([F:31])[F:32])[CH:23]=2)=[O:19])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(CNc1ccccc1)Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=C(CN(C(=O)c1cccc(C(F)(F)F)c1)c1ccccc1)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
To N-(3,4-dichloro-phenyl)-2-phenylamino-acetamide (73 mg) in THF (3.1 mL) was added tiethylamine (52 μL) and 3-trifluoromethylbenzoyl chloride (62 mg) and the reaction mixture was stirred at room temperature for 30 minutes. To the mixture was then added water under precipitation occurred and the mixture was stirred for 5 minutes. Then the precipitate was isolated by filtration and washed with a mixture water-ethanol (1:1) to yield the title compound as a white solid (64 mg, mp=130-132° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:45])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:42]=[CH:41][C:34]([C:35]([O:37][CH2:38][CH2:39][OH:40])=[O:36])=[CH:33][C:32]=2[O:43][CH3:44])=[O:29])[CH:5]=[CH:6][CH:7]=1.[C:46]([O:50][C:51]([NH:53][CH:54]([CH3:58])[C:55](O)=[O:56])=[O:52])([CH3:49])([CH3:48])[CH3:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.CN(C1C=CC=CN=1)C>CN(C)C=O>[C:46]([O:50][C:51]([NH:53][C@H:54]([CH3:58])[C:55]([O:40][CH2:39][CH2:38][O:37][C:35](=[O:36])[C:34]1[CH:41]=[CH:42][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:45])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:29])=[C:32]([O:43][CH3:44])[CH:33]=1)=[O:56])=[O:52])([CH3:49])([CH3:48])[CH3:47]
Reactant: COc1cc(C(=O)OCCO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccccn1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OCCOC(=O)[C@@H](C)NC(=O)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 90 %

Procedure:
In a manner similar to the method described in Example 3, chiral 2-hydroxyethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (Example 1, 105.2 mg, 0.159 mmol) was reacted with (R)-(2-(tert-butoxycarbonylamino)propanoic acid (Chem-Impex, 75 mg, 0.398 mmol), HATU (Bachem, 151 mg, 0398 mmol), N,N-diisopropylethylamine (104 mg, 0.14 mL, 0.802 mmol) and dimethylaminopyridine (Aldrich, 10.8 mg, 0.088 mmol) in dimethyl formamide (8 mL) to give chiral 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-((R)-2-tert-butoxycarbonylamino-propionyloxy)-ethyl ester as a white solid (119 mg, 89% yield). MS (ES+) m/z calcd. for C41H47Cl2F2N4O8 [(M+H)+]: 831. found: 831.
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].Cl[C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1.CN(C=O)C>O>[CH2:1]([S:3][C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[N:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Nc1cccc(C(F)(F)F)n1)c1ncccc1Cl
Reactant: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1cccnc1C(=O)Nc1cccc(C(F)(F)F)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
0.86 g of sodium ethanethiolate was added to a mixture of 1.23 g of 3-chloro-N-(6-trifluoromethylpyridin-2-yl)picolinamide and 3 mL of DMF, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture cooled to room temperature was poured to water, and the precipitated solid was taken by filtration. The resulting solid was dissolved in ethyl acetate, and the mixture was extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 1.30 g of 3-ethylsulfanyl-N-(6-trifluoromethylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 7).
Reaction SMILES: [C:1](O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[NH:33][C:32]3[CH:34]=[CH:35][C:36]([C:38]([NH2:40])=[O:39])=[CH:37][C:31]=3[N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:1]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH2:20][CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[NH:33][C:32]3[CH:34]=[CH:35][C:36]([C:38]([NH2:40])=[O:39])=[CH:37][C:31]=3[N:30]=2)=[CH:27][CH:28]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(OCCC4CCCCN4)cc3)nc2c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: NC(=O)c1ccc2[nH]c(-c3ccc(OCCC4CCCCN4C(=O)c4ccccc4)cc3)nc2c1
Reaction time: 18 h
Yield: 46.8 %

Procedure:
A solution of benzoic acid (75 mg, 0.62 mmol) and EDC (59 mg, 0.31 mmol) in DMF (1 mL) was stirred for 2 h and then was treated with 2-[4-(2-piperidin-2-yl-ethoxy)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide (75 mg, 0.21 mmol) and DMAP (65 mg, 0.53 mmol). The mixture was stirred for 18 h, and the crude material was purified by reverse phase HPLC (C18; H2O/CH3CN/0.01% TFA), providing 46 mg (66%) of the title compound. HPLC (Method C): Rt=5.15. MS (ESI+): mass calcd. for C28H28N4O3, 468.22; m/z found, 469.4 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.19 (s, 1H), 8.00-7.96 (m, 3H), 7.72 (d, J=8.6 Hz, 1H), 7.36-7.25 (m, 2H), 7.25-7.10 (m, 4H), 6.95-6.90 (m, 1H), 4.20-4.07 (m, 2H), 3.92-3.90 (m, 1H), 3.48-3.43 (m, 1H), 2.45-2.35 (m, 1H), 2.12-1.81 (m, 1H), 1.81-1.30 (m, 7H).
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[CH2:28]([Sn](CCCC)(CCCC)C=C)[CH2:29]CC>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([S:20][C:11]2[C:12]3[C:13]([CH:28]=[CH2:29])=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:22][CH:23]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Product: C=Cc1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O

Procedure:
Starting from (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate and tributyl(vinyl)stannane, the title compound was synthesized following the procedures described in Example 42 and Step 10 of Example 7.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:11][C:10]=1[C:18]1[C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=O)[C:22]=2[CH:21]=[CH:20][CH:19]=1>C(O)C.O>[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:11][C:10]=1[C:18]1[C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[N:2][OH:3])[C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: NO
Reactant: O=C1c2ccccc2-c2c1cccc2-c1nc2ccncc2[nH]1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1c2ccccc2-c2c1cccc2-c1nc2ccncc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
In a 500-ml three-necked flask, dissolve 20 g of 4-(3H-imidazo[4,5-c]pyridin-2-yl)-fluoren-9-one, obtained in Example 1, in 328 ml of ethanol, then add successively 14.02 g of hydroxylamine hydrochloride and 27.59 g of dry sodium acetate. After stirring overnight at room temperature, dilute with 328 ml of water. The precipitate that formed is drained, washed with water and dried in the stove at 500. In this way we obtain 18.6 g of equimolecular mixture of the Z and E oximes of 4-(3H-imidazo[4,5-c]pyridin-2-yl)-fluoren-9-one, in the form of a pale yellow powder, witH-NMR purity over 95%, with the following characteristics:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[CH2:11][CH:10]([C:25]([OH:27])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.O[N:62]=[C:63]([O:65][CH2:66][CH3:67])[NH2:64]>CN(C)C=O>[CH2:66]([O:65][C:63]1[N:64]=[C:25]([CH:10]2[CH2:11][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=3)[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9]2)[O:27][N:62]=1)[CH3:67]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)CC(c2ccc(CC(F)(F)F)cc2)C1
Reactant: CCOC(N)=NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)OC(C)(C)C)C2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 459 mg (0.889 mmol, purity 75%, 2:1 cis/trans isomer mixture) of the carboxylic acid from Example 59A in 19 ml of N,N-dimethylformamide were added, at RT, 541 mg (1.42 mmol) of HATU and 0.45 ml (337 mg, 2.61 mmol) of N,N-diisopropylethylamine, and the mixture was stirred for 30 min. Subsequently, the mixture was admixed with 136 mg (1.30 mmol) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] and then stirred at room temperature overnight. The reaction solution was purified directly by means of preparative HPLC. The resulting intermediate was taken up in toluene (50 ml), admixed with 4 Å molecular sieve and stirred under reflux overnight. The reaction solution was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by means of preparative HPLC. Yield: 124 mg (31% of theory)
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][N:15]1[C:23]([C:24]2[N:25]([CH3:35])[CH:26]=[C:27]([C:29](=O)[C:30]([F:33])([F:32])[F:31])[CH:28]=2)=[C:22]2[C:17]([N:18]([CH2:39][CH:40]3[CH2:42][CH2:41]3)[C:19](=[O:38])[N:20]([CH3:37])[C:21]2=[O:36])=[N:16]1.C(N(CC)CC)C>CC(N(C)C)=O>[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][N:15]1[C:23]([C:24]2[N:25]([CH3:35])[CH:26]=[C:27](/[C:29](=[N:2]/[OH:3])/[C:30]([F:33])([F:32])[F:31])[CH:28]=2)=[C:22]2[C:17]([N:18]([CH2:39][CH:40]3[CH2:42][CH2:41]3)[C:19](=[O:38])[N:20]([CH3:37])[C:21]2=[O:36])=[N:16]1
Reactant: NO
Reactant: Cn1cc(C(=O)C(F)(F)F)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: Cn1cc(/C(=N/O)C(F)(F)F)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1c[nH]c2ccc(Cl)cc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 29.2 %

Procedure:
Hydroxylamine hydrochloride (0.062 g) was added to a solution of 2-[(5-chloro-1H-indol-3-yl)methyl]-7-(cyclopropylmethyl)-5-methyl-3-[1-methyl-4-(trifluoroacetyl)-1H-pyrrol-2-yl]-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (0.05 g) and triethylamine (0.063 ml) in dimethylacetamide (5 ml) and the mixture heated at 80° C. for 2 hours. Additional hydroxylamine hydrochloride (0.062 g) was added and the reaction continued at 80° C. for another 3 hours. Cooled, concentrated, and the crude residue purified on preparative HPLC to give the title compound (0.015 g). Mass: 574.17 (M+H).