Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].Cl.[CH3:13][O:14][C:15](=[O:26])[C@@H:16]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[NH2:17].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:13][O:14][C:15](=[O:26])[C@@H:16]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)[NH:17][C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:11]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)[C@H](N)Cc1ccc(O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2,6-dichlorobenzoylchloride (0.68 mL) in CH2Cl2 (5 mL) was added to a solution of an ice-cold solution of D-tyrosine methyl ester HCl salt (1.0 g) and DIEA (2.26 mL) in CH2Cl2 (15 mL). The mixture was stirred at room temperature for 24 h. The mixture was diluted with CH2Cl2 (50 mL) and washed successively with H2O, 1 N HCl and brine. The organic layer was dried (MgSO4) and evaporated, and the residue was recrystallized from EtOAc and hexanes to yield 1.46 g of N-(2,6-dichlorobenzoyl)-D-tyrosine methyl ester. ESMS: m/z 369 (MH+).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2I)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:30][CH:31]1[CH2:36][CH2:35][CH:34](B(O)O)[CH:33]([CH3:40])[NH:32]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2[C:34]2[C:33]([CH3:40])=[N:32][C:31]([F:30])=[CH:36][CH:35]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1I
Reactant: CC1NC(F)CCC1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-(6-chloro-4-iodo-3-pyridinyl)-N,2-dimethylpropanamide (200 mg, 0.363 mmol), 2-fluoro-6-methylpiperidine-5 boronic acid (73 mg, 0.472 mmol), sodium carbonate solution (0.4 mL, 2M), tetrakistriphenylphosphinepalladium (4 mg, 0.00363 mmol) in dioxan (2 mL) were heated together in the microwave at 110° C. for 30 minutes. The mixture was partitioned between EtOAc and sat NaHCO3 solution. Aqueous layer extracted with EtOAc×3. Combined extracts dried and evaporated. Residue purified on a 12+M horizon column eluting with Pet Et2O to 60% EtOAc/Pet Et2O, Solvent evaporated under reduced pressure to afford the title compound in quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:5].[Cl:21][CH2:22][C:23](Cl)=O>C(O)(=O)C>[Cl:21][CH2:22][C:23]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:4](=[O:5])[C:3]2[C:2](=[CH:17][C:16]([N+:18]([O-:20])=[O:19])=[CH:15][CH:14]=2)[N:1]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)Nc1ccccc1Cl
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Product: O=c1c2ccc([N+](=O)[O-])cc2nc(CCl)n1-c1ccccc1Cl
Yield: 56.4 %

Procedure:
Prepared according to Procedure B with 1o (500 mg, 1.71 mmol) and chloroacetyl chloride (0.41 mL, 5.14 mmol) in acetic acid (10 mL). Purified by extraction from aqueous K2CO3, followed by two chromatographies in CH2Cl2 to afford 338 mg of a yellow oil (56%). 1H NMR (CDCl3) δ: 8.64 (d, J=2.2 Hz, 1H); 8.48 (d, J=8.8 Hz, 1H); 8.32 (dd, J=2.2, 8.7 Hz, 1H); 7.66 (dd, J=2.5, 6.0 Hz, 1H); 7.52-7.59 (m, 3H); 4.41 (d, J=12 Hz, 1H), 4.10 (d, J=12 Hz, 1H). MS (ES): m/z 350.0 (M+)
Reaction SMILES: [I:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[C:9]2[CH:8]=[C:7]3[O:22][CH2:23][CH2:24][O:25][C:6]3=[CH:5][C:4]=2[N:3]=1.[BH4-].[Na+]>CO>[I:1][C:2]1[C:11]([CH2:12][OH:13])=[C:10]([CH2:14][N:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)[C:9]2[CH:8]=[C:7]3[O:22][CH2:23][CH2:24][O:25][C:6]3=[CH:5][C:4]=2[N:3]=1
Reactant: CN1CCN(Cc2c(C=O)c(I)nc3cc4c(cc23)OCCO4)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCN(Cc2c(CO)c(I)nc3cc4c(cc23)OCCO4)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 3-necked 2-L round-bottom flask is equipped with an overhead mechanical stirrer and nitrogen flow is maintained. The flask is charged with 7-iodo-9-(4-methylpiperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-carbaldehyde (105 g, 232 mmol), as prepared above, as a suspension in 700 mL of methanol. The mixture is cooled to 0° C., then sodium borohydride (8.76 mmol) is added in three portions over 15 min. The mixture is allowed to warm to ambient temperature and stirred for 2 hours. The solvent is mostly removed in vacuo and the resultant residue is treated with 2.5 L of water and extracted with methylene chloride (4×1.5 L). The combined organic layers are washed with brine (2.5 L), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resultant solid residue is successively treated with 300 mL of methylene chloride and 300 mL of MeOH-EtOAc (1:1). The mixture is swirled at 0° C. for 30 min. The precipitate is filtered by suction, washed with 500 mL of hexane and dried in vacuo at 30° C. yielding [7-iodo-9-(4-methylpiperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-yl]-methanol as an off-white powder: mp 201-203° C. (dec.). 1H NMR (CDCl3, 200 MHz): d 2.26 (s, 3H), 2.62 (m, 8H), 4.02 (s, 2H). 4.39 (s, 4H), 4.93 (m, 2H), 6.05 (br. s, 1H), 7.49 (s, 1H), 7.51 (s, 1H). HRMS (EI+): Calculated for C18H22N3O 3: 455.0706. Found: 455.0699.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[NH2:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=[O:6].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]=[C:27]=S)[C:21]=1[C:29]([F:32])([F:31])[F:30].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:5]([C:4]2[CH:15]=[CH:16][C:17]3[NH:18][C:27]([NH:26][C:22]4[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[C:21]=4[C:29]([F:32])([F:30])[F:31])=[N:1][C:2]=3[CH:3]=2)=[O:6])=[CH:13][CH:12]=1
Reactant: FC(F)(F)c1c(Cl)cccc1N=C=S
Reactant: Nc1ccc(C(=O)Nc2ccc(Br)cc2)cc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Br)cc1)c1ccc2[nH]c(Nc3cccc(Cl)c3C(F)(F)F)nc2c1

Procedure:
Prepared analogously to example 106a from 3,4-diamino-N-(4-bromo-phenyl)-benzamide, 1-chloro-3-isothiocyanato-2-trifluoromethyl-benzene and DCC in DMF.
Reaction SMILES: [CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=O)[CH:12]=2)[N:7]([CH3:17])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:18][C@@H:19]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[C:36]([F:41])[CH:35]=1)[C@H:20]([OH:32])[CH2:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH3:31])[CH:25]=1>C(Cl)Cl.O1CCCC1>[CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([NH:18][C@@H:19]([CH2:33][C:34]3[CH:35]=[C:36]([F:41])[CH:37]=[C:38]([F:40])[CH:39]=3)[C@H:20]([OH:32])[CH2:21][NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH3:31])[CH:25]=3)=[O:16])[CH:12]=2)[N:7]([CH3:17])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCc1cn(C)c2ccc(C(=O)O)cc12
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCc1cn(C)c2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc12
Temperature: 40 °C
Reaction time: 18 h
Yield: 31.1 %

Procedure:
To a mixture of 3-Butyl-1-methyl-1H-indole-5-carboxylic acid (0.15 g) in methylene chloride (5 mL) and tetrahydrofuran (10 mL) was added 1,1-carbonyldiimidazole (0.105 g). The mixture was stirred at 40° C. at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.2 g) in methylene chloride (5 mL) was added. The mixture was stirred at 40° C. for 18 h then poured into methylene chloride (50 mL). The mixture was washed with water then brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using 85:10:5 (methylene chloride: hexanes: methanol) as eluent to give 0.102 g of the title compound: MS (ESI+) for C33H39F2N3O2 m/z 547.9 (M+H)+.
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]Br>C1COCC1>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:2]([CH3:4])([CH3:3])[C:1]#[N:5]
Reactant: BrCc1ccccc1Br
Reactant: CC(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C#N)Cc1ccccc1Br
Reaction time: 0.33 h
Yield: 99.7 %

Procedure:
To a solution of isobutyronitrile (3.58 g, 52 mmol) in dry THF (30 mL) was added LiHMDS (1.0 M in THF) (80 mL, 80 mmol) at 0° C., stirred for 20 min, and to this solution was added 1-bromo-2-(bromomethyl)benzene (10 g, 40 mmol) in THF (70 mL). After 3 h at room temperature, the reaction mixture was quenched with saturated NH4Cl solution, extracted with EtOAc (2×), the combined organics were washed with H2O, brine, dried over Na2SO4, filtered and concentrated to give 9.5 g (99%) of Intermediate 6A as red liquid. 1H NMR (400 MHz, CDCl3) δ 7.57-7.60 (2H, m), 7.30-7.34 (1H, m), 7.12-7.17 (1H, m), 3.08 (2H, s), 1.4 (6H, s) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1.C(N(C(C)C)CC)(C)C.[CH3:31][O:32][CH2:33]/[CH:34]=[CH:35]/[C:36](Cl)=[O:37].C(=O)(O)[O-].[Na+]>>[Br:21][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:36](=[O:37])[CH:35]=[CH:34][CH2:33][O:32][CH3:31])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][CH:18]=1
Reactant: COC/C=C/C(=O)Cl
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COCC=CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Reaction time: 1.5 h

Procedure:
To a solution of 1.0 g (2.95 mmol) of of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile and 0.57 g (4.42 mmol) of diisopropylethyl amine at 0° C. with stirring was added 0.43 g (3.24 mmol) of 4-methoxycrotonyl chloride. After 1.5 hr at 0° C., the mixture was poured into a saturated solution of sodium bicarbonate and then extracted with ethyl acetate. The organic solution was dried over magnesium sulfate and the sovent was removed. The residue was recrystallized from 1-butanol giving 1.3 g of 4-Methoxy-but-2-enoic acid [4-(3-bromo-phenylamino)-3-cyano-quinolin-6-yl]-amide as a yellow solid: mass spectrum (electrospray, m/e,): M+H 436.4, 438.9.
Reaction SMILES: C([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=[C:13]([NH:27][C:28](=[O:30])[CH3:29])[C:12]=2[N:11]2[CH2:31][CH2:32][N:33]([CH3:36])[C:34](=[O:35])[C:10]=12)C1C=CC=CC=1.[CH3:37][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>CN(C=O)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:15]2[C:16](=[O:18])[C:17]3[C:9]([OH:8])=[C:10]4[C:34](=[O:35])[N:33]([CH3:36])[CH2:32][CH2:31][N:11]4[C:12]=3[C:13]([N:27]([CH3:37])[C:28](=[O:30])[CH3:29])=[N:14]2)=[CH:21][CH:22]=1
Reactant: CC(=O)Nc1nn(Cc2ccc(F)cc2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1nn(Cc2ccc(F)cc2)c(=O)c2c(O)c3n(c12)CCN(C)C3=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-[10-(benzyloxy)-2-(4-fluorobenzyl)-8-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazin-4-yl]acetamide (0.13 g, 0.27 mmol) in anhydrous DMF (5 mL), a solution of lithium bis(trimethylsilyl)amide (0.4 mL, 0.4 mmol; 1 M in THF) was added. The mixture was stirred at room temperature for 10 minutes, treated with iodomethane (25 μL, 0.40 mmol), and stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum and the residue partitioned between chloroform and dilute hydrochloric acid. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The title compound was debenzylated in accordance with the procedure set forth in Example 62, step 12.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)#[N:4].CC1C=CC(S([O-])(=O)=O)=CC=1.[CH3:29][C@@H:30](O)[CH2:31][C@H:32]([OH:34])[CH3:33]>CN(C)C=O>[OH:34][C@@H:32]([CH3:33])[CH2:31][C@@H:30]([CH3:29])[O:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]#[N:4])=[CH:10][CH:9]=2)=[CH:12][CH:13]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: C[C@@H](O)C[C@@H](C)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](O)C[C@@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.68 g of 55% sodium hydride was mixed with 10 ml of dimethylformamide. A solution of 2.50 g of 4-(4'-cyanophenyl)phenol in 5 ml of dimethylforamide was added dropwise thereto under ice-cooling. Then the obtained mixture was stirred at room temperature for one hour. A solution of 3.7 g of monotosylate of (R,R)-2,4-pentanediol in 5 ml of dimethylforamide was added dropwise thereto and the obtained mixture was stirred at 80° C. for two hours. After cooling, the reaction mixture was poured into 100 ml of ice-water and extracted with diethyl ether. After washing with water, drying and desolvating, the obtained residue was purified by silica gel column chromatography with the use of a mixture of n-hexane and ethyl acetate (3:2) as a developing solvent. Thus 1.8 g of (R,S)-4-[4'-(3"-hydroxy-1"-methylbutoxy)phenyl]benzonitrile was obtained.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11](O)[C:10]=1[N+:20]([O-:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(Cl)([Cl:31])=O)C=CC=CC=1.CCCCCC>C(OCC)C>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([Cl:31])[C:10]=1[N+:20]([O-:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1c(NCc2ccccc2)cc(C(F)(F)F)nc1O
Solvent: CCCCCC
Solvent: CCOCC
Product: O=[N+]([O-])c1c(NCc2ccccc2)cc(C(F)(F)F)nc1Cl
Temperature: 100 °C
Yield: 92 %

Procedure:
4-Benzylamino-3-nitro-6-trifluoromethyl-pyridin-2-ol (61.7 gm 197 mmol) was added to phenylphosphonic dichloride (180 mL) and heated to 100° C. in an oil bath, under N2 overnight. The starting material dissolved on heating to give a light yellow solution. The mixture was then quenched on to ice water (600 gm of ice+100 mL water) to give a pale yellow solid. Filtered off and washed the solid well with water. The solid was dissolved in ethyl acetate (600 mL) and washed with aqueous sodium hydrogen carbonate solution (10% w/v) until there was no further effervescence and the pH of the aqueous washings were basic. The organic layer was dried over sodium sulphate, filtered and evaporated to give a dirty yellow solid. The solid was then dissolved in diethyl ether. To this was then added n-hexane until the solution was cloudy. Within a few minutes a thick flocculent solid had formed, which was then filtered off, washed with n-hexane and dried to give the title compound (60.59 gm 92% yield).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][N:4]=1)[NH2:2].[C:13]([C:21]([C:27]#[N:28])=[C:22](SC)[S:23][CH3:24])(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C.O>[CH3:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([N:1]2[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:21]([C:27]#[N:28])[C:22]([S:23][CH3:24])=[N:2]2)=[N:4][CH:5]=1)(=[O:10])=[O:11]
Reactant: CS(=O)(=O)c1ccc(NN)nc1
Reactant: CSC(SC)=C(C#N)C(=O)c1ccccc1
Solvent: O
Solvent: CCO
Product: CSc1nn(-c2ccc(S(C)(=O)=O)cn2)c(-c2ccccc2)c1C#N
Temperature: 25 °C
Yield: 8.7 %

Procedure:
A mixture of the 2-hydrazino-5-methylsulfonyl pyridine (180 mg, 0.81 mmol) and 1-benzoyl-2,2-bis(methylthio)-1-cyano ethene (201 mg, 0.81 mmol) in anhydrous ethanol was refluxed overnight. The resulting solution was cooled to room temperature, diluted with water (25 ml) and extracted with ethyl acetate (2×25 ml). The ethyl acetate layer was dried with sodium sulfate and concentrated to give crude product. Chromatography of the mixture led to the isolation of the desired product (26 mg, 9%) in the form of a white solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[OH:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25]>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:14][N:15]1[C:16](=[O:25])[C:17]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]2[C:19]1=[O:20]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C1c2ccccc2C(=O)N1O
Product: O=C1c2ccccc2C(=O)N1Oc1cccc(C(F)(F)F)c1
Yield: 88 %

Procedure:
3-Trifluoromethylphenylboronic acid (380 mg, 2.0 mmol) was subjected to the representative coupling procedure with N-hydroxyphthalimide (NHP) as outlined above (method 1). Flash chromatographic purification over silica (40% EtOAc in hexanes) afforded 10 as a white solid (270 mg, 88%). 1H-NMR (500 MHz, CDCl3) δ 7.34-7.38 (m, 1H), 7.40-7.45 (m, 2H), 7.47 (m, J=0.9, 8.1 Hz, 1H), 7.82-7.87 (m, 2H), 7.92-7.97 (m, 2H); 13C-NMR (125 MHz, CDCl3) δ 111.6, 117.8, 118.1, 121.4, 122.3, 124.2, 128.8, 130.5, 132.2, 135.1, 159.0, 162.8; LC-MS 309 m/z [MH]+, C15H9F3NO3 requires 309.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]=1.[N:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[C:26]=[O:27]>C(Cl)Cl>[C:28]([NH:25][C:26]([NH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:4]=1)=[O:27])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)N=C=O
Reactant: NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Solvent: ClCCl
Product: CC(C)(C)NC(=O)NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
A mixture of the product from Example 42 (13.8 mg, 0.040 mmol) and 2-isocyanato-2-methylpropane (5.2 μL, 0.044 mmol) in DCM (0.4 mL) was stirred at room temperature for 2 hours, concentrated, and chromatographed (5% MeOH/DCM) to give 12.1 mg of the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 11.58-11.61 (bs, 1H), 8.32 (dd, J=7.8, 1.4 Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.98 (ddd, J=8.0, 7.2, 1.5 Hz, 1H), 7.90 (ddd, J=7.9, 7.2, 1.3 Hz, 1H), 7.41 (s, 4H), 6.19 (t, J=5.8 Hz, 1H), 5.81 (s, 1H), 4.50 (d, J=5.8 Hz, 2H), 3.68 (s, 2H), 1.22 (s, 9H); MS (ESI−) M/Z 440 (M−H)−, 486 (M+COOH)−.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:18][CH:19]=[C:20]([C:22](=[O:35])[C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)[N:21]=2)=[CH:13][CH:12]=1)C(=O)OC(C)(C)C.[ClH:36]>C(Cl)Cl.O1CCOCC1>[ClH:36].[CH3:1][NH:2][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[S:18][CH:19]=[C:20]([C:22]([C:23]3[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=3)=[O:35])[N:21]=2)=[CH:15][CH:16]=1
Reactant: COc1cc(C(=O)c2csc(-c3ccc(CN(C)C(=O)OC(C)(C)C)cc3)n2)cc(OC)c1OC
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNCc1ccc(-c2nc(C(=O)c3cc(OC)c(OC)c(OC)c3)cs2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
At 0° C., to a solution of 71a (60 mg) in 5 mL CH2Cl2 was added a solution of HCl in 1,4-dioxane (4 N, 2 mL) and stirred at RT for overnight. The precipitate (2s-HCl) was filtered and washed with diethyl ether. Yield: 81.3%. 1H NMR (500 MHz, CDCl3) δ 10.0 (s, 1H), 8.29 (s, 1H), 8.05 (d, 2H, J=6.0 Hz), 7.74 (s, 2H), 7.72 (d, 2H, J=6.0 Hz), 4.15 (s, 2H), 3.99 (s, 3H), 3.96 (s, 6H), 2.61 (s, 3H). MS (ESI) m/z 399.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:28]([NH:32][S:33]([C:36]1[S:37][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:40]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[S:37][C:38]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=[C:10]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=4)[N:9]=3)[CH:3]=2)=[CH:39][CH:40]=1)(=[O:34])=[O:35])([CH3:31])([CH3:29])[CH3:30]
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)s1

Procedure:
N-tert-Butyl-5-{3-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.3) (0.45 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.41 g, 1.2 mmol) according to the general procedure VI. Obtained as a light brown solid (0.44 g), which was subsequently deprotected.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1.C([O-])(=[O:18])C.[NH4+]>C(O)=O.O>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:6]1[CH:5]=[CH:4][NH:3][C:2](=[O:18])[CH:7]=1
Reactant: Clc1cc(OCc2ccccn2)ccn1
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: O=CO
Solvent: O
Product: O=c1cc(OCc2ccccn2)cc[nH]1
Yield: 82.9 %

Procedure:
2-Chloro-4-(pyridin-2-ylmethoxy)pyridine (4.10 g, 18.5 mmol) and ammonium acetate (7.21 g, 92.3 mmol) were heated to 110° C. in a mixture of formic acid (20 mL) and water (20 mL) for 5 days. The mixture was concentrated to remove most of the liquid and then adjusted to pH 8 with NaHCO3 solution. The resulting solid was filtered off to provide the title compound (3.1 g, 83%) as a white solid: ESI MS m/z 203 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:24]([CH3:25])=[C:23]([CH:26]=[CH:27][C:28](=[O:30])[CH3:29])[C:22]([CH3:31])=[C:21]([CH3:32])[C:20]=2[OH:33])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:19]2[C:24]([CH3:25])=[C:23]([CH:26]=[CH:27][C:28](=[O:30])[CH3:29])[C:22]([CH3:31])=[C:21]([CH3:32])[C:20]=2[OH:33])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCCCC(c1ccc(F)cc1)c1c(C)c(C=CC(C)=O)c(C)c(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)C=Cc1c(C)c(C)c(O)c(C(CCCCCC(=O)O)c2ccc(F)cc2)c1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.4 %

Procedure:
To a solution of ethyl 7-(4-fluorophenyl)-7-[2-hydroxy-5-(3-oxobutenyl)-3,4,6-trimethylphenyl]heptanoate (0.95 g) in tetrahydrofuran (15 ml) was added aqueous 1N sodium hydroxide (5 ml) and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure and the residue was acidified by addition of 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed in turn with water and saturated saline and dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from acetonitrile to obtain 7-(4-fluorophenyl)-7-[2-hydroxy-5-(3-oxobutenyl)-3,4,6-trimethylphenyl]heptanoic acid (0.85 g) (Compound 41). The physical properties and spectrum data thereof are shown in Tables 3 and 4.