Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N([O-])=O.[Na+].C1C=CN=CC=1.[FH:22]>>[F:22][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: F
Reactant: COC(=O)c1cncc(N)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)c1cncc(F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a stirring solution of 243 mg (1.6 mmol) of methyl 5-aminonicotinate in 5 mL of HF-pyridine at 0° C. was added 119 mg (1.72 mmol) of NaNO2. The mixture was stirred at 0° C. for 30 min. and at 50° C. for 1 h. The reaction was quenched by ice and sat. NaHCO3 solution. The aqueous layer was extracted with CHCl3, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (1% MeOH/CHCl3) provided 139 mg of methyl 5-fluoronicotinate as a yellow solid in 56% yield.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9][CH2:8]1.[CH3:28][NH:29][CH2:30][CH2:31][CH3:32]>CO>[CH3:27][N:13]([C@H:10]1[CH2:11][CH2:12][C@H:7]([C:6]#[C:5][CH2:4][CH2:3][CH2:2][N:29]([CH3:28])[CH2:30][CH2:31][CH3:32])[CH2:8][CH2:9]1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: CN([C@H]1CC[C@H](C#CCCCI)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCCNC
Solvent: CO
Product: CCCN(C)CCCC#C[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
320 mg (corresponds to 0.59 mmol) of crude trans-N-[4-(5-Iodo-pent-1-ynyl)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide in 6 ml MeOH was treated with 0.6 ml (5.93 mmol) of N-methylpropylamine. The reaction was stirred overnight at 65° C. and partitioned between aqueous 1N NaOH /Et2O (3×), the organic phases were dried over Na2SO4 and evaporated. Purification by flash column chromatography on silica gel (CH2Cl2, then CH2Cl2/MeOH 95:5 to 9:1) gave 128 mg (47% over two steps) of trans-N-Methyl-N-{4-[5-(methyl-propyl-amino)-pent-1-ynyl]-cyclohexyl}-4-trifluoromethyl-benzenesulfonamide, MS: 459 (MH+). The following compounds can be obtained in analogy:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([I:9])=[CH:4][N:3]=1.[S-:10][C:11]#[N:12].[K+].C(O)=O>O>[Cl:1][C:2]1[N:7]=[C:6]([S:10][C:11]#[N:12])[C:5]([I:9])=[CH:4][N:3]=1
Reactant: N#C[S-]
Reactant: Clc1ncc(I)c(Cl)n1
Agent: [K+]
Solvent: O=CO
Solvent: O
Product: N#CSc1nc(Cl)ncc1I
Temperature: 20 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
Into a 300-ml four-necked flask fitted with a thermometer and a stirrer were charged 35.0 g of 2,4-dichloro-5-iodopyrimidine, 15.0 g of potassium thiocyanate, and 150 ml of formic acid. This reaction mixture was stirred at room temperature (20° C.) for 3 hours. After completion of the reaction, the reaction mixture was poured into a large volume of water and the resulting precipitate was filtered off and dried to obtain crude crystals. Then, these crystals were recrystallized from toluene to obtain 28.5 g (75.4% yield) of 2-chloro-5-iodo-4-thiocyanopyrimidine, m.p. 185°-186.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:10][C:11](=O)[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:7][CH:8]=1.CS(O)(=O)=O.[OH-].[Na+].C(OC)(C)(C)C>C(Cl)Cl>[C:14]1([CH2:13][CH2:12][C:11]2[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[S:9][CH:10]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(SCC(=O)CCc2ccccc2)c1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: COc1ccc2c(CCc3ccccc3)csc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The product from Step C (8.495 grams), dissolved in dry CH2Cl2 (85 mL) was added dropwise to a 0° C. CH2Cl2 solution (34 mL) of methanesulfonic acid (17 mL). The reaction was kept at 0° C. for 20 minutes, then briefly warmed to ambient temperature. The reaction was rapidly poured into a vigorously stirred cold mixture of excess 5N NaOH and methyl tert-butyl ether. The organic was dried over magnesium sulfate and filtered. Concentration and chromatography over silica gel (5:1 hex/CH2Cl2) gave the title compound as a clear oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[C:24]([C:26]([NH:28][C:29]4[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=4[F:36])=[O:27])[CH:23]=[CH:22][C:21]=3[F:37])[CH:16]=[CH:15][N:14]=2)[NH:10][CH:9]=1)=[O:7].C(N(CC)C(C)C)(C)C.Br[CH2:48][C:49]([O:51][CH3:52])=[O:50].O>CN(C=O)C>[F:37][C:21]1[CH:22]=[CH:23][C:24]([C:26]([NH:28][C:29]2[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=2[F:36])=[O:27])=[CH:25][C:20]=1[O:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([C:11]2[NH:10][CH:9]=[C:8]([C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][CH2:48][C:49]([O:51][CH3:52])=[O:50])=[O:7])[CH:12]=2)[CH:18]=1
Reactant: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCCCN)c[nH]4)c3)c2)c1
Reactant: COC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CNCCCNC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a stirred solution of N-(3-aminopropyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide (100 mg, 0.20 mmol) and N,N-diisopropylethylamine (52 mg, 0.40 mmol) in 10 ml of anhydrous DMF was added methyl bromoacetate (30 mg, 0.20 mmol). The mixture was stirred at room temperature for 50 minutes and poured into 100 ml of water with vigorous stirring. The precipitates were filtered and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 2˜3% of MeOH in CHCl3 to afford methyl ({3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]propyl}amino)acetate as white solid. Yield: 40 mg, 35%.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[Na].Br[C:8]1[N:15]=[C:14]([NH2:16])[CH:13]=[C:12]([NH2:17])[C:9]=1[C:10]#[N:11]>C1(C)C=CC=CC=1>[NH2:17][C:12]1[C:9]([C:10]#[N:11])=[C:8]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:15]=[C:14]([NH2:16])[CH:13]=1
Reactant: N#Cc1c(N)cc(N)nc1Br
Reactant: CCCCO
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCCCOc1nc(N)cc(N)c1C#N
Temperature: 150 °C

Procedure:
A heavy walled, sealable tube suitable for microwave heating was charged with 3 mL of n-butanol and 40 mg (1.7 mmol) of sodium. The mixture was stirred until all of the sodium had reacted, then 212 mg (1.00 mmol) of 2-bromo-4,6-diaminonicotinonitrile was added. The tube was sealed, and the mixture was heated with a microwave apparatus at 150° C. for 10 minutes then cooled and poured into 10 mL of toluene. The solvents were removed under reduced pressure, then the residue was partitioned between 2 mL of saturated NaHCO3(aq.) solution and 10 mL of toluene. This was concentrated again under reduced pressure, and the residue was taken up in 5 mL of water, then extracted with ethyl acetate (1×10 mL, then 2×5 mL). The combined ethyl acetate layers were back extracted with brine (1×5 mL), dried over MgSO4, filtered, and concentrated to a yellow solid. This was purified via silica gel chromatography, eluting with 50% ethyl acetate/hexanes to provide a white solid. 1H NMR (300 MHz, d6-DMSO) δ 6.19 (s, 2H), 6.14 (s, 2H), 5.31 (s, 1H), 4.18 (t, 2H, J=6.6 Hz), 2.50 (m, 1H), 1.62 (m, 2H), 1.38 (m, 2H), 0.92 (m, 3H, J=7.1 Hz); MS (ESI) m/e=151 (M−Bu+H)+, 207 (M+H)+, 205 (M−H)−.
Reaction SMILES: B.COC(=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[C:12]([N+:14]([O-])=O)[CH3:13].[BH4-].[Na+].C1C[O:23][CH2:22]C1>>[NH2:14][CH:12]([CH3:13])[CH2:11][C:6]1[CH:5]=[C:10]([CH:9]=[CH:8][CH:7]=1)[CH2:22][OH:23]
Reactant: COC(=O)c1ccccc1C=C(C)[N+](=O)[O-]
Reactant: C1CCOC1
Agent: B
Agent: [BH4-]
Agent: [Na+]
Product: CC(N)Cc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In an oven-dried flask under nitrogen atmosphere was placed 12.15 mL (12.15 mmol) of 1.0 M borane in THF. This was chilled in an ice bath. A solution of 596 mg (2.7 mmol) of 3 (2 nitro 1 propenyl)benzoic acid-methyl ester in 10 mL dry THF was added to the stirred solution via syringe. Solid sodium borohydride (51.3 mg, 1.35 mmol) was then added to the mixture quickly. The mixture was stirred in the ice bath an additional 5 minutes, then at room temperature for 15 minutes The yellow color faded to colorless after about 5 minutes at room temperature. The solution was then heated at a gentle reflux under nitrogen overnight. The reaction mixture was cooled to room temperature and quenched by dropwise addition of 500 mL of water, then reheated at a gentle reflux for 2 hours. The reaction mixture was again cooled to room temperature and filtered and the residue was washed with water. The combined filtrate and washings were then basified to pH 14 with KOH pellets. Methylene chloride was used to extract the product, with the extraction being repeated 3 times (3x5ml). The solution was dried with sodium sulfate, and volatile materials were removed with a rotary evaporator. The crude amine weighed 273 mg (57%). It was carried on without purification.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)O.[NH2:19][C:20]([NH2:22])=[NH:21]>C(O)C>[NH2:21][C:20]1[NH:22][C:10](=[O:12])[CH:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:19]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CCO
Product: Nc1nc(-c2ccccc2)cc(=O)[nH]1
Temperature: 80 °C
Yield: 89 %

Procedure:
Following the method of Jaeger (Liebigs. Ann. Chem. 1891, 262, 365), a mixture of 12.4 ml (72 mmol) ethyl benzoylacetate and 7.79 g (43.2 mmol) guanidine carbonate in 25 ml ethanol was heated at 80° C. for 4 h. The reaction mixture was then cooled to room temperature and the resulting crystals collected by filtration and washed sequentially with ice-cold water and ethanol to afford 7.2 g (53%) 2-amino-6-phenyl-3H-pyrimidin-4-one as a white crystalline solid. EI-MS m/e (%): 187 (M+, 100).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[S:26]([NH:29][C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32](Cl)=[O:33])(=[O:28])=[O:27])[CH:19]=[CH:18][CH:17]=1>>[CH2:1]([N:8]([CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[C:32](=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[NH:29][S:26]([C:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:25]=1[N:16]=[CH:17][CH:18]=[CH:19]2)(=[O:28])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNCc2cccnc2)cc1
Reactant: O=C(Cl)c1ccccc1NS(=O)(=O)c1cccc2cccnc12
Product: O=C(c1ccccc1NS(=O)(=O)c1cccc2cccnc12)N(Cc1ccccc1)Cc1cccnc1
Yield: 51.7 %

Procedure:
99 mg of N-benzyl-N-(3-pyridylmethyl)amine (precursor 3b) were reacted with 87 mg of 2-(quinoline-8-sulfonylamino)-benzoyl chloride in analogy to example 1 which resulted in 66 mg of an amorphous white solid. MS (ES): 509 (M+H)+
Reaction SMILES: [C-:1]#[N:2].C([Al+]CC)C.[CH3:8][C@H:9]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:10]=[O:11].[NH4+].[Cl-].O>C1(C)C=CC=CC=1>[C:1]([CH:10]([OH:11])[C@@H:9]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:8])#[N:2]
Reactant: [C-]#N
Reactant: C[C@@H](C=O)NC(=O)OCc1ccccc1
Agent: CC[Al+]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H](NC(=O)OCc1ccccc1)C(O)C#N
Temperature: -78 °C
Reaction time: 6 h

Procedure:
Diethylaluminum cyanide (4.53 mL, 1M in toluene, 4.53 mmol) was added dropwise to a stirred solution of benzyl [(1S)-1-methyl-2-oxoethyl]carbamate (0.853 g, 4.12 mmol) in dry toluene (33 mL) at −78° C. under N2. The mixture was stirred at −78° C. for 6 h and then allowed to warm to room temperature overnight. Saturated NH4Cl (20 mL) and water (10 mL) were added then the mixture was extracted with EtOAc (3×50 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Si, 40×160 mm, 0-40% EtOAc in hexanes gradient) to afford benzyl [(1S)-2-cyano-2-hydroxy-1-methylethyl]carbamate as a 3:1 mixture of diastereoisomers. Rf=0.63 (50% EtOAc in hexanes). LCMS calc.=257.1; found=257.1 (M+1)+. 1H NMR (500 MHz, CDCl3) major diastereoisomer: δ 7.39-7.31 (m, 5H), 5.11 (m, 2H), 4.60 br (s, 1H), 3.96 (m, 1H), 1.34 (d, J=6.7 Hz, 3H), minor diastereoisomer: δ 7.39-7.31 (m, 5H), 5.14 (m, 2H), 4.50 br (s, 1H), 4.10 (m, 1H), 1.30 (d, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.Cl.Cl.[CH3:14][N:15]([CH3:17])[NH2:16].C(N(CC)C1C=CC=CC=1)C>C1(C)C=CC=CC=1>[CH3:14][N:15]([CH3:17])[N:16]1[C:4](=[O:5])[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1]1=[O:6]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CN(C)N
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: CN(C)N1C(=O)c2ccccc2C1=O
Yield: 85 %

Procedure:
To the suspension of phthalic anhydride (62.5 mmol) in toluene (500 ml), N,N-dimethyl hydrazine dihydrochloride (50 mmol) and diethyl-phenyl-amine (90 mmol) were added. The reaction mixture was refluxed for 18 hours while removing the formed water via a Dean-Stark trap. Then, toluene was evaporated under reduced pressure and the resulting crude was purified on silica gel chromatography with (1:5) EtOAc:dichloromethane, to give the desired product in 85% yield.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:12](#[N:15])[CH:13]=[CH2:14].Cl>CO.O1CCOCC1>[C:12]([CH2:13][CH2:14][C:2]([CH2:14][CH2:13][C:12]#[N:15])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])#[N:15]
Reactant: C=CC#N
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)C(CCC#N)(CCC#N)C(=O)OCC
Temperature: 60 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of diethyl malonate (1 g, 6.2 mmol) and Triton B (40% in MeOH, 0.13 g, 0.31 mmol) in dioxane (1.2 cm3) was added dropwise acrylonitrile (0.658 g, 12.4 mmol) and the mixture was stirred at 60° C. overnight. The mixture was then cooled to room temperature and neutralized with 0.1 M HCl (3 cm3) and poured to ice-water (10 cm3). Crystals precipitated during 30 min. These were collected by filtration and recrystallised from EtOH (cooling in freezer before filtering off) to give diethyl 2,2-bis(2-cyanoethyl)malonate (1.25 g, 75.8%) as a white solid, mp 62.2-63.5° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[CH3:12][Mg]Cl.O>C1COCC1>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([OH:3])([CH3:12])[CH3:1])=[CH:5][CH:6]=1
Reactant: C[Mg]Cl
Reactant: COc1ccc(C(C)=O)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)O)cc1
Temperature: 12.5 °C
Yield: 93.9 %

Procedure:
This was synthesized using a synthesis based on that described by Archer et al., J. Org. Chem., Vol. 42, No. 13, 1977, page 2282, column 2 (see synthesis of (22)). A solution of 4-methoxy acetophenone (151.18 g, 1 mol) in 300 ml of anhydrous THF was added for 1 h to the solution of 1N methyl magnesium chloride (1360 ml, 1.36 mol) in THF while maintaining the internal temperature at 10-15° C. After completion of the addition, the reaction mixture was heated for about 4.5 hrs. After completion of the reaction (as determined by TLC), 0.2 L of water was slowly added during 3 hrs to quench the reaction while maintaining the internal temperature at <15° C. The reaction mixture was decanted from the precipitate and evaporated under vacuum. The remaining white residue was washed with methyl t-butyl ether (MTBE) (2×200 mL) and evaporated. The combined residue was dissolved in 400 mL of MTBE and 200 mL of water was added. The organic layer was extracted and the aqueous layer was washed with MTBE (3×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and evaporated to dryness to afford 156 g of 2-(4-Methoxy-phenyl)-propan-2-ol as yellow oil (94% yield, 96% purity by HPLC).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH2:15][CH2:16][N:17]3[C:21]([CH3:23])([CH3:22])[C:20](=[O:24])[NH:19][C:18]3=[O:25])[N:9]=2)[S:5][C:6]=1[Cl:7].CO.C(O)(=O)C.[Br:32]Br>ClCCl>[Br:32][C:13]1[C:8]([C:4]2[S:5][C:6]([Cl:7])=[C:2]([Cl:1])[CH:3]=2)=[N:9][C:10]([NH:14][CH2:15][CH2:16][N:17]2[C:21]([CH3:22])([CH3:23])[C:20](=[O:24])[NH:19][C:18]2=[O:25])=[N:11][CH:12]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2cc(Cl)c(Cl)s2)n1
Reactant: BrBr
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc(Cl)c(Cl)s2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
1-(2-(4-(4,5-Dichlorothiophen-2-yl)pyrimidin-2-ylamino)ethyl)-5,5-dimethyl imidazolidine-2,4-dione (300 mg, 0.75 mmol) was suspended in a 10% solution of methanol in dichloromethane (7 mL). Glacial acetic acid (1 mL) followed by bromine (120 mg, 0.75 mmol, 39 μL) [material immediately went into solution] were added, and the mixture was stirred at room temperature for 3 h. The reaction was concentrated in vacuo, diluted with deionized water (25 mL), stirred for 5 min, and then the product was collected by filtration to give a yellow solid (265 mg). The crude product was purified by flash chromatography (MeOH/DCM) to yield the title compound as a yellow powder (162 mg, 45%). MS (M+H)+ 478/480.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1([CH:15]([OH:27])[CH2:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([CH3:19])[CH3:18])[CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[F:11][C:12]1([C:15](=[O:27])[CH2:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)([CH3:19])[CH3:18])[CH2:13][CH2:14]1
Reactant: CC(C)(CC(O)C1(F)CC1)c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(CC(=O)C1(F)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.8 %

Procedure:
2.2 mL of a 2 M solution of oxalyl chloride in dichloromethane was diluted with 2.5 mL of dichloromethane and cooled on dry ice/acetone bath. To this solution was added a dropwise a solution of 0.7 mL of DMSO in 2.5 mL of dichloromethane. After 10 minutes, a solution of the above crude 1-(1-fluorocyclopropyl)-3-(4-fluorophenyl)-3-methylbutan-1-ol (0.72 g, 3.0 mmol) in 2 mL of dichloromethane was added and the mixture was stirred for 15 minutes. 4 mL of triethylamine was added, the cooling bath was removed, the mixture was allowed to warm to room temperature and was then quenched with water and diluted with hexanes. The organic layer was separated, washed with water, dried, filtered, and concentrated in vacuo. The residue was purified by chromatography over silica gel (eluent: hexanes to hexanes-dichloromethane (4:1) gradient) to give 0.37 g of the title product as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([CH3:15])[CH3:14].C(O)(C(F)(F)F)=O>>[CH:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)=[CH:18][CH:17]=1)([CH3:15])[CH3:14]
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CC(C)c1ccc(C=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Yield: 65.1 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (5.0 g, 31.2 mmol), 4-isopropylbenzaldehyde (5.08 g, 1.1 equiv.) and TFA (4.8 mL, 2 equiv.) to give the title compound (5.9 g, 67%) as white crystals after recrystallization from iPr2O.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH2:12])=[S:11].Br[CH2:14][C:15]([C:17]1[CH:26]=[CH:25][C:24]2[NH:23][C:22](=[O:27])[C:21]3[NH:28][CH:29]=[CH:30][C:20]=3[C:19]=2[CH:18]=1)=O.[CH2:31]([C:33]([O-:35])=[O:34])[CH3:32]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[S:11][CH:14]=[C:15]([C:17]2[CH:26]=[CH:25][C:24]3[NH:23][C:22](=[O:27])[C:21]4[NH:28][CH:29]=[CH:30][C:20]=4[C:19]=3[CH:18]=2)[N:12]=1.[CH2:31]([C:33]([O-:35])=[O:34])[CH3:32]
Reactant: NC(=S)Nc1c(Cl)cccc1Cl
Reactant: O=C(CBr)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: CCC(=O)[O-]
Solvent: CCO
Product: O=c1[nH]c2ccc(-c3csc(Nc4c(Cl)cccc4Cl)n3)cc2c2cc[nH]c12
Temperature: 90 °C
Reaction time: 6 h
Yield: 26 %

Procedure:
87 mg (1.2 mmol) of (2,6-dichlorophenyl)-thiourea is added to a suspension of 124 mg (0.33 mmol) of 8-(2-bromo-acetyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 3.5 mL of ethanol. The mixture is stirred at 90° C. for 6 hours then the mixture is cooled to room temperature. The solvent is evaporated, then the product is purified by preparative LCMS. After drying, 43 mg (26%) of 8-[2-(2,6-dichlorophenylamino)-thiazol-4-yl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a beige solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[C@@H:17]1([NH2:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH:27][C@@H:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: FC(F)(F)c1cc(CN[C@H]2CCCc3ccccc32)cc(C(F)(F)F)c1

Procedure:
3,5-bis(Trifluoromethyl)benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2O[C:34](C=O)=[CH:35][CH:36]=2)=[CH:4][N:3]=1.C([NH:41]CC)C>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[NH:41][CH:34]=[CH:35][CH:36]=2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(-c4ccc(C=O)o4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CCNCC
Product: COc1cc(-c2csc3c(-c4ccc[nH]4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-{4-[4-Amino-7-(5-formyl-2-furyl)thieno[3,2-c]pyridin-3-yl]-2-methoxyphenyl}-1-methyl-1H-indole-2-carboxamide, diethylamine, and the procedure described in General Procedure B.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[NH:9]1[CH2:13][CH2:12][N:11]=[C:10]1S(O)(=O)=O.[OH-].[Na+]>CC#N>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:1]=[C:10]1[NH:11][CH2:12][CH2:13][NH:9]1
Reactant: O=S(=O)(O)C1=NCCN1
Reactant: Cc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1ccccc1N=C1NCCN1
Yield: 5.4 %

Procedure:
Ortho toluidine (536 mg, 531 μl, 5 mmol) and imidazoline-2-sulfonic acid (750 mg, 5 mmol, (Compound 7 obtained as described above)) and CH3CN (6ml) were heated in a thick-walled glass tube at 150° C. for 16 hours. The reaction mixture was then cooled to 0° and made basic to pH 14 by addition of 2.5N NaOH solution. The mixture was extracted with methylene chloride, the combine extracts were died (K2CO3) and evaporated to dryness. Flash chromatography on silica gel yielded the title compound as a tan colored solid (47.0 mg, 5.37%).