Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C@H:5]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([NH:11][C:12]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:13])[CH2:6]1)=[O:4].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]2=[O:33])=[CH:23][C:22]=1[CH3:34]>>[OH:10][C@H:8]1[CH2:9][C@H:5]([C:3](=[O:4])[NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]3=[O:33])=[CH:23][C:22]=2[CH3:34])[CH2:6][C@@H:7]1[NH:11][C:12]([C:14]1[S:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[O:13]
Reactant: Cc1cc(-n2ccccc2=O)ccc1N
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1
Product: Cc1cc(-n2ccccc2=O)ccc1NC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1

Procedure:
In analogy to example 1C, (1R,3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-cyclopentanecarboxylic acid methyl ester (example 1B) was reacted with 1-(4-amino-3-methyl-phenyl)-1H-pyridin-2-one to give 5-chloro-thiophene-2-carboxylic acid {(1S,2S,4R)-2-hydroxy-4-[2-methyl-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopentyl}-amide. Off-white solid. MS: 472.4 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([C@:15]([C@@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([NH:31][C@H:32]3[CH2:37][CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]3)=[O:30])[CH2:24]2)([OH:22])[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.ClCCl>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([C@:15]([C@@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([NH:31][CH:32]3[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]3)=[O:30])[CH2:24]2)([OH:22])[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:5]=[CH:4][CH:3]=1
Reactant: COCCCC[C@@](O)(c1cccc(F)c1-c1cccc(C)c1)[C@@H]1CCCN(C(=O)N[C@H]2CCCN(C(=O)OC(C)(C)C)C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCC[C@@](O)(c1cccc(F)c1-c1cccc(C)c1)[C@@H]1CCCN(C(=O)NC2CCCNC2)C1
Reaction time: 0.33 h
Yield: 55.6 %

Procedure:
(S)-tert-Butyl 3-((R)-3-((S)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)piperidine-1-carboxylate (20 mg, 0.033 mmol) was dissolved in TFA/dichloromethane (1 mL, 1:3, v/v), stirred 20 min, evaporated, and purified by preparative HPLC to give the (3R)-3-((S)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)-N-(piperidin-3-yl)piperidine-1-carboxamide (9.39 mg) as its TFA salt. 1H NMR (400 MHz, CD3OD): δ ppm 7.57 (d, J=8.4 Hz, 1 H), 7.36-7.20 (m, 3 H), 7.04-7.02 (m, 2 H), 6.92 (m, 1 H), 4.03 (m, 1 H), 3.85-3.75 (m, 2 H), 3.39-3.32 (m, 3 H), 3.29 (s, 3 H), 2.86 (m, 1 H), 2.71-2.56 (m, 3 H), 2.37, 2.35 (two s, 3H, rotamer), 1.99 (m, 2 H), 1.88-1.26 (m, 13 H), 0.92 (m, 1 H). MS m/z 512 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[C:12]1([NH:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:20][C:19]1[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]2[C:3]([CH3:11])=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: Cc1cccc([N+](=O)[O-])c1Cl
Product: Cc1cccc2nc(C)n(-c3ccccc3)c12

Procedure:
Method A applied to 2-chloro-3-nitrotoluene (68 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) yielded the title compound as a pale yellow solid. mp 107-109° C. 1H NMR (DMSO) δ 1.83 (s, 3H), 2.34 (s, 3H), 7.02 (d, J=7.8Hz, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.53 (d, J=7.8Hz, 1H), 7.55-7.63 (m, 5H); 13C NMR δ 13.3, 17.1, 114.8, 121.7, 123.0, 125.5, 128.6, 129.4, 129.9, 136.0, 144.5, 151.2, 157.2. HRMS (FAB): cal. for C15H15N2 [M+H+]: 223.1235; found: 223.1231.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[C:4]([CH3:13])[CH:3]=1.C([O-])(=O)C.[Na+].[Br:19]Br.[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:19][C:10]1[S:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[CH3:13])=[CH:12][CH:11]=1
Reactant: BrBr
Reactant: Cc1cc(Br)ccc1-c1cccs1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)ccc1-c1ccc(Br)s1
Reaction time: 1 h

Procedure:
To a stirred homogeneous solution of 2-(4-bromo-2-methylphenyl)thiophene (5.0 mmol, from Step A) and sodium acetate (10 mmol) in acetic acid (25 mL), bromine (5.0 mmol) was added dropwise via syringe at rt over 20-30 min and the resulting mixture was stirred for 1 h. The reaction mixture was combined with 1 M sodium hydroxide (250 mL) and ethyl acetate (250 mL). Organic layer was separated, washed sequentially with 1M sodium hydroxide (100 mL) and brine (100 mL), and dried over sodium sulfate. Silica gel chromatography using hexanes as the eluant afforded the title compound: 1H NMR (CDCl3) 7.46 (d, J=0.6, 1H), 7.38 (dd, J=3.9, 0.6, 1H), 7.24 (d, J=3.9, 1H), 7.09 (d, J=2.9, 1H), 6.83 (d, J=2.9, 1H), 2.43 (s, 3H); HPLC A 4.41 min, ESI-MS (m/z)=334.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([N:18]([CH3:20])[CH3:19])[C:15]=1[O:16][CH3:17])[CH:6](O)CS(C)(=O)=O.C[O-].[Na+].[NH:25]([CH2:32][CH2:33][C:34]#[N:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CS(C)=O>[NH:25]([CH:32]=[C:33]([CH2:6][C:5]1[CH:13]=[C:14]([N:18]([CH3:19])[CH3:20])[C:15]([O:16][CH3:17])=[C:3]([N:2]([CH3:21])[CH3:1])[CH:4]=1)[C:34]#[N:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: N#CCCNc1ccccc1
Reactant: COc1c(N(C)C)cc(C(O)CS(C)(=O)=O)cc1N(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1c(N(C)C)cc(CC(C#N)=CNc2ccccc2)cc1N(C)C

Procedure:
A mixture of 9.76 g. of 3,5-bis(dimethylamino)-4-methoxy-α-[(methylsulfonyl)methyl]benzyl alcohol, 1.8 g. of sodium methylate and 4.8 g. of β-anilinopropionitrile in 20 ml. of dimethylsulfoxide was stirred with the exclusion of moisture for 5 hours at 50° C. The mixture was poured into 250 ml. of water, the precipitated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and evaporated. By recrystallization of the residue from high-boiling petroleum ether, there was obtained α-(anilinomethylene)-3,5-bis(dimethylamino)-4-methoxyhydrocinnamonitrile, having a melting point of 103°-105° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:17])=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[S:7][C:6]=2[C:15]=1[Cl:16].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC.O>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][O:17][C:3]1[C:2]([Cl:1])=[C:15]([Cl:16])[C:6]2[S:7][C:8]([CH:10]3[CH2:11][CH2:12][CH2:13][CH2:14]3)=[CH:9][C:5]=2[CH:4]=1)[CH3:24]
Reactant: Oc1cc2cc(C3CCCC3)sc2c(Cl)c1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cc2cc(C3CCCC3)sc2c(Cl)c1Cl
Yield: 76.1 %

Procedure:
A mixture of 9.0 g of 6,7-dichloro-2-cyclopentyl-5-hydroxybenzo[b]thiophene, 6.35 g of ethyl bromacetate, 4.0 g of potassium carbonate and 10 ml of dimethylformamide in 200 ml of 2-butanone is refluxed for 16 hours. The cooled mixture is diluted with water (200 ml), extracted with 3×300 ml-portions of dichloromethane, and the combined organic solution is dried over anhydrous magnesium sulfate. Removal of solvents leaves a colorless oil which crystallizes on cooling to give 8.9 g of ethyl[(6,7-dichloro-2-cyclopentylbenzo[b]thien-5-yl)oxy]acetate or prisms, mp 65°-67°.
Reaction SMILES: [Cl:1][C:2]1[C:9](F)=[N:8][CH:7]=[C:6]([Cl:11])[C:3]=1[C:4]#[N:5].[NH2:12][C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1>C(OCC)(=O)C>[Cl:1][C:2]1[C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[N:8][CH:7]=[C:6]([Cl:11])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(Cl)cnc(F)c1Cl
Reactant: Cc1ccccc1N
Solvent: CCOC(C)=O
Product: Cc1ccccc1Nc1ncc(Cl)c(C#N)c1Cl
Temperature: 150 °C
Yield: 75.5 %

Procedure:
A mixture of 3,5-dichloro-2-fluoroisonicotinonitrile (1.00 g, 5.24 mmol) and o-toluidine (10 g, 93 mmol) was heated to 150° C. for 20 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (200 mL), washed with 1 N HCl (2×20 mL), saturated sodium bicarbonate (20 mL), and brine (20 mL), dried (MgSO4) and concentrated. Silica gel chromatography, loading with dichloromethane-hexanes (1:1) and eluting with 0 to 20% ethyl acetate in hexanes, gave 3,5-dichloro-2-(o-tolylamino)isonicotinonitrile as yellow solid (1.10 g, 76% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.18 (1H, s), 7.71 (1H, δ, J=7.78 Hz), 7.23-7.40 (2H, m), 7.01-7.13 (1H, m), 6.70-6.94 (1H, m), 2.29 (3H, s); MS (ES+) m/z: 278 (M+H); LC retention time: 3.68 min (analytical HPLC Method A).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1.Br[C:16]([C:18]([F:21])([F:20])[F:19])=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.O>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:16]([C:18]([F:21])([F:20])[F:19])=[CH2:17])[CH:5]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cccc(OC(F)(F)F)c1)C(F)(F)F
Temperature: 60 °C
Reaction time: 7 h

Procedure:
To a solution of 3-Trifluoromethoxy-benzeneboronic acid (2.5 g) in a 2:1 mixture THF/H2O (36 ml) was added 2-Bromo-3,3,3-trifluoro-propene (3.1 ml), potassium carbonate (3.35 g), then Bis(triphenylphosphine)palladium(II) dichloride (169 mg). The reaction mixture was stirred at 60° C. for 7 hours. The solution was allowed to cool to room temperature then filtered on a Celite pad. The filtrate was concentrated in vacuo and the residue was then dissolved with ethyl acetate, extracted with water, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel to give 1-Trifluoromethoxy-3-(1-trifluoromethyl-vinyl)-benzene (1.23 g). 19F-NMR (CDCl3, 75 MHz): −57.87 ppm and −64.94 ppm.
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][C@@:8]1([CH2:17][N+:18]([O-])=O)[CH2:14][C@@H:13]2[C@H:9]1[CH:10]=[C:11]([CH2:15][CH3:16])[CH2:12]2)(C)(C)C.[Cl-].[NH4+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C(N(CC)CC)C>C(O)C.O.ClCCl.[Fe]>[NH2:18][CH2:17][C@:8]1([CH2:7][C:6]([OH:21])=[O:5])[CH2:14][C@@H:13]2[C@H:9]1[CH:10]=[C:11]([CH2:15][CH3:16])[CH2:12]2
Reactant: CCC1=C[C@@H]2[C@H](C1)C[C@@]2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Agent: [Fe]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCC1=C[C@@H]2[C@H](C1)C[C@]2(CN)CC(=O)O
Reaction time: 5.5 h

Procedure:
Tert-butyl[(1R,5S,6S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (peak 1, 7.0 g, 23.7 mmol) was dissolved in ethanol (60 mL) and water (21 mL). To the solution, iron powder (13.27 g, 237 mmol) and ammonium chloride (628.1 mg, 11.9 mmol) were added, and the mixture was stirred for 5.5 hours under heating to reflux. The mixture was allowed to cool, then diluted with saturated saline, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate, and filtered through Celite to remove insoluble matter. The filtrate was separated into organic and aqueous layers. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain a pale yellow oil substance (7.02 g). This substance was dissolved in dichloromethane (200 mL). To the solution, (Boc)2O (5.25 g, 25 mmol) and triethylamine (5.01 g, 50 mmol) were added, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel chromatography to obtain the title compound of interest as a pale yellow oil substance (8.82 g, <100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.I[CH:10]1[CH2:13][O:12][CH2:11]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH:10]2[CH2:13][O:12][CH2:11]2)[CH:7]=1
Reactant: IC1COC1
Reactant: O=c1ccc(Br)c[nH]1
Product: O=c1ccc(Br)cn1C1COC1

Procedure:
The title compound was prepared from 5-bromopyridin-2(1H)-one and 3-iodooxetane following a procedure analogous to that described for Intermediate 22.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[CH:7]=[CH:6]2>[Rh]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([CH3:13])[CH2:7][CH2:6]2
Reactant: COc1ccc2nc(C)ccc2c1
Agent: [Rh]
Product: COc1ccc2c(c1)CCC(C)N2

Procedure:
6-Methoxyquinaldine was reduced with rhodium on carbon to give 6-methoxy-2-methyltetrahydroquinoline.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:21]=3[CH2:22][N:23]([CH2:26][C@H:27]3[CH2:32][CH2:31][C@H:30]([CH2:33][C:34]([O:36]CC)=[O:35])[CH2:29][CH2:28]3)[CH2:24][CH3:25])[C@H:14]2[CH3:47])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[K+].CO>CCO.O>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:42]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:40]=[CH:39][C:21]=3[CH2:22][N:23]([CH2:26][C@H:27]3[CH2:28][CH2:29][C@H:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:31][CH2:32]3)[CH2:24][CH3:25])[C@H:14]2[CH3:47])[CH:4]=[C:3]([C:2]([F:1])([F:49])[F:48])[CH:8]=1
Reactant: CCOC(=O)C[C@H]1CC[C@H](CN(CC)Cc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CO
Product: CCN(Cc1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C)C[C@H]1CC[C@H](CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)benzyl](ethyl)amino]methyl}cyclohexyl)acetate (51 mg, 0.0718 mmol) in EtOH (3 mL) and water (2 mL) was added 4 M KOH (500 μL). The mixture was stirred at room temperature for 30 minutes and then water (1 mL) and MeOH (100 μL) were added. After an additional hour, the reaction was quenched with 1 N HCl (5 mL), diluted with EtOAc (20 mL) and washed with brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by PTLC (50% EtOAc/hexanes with 1% AcOH) was followed by azeotroping of the product with toluene to afford (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)benzyl](ethyl)amino]methyl}cyclohexyl)acetic acid. Rf=0.13 (50% EtOAc/hexanes with 1% AcOH). LCMS=683.2 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H), 7.79 (s, 2H), 7.61-7.53 (m, 2H), 7.48 (s, 1H), 5.74 (d, J=7.8 Hz, 1H), 5.00 (d, J=16.4 Hz, 1H), 4.44 (d, J=16.2 Hz, 1H), 4.04-3.98 (m, 1H), 3.72-3.61 (m, 2H), 2.54-2.53 (m, 2H), 2.23-2.19 (m, 4H), 1.82-1.76 (m, 4H), 1.72-1.64 (m, 1H), 1.39-1.38 (m, 1H), 1.04 (t, J=6.8 Hz, 3H), 0.99-0.78 (m, 4H), 0.76 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([C:12]2[NH:13][C:14](=[O:22])[NH:15][C:16](=[O:21])[C:17]=2[CH:18]([CH3:20])[CH3:19])=[O:11])[CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+].Cl[CH2:32][C:33]1[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([N:40]2[C:48](=[O:49])[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]2=[O:50])[CH:34]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([C:12]2[N:13]([CH2:32][C:33]3[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([N:40]4[C:48](=[O:49])[C:47]5[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=5)[C:41]4=[O:50])[CH:34]=3)[C:14](=[O:22])[NH:15][C:16](=[O:21])[C:17]=2[CH:18]([CH3:20])[CH3:19])=[O:11])[CH:9]=1)[C:5]#[N:6]
Reactant: Cc1cc(CCl)cc(N2C(=O)c3ccccc3C2=O)n1
Reactant: CC(C)c1c(C(=O)c2cc(Cl)cc(C#N)c2)[nH]c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Cn2c(C(=O)c3cc(Cl)cc(C#N)c3)c(C(C)C)c(=O)[nH]c2=O)cc(N2C(=O)c3ccccc3C2=O)n1
Reaction time: 8 h
Yield: 49.3 %

Procedure:
To a stirred solution of 3-Chloro-5-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-benzonitrile (317 mg, 1 mmol), anhydrous powdered potassium carbonate (134 mg, 1 mmol), and lithium iodide (134 mg, 1 mmol) in DMF (5 ml) at room temperature, was added 2-(4-Chloromethyl-6-methyl-pyridin-2-yl)-isoindole-1,3-dione (286 mg, 1 mmol). After stirring for overnight, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:1); Rf˜0.3 fraction was collected.) to afford 280 mg (49%) a yellow solid.
Reaction SMILES: O1CCCC1.[NH3:6].Cl[C:8]1[C:9]2[C:16]([I:17])=[CH:15][N:14]([CH:18]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]3)[C:10]=2[N:11]=[CH:12][N:13]=1.C(Cl)(Cl)Cl>O>[NH2:6][C:8]1[C:9]2[C:16]([I:17])=[CH:15][N:14]([CH:18]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]3)[C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(I)c3c(Cl)ncnc32)C1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(n2cc(I)c3c(N)ncnc32)C1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
Tetrahydrofuran (2.5 ml) and 28% aqueous ammonia (2.5 ml) were added to the tert-butyl 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidine-1-carboxylate (350 mg) obtained in Step 1 above. The reaction mixture was stirred at 100° C. for 1.5 hours using a microwave reactor. Chloroform and water were added thereto to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a white solid (340 mg). Physical properties: m/z [M+H]+ 416.0
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[F:12][C:13]1[CH:14]=[CH:15][C:16](B2OC(C)(C)C(C)(C)O2)=[C:17]([CH:20]=1)[C:18]#[N:19]>>[F:12][C:13]1[CH:20]=[C:17]([C:18]#[N:19])[C:16]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=2[CH3:11])=[CH:15][CH:14]=1
Reactant: CC1(C)OB(c2ccc(F)cc2C#N)OC1(C)C
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Product: Cc1c(-c2ccc(F)cc2C#N)cccc1[N+](=O)[O-]

Procedure:
2-Bromo-6-nitrotoluene and 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile were coupled using the procedure described in Example 1 to afford crude 4-fluoro-2′-methyl-3′-nitrobiphenyl-2-carbonitrile as a black solid: δH (360 MHz, CDCl3) 2.32 (3H, s), 7.34-7.46 (5H, m), 7.95 (1H, m).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([CH3:13])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[CH3:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(N(CC)CC)C>[C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:29](=[O:30])[NH:28][C:25]3[CH:26]=[CH:27][C:22]([S:21][CH3:20])=[CH:23][CH:24]=3)[C:9]([CH3:13])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1ccc(N=C=O)cc1
Reactant: CC1=NN(c2ccccc2)C(=O)C1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CSc1ccc(NC(=O)C2C(=O)N(c3ccccc3)N=C2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 2.6 g of 1-phenyl-3-methyl-2-pyrazolin-5-one, 75 ml of benzene, 1.8 g of triethylamine and 2.5 g of p-methylthiophenylisocyanate is stirred at ambient temperature and allowed to stand overnight. It is evaporated; the residue taken up in methanol, the solution is filtered and combined with the mixture of 10 ml of 5 N hydrochloric acid and 250 ml of water. The precipitate formed is collected, washed with water, dried, triturated with diethyl ether and dissolved in 2 N aqueous sodium hydroxide. The solution is filtered, acidified with 5 N hydrochloric acid, the precipitate washed with water, dried, triturated with methanol and recrystallized from ethyl acetate, to yield the 1-phenyl-3-methyl-4-(p-methylthiophenylcarbamoyl)-2-pyrazolin-5-one melting at 196°-199°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][CH2:14][C:15]([NH2:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CN1CCCC1=O>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][CH2:14][C:15]([CH3:17])([NH2:18])[CH3:16])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: CC(C)(N)CN
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)(N)CNc1ccnc2cc(Cl)ccc12
Yield: 50.7 %

Procedure:
198 g of 4,7-dichloroquinoline, 97 g of 1,2-diamino-2-methyl-propane and 101 g of triethylamine were stirred in 1 l of N-methyl-2-pyrrolidone at 150° C. under argon for 5 hours. The solvent was evaporated in a vacuum and the residue was taken up in 1 l of water. The pH was adjusted to 1 using 220 ml of 25% hydrochloric acid and the mixture was diluted with 6 l of water and extracted four times with 0.5 l of ethyl acetate each time. The clear aqueous solution was treated with about 900 g of KOH, whereby the pH rose to 14 and the product separated in crystalline form. This was filtered off under suction, rinsed with about 3 l of water and, for further purification, recrystallized from 4 l of acetonitrile. There were obtained 126.7 g (73%) of N1 -(7-chloro-quinolin-4-yl)-2-methyl-propane-1,2-diamine, m.p. 182-184° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH:2]=1.[Cl-].[NH4+]>O.O1CCCC1.CO.[Fe]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:2]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cccnc2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2cccnc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
4-(Pyridin-3-yl)oxy-1-nitrobenzene prepared in Step A was dissolved in the mixture of water (100 mL), tetrahydrofuran (100 mL) and methanol (100 mL). Iron powder (103 g, 1.84 mol) and ammonium chloride (99 g, 1.84 mol) were added thereto, and the mixture was stirred for 3 h at 80° C. using a mechanical stirrer. After completion of the reaction, the reaction mixture was filtered through a cellite, washed with methanol, and concentrated under reduced pressure. The solid thus obtained was filtered, washed with ether, and dried to give the title compound (17 g, Yield 36%).
Reaction SMILES: [CH3:1][C:2]1(C)OC(=O)[CH:5]([CH:9]([C:20]2[C:28]3[C:23](=[C:24]([CH2:29][S:30][CH3:31])[CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[C:4](=[O:32])[O:3]1>N1C=CC=CC=1.C(O)C.[Cu]>[CH3:31][S:30][CH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[NH:22][CH:21]=[C:20]2[CH:9]([C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=1)[CH2:5][C:4]([O:3][CH2:2][CH3:1])=[O:32]
Reactant: CSCc1cccc2c(C(c3ccc(C(F)(F)F)cc3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CC(c1ccc(C(F)(F)F)cc1)c1c[nH]c2c(CSC)cccc12

Procedure:
0.7 mg (0.01 mmol) of copper powder was added to 504 mg (1.06 mmol) of the compound from Example 12A in 8 ml of pyridine and 2 ml of ethanol. The reaction mixture was heated under reflux for 1 h. It was concentrated, and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 241 mg (54% of theory) of the title compound.