Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:18])[CH:5]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH:7]([CH3:9])[CH3:8].C(N(CC)CC)C.[C:26](Cl)(=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29]>C(Cl)(Cl)Cl>[C:14]([O:13][C:11]([NH:10][CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH:4]([OH:18])[CH2:3][NH:2][C:26](=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:12])([CH3:16])([CH3:15])[CH3:17]
Reactant: CC(C)CC(=O)Cl
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)C(O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)CC(=O)NCC(O)C(CC(C)C)NC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
To a solution of the resultant compound of Example 76 (1.0 mmol) and triethyl amine (2.0 mmol) in chloroform (10 ml) cooled to 0° C. was added isovaleryl chloride (1.0 mmol) in CHCl3 (2 ml). After 3 h, the solution was washed sequentially with 10% citric acid, saturated NaHCO3, and brine. Drying and evaporating provided the desired compound.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([S:13]([N:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]([S:13]([N:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(S(=O)(=O)N(C)C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of BBr3 (1 M in CH2Cl2, 2.0 mL, 2.0 mmol) was added dropwise to a −78° C. solution of 3-methoxy-N,N,-dimethyl-benzenesulfonamide (0.15 g, 0.7 mmol) in CH2Cl2 (2 mL). The mixture was warmed to rt and stirred for 2 h, then cooled to 0° C. and quenched with saturated NaCO3. The aqueous phase was neutralized with saturated NH4Cl and extracted with EtOAc. The organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to give an oil which was directly in the next step. MS (ESI) 202 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([F:16])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[NH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[C:5]([F:16])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: NCCc1ccc(O)cc1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c(F)c(-c2ccco2)n1
Solvent: COCCOC
Product: Nc1nc(NCCc2ccc(O)cc2)c(F)c(-c2ccco2)n1

Procedure:
From trifluoromethanesulfonic acid 2-amino-5-fluoro-6-furan-2-yl-pyrimidin-4-yl ester and tyramine in DME. ES-MS m/e (%): 315 (M+H+, 100).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C@H:11]2[C:23](OC)=[O:24])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[BH4-]>>[C:1]1([C@H:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]2[CH2:23][OH:24])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Product: C[C@@H](N[C@@H]1CCNC[C@H]1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 261B (270 mg, 0.75 mmol) was added LiBH4 (15.5 mg, 0.71 mmol). The mixture was heated to reflux for 1.0 hr. HPLC showed still some starting material remaining. More LiBH4 (15.5 mg, 0.71 mmol) was added, and the mixture was heated for another 2.0 hrs. After cooling to room temperature, ice water was added, and the mixture was concentrated in vacuo to remove the THF. The aqueous residue was extracted with EtOAc (×3) and the combined extracts were dried (Na2SO4), and concentrated in vacuo. The residue was taken into 2 mL of CH2Cl2 and 2 mL of TFA was added. The mixture was stirred at room temperature for 30 min. The mixture was concentrated in vacuo, followed by drying under high vacuum overnight to afford 261C as an oil. It had an analytical HPLC retention time=0.590 min. (Chromolith SpeedROD column 4.5×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 min, 4 mL/min, monitoring at 220 nm) and a LC/MS M++1=235. This material was used directly in the next reaction step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9](Br)=[C:8]([NH2:11])[CH:7]=[CH:6][C:5]=1[Cl:12].[C:14](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([NH2:11])[C:7]([CH3:14])=[CH:6][C:5]=1[Cl:12]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c(Cl)ccc(N)c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB1OB(C)OB(C)O1
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(N)c(C)cc1Cl
Temperature: 110 °C
Reaction time: 18 h
Yield: 71.6 %

Procedure:
To a solution of 5-amino-6-bromo-2-chloro-benzoic acid methyl ester (0.5 g, 1.89 mmol) in dioxane (10 ml) and water (1 ml) was added potassium carbonate (0.784 g, 5.67 mmol), PdCl2(dppf) (0.54 g, 0.189 mmol) and trimethyl boroxine (0.276 ml, 1.985 mmol). The mixture was stirred at 110° C. for 18 hours, then cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hexanes:EtOAc 8:2) gave 0.270 g (71%) of 5-amino-2-chloro-4-methyl-benzoic acid methyl ester as a tan solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([C:15]([O:17]CC)=[O:16])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:22][CH:21]=3)[N:10]2[CH3:32])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].C(O)C>O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=[O:16])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:22][CH:21]=3)[N:10]2[CH3:32])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)c1c(-c2ccc(-c3ccccn3)cc2)n(C)n(-c2ccc(C#N)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cn1c(-c2ccc(-c3ccccn3)cc2)c(C(=O)O)c(=O)n1-c1ccc(C#N)cc1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A mixture of 2.7 g of 1-(4-cyanophenyl)-4-ethoxycarbonyl-2-methyl-3-[4-(2-pyridyl)phenyl]-2H-pyrazol-5-one, 1.8 g of potassium carbonate, 73 ml of ethanol and 8 ml of water was refluxed under heating for 9 hours. The reaction solution was cooled to room temperature, and the precipitated crystals were collected by filtration and dried under reduced pressure. The resulting crude crystals were suspended in chloroform, and the suspension was adjusted to pH 2 to 3 with dilute hydrochloric acid. The crystals were collected by filtration and dried under reduced pressure to give 1.6 g of the title compound as pale gray crystals.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)O1.Br[C:18]1[CH:19]=[CH:20][C:21]([CH3:25])=[C:22]([CH:24]=1)[NH2:23].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C:18]2[CH:19]=[CH:20][C:21]([CH3:25])=[C:22]([NH2:23])[CH:24]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(Br)cc1N
Reactant: CC1(C)OB(c2ccc(F)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(F)cc2)cc1N
Yield: 43 %

Procedure:
5.0 g (22.5 mmol) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-fluorobenzene, 1.87 mL (15 mmol) of 5-bromo-2-methylaniline, 1.73 g (1.5 mmol) of tetrakis(triphenyl phosphine)palladium (0), and 7.33 g (15 mmol) of cesium carbonate were heated under reflux for 8 hours in 150 mL of THF. After completion of the reaction, THF was distilled off under reduced pressure, and ethyl acetate was added to separate the solid by filtration. The organic layer was then washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off under reduced pressure. The resulting crude product was separated and purified using silica gel column chromatography, thereby giving 4′-fluoro-4-methylbiphenyl-3-amine (yield: 43%).
Reaction SMILES: [Cl:1][C:2]1[C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:21])[N:6]2[CH3:20].[Br:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27](Br)[CH:28]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[Br:22][C:23]1[CH:28]=[C:27]([C:10]2[C:2]([Cl:1])=[C:3]3[C:7](=[CH:8][CH:9]=2)[N:6]([CH3:20])[C:5](=[O:21])[CH2:4]3)[CH:26]=[N:25][CH:24]=1
Reactant: CN1C(=O)Cc2c1ccc(B1OC(C)(C)C(C)(C)O1)c2Cl
Reactant: Brc1cncc(Br)c1
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: COCCOC
Solvent: ClCCl
Product: CN1C(=O)Cc2c1ccc(-c1cncc(Br)c1)c2Cl
Temperature: 120 °C

Procedure:
To 4-chloro-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (525 mg, 1.71 mmol), prepared as described in Example 27a, was added 3,5-dibromopyridine (CAS#625-92-3, 1.2 g, 5.1 mmol), 1,2-dimethoxyethane (5.0 mL), and 2 M aqueous sodium carbonate (2.05 mL, 4.1 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (0.93 g, 0.10 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 3.5 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 3.55%) to furnish 5-(5-bromo-pyridin-3-yl)-4-chloro-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 336.9753 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 3.27 (a, 3H), 3.62 (s, 2H), 6.85 (d, J=8.1 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.95-8.04 (m, 1H), 8.61 (d, J=1.8 Hz, 1H), 8.70 (d, J=2.3 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:30])[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27](O)=[O:28])=[CH:21][CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:27](=[O:28])/[CH:26]=[CH:25]/[C:22]3[CH:23]=[CH:24][C:19]([CH3:30])=[CH:20][CH:21]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: Cc1ccc(/C=C/C(=O)O)cc1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3ccc(C)cc3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-p-tolyl-acrylic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:15]#[N:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[OH-:24].[Na+]>OS(O)(=O)=O>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:15]([NH2:16])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C#N)c2ccccc2Cl)CC1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)C(c1ccccc1Cl)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
4-[(2-Chloro-phenyl)-cyano-methyl]-piperazine-1-carboxylic acid tert-butyl ester (11) (1.0 g, 2.98 mmol) was dissolved in H2SO4 (5.0 mL) and allowed to stir at room temperature for 18 h. The reaction mixture was cautiously poured over ice (50 mL) and made basic with 5N NaOH (50 mL). The desired product was extracted into EtOAc (100 mL) The organic phase was concentrated to dryness yielding 0.64 g (85%) product.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:49]1[CH2:54][CH2:53][S:52](=[O:56])(=[O:55])[CH2:51][CH2:50]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:49]3[CH2:54][CH2:53][S:52](=[O:56])(=[O:55])[CH2:51][CH2:50]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: O=S1(=O)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Yield: 58 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), thiomorpholine 1,1-dioxide (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product as a light yellow solid (58%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][C:5]([S:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([C@H:33]([NH2:35])[CH3:34])=[CH:29][N:28]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[C:7]([C:8]([NH:35][C@@H:33]([C:30]2[CH:29]=[N:28][C:27]([CH3:26])=[N:32][CH:31]=2)[CH3:34])=[O:9])=[CH:6][C:5]([S:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1
Reactant: Cc1ncc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(S(=O)(=O)N3CCCC3)cc(C(=O)O)c2C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(S(=O)(=O)N3CCCC3)cc(C(=O)N[C@H](C)c3cnc(C)nc3)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction vial was charged with 2,4′-dimethyl-5-(pyrrolidin-1-ylsulfonyl)biphenyl-3-carboxylic acid (40 mg, 0.11 mmol), (R)-1-(2-methylpyrimidin-5-yl)ethanamine (20 mg, 0.14 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (106 mg, 0.28 mmol), N,N-diisopropylethylamine (39 μL, 0.22 mmol) and N,N-dimethylformamide (1.33 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by preparative HPLC to afford the compound as a light brown solid.
Reaction SMILES: C(Br)(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([C:28]#[N:29])[C:9]2[CH:10]=[CH:11][N:12]([C:15]3[C:20]([CH:21]([CH3:23])[CH3:22])=[C:19]([O:24]C)[N:18]=[C:17]([O:26]C)[N:16]=3)[C:13]=2[CH:14]=1>>[CH:21]([C:20]1[C:19](=[O:24])[NH:18][C:17](=[O:26])[NH:16][C:15]=1[N:12]1[C:13]2[CH:14]=[C:6]([CH3:5])[CH:7]=[C:8]([C:28]#[N:29])[C:9]=2[CH:10]=[CH:11]1)([CH3:23])[CH3:22]
Reactant: COc1nc(OC)c(C(C)C)c(-n2ccc3c(C#N)cc(C)cc32)n1
Agent: CC(=O)Br
Product: Cc1cc(C#N)c2ccn(-c3[nH]c(=O)[nH]c(=O)c3C(C)C)c2c1
Temperature: 70 °C
Yield: 64.9 %

Procedure:
AcBr (3 mL) was added to 6-methyl-1-(5-isopropyl-2,6-dimethoxy-pyrimidin-4-yl)-1H-indole-4-carbonitrile (470 mg, 1.40 mmol). The reaction mixture was heated at 70° C. for 6 hours. The reaction mixture was then cooled to room temperature and concentrated. The crude reaction product was purified (silica gel, 0-80% EtOAc/hexane) to give a white solid (280 mg, 65%). LC-MS shows 307.1 (M−1).
Reaction SMILES: [CH3:1]I.[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[S:21])[NH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Cl>C1COCC1>[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([S:21][CH3:1])=[N:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: S=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CSc1ncnc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
Methyl iodide (0.97 ml, 15.4 mmol) was added dropwise to a solution of 7-benzyloxy-3,4-dihydroquinazolin-4-thione (3.45 g, 12.9 mmol) in THF (13 ml) containing 1M sodium hydroxide (25.7 ml). After stirring for 30 minutes at ambient temperature, the mixture was adjusted to pH7 with 2M hydrochloric acid. After dilution with water, the solid was collected by filtration, washed with water and dried under vacuum to give 7-benzyloxy-4-methylsulphanylquinazoline (3.3 g, 92%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH3:26][CH:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[N:28]1[CH2:29][CH2:30][CH2:31][CH:27]1[CH3:26])=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Reactant: CC1CCCN1
Product: CC1CCCN1c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccccc1

Procedure:
5-(2-Methyl-pyrrolidin- 1-y1)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and 2-methylpyrrolidine. Mass spectrum (ES) MH+=405.
Reaction SMILES: F[B-](F)(F)F.[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11]([N+]#N)=[CH:10][CH:9]=1.[F:20][C:21]([F:34])([C:24]([F:33])([F:32])[C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])[CH:22]=[CH2:23]>C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:20][C:21]([F:34])([C:24]([F:32])([F:33])[C:25]([F:30])([F:31])[C:26]([F:27])([F:29])[F:28])/[CH:22]=[CH:23]/[C:11]1[CH:12]=[CH:13][C:8]([S:7]([F:19])([F:18])([F:17])([F:16])[F:6])=[CH:9][CH:10]=1
Reactant: C=CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)/C=C/c1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.8 %

Procedure:
Palladium(II) acetate (0.5 mg, 0.002 mmol) was added to a solution of 1 (15.0 mg, 0.0472 mmol) and 3,3,4,4,5,5,6,6,6-nonafluorohex-1-ene (8.9 mg, 0.089 mmol) in 0.44 g of 95% aqueous ethanol. The reaction mixture was stirred at room temperature for 1 d and filtered through a pad of Celite 545. Removal of the solvent gave a pale yellow oil which was purified by SiO2 column chromatography with hexane to give 7a as colorless oil (17.1 mg; 81%): IR (ATR): {tilde over (v)}=2918, 2849, 1663, 1234, 1134, 844 cm−1. MS (GC, EI): m/z=448 [M+], 429 [M+-F], 302 [M+-SF6], 279 [M+-C3F7], 152 [M+-C3F12S]. 1H NMR (500 MHz, CDCl3): δ=7.80 (d, J=8.7 Hz, 2H), 7.57 (d, J=8.7 Hz, 2H), 7.20 (d, J=16.2 Hz, 1H), 6.30 (dt, J=16.2, 12.0 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3): δ=154.7 (C), 137.7 (CH), 136.5 (C), 127.8 (2CH), 126.7 (2CH), 117.7 (CH) ppm. 19F NMR (470 MHz, CDCl3): δ=83.4 (quint, J=150 Hz, 1 F), 62.6 (d, J=150 Hz, 4 F), −81.0 (s, 3 F), −112.0 (s, 2 F), −124.0 (s, 2 F), −125.7 (s, 2 F) ppm.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([I:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.IC1C=C(NC(=O)C2C=CC(N3CCOCC3)=NC=2)C=CC=1C>>[I:16][C:11]1[CH:10]=[C:9]([NH:8][C:6]([C:5]2[CH:17]=[CH:18][C:2]([N:31]3[CH2:32][CH2:33][CH:28]([C:24]4[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:34])[F:35])[CH:23]=4)[CH2:29][CH2:30]3)=[N:3][CH:4]=2)=[O:7])[CH:14]=[CH:13][C:12]=1[CH3:15]
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1I
Reactant: FC(F)(F)c1cccc(C2CCNCC2)c1
Agent: Cc1ccc(NC(=O)c2ccc(N3CCOCC3)nc2)cc1I
Agent: Cl
Product: Cc1ccc(NC(=O)c2ccc(N3CCC(c4cccc(C(F)(F)F)c4)CC3)nc2)cc1I

Procedure:
4-(3-Trifluoromethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (3-iodo-4-methyl-phenyl)-amide was prepared from 6-chloro-N-(3-iodo-4-methyl-phenyl)-nicotinamide and 4-(3 trifluoromethyl-phenyl)piperidine hydrochloride in a manner similar to the one described in the synthesis of N-(3-iodo-4-methyl-phenyl)-6-morpholin-4-yl-nicotinamide above. The product was isolated after silica gel column purification with 20-40% EtOAc in hexanes. HRMS m/z calcd for C25H23N3OF3I [M+H]+: 566.0911. Found: 566.0910. START
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:25]N)[CH:22]=[CH:23][CH:24]=1>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:22]([C:3]([S:4][C:5]3[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)=[C:2]([CH3:15])[NH:25]2)=[CH:23][CH:24]=1
Reactant: COc1cccc(NN)c1
Reactant: CC(=O)CSc1cccc(CC(=O)O)c1
Agent: Cl
Product: COc1ccc2c(Sc3cccc(CC(=O)O)c3)c(C)[nH]c2c1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: [3-(2-oxo-propylsulfanyl)-phenyl]-acetic acid and 3-methoxyphenylhydrazine hydrochloride.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:17]3[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]3)[S:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(-c2csc(Br)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(F)cc3)cs2)CC1
Yield: 52 %

Procedure:
A solution of 2-bromo-4-(4-fluorophenyl)-1,3-thiazole (4.49 g, 17.4 mmol), tert-butyl piperazine-1-carboxylate (6.48 g, 34.8 mmol) and potassium carbonate (2.4 g, 17.4 mmol) in dimethylformamide (55 ml) was stirred at 120° C. for 8 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the desired product (3.29 g, 52%) as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.C[O-].[Na+].[C:16](O)(=[O:18])C>C(OCC)C>[Cl:12][C:4]1[N:3]=[C:2]([O:18][CH3:16])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=1
Reactant: CC(=O)O
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: COc1nc(Cl)cc(N)c1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
2,6-Dichloro-3-nitro-pyridin-4-ylamine (733 mg, 3.52 mmol) was placed in a 48 mL pressure vessel fitted with a magnetic stir bar and treated with NaOMe (7.05 mL, 3.52 mmol, 0.5 M in MeOH). The vessel was sealed and heated to 100° C. for 2 h. The cooled mixture was treated with acetic acid (0.25 mL) in diethyl ether (50 mL). The precipitate was filtered and washed with ether, and the filtrate was concentrated in vacuo. The residue was purified on a 40-g SEPRA Si 35 SPE column (Flow rate=25 mL/min; Eluent=EtOAc-hexanes, 1:19 for 15 min, then 1:19 to 1:4 over 40 min) to yield 6-chloro-2-methoxy-3-nitro-pyridin-4-ylamine as a pale yellow solid. 1H-NMR (400 MHz, CDCl3) δ: 6.36 (s, 1H), 6.14 (br. s., 2H), 4.04 (s, 3H).