Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])=[CH:4][CH:3]=1.C1COCC1.C(N(CC)CC)C.[CH3:26][O:27][C:28]([CH:30]([C:34]1[CH:43]=[CH:42][C:41]2[C:40]([CH3:45])([CH3:44])[CH2:39][CH2:38][C:37]([CH3:47])([CH3:46])[C:36]=2[CH:35]=1)[C:31](Cl)=[O:32])=[O:29]>O>[CH3:26][O:27][C:28]([CH:30]([C:34]1[CH:43]=[CH:42][C:41]2[C:40]([CH3:45])([CH3:44])[CH2:39][CH2:38][C:37]([CH3:47])([CH3:46])[C:36]=2[CH:35]=1)[C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH:10]=[CH2:11])=[O:7])=[CH:12][CH:13]=1)=[O:32])=[O:29]
Reactant: COC(=O)C(C(=O)Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: C=CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCOC(=O)c1ccc(NC(=O)C(C(=O)OC)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.8 g (10 mmol) of allyl 4-aminobenzoate, 50 ml of THF and 1.7 ml (12 mmol) of triethylamine were introduced into a round-bottomed flask. A solution of 3.3 g (10 mmol) of α-methoxycarbonyl-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetic acid chloride in 25 ml of THP was added dropwise and the mixture was stirred at room temperature for 2 hours. The reaction medium was poured into water, and extracted with ethyl acetate. The organic phase was decanted off, dried over magnesium sulfate and evaporated. The residue obtained was recrystallized from ethanol; 3.3 g (69%) of the expected compound of melting point 155°-156° C. were recovered after filtration and drying.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH2:9][CH:10]1[CH2:12][CH:11]1[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2)[CH3:8].[OH-].[Na+].CN([CH:27]=[O:28])C>O>[CH3:8][N:7]([CH2:9][CH:10]1[CH2:12][CH:11]1[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH:27]=[O:28])[CH3:6]
Reactant: CN(C)CC1CC1c1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)CC1CC1c1ccc2[nH]cc(C=O)c2c1
Reaction time: 0.25 h

Procedure:
Phosphorous oxychloride (0.08 mL, 0.85 mmol, 0.91 equiv.) and dimethyl formamide (0.32 mL, 4.09 mmol, 4.4 equiv.) were combined at room temperature with stirring. After 15 min, N,N-dimethyl-2-(indol-5-yl)cycloprop-1-yl-methylamine was added dropwise in DMF (5 mL). After 2 hs of stirring at room temperature, ice and 1 N NaOH were added, then the mixture was diluted further with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give N,N-dimethyl-2-(3-formyl-indol-5-yl)cycloprop-1-yl-methylamine (120 mg) as an oil. 1H NMR (MeOH-d4): δ9.84 (s, 1H), 8.04 (s, 1H), 7.97 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.05 (dd, J=15.5, 1.7 Hz, 1H), 2.59 (dd, J=12.7, 6.7, 1H), 2.35 (s, 6H), 2.30 (m, 1H), 1.80 (m, 1H), 1.20 (m, 1H), 1.05 (m, 1H), and 0.88 (m, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[F:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17](O)=O.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[F:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:8]2[N:9]=1
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: O=C(O)c1ccncc1F
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: Cn1c(-c2ccncc2F)nc2cc(C(F)(F)F)cnc21
Temperature: 120 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
A mixture of 5.51 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 6.10 g of 3-fluoroisonicotinic acid, 8.28 g of WSC and 58 ml of pyridine was stirred for 3 hours while heating at 120° C. After cooling down to room temperature, water was poured, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 6.77 g of 2-(3-fluoropyridin-4-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as present active compound 36).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:15][C:14]4[N:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl-].[N:27]1[CH:32]=[CH:31][CH:30]=[N:29][C:28]=1[NH:33][S:34]([C:37]1[CH:42]=[CH:41][C:40]([NH:43][CH:44]=[S:45])=[CH:39][CH:38]=1)(=[O:36])=[O:35].CO>ClCCl>[N:27]1[CH:32]=[CH:31][CH:30]=[N:29][C:28]=1[NH:33][S:34]([C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[N:12]=[CH:11][N:10]=[C:9]4[C:8]=3[S:15][C:14]3[N:16]=[CH:17][CH:18]=[CH:19][C:13]4=3)[CH2:6][CH2:5]2)=[S:45])=[CH:39][CH:38]=1)(=[O:36])=[O:35]
Reactant: c1cnc2sc3c(N4CCNCC4)ncnc3c2c1
Reactant: O=S(=O)(Nc1ncccn1)c1ccc(NC=S)cc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ncccn1)c1ccc(NC(=S)N2CCN(c3ncnc4c3sc3ncccc34)CC2)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-piperazinopyrido[3′,2′;4,5]thieno[3,2-d]pyrimidine (200 mg, 0.74 mmol) and pyridine (0.5 mL, 7.9 mmol) in dichloromethane (20 mL) was added a solution of product 1d in dichloromethane (20 mL) and this was stirred overnight. Methanol was added to quench excess thiophosgene, and the residue after removal of solvent was purified by silica gel column chromatography eluting with 5% methanol/dichloromethane and further recrystallized from dichloromethane/hexane to give 60 mg (15%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[CH3:11])[C:5](O)=[O:6].S(Cl)([Cl:15])=O.CN(C)C=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[CH3:11])[C:5]([Cl:15])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(Cl)cc(C(=O)O)cc1Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(Cl)cc(C(=O)Cl)cc1Cl
Reaction time: 2 h
Yield: 110.3 %

Procedure:
A mixture of 3,5-dichloro-4-methylbenzoic acid (230 g, 1.12 moles), thionyl chloride (204 g, 1.71 moles), and dimethylformamide (30 milliliters(ml), in toluene (1 liter) was slowly warmed to 70° C. and stirred at that temperature for 2 hours. The toluene was eliminated in the rotavap to yield 276 g of 3,5-dichloro-4-methylbenzoyl chloride, used in the next step as such.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH:24]([CH2:36][CH3:37])[CH2:25][NH:26]CC2C=CC(OC)=CC=2)[C:5]1=[O:38])[CH:2]=[CH2:3]>C(#N)C.O>[CH2:1]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([CH:24]([CH2:36][CH3:37])[CH2:25][NH2:26])[C:5]1=[O:38])[CH:2]=[CH2:3]
Reactant: C=CCC1CC(c2cccc(Cl)c2)C(c2ccc(Cl)cc2)N(C(CC)CNCc2ccc(OC)cc2)C1=O
Solvent: O
Solvent: CC#N
Product: C=CCC1CC(c2cccc(Cl)c2)C(c2ccc(Cl)cc2)N(C(CC)CN)C1=O

Procedure:
To a solution of (3SR,5RS,6SR)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((SR)-1-(4-methoxybenzylamino)butan-2-yl)piperidin-2-one (88 mg, 0.160 mmol) in acetonitrile (1899 μL) and water (380 μL) was added ceric ammonium nitrate (350 mg, 0.638 mmol) at 25° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[N:23]1[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[C:24]1=[O:31].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(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:28]([CH:25]1[CH2:26][CH2:27][N:23]([C:17]2[C:16]([F:15])=[CH:21][CH:20]=[CH:19][C:18]=2[F:22])[C:24]1=[O:31])=[O:29]
Reactant: O=C(O)C1CCN(c2c(F)cccc2F)C1=O
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2c(F)cccc2F)C1=O
Yield: 18.6 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(2,6-difluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.107 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) to give 0.033 g (20%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(2,6-difluorophenyl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1)=[O:10].[N:19]1([CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.Cl>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[C:16]([NH:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH2:27][CH2:26][CH2:25][N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:30][CH:31]=2)[N:15]=[CH:14][N:13]=1)=[O:10]
Reactant: Nc1ccc(OCCCN2CCOCC2)cc1
Reactant: O=C(Nc1cc(Cl)ncn1)Nc1ccccc1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(Nc1cc(Nc2ccc(OCCCN3CCOCC3)cc2)ncn1)Nc1ccccc1Cl
Temperature: 25 °C

Procedure:
A solution of 1-(2-chloro-phenyl)-3-(6-chloro-pyrimidin-4-yl)-urea (99 mg, 0.35 mmol), 4-(3-morpholin-4-yl-propoxy)-phenylamine [Chabrier et al. Bull. Soc. Chim. Fr. 1955; 1353] (83 mg, 0.35 mmol), and concentrated HCl (0.1 ml, 1.4 mmol) in ethanol (5 ml) was refluxed for 32 h. The reaction mixture is cooled to RT, and diluted with water. The acidic solution is washed with ethyl acetate, basified with aqueous ammoniac, and extracted with DCM. The combined organic phases are dried over sodium sulfate, evaporated in vacuo, the residue is crystallized from water/methanol/1 N HCl to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[C:2]1([NH:1][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C1CCCCC1
Product: c1ccc(Nc2ccccc2)cc1

Procedure:
A reaction tube having a diameter of 32 mm and a length of 80 cm was used for reacting aniline and cyclohexanone to give diphenylamine. 200 ml (175.4 g) of catalyst were used which had been prepared according to German Offenlegungsschrift 3,801,754, Example 2, from spherical (2-6 mm) γ-Al2O3 by impregnating this support with 1% of Cr, 1.1% of Mn, 0.5% of Rh, 0.5% of Pt, 2.7% of NaOH and 2.7% of K2SO4.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]([OH:11])=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN(CC)CC>C(Cl)Cl>[C:37]1([NH:36][C:9]([C:6]2([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]2)=[O:11])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C(=O)Nc2ccccc2)CC1
Reaction time: 0.17 h
Yield: 88.8 %

Procedure:
To a solution of 1-(ethoxycarbonyl)cyclopropane carboxylic acid (7.4 g, 46.84 mmol) in dry CH2Cl2 (70 mL) was added HATU (35.62 g, 93.67 mmol) at 0° C. After stirring for 10 minutes, a solution of the aniline (8.71 g, 93.67 mmol) and Et3N (9.48 g, 93.67 mmol) in dry CH2Cl2 (30 mL) was then added and the reaction mixture was continued to stir at 40° C. for 24 hrs. The reaction mixture was quenched with water (30 mL) and extracted with CH2Cl2 (100 mL×3). The combined organic phases were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was chromatographed with a silica gel column (1:5 (v/v) EtOAc/n-hexane) to afford the title compound as a pale yellow solid (9.7 g, 89%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:25]([O-:27])=[O:26])=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.C(N(CC)CC)C>ClCCl>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([N+:25]([O-:27])=[O:26])=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1)=[O:8])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccccc1C(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Oc1ccccc1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-Isopropoxy-benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Isopropoxy-N-(4-nitro-3-trifluromethyl-phenyl)-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [Br:1]Br.[CH3:3][CH:4]([CH3:19])[C:5]([C:7]1[CH:18]=[CH:17][C:10]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=1)=[O:6]>C(Cl)(Cl)(Cl)Cl>[Br:1][C:4]([CH3:19])([CH3:3])[C:5]([C:7]1[CH:18]=[CH:17][C:10]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=1)=[O:6]
Reactant: BrBr
Reactant: COC(=O)COc1ccc(C(=O)C(C)C)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)COc1ccc(C(=O)C(C)(C)Br)cc1
Reaction time: 16 h

Procedure:
Bromine (2.09 ml) has added dropwise over ten minutes to a stirred solution of the product of step (i) above (9.44 g) in carbon tetrachloride (2001 ml). The solution was stirred for 16 hours, then the solvent was evaporated invacuo to give an orange oil. A solution of this oil, in a small volume of dichloromethane, was filtered through silica and the clear filtrate, on evaporation, gave methyl 4-(2-bromo-2,2-dimethylacetyl)phenoxyacetate, 11.3 g, as a white crystalline solid: m.p. 46°-50° C.; NMR (d6DMSO) δ 8.09 (2H, d), 7.05 (2H, d), 4.92 (2H, s), 3.72 (3H, s), 2.00 (6H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH:25]=2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:29][CH2:28][N:27]([CH:13]3[CH2:14][CH2:15][N:10]([C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)[CH2:11][CH2:12]3)[CH2:26][CH:25]=2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Product: O=[N+]([O-])c1ccc(N2CCC(N3CC=C(c4ccc(F)cc4)CC3)CC2)cc1

Procedure:
5.5 g of 1-(4-nitrophenyl)-4-piperidone and 4.4 g of 4-(4-fluorophenyl)-1,2,5,6-tetrahydropyridine were reacted as in Example 1. The product crystallized as fumarate.
Reaction SMILES: [C:1]12(N)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:12][CH:13]1[S:17](=[O:19])(=[O:18])[O:16][CH2:15][CH2:14]1.C(#[N:22])C>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:22][CH2:15][CH2:14][CH:13]([S:17]([OH:16])(=[O:19])=[O:18])[CH3:12])[CH2:8]2
Reactant: CC#N
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CC1CCOS1(=O)=O
Product: CC(CCNC1C2CC3CC(C2)CC1C3)S(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of 1-adamantanamine (1.99 g, 13.1 mmol) in acetonitrile (15 mL) was added 2,4-butane sultone (1.87 g, 13.8 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with acetonitrile (2×25 mL) and dried in vacuo. 1H NMR (DMSO, 500 MHz) δ ppm 3.20 (m, 1H), 3.05 (m, 2H), 2.67 (m, 1H), 2.07 (m, 2H), 2.00 (m, 1H), 1.95 (m, 4H), 1.82 (m, 4H), 1.69 (m, 4H), 1.55 (m, 4H), 1.12 (d, 1H, J=8.0 Hz). 13C (DMSO, 125 MHz) δ ppm 62.27, 53.91, 44.33, 37.30, 36.82, 36.77, 30.30, 30.20, 29.57, 29.50, 28.95, 17.12, 26.85, 17.44. ES-MS 288 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[C:8](=[O:14])[CH2:7][C:6]([CH3:16])([CH3:15])[CH2:5][C:4]=2[N:3]=1.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.O>C(O)C>[CH3:15][C:6]1([CH3:16])[CH2:5][C:4]2[N:3]=[C:2]([N:26]3[CH2:27][CH2:28][N:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:24][CH2:25]3)[C:11]([C:12]#[N:13])=[CH:10][C:9]=2[C:8](=[O:14])[CH2:7]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC1(C)CC(=O)c2cc(C#N)c(Cl)nc2C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CC1(C)CC(=O)c2cc(C#N)c(N3CCN(c4ccccc4)CC3)nc2C1
Yield: 62 %

Procedure:
A solution of 2-chloro-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile (0.22 g, 0.94 mmol), 1-phenylpiperazine (0.23 g, 1.4 mmol) and triethylamine (0.14 ml, 0.1 g, 1.0 mmol) in ethyl alcohol (3 ml) was heated at reflux for 4 h. Then water (20 ml) was added and the mixture was extracted by dichloromethane. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (CH2Cl2-hexane, 1:2). The product obtained was recrystallized from ethyl alcohol to give the title compound (0.21 g, 62%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:18]#[N:19])[C:5]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[F:17])=[CH:6][CH:7]=1>C(O)C.C(OCC)(=O)C.[Pt](=O)=O>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]([F:17])=[C:8]([C:5]2[C:4]([C:18]#[N:19])=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:13]=1
Reactant: N#Cc1cc(F)ccc1-c1cc([N+](=O)[O-])ccc1F
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1cc(F)ccc1-c1cc(N)ccc1F
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A suspension of 4,2′-difluoro-5′-nitrobiphenyl-2-carbonitrile (26 g, 100 mmol) in ethanol (180 ml) and ethyl acetate (180 ml) was treated with platinum(IV) oxide (1.02 g, 4.5 mmol) and then shaken under an atmosphere of hydrogen (40 psi) for 1 h. [The reaction was very exothermic and complete solution is brought about by the increase in temperature]. The catalyst was removed by filtration through glass microfibre filter paper [if any crystalline product is present the filter cake is washed with dichloromethane] and the filtrate evaporated to dryness to afford 5′-amino-4,2′-difluorobiphenyl-2-carbonitrile as a straw-coloured solid (23 g, 100%): 1H NMR (360 MHz, CDCl3) δ 3.66 (2H, s), 6.66-6.70 (1H, m), 6.71-6.74 (1H, m), 7.00 (1H, dd, J 9, 9 Hz), 7.33-7.38 (1H, m), 7.44-7.49 (1H, m).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2C(C#N)[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[O:10][CH2:11][C:2]=12.Cl.[C:19]([OH:22])(=[O:21])[CH3:20].[OH-].[Na+]>ClCCl.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH:20]([C:19]([OH:22])=[O:21])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:8][C:9]=3[O:10][CH2:11][C:2]=12
Reactant: N#CC1c2ccccc2OCc2ncccc21
Reactant: CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(O)C1c2ccccc2OCc2ncccc21

Procedure:
A mixture of 2.03 g of 5,11-dihydrobenzoxepino[3,4-b]pyridin-5-carbonitrile, 30 ml of hydrochloric acid and 30 ml of acetic acid was heated under reflux for 19 hours. The reaction mixture was allowed to stand at room temperature. Water and dichloromethane were added to the reaction mixture and the pH was adjusted to 3.4 with 10N sodium hydroxide. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain 1.95 g of Compound U.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][CH:10]2[CH2:12][CH2:11]2)[CH:5]=[C:6]([F:8])[CH:7]=1.O1CCCC1.C([Li])CCC.[CH2:23]([O:25][C:26](Cl)=[O:27])[CH3:24]>CCOCC.[Cl-].[Na+].O>[CH:10]1([O:9][C:4]2[CH:3]=[C:2]([F:1])[C:7]([C:26]([O:25][CH2:23][CH3:24])=[O:27])=[C:6]([F:8])[CH:5]=2)[CH2:12][CH2:11]1
Reactant: CCOC(=O)Cl
Reactant: Fc1cc(F)cc(OC2CC2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(F)cc(OC2CC2)cc1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 87.6 %

Procedure:
To a 250 ml round bottom flask was added cyclopropyl 3,5-difluorophenyl ether (3.6 g, 21.2 mmol) and 60 ml tetrahydrofuran. n-Butyllithium (nBuLi) (2.5 M, 8.9 ml, 22.2 mmol) was added via a syringe at −78° C. The resulting solution was stirred at −78° C. for 20 minutes. Ethylchloroformate (3.05 ml, 31.7 mmol) was added by a syringe. The resulting solution was left stirring for 5 more minutes. The reaction mixture was diluted with 100 ml ether and 60 ml brine. The layers were separated, and the organic portion was dried over sodium sulfate, filtered and concentrated. The crude product was purified on silica gel column eluted with hexane to 1:9 ethyl acetate/hexane gradient solvent to give 4.5 g desired product as yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[CH3:33])[C:27](O)=[O:28].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[CH3:33])[C:27]([N:16]([CH2:15][C:14]([N:10]1[CH2:11][C:12](=[O:13])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:22])[CH2:9]1)=[O:21])[CH2:17][CH2:18][O:19][CH3:20])=[O:28]
Reactant: Cc1ccc(C(=O)O)cc1Cl
Reactant: COCCNCC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: COCCN(CC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1)C(=O)c1ccc(C)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial was taken 100 mg of 3-(3-chloro-2-methyl-phenyl)-1-[2-(2-methoxy-ethylamino)-acetyl]-imidazolidin-4-one (0.31 mmol, 1.00 eq), 52 mg of 3-chloro-4-methylbenzoic acid (0.31 mmol, 1.00 eq), 163 mg BOP (0.37 mmol, 1.20 eq), 171 uL (1.23 mmol, 4.00 eq), and 1.5 mL NMP. The mixture was stirred overnight at room temperature and the crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 3-chloro-N-{2-[3-(3-chloro-2-methyl-phenyl)-4-oxo-imidazolidin-1-yl]-2-oxo-ethyl}-N-(2-methoxy-ethyl)-4-methyl-benzamide. MS (ES) M+H expected=478.0, found=478.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].CS(O[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]1)(=O)=O>CN(C=O)C.C(OCC)(=O)C>[C:36]([O:35][C:33]([N:29]1[CH2:30][CH2:31][CH2:32][CH:27]([CH2:26][O:1][C:2]2[CH:3]=[C:4]([O:8][S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH2:28]1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: O=S(=O)(Oc1cccc(O)c1)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(COS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(COc2cccc(OS(=O)(=O)c3ccccc3Cl)c2)C1
Reaction time: 0.17 h
Yield: 52.9 %

Procedure:
To a solution of 2-chlorobenzenesulfonic acid 3-hydroxyphenyl ester (570 mg, 2.0 mmol), as prepared in step d of Example 1, in DMF (8 mL) was added NaH (95%, 53 mg, 2.2 mmol). The reaction mixture was stirred under nitrogen for 10 min. N-(tert-Butoxycarbonyl)-3-piperidinemethanol methanesulfonate (586 mg, 2.0 mmol), as prepared in step b, was added and the reaction mixture was stirred at 40° C. under nitrogen overnight. The reaction mixture was diluted with ethyl acetate (150 mL), washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (2:1 hexane:ethyl acetate) to give the title compound as a colorless syrup (510 mg, 54%). 1H-NMR (300 MHz, CDCl3) δ 1.32 (m, 1H), 1.45 (s, 9H), 1.65-1.98 (m, 4H), 2.88 (m, 2H), 3.73 (m, 2H), 3.79 (d, 2H), 6.69 (m, 2H), 7.13 (t, 1H), 7.37 (t, 1H), 7.61 (m, 2H), 7.94 (d, 1H).