Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[C:15]1([S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([S:21]([NH:24][C:25]([NH:14][C:9]2[C:10]([CH3:13])=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[O:26])(=[O:22])=[O:23])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)NS(=O)(=O)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and benzenesulfonyl isocyanate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=1>CN(C=O)C>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:25])=[O:26])[CH:20]=[CH:21][CH:22]=2)[N:7]=1
Reactant: Nc1cccc(CS(N)(=O)=O)c1
Reactant: COc1ccccc1-c1ccnc(Cl)n1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1ccnc(Nc2cccc(CS(N)(=O)=O)c2)n1

Procedure:
A solution of 2-chloro-4-(2-methoxy-phenyl)-pyrimidine (0.882 g, 0.004 mol), and (3-amino-phenyl)-methanesulfonamide (0.865 g, 0.005 mol) in DMF (12 ml) was stirred for 2 hours at 80° C. (TLC control). The solvent was removed under reduced pressure to afford {3-[4-(2-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-methanesulfonamide.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N+:18]([O-])=O)=[CH:7][CH:6]=1)(=[O:4])[CH3:3].[OH-].[Na+].ClCCl>C(O)C>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH2:18])=[CH:9][CH:10]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1ccc(Nc2ccncc2[N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CC(=O)c1ccc(Nc2ccncc2N)cc1

Procedure:
4-(4-Acetylphenyl)amino-3-nitropyridine hydrochloride (2.0 g, 71.8 mmol) was partitioned between aqueous sodium hydroxide and dichloromethane (3×20 ml). The combined organic phases were (kPa) for 3.5 hours. The catalyst was filtered off, and the solvent removed under reduced pressure to give a brown solid, (1.8 g) which was used directly for the next reaction without purification, m.p. 165°-166° C. (after recrystallisation from ethanol).
Reaction SMILES: C[O:2][C:3](=[O:52])[C@@H:4]([NH:18][C:19](=[O:51])[C:20]1[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:31]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:30]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Li+].[OH-]>C1COCC1.CO>[C:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([NH:18][C:19](=[O:51])[C:20]2[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[C:31]([O:43][CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:30]=2)[C:3]([OH:52])=[O:2])=[CH:11][CH:10]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Br)ccc1OCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1cc(Br)ccc1OCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
3-Biphenyl-4-yl-2-(S)-[2-(3,4-bis-benzyloxy-benzyloxy)-5-bromo-benzoylamino]-propionic acid methyl ester (60 mg, 0.079 mmol) was dissolved in 5 mL of THF-MeOH (4-1), cooled to 0° C. and 1.1 equiv of 2 N LiOH added. After 30 minutes, 2.2 additional equiv of 2N LiOH was added and the reaction stirred for 30 minutes. The reaction was worked up according to general procedure C to give 3-biphenyl-4-yl-2-(S)-[2-(3,4-bis-benzyloxy-benzyloxy)-5-bromo-benzoylamino]-propionic acid (47 mg). 1H-NMR(400 MHz, DMSO-d6): 2.83 (m, 1H), 3.13 (m, 1H), 4.67 (m, 1H), 5.02 (s, 2H), 5.06 (s, 2H), 5.17, (m, 2H), 6.92 (m, 1H), 6.96 (m, 1H), 7.13 (d, 2H), 7.18-7.22 (m, 2H), 7.27-7.41 (m, 13H), 7.44 (d, 2H), 7.56 (m, 2H), 7.61 (m, 1H), 7.83 (m, 1H), 8.50 (d, 1H); LC/MS (m/z): 742 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2(O)[CH2:11][S:10](=[O:13])(=[O:12])[CH2:9]2)=[N:6][CH:7]=1.C(N(S(F)(F)[F:21])CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([F:21])[CH2:11][S:10](=[O:13])(=[O:12])[CH2:9]2)=[N:6][CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=S1(=O)CC(O)(c2ccc(Br)cn2)C1
Solvent: ClCCl
Product: O=S1(=O)CC(F)(c2ccc(Br)cn2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
To a stirred solution of the product of step 2, Example 18 (0.3 g, 1.097 mmol, 1 eq) in methylene chloride (30 mL) is added diethylaminosulfur trifluoride (0.175 mL, 1.295 mmol, 1.1 eq) at −78° C. Resulting reaction mixture is stirred at −78° C. for 1 hour. The reaction mixture is quenched with aqueous bicarbonate solution (15 mL) and extracted with methylene chloride (3×20 mL). Combined organic layer dried over sodium sulphate and concentrated in vacuo. The crude compound is purified by column chromatography using (100-200 mesh silica). Desired compound is eluted in 10% ethyl acetate/hexane to afford title compound (0.15 g): 1H NMR (400 MHz, DMSO) δ: 4.77-4.86 (m, 2H), 4.94-5.05 (m, 2H), 7.62 (d, 1H, J=8.4 Hz), 8.21-8.24 (dd, 1H, J1=8.44 Hz, J2=2.12 Hz), 8.85 (s, 1H). LC-MS (m/z): [M+H] 281.9.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N+:13]([O-:15])=O)[C:6]([NH2:12])=[CH:7][CH:8]=2)[CH2:3]1.[N:16]#[C:17][NH2:18].[CH]Cl.[OH-].[Na+]>O>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[CH:8]=[CH:7][C:6]3[N:12]=[C:17]([NH2:18])[N:16]=[N+:13]([O-:15])[C:5]=3[C:4]=2[CH2:3]1
Reactant: N#CN
Reactant: CN1CCc2ccc(N)c([N+](=O)[O-])c2C1
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCc2ccc3nc(N)n[n+]([O-])c3c2C1
Temperature: 60 °C
Yield: 62.3 %

Procedure:
A mixture of 8-nitroaniline 254 (510 mg, 2.5 mmol) and cyanamide (460 mg, 10.9 mmol) was melted at 100° C. The mixture was cooled to 60° C. and cHCl (4 mL) was added slowly. The solution was heated at 100° C. for 1 h, then three more aliquots of cyanamide (460 mg, 10.9 mmol) and cHCl (5 mL) were added over 3 h. The solution was cooled to 60° C. and the solution made basic with NaOH solution (7.5 M, 10 mL). The solution was heated at 100° C. for another 1 h, cooled and diluted with water (50 mL). The solid was filtered and washed with water (30 mL) to give 1-oxide 262 (360 mg, 63%) as a brown solid: mp 226-229° C.; 1H NMR [(CD3)2SO] δ 7.50 (d, J=8.6 Hz, 1H, H-5), 7.32 (d, J=8.6 Hz, 1H, H-6), 7.09 (br s, 2H, NH2), 4.09 (s, 2H, H-10), 2.88 (t, J=5.7 Hz, 2H, H-7), 2.58 (t, J=5.7 Hz, 2H, H-8), 2.40 (s, 3H, NCH3); MS (APCI) m/z 232 (MH+, 100%). Anal. calcd for C11H13N5O.¼CH3OH: C, 56.5; H, 5.9; N, 29.3. Found: C, 56.6; H, 5.6; N, 29.1%.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:8])[CH:7]=1)[CH3:2].[F:15][C:16]([F:24])([F:23])[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19]>C(Cl)(Cl)Cl>[CH3:21][O:20][C:18](=[O:19])[C:17]([OH:22])([C:16]([F:24])([F:23])[F:15])[C:7]1[C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][C:3]=1[CH2:1][CH3:2]
Reactant: COC(=O)C(=O)C(F)(F)F
Reactant: CCc1cc(=O)n(-c2ccccc2)[nH]1
Solvent: ClC(Cl)Cl
Product: CCc1[nH]n(-c2ccccc2)c(=O)c1C(O)(C(=O)OC)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a chloroform solution (5 ml) of 3-ethyl-1-phenyl-5-pyrazolone (94 mg, 0.5 mmol), methyl trifluoropyruvate (78 mg, 0.5 mmol) was added at room temperature and the mixture was stirred at 80° C. for 2 hours. After removing the solvent under reduced pressure, the title compound was obtained as a colorless solid (172 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)[CH2:4]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:32]=1[C:33](O)=[O:34]>C(#N)C.O.CN(C=O)C>[CH3:17][N:2]([CH3:1])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([C:10]3[O:12][C:33](=[O:34])[C:32]4[C:36]([CH3:40])=[CH:37][CH:38]=[CH:39][C:31]=4[N:30]=3)=[CH:13][CH:14]=[CH:15][N:16]=2)[CH2:4]1
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: CN(C)C1CCN(c2ncccc2C(=O)O)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1cccc2nc(-c3cccnc3N3CCC(N(C)C)C3)oc(=O)c12
Temperature: 60 °C
Reaction time: 8 h
Yield: 11.6 %

Procedure:
A solution of compound C (133 mg, 0.56 mmol) and CDI (91 mg, 0.56 mmol) in anhydrous acetonitrile (1.0 mL) was stirred for 1 hour at ambient temperature. 2-Amino-6-methyl-benzoic acid (41 mg, 0.27 mmol) was added, and the mixture was stirred at 60° C. overnight. The reaction solution was diluted with water (2 mL) and DMF (2 mL), filtered, then purified by C18 reverse phase chromatography to afford compound 46 as an off-white powder (11 mg, 35% yield). 1H-NMR δ (CDCl3): 8.32 (dd, 1H, J=4.8 Hz, J=2.0 Hz), 8.09 (dd, 1H, J=8.0 Hz, J=1.6 Hz), 7.68 (t, 1H, J=15.6 Hz, J=0.8 Hz), 7.52 (t, 1H, J=4.0 Hz, J=7.6 Hz), 7.33 (d, 1H, J=7.2 Hz), 6.82 (dd, 1H, J=8 Hz, J=4.8 Hz), 3.95 (br s, 1H), 3.81 (br s, 1H), 3.57-3.64 (m, 2H), 3.48-3.53 (m, 2H), 2.83 (s, 3H), 2.64 (br s, 6H), 2.30 (br s, 1H). ESMS: 351.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:14]([O-:17])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1>[N+:11]([C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([N:11]2[CH2:9][CH2:8][CH2:4][C:14]2=[O:17])[CH:10]=1)[C:5]([OH:7])=[O:6])([O-:13])=[O:12]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(O)c1cc(N2CCCC2=O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 148.7 %

Procedure:
A flask was charged under nitrogen with 3-bromo-5-nitro-benzoic acid (D5) (12.3 g, 50 mmol, 1 equiv), Cs2CO3 (24.4 g, 75 mmol, 1.5 equiv), tris(dibenzylideneacetone)dipalladium(0) (229 mg, 0.25 mmol, 0.005 equiv), Xantphos (433 mg, 0.75 mmol, 0.015 equiv) and dioxan (120 ml). 2-Pyrrolidin-2-one (5.7 ml, 75 mmol, 1.5 equiv) was then added via syringe and the resulting mixture was stirred at reflux for 60 h then cooled to room temperature and concentrated in vacuo. The residue was diluted with H2O and 1N aqueous NaOH solution and extracted twice with Et2O. The aqueous phase was then acidified to pH 1 and extracted three times with AcOEt. The combined organic phases were dried over MgSO4 and concentrated in vacuo to give 3-nitro-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid (A27) (9.3 g, 75%) as a pale brown solid.
Reaction SMILES: [ClH:1].[CH:2]1([N:5]2[C:14]3[C:9](=[CH:10][C:11]([F:28])=[C:12]([N:16]4[CH2:20][CH2:19][CH:18]([CH2:21][N:22](CC)[C:23](=O)[CH3:24])[CH2:17]4)[C:13]=3[CH3:15])[C:8](=[O:29])[C:7]([C:30]([OH:32])=[O:31])=[CH:6]2)[CH2:4][CH2:3]1>[OH-].[Na+]>[ClH:1].[CH:2]1([N:5]2[C:14]3[C:9](=[CH:10][C:11]([F:28])=[C:12]([N:16]4[CH2:20][CH2:19][CH:18]([CH2:21][NH:22][CH2:23][CH3:24])[CH2:17]4)[C:13]=3[CH3:15])[C:8](=[O:29])[C:7]([C:30]([OH:32])=[O:31])=[CH:6]2)[CH2:4][CH2:3]1
Reactant: CCN(CC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2C)C1)C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To 1-cyclopropyl-7-[3-(N-ethylacetamido)methyl-1-pyrrolidinyl]-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride (0.22 g) is added 5% aqueous sodium hydroxide (10 ml), and the mixture is refluxed for 24 hours. After cooling, the insoluble materials are filtered off, and the filtrate is acidified with conc. hydrochloric acid. The mixture is extracted with dichloromethane, and the aqueous layer is made alkaline with aqueous sodium hydroxide, and thereto is added t-butoxycarboxylic anhydride (200 mg). The mixture is stirred at room temperature for 30 minutes. The reaction mixture is acidified with 10% hydrochloric acid and is extracted with dichloromethane. After removing the solvent by concentration, to the resulting residue are added 10% hydrochloric acid (5 ml) and methanol (10 ml), and the mixture is heated at 70° C. for 30 minutes. After concentrating, the resulting residue is recrystallized from methanol-acetonitrile to give 1-cyclopropyl-7-(3-ethylaminomethyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride (30 mg), as yellow crystals, m.p. 267°-271° C.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][C:8]([CH2:11]O)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:13]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:13][CH2:11][C:8]1[O:9][C:10]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=2[CH:7]=1
Reactant: OCc1cc2cccc(F)c2o1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cccc2cc(CBr)oc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A mixture of (7-fluorobenzofuran-2-yl)methanol (1.38 g, 8.31 mmol), tetrabromomethane (4.41 g, 13.3 mmol) and triphenylphosphine (2.61 g, 9.97 mmol) in dichloromethane (42 mL) was stirred at 0° C. for 2 h and concentrated in vacuo to dryness. The residue was purified by column chromatography (hexanes/ethyl acetate, 49/1) to afford 2-(bromomethyl)-7-fluorobenzofuran (1.85 g, 97%) as a colorless solid: 1H NMR (300 MHz, CDCl3) 7.34-7.29 (m, 1H), 7.20-7.12 (m, 1H), 7.10-7.02 (m, 1H), 6.82-6.77 (m, 1H), 4.60 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:19][CH:20]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(NCCCCC#Cc2ccc(Cl)cc2)cc1
Solvent: CC(C)=O
Solvent: c1ccc2ncccc2c1
Product: CCOC(=O)Cc1ccc(NCCCCC=Cc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 10.0 g. ethyl 4-[6-(4-chlorophenyl)hexa-5-ynylamino]phenylacetate in 75 ml. acetone is added 1.0 ml. quinoline and 0.2 g. of palladium-on-calcium carbonate. The solution is hydrogenated at slightly above atmospheric pressure until 600 ml. hydrogen has been absorbed. The catalyst is filtered and washed with several small portions of acetone. The organic solution is diluted with 200 ml. water, the precipitate is collected, dried, and recrystallized from acetonitrile to yield the title compound as white crystals.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:4](F)=[C:5]([C:8]([F:11])=[CH:9][CH:10]=1)[C:6]#[N:7]>C(#N)C>[NH2:1][C:4]1[C:3]([Cl:2])=[CH:10][CH:9]=[C:8]([F:11])[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c(F)ccc(Cl)c1F
Reactant: N
Solvent: CC#N
Product: N#Cc1c(F)ccc(Cl)c1N
Temperature: 60 °C

Procedure:
Aqueous ammonia (d 0.880, 2 ml) was added to a solution of 3-chloro-2,6-difluorobenzonitrile (1.93 g, 11.1 mmol) in acetonitrile (10 ml), and the mixture heated to 60° C. for 16 h. The resulting brown solution was evaporated and purified by flash chromatography eluting with 5% ethyl acetate/hexane, increasing the gradient to 20% ethyl acetate/hexane, to furnish a white solid (410 mg), MS (+EI) 173/171 (M+); 1H NMR (CDCl3) 7.39 (1H, dd, J5.7, 9.0 Hz), 6.46 (1H, t, J8.7 Hz), 4.95 (2H, br. s).
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:8]=1)#[N:2].C1(P(Cl)([Cl:25])=O)C=CC=CC=1.[NH4+].[OH-]>>[Cl:25][C:4]1[C:3]([C:1]#[N:2])=[CH:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][N:5]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c[nH]c1=O
Agent: [NH4+]
Agent: [OH-]
Product: N#Cc1cc(-c2ccc(Cl)cc2)cnc1Cl
Temperature: 175 °C

Procedure:
A mixture of 3-cyano-5-(4-chlorophenyl)-2-(1H)-pyridone (2.0 grams) and phenylphosphonic dichloride (3.8 grams) was heated for 4 hours at 175° C. in an oil bath. The mixture was poured into ice water and was made alkaline by stirring with NH4OH. The resulting brownish solid product was used without further purification, yield 2.0 g., m.p. 185°-187° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:13]([O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:14](=[O:21])[C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17]Cl>C1(C)C=CC=CC=1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C:13]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[C:14]2[C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][O:21]2)=[CH:24][CH:25]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)(CCCl)C(=O)C(Br)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1(C)CCOC1=C(Oc1ccc(Cl)cc1)n1ccnc1
Temperature: 90 °C
Reaction time: 10 h
Yield: 15.9 %

Procedure:
35 g (0.5 mol) of imidazole and 70 g (0.5 mol) of potassium carbonate are dissolved in 700 ml of toluene. 93 g (0.26 mol) of 1-bromo-1-(4-chlorophenoxy)-5-chloro-3,3-dimethyl-2-pentanone in 200 ml of toluene are added to this mixture at 80° C. The reaction mixture is subsequently stirred at 90° C. for 10 hours and is cooled and the inorganic residue is filtered off with suction. The filtrate is washed with water, dried over sodium sulphate and concentrated. The residue is purified by column chromatography (silica gel: ethyl acetate/cyclohexane=3/1). 12.6 g (14.2% of theory) of (4-chlorophenoxy)-(imidazol-1-yl)-(3,3-dimethyltetrahydrofuran-2-ylidene)-methane of melting point 85°-88° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14].C(N(CC)CC)C.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27]>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:12]([C:5]1([CH2:15][CH2:16][CH3:17])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])[CH:3]=2)[S:8][CH2:7][CH2:6]1)[CH2:13][CH3:14]
Reactant: CCCC1(CCC)CCSc2ccc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCC1(CCC)CCSc2ccc(C#C[Si](C)(C)C)cc21
Temperature: 0 °C

Procedure:
A mixture of 2.04 g (6.54 mmol) of 6-bromo-4,4-dipropylthiochroman (Compound 29), 0.12 g(0.64 mmol) of copper (I) iodide and 5.4 g (54 mmol) of triethylamine was degassed using argon for 15 minutes at -78° C. To the suspension was added 1.95 g (19.8 mmol) of (trimethylsilyl)acetylene then 0.41 g (58 mmol) of bis(triphenylphosphine]palladium (II) chloride. The solution was degassed with argon for an additional 5 minutes and the resulting mixture was allowed to warm to 0° C. The tube was sealed and the mixture heated to 55° C. for 15 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([NH2:15])=[NH:14])[CH:7]=[CH:6]2.[Cl:16][C:17]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:18]=1[CH:19]=[C:20]([C:23]#[N:24])[C:21]#[N:22]>>[NH2:24][CH2:23][C:20]1[C:21]([NH2:22])=[N:14][C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)=[N:15][C:19]=1[C:18]1[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:17]=1[Cl:16]
Reactant: COc1ccc2cc(C(=N)N)ccc2c1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: COc1ccc2cc(-c3nc(N)c(CN)c(-c4ccc(Cl)cc4Cl)n3)ccc2c1

Procedure:
The title compound, MS: m/e=425.0 (M+H+), was prepared from 6-methoxy-naphthalene-2-carboxamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.F[C:12](F)(F)[C:13]([OH:15])=O.[Br:18][C:19]1[CH:24]=[C:23]([Br:25])[CH:22]=C[C:20]=1[OH:26]>>[Br:18][C:19]1[C:20]([OH:26])=[C:12]([CH:22]=[C:23]([Br:25])[CH:24]=1)[CH:13]=[O:15]
Reactant: Oc1ccc(Br)cc1Br
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1cc(Br)cc(Br)c1O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Hexamine (3.35 g, 23.92 mmol) was added portionwise to trifluoroacetic acid (25 ml) keeping the temperature below 40° C. with a water bath. 2,4-Dibromophenol was then added slowly and the reaction mixture heated at 80° C. for 31/2 hours. The reaction mixture was cooled, partially evaporated and then poured into ice/water. This mixture was stirred at ambient temperature overnight and the precipitate that formed filtered, dried and purified by chromatography (CH2Cl2 /hexane) to give the title compound (2.1 g).
Reaction SMILES: [Br:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(Cl)(=O)C(Cl)=O.ClC1N(CC([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[S:37][CH:38]=[C:39]([C:41]4[CH2:45][CH:44]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[O:43][N:42]=4)[N:40]=3)[CH2:32][CH2:31]2)=O)N=C(C(F)(F)F)C=1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[Br:1][C:2]1[N:6]([CH2:7][C:8]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[S:37][CH:38]=[C:39]([C:41]4[CH2:45][CH:44]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[O:43][N:42]=4)[N:40]=3)[CH2:32][CH2:31]2)=[O:10])[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: O=C(O)Cn1nc(C(F)(F)F)cc1Br
Reactant: O=C(Cn1nc(C(F)(F)F)cc1Cl)N1CCC(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cn1nc(C(F)(F)F)cc1Br)N1CCC(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-3-(trifluoromethyl)-1H-pyrazole-1-acetic acid (i.e. the product of Example 11, Step D) (0.12 g, 0.61 mmol) in dichloromethane (5 mL) was added N,N -dimethylformamide (1 drop) followed by oxalyl chloride (0.25 mL, 2.86 mmol). The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue containing crude acid chloride was taken up in dichloromethane (5 mL), and the solution was added dropwise to a mixture of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-1-piperidine hydrochloride (i.e. the intermediate product of Example 10, Step F) (0.15 g, 0.43 mmol) and triethylamine (0.25 mL, 1.8 mmol) in dichloromethane (5 mL) at 0 ° C. The reaction mixture was allowed to warm to room temperature, and then stirred overnight at room temperature. The mixture was then partitioned between 1.0 N aqueous hydrochloric acid solution and dichloromethane. The organic layer was washed with water, dried (MgSO4), concentrated under reduced pressure, and purified by medium-pressure liquid chromatography using ethyl acetate in hexanes as eluant to give 90 mg of the title product, a compound of the present invention, as an amorphous solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[CH2:24]([NH:28][CH:29]([CH2:34][CH2:35][S:36][CH3:37])[C:30]([O:32][CH3:33])=[O:31])[CH:25]([CH3:27])[CH3:26].O>ClCCl>[CH2:24]([N:28]([S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:9][CH:10]=1)(=[O:16])=[O:15])[CH:29]([CH2:34][CH2:35][S:36][CH3:37])[C:30]([O:32][CH3:33])=[O:31])[CH:25]([CH3:27])[CH3:26]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: COC(=O)C(CCSC)NCC(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(CCSC)N(CC(C)C)S(=O)(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 12 h

Procedure:
3.71 mmol of triethylamine and 1.8 mmol of 4-biphenylsulphonyl chloride are added at 0° C. to a solution of 1.8 mmol of the compound obtained in Step I in 15 ml of dichloromethane. The reaction mixture is brought to ambient temperature and stirred for 12 hours, and then poured into water and extracted with dichloromethane. The combined organic phases are washed with a 2N hydrochloric acid solution and then with an NaHCO3 solution, dried, filtered, and concentrated under reduced pressure. Chromatography on silica gel (dichloromethane/methanol: 20/1) allows the expected product to be isolated in the form of syrup.