Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][CH:13]([C:18]#[N:19])[CH2:12]2.[C:20](OC(=O)C)(=O)[CH3:21]>C(O)(=O)C>[C:18]([CH:13]1[CH2:12][C:11]2[C:15](=[CH:16][CH:17]=[C:9]([N:8]3[C:7]4[CH:6]=[CH:5][N:4]=[CH:3][C:2]=4[N:1]=[C:20]3[CH3:21])[CH:10]=2)[CH2:14]1)#[N:19]
Reactant: CC(=O)OC(C)=O
Reactant: N#CC1Cc2ccc(Nc3ccncc3N)cc2C1
Solvent: CC(=O)O
Product: Cc1nc2cnccc2n1-c1ccc2c(c1)CC(C#N)C2
Yield: 79 %

Procedure:
A mixture of 5-(3-aminopyrid-4-ylamino)-2-cyanoindane (12.28 g, ca 44.5 mmol from step (d) above), acetic acid (70 ml) and acetic anhydride (70 ml) was heated at reflux under nitrogen for 1.75 hours, cooled, and concentrated under reduced pressure. The residual brown gum was dissolved in 2M hydrochloric acid (40 ml) and washed with ethyl acetate (50 ml). The aqueous layer was rendered basic by the addition of 2M aqueous sodium hydroxide, and the product was extracted into dichloromethane. The combined extracts were wahsed with water (50 ml), dried over magnesium sulphate and the solvent evaporated. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/methanol (7:1), to give a brown gum, which was recrystallised from ethyl acetate/methanol, to give the 2-cyano-5-(2-methylimidazo[4,5-c]pyrid-1-yl)indane as an off-white powder (9.67 g, 79%), m.p. 174°-176° C. Found: C,74.4; H,5.2; N,20.7. C17H14N4 requires C,74.4; H,5.1; N,20.4%.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([O:32][C:33]1[C:40]([O:41][CH3:42])=[CH:39][C:36]([CH:37]=O)=[CH:35][C:34]=1[O:43][CH3:44])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:37][C:36]1[CH:39]=[C:40]([O:41][CH3:42])[C:33]([O:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:34]([O:43][CH3:44])[CH:35]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(C=O)cc(OC)c1OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(C=C(Br)Br)cc(OC)c1OCc1ccccc1

Procedure:
The starting material is prepared as follows: To the mixture of 31.5 g of carbon tetrabromide and 65 ml of methylene chloride the solution of 50.0 g of triphenylphosphine in 175 ml of methylene chloride is added dropwise while stirring at 0°-5° under nitrogen. After 20 minutes the solution of 13.5 g of 4-benzyloxy-3,5-dimethoxybenzaldehyde in 50 ml of methylene chloride is added dropwise and the mixture stirred at room temperature for 2 hours. It is washed with 200 ml of water, dried and evaporated. The residue is extracted with hexane-diethyl ether (5:1), the extract evaporated, the residue chromatographed on silica gel, eluted with diethyl ether, the eluate evaporated and the residue recrystallized from hexane, to yield the β,β-dibromo-4-benzyloxy-3,5-dimethoxy-styrene melting at 76°-77°.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:10]=[C:9]([O:11][CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2,4-dihydroxybenzoic acid (5 g), anhydrous K2CO3 (40 g) and benzyl bromide (16 mL) in acetone (100 mL) was refluxed for 4 hours. After filtration of solid, the filtrate was concentrated. The residue was stirred at room temperature with KOH (6 g), and methanol (20 mL) for 4 hours, and neutralized with dilute HCl (pH 2). The solid thus formed was filtered and recrystallized from a methanol-chloroform mixture (3:1) to get 3.5 g of the product. Concentration of mother liquor gave an additional 1 g of the product.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:12]([CH3:15])([O-:14])=[O:13].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:11][O:10][C:8]1[CH:7]=[CH:6][C:3](/[CH:4]=[CH:15]/[N+:12]([O-:14])=[O:13])=[C:2]([OH:1])[CH:9]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C=O)c(O)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1ccc(/C=C/[N+](=O)[O-])c(O)c1
Temperature: 100 °C

Procedure:
A mixture of 2-hydroxy-4-methoxybenzaldehyde (5.0 g, 32.9 mmol), nitromethane (5.5 g 90.0 mmol), ammonium acetate (6.9 g 90.0 mmol) and 40 mL of glacial acetic acid was heated at 100° C. for 4 hours. The reaction was then cooled, concentrated and partitioned between ethyl acetate and water. The organic extract was washed with 10% sodium bicarbonate solution, water, and brine and dried over sodium sulfate. The organic solution was concentrated and chromatographed on a silica gel column eluting with 1:4 ethyl acetate/hexane to afford the titled compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.78 (s, 3H) 6.49-6.55 (m, 2H) 7.65 (d, J=8.33 Hz, 1H) 8.00-8.06 (d, J=13.5 Hz, 1H) 8.13-8.19 (d, J=13.5 Hz 1H) 11.00 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16](=O)[C:11]2[C:12]([CH3:15])=[CH:13][O:14][C:10]=2[CH2:9]1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17]/[C:16](=[N:23]\[NH:22][C:19]([NH2:21])=[NH:20])/[C:11]2[C:12]([CH3:15])=[CH:13][O:14][C:10]=2[CH2:9]1
Reactant: Cc1coc2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1coc2c1/C(=N/NC(=N)N)CC(c1ccccc1Cl)C2
Temperature: 90 °C
Reaction time: 2 h
Yield: 160.3 %

Procedure:
To a mixture of 6-(2-chlorophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.35 g) and aminoguanidine hydrochloride (148 mg) were added ethanol (27 ml) and 6N hydrochloric acid (0.12 ml), and the mixture was stirred at 90° C. for 2 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-6-(2-chlorophenyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 42) (0.38 g).
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([F:13])=[CH:8][C:7]=1[Cl:14])([CH3:3])[CH3:2].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[Cl:14][C:7]1[C:6]([C:5](=[O:15])[NH:4][CH:1]([CH3:3])[CH3:2])=[CH:11][C:10]([NH:12][C:17](=[O:18])[O:19][CH2:20][CH3:21])=[C:9]([F:13])[CH:8]=1
Reactant: CCOC(=O)Cl
Reactant: CC(C)NC(=O)c1cc(N)c(F)cc1Cl
Product: CCOC(=O)Nc1cc(C(=O)NC(C)C)c(Cl)cc1F

Procedure:
Analogously to the procedure described in Example 65, starting from N-isopropyl-5-amino-2-chloro-4-fluorobenzamide and ethyl chloroformate there is obtained ethyl 4-chloro-2-fluoro-5-(N-isopropylcarbamoyl)-carbanilate, m.p. 127°-130° C., used as the starting material in Example 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5](=[O:8])[NH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:24])=[C:20]([CH:23]=1)[CH2:21]Br.O>C(#N)C>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:24])=[C:20]([CH:23]=1)[CH2:21][N:4]1[C:3]([O:2][CH3:1])=[N:7][NH:6][C:5]1=[O:8]
Reactant: Clc1ccc(Br)cc1CBr
Reactant: COc1n[nH]c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1n[nH]c(=O)n1Cc1cc(Br)ccc1Cl
Temperature: 55 °C
Reaction time: 5 h
Yield: 35.6 %

Procedure:
To a solution of 0.91 g (7.93 mmol) of 5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one in 8 ml of dry acetonitrile was added 0.96 g (6.94 mmol) of potassium carbonate. To the mixture was added dropwise a solution of 1.88 g (6.61 mmol) of 5-bromo-2-chlorobenzylbromide in 20 ml of dry acetonitrile at 55° C. After the mixture was stirred at 55° C. for 5 hours, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. To the resultant solid residue (1.90 g) was added cold tert-butyl methyl ether and the solid was thoroughly washed, collected by filtration and dried to obtain 0.75 g of 4-(5-bromo-2-chlorobenzyl)-5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one as white powder.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([O:14][CH3:15])=[N:12][N:11]([CH3:16])[C:10]1=[O:17].[Cl:18][C:19]1[CH:29]=[CH:28][C:22]([NH:23][C:24](=[S:27])[CH2:25][CH3:26])=[CH:21][CH:20]=1.CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[CH3:15][O:14][C:13]1[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2][S:27][C:24](=[N:23][C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:29][CH:28]=2)[CH2:25][CH3:26])[C:10](=[O:17])[N:11]([CH3:16])[N:12]=1
Reactant: CCC(=S)Nc1ccc(Cl)cc1
Reactant: COc1nn(C)c(=O)n1-c1ccccc1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(=Nc1ccc(Cl)cc1)SCc1ccccc1-n1c(OC)nn(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
To a solution of 0.50 g of the title compound of Step D in 2 mL of THF was added 0.37 g of 4'-chlorothiopropionanilide and then 0.23 g of potassium tert-butoxide. (An exotherm occurred during this addition). The reaction was allowed to stir at room temperature overnight and then was heated briefly to reflux and allowed to cool. The reaction mixture was diluted with ethyl acetate and washed successively with water and then with saturated aqueous NaCl. The organic phase was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (50-60% ethyl acetate/hexanes) to afford 0.48 g of the title compound of Step E (about 95% pure), a compound of the invention. 1H NMR (CDCl3): δ 7.58 (m,1H), 7.37 (m,2H), 7.23 (m,3H), 6.60 (d,2H), 4.23 (s,2H), 3.86 (s,3H), 3.41 (s,3H).
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([S:11]([CH2:13][CH3:14])=[O:12])[CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[CH2:13]([S:11]([C:4]1[CH:3]=[C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:9]=[C:8]([CH3:10])[C:5]=1[C:6]#[N:7])=[O:12])[CH3:14]
Reactant: C1COCCN1
Reactant: CCS(=O)c1cc(Cl)cc(C)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCS(=O)c1cc(N2CCOCC2)cc(C)c1C#N
Temperature: 100 °C
Yield: 58.1 %

Procedure:
4-Chloro-2-(ethylsulfinyl)-6-methyl-benzonitrile (0.31 g, 1.36 mmol), morpholine (0.36 ml, 4.09 mmol) and potassium carbonate (0.24 g, 1.77 mmol) are taken up in N-methyl-2-pyrrolidone (3 ml) in a sealed tube and the resulting mixture is heated at 100° C. for 16 h. The mixture is then diluted with water (6 ml) and extracted with ethyl acetate (3×10 ml). The organic layer is washed with water (2×10 ml), brine (20 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 50% ethyl acetate/hexane) to yield 2-(ethylsulfinyl)-6-methyl-4-morpholin-4-yl-benzonitrile (0.22 g, 0.79 mmol, 58%).
Reaction SMILES: I[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])(C)(C)C.C(OC([N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=[O:29])[CH2:24][CH2:23]1)=O)(C)(C)C.[NH4+].[Cl-]>CCOCC>[C:4]1([CH2:3][CH2:2][CH:28]([CH:25]2[CH2:26][CH2:27][NH:22][CH2:23][CH2:24]2)[OH:29])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: ICCc1ccccc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Product: OC(CCc1ccccc1)C1CCNCC1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5 mL (34.5 mmol) of (2-iodoethyl)benzene in 100 mL of ether at −78° C. was added 42.6 mL (72.5 mmol) of t-butyl lithium. The reaction mixture was warmed to −20° C. for 20 min, then cooled to −78° C. TO this solution, was added a solution of 5.6 g (23.2 mmol) of 1-t-butoxy carbonyl-4-formylpiperidine in 50 mL of ether and the reaction mixture was stirred 15 min at −78° C. To the reaction mixture was added 150 mL of a sat'd solution of NH4Cl and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. Removal of the BOC protecting group was achieved as described in Example 233, Step 6 to give the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[S:22][CH2:21][CH2:20][C:19]([C:23](O)=[O:24])=[CH:18][C:17]=4[CH:26]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:49][N:50]([CH2:57][C:58]1[CH:64]=[CH:63][C:61]([NH2:62])=[CH:60][CH:59]=1)[CH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>CN(C=O)C.C(N(CC)CC)C>[CH3:49][N:50]([CH2:57][C:58]1[CH:59]=[CH:60][C:61]([NH:62][C:23]([C:19]2[CH2:20][CH2:21][S:22][C:16]3[CH:15]=[CH:14][C:13]([C:10]4[CH:11]=[CH:12][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:8][CH:9]=4)=[CH:26][C:17]=3[CH:18]=2)=[O:24])=[CH:63][CH:64]=1)[CH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1
Reactant: O=C(O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2SCC1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(N5CCOCC5)cc4)ccc3SCC2)cc1)C1CCOCC1
Reaction time: 1 h
Yield: 49 %

Procedure:
To a solution of 7- (4-morpholinophenyl) -2,3-dihydro-1-benzothiepine-4-carboxylic acid (150 mg) and 1-hydroxy-benzotriazole (0.11 g) in DMF (5 ml) was added at room temperature 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.16 g), and the mixture was stirred for 1 hour. To the mixture was added a solution of 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (135 mg) and triethylamine (0.11 ml) in DMF (5 ml), and the mixture was stirred for 18 hours. Under reduced pressure, the mixture was concentrated, and to the mixture was added water. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with column chromatography (ethanol/ethyl acetate=1:2) to give yellow crystals of N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-(4-morpholinophenyl)-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 285) (113.9 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[O:29]=[C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:30])[N:20]1[CH2:19][C@@H:18]([NH:17][C:8]([C:6]1[S:7][C:3]([O:2][CH3:1])=[C:4]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)[CH:5]=1)=[O:10])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:40])([F:39])[F:41]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: COc1sc(C(=O)O)cc1-c1ccnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a 50 mL round-bottomed flask was added 5-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (148 mg, 0.62 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (242 mg, 0.63 mmol) [prepared according to the procedure of Preparation 6] and PyBrop (356 mg, 0.76 mmol) in Chloroform (6 mL). DIEA (550 μL, 3.15 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (303 mg, 0.51 mmol, 82%): LC-MS (ES) m/z=569 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)=[CH:13][CH:12]=1>C1COCC1.CCO.[OH-].[Na+]>[CH3:26][O:25][C:23]1[CH:24]=[C:19]([CH2:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:31])=[O:2])=[CH:12][CH:13]=2)[CH:20]=[C:21]([O:29][CH3:30])[C:22]=1[O:27][CH3:28]
Reactant: COC(=O)c1ccccc1Nc1ccc(CCc2cc(OC)c(OC)c(OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(CCc2ccc(Nc3ccccc3C(=O)O)cc2)cc(OC)c1OC

Procedure:
To a solution of 2-{4-[2-(3,4,5-trimethoxyphenyl)ethyl]phenylamino}-benzoic acid methyl ester (0.62 g, 1.47 mmol) in THF-EtOH (2:1, 6 mL), 1N NaOH solution (4 mL) was added, and the reaction mixture was heated to reflux for 5 hours. The reaction mixture was then concentrated in vacuo to remove the organic solvent. The residue was acidified with concentrated HCl (pH 3). This precipitate was collected by filtration, triturated with boiling MeOH—H2O (4:1) and dried in vacuum at room temperature for 16 hours to give the title compound as a white solid, 0.59 g (1.45 mmol, 98.5%). mp 146.0-147.0° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([CH2:19][CH2:20][N:15]3[C:14](=[O:21])[CH:13]=[C:12]2[CH3:22])[CH:18]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].FC(F)(F)C(O)=O.[N+:32]([O-])([O-:34])=[O:33].[K+]>O>[F:5][C:4]([F:7])([F:6])[C:3]([C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([CH2:19][CH2:20][N:15]3[C:14](=[O:21])[C:13]([N+:32]([O-:34])=[O:33])=[C:12]2[CH3:22])[CH:18]=1)([OH:8])[C:2]([F:1])([F:23])[F:24]
Reactant: Cc1cc(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)F)cc13)CC2
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1c([N+](=O)[O-])c(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)F)cc13)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
To a stirred mixture of 7.0 g (0.02 mole) of 1,2-dihydro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-6-methyl-4H-pyrrolo[3,2,1-ij]quinolin-4-one and 70 ml of trifluoroacetic acid is added 4.2 g (0.042 mole) of potassium nitrate. The mixture is stirred for 16 hours at room temperature and then is refluxed for 30 minutes. The mixture is poured into 300 ml of water. The solid is filtered off, washed with water, and dried. Recrystallization from 250 ml of acetonitrile gives 3.3 g (42%) of 1,2-dihydro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-6-methyl-5-nitro-4H-pyrrolo[3,2,1-ij]quinolin-4-one, m.p. 289°-290° (dec).
Reaction SMILES: [C:1]1([C@@H](N)C)[CH:6]=CC=[CH:3][CH:2]=1.[CH:10]1([CH2:16][NH:17][CH2:18][C:19]([N:21]2[CH2:26]COC[CH2:22]2)=[O:20])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH3:26][N:21]([CH3:22])[C:19](=[O:20])[CH2:18][NH:17][CH2:16][C:10]1[C:11]2[C:12](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=C(CNCC1CCCCC1)N1CCOCC1
Product: CN(C)C(=O)CNCc1cccc2ccccc12

Procedure:
By following the procedure of section (a) of this example but replacing (S)-1-phenylethylamine with twice the equivalent amount of 1-(naphthylmethyl)amine and omitting the triethylamine, N,N-dimethyl-2-[(1-naphthylmethyl)-amino]acetamide [1H NMR(CDCl3) δ 8.25 (dd, J=1.2 Hz,8.0 Hz,1H), 7.86 (dd, J=1.8 Hz,7.6 Hz,1H), 7.79 (broad d, J=8.1 Hz,1H), 7.60-7.39 (m,4H), 4.30 (s,2H), 3.52 (s,2H), 2.97 (s,3H), 2.90 (s,3H)] was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=2)[C:3]=1[C:14]([NH2:16])=[O:15].C(N(CC)C(C)C)(C)C.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCOCC1>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:33]([NH:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:34])[CH:8]=2)[C:3]=1[C:14]([NH2:16])=[O:15]
Reactant: NC(=O)c1c(-c2cccc(N)c2)nsc1N
Reactant: O=C=Nc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1c(-c2cccc(NC(=O)Nc3ccccc3)c2)nsc1N
Yield: 97.5 %

Procedure:
A mixture of 5-amino-3-(3-aminophenyl)isothiazole-4-carboxamide (21 mg, 0.090 mmol), N,N-diisopropylethylamine (0.039 mL, 0.23 mmol), and phenyl isocyanate (0.014 mL, 0.13 mmol) in 1.0 mL dioxane was reacted at rt for 1 hour. The precipitant was filtered and rinsed with 30% EtOAc/hexane to give the title compound as a white solid (31 mg, 96%).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10](Cl)[C:5]2=[N:4][CH:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13].CCN(C(C)C)C(C)C>C(O)CCC>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:15][CH2:14][CH2:12][OH:13])[C:5]2=[N:4][CH:3]=1
Reactant: NCCO
Reactant: Clc1nccn2c(Br)cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: OCCNc1nccn2c(Br)cnc12
Temperature: 100 °C

Procedure:
3-Bromo-8-chloro-imidazo[1,2-a]pyrazine (0.70 g, 3.0 mmol) (from Example 1 supra) was stirred in nBuOH (10 mL) and ethanolamine (0.22 mL, 3.65 mmol) followed by Hunig's base (1.04 mL, 6.0 mmol) Reaction mixture was then heated at 100° C. overnight. The mixture was concentrated to dryness and water was added (150 mL) followed by a saturated aqueous solution of NaHCO3 (50 mL). The reaction was then extracted with EtOAc (3×20 mL) and the organic phases were combined, washed with water (2×20 mL), dried over MgSO4 and concentrated to dryness to give 2-(3-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-ethanol. (Yield 0.59 g, 77%). 1H (400 MHz; DMSO-d6) δ 3.52-3.56 (2 H, m), 3.58-3.62 (2 H, m), 4.79 (1 H, t, J=5.4 Hz), 7.42 (2 H, d, J=5 Hz), 7.56 (1 H, d, J=5 Hz), 7.66 (1 H, s).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][C:28]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:29]=1[CH2:30][OH:31]>>[F:27][C:28]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:29]=1[CH2:30][O:31][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1
Reactant: OCc1cc(F)ccc1F
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3cc(F)ccc3F)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and 2,5-difluorobenzyl alcohol (107 mg; 0.736 mmol), example 81 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][S:9][CH2:10][CH2:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[N:3]=1.[F:23][C:24]([F:30])([F:29])[CH2:25][N:26]=[C:27]=[S:28]>C(#N)C>[F:23][C:24]([F:30])([F:29])[CH2:25][NH:26][C:27](=[S:28])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][S:9][CH2:10][CH2:11][N:12]2[C:13](=[O:22])[C:14]3=[CH:21][CH:20]=[CH:19][CH:18]=[C:15]3[C:16]2=[O:17])[N:3]=1
Reactant: FC(F)(F)CN=C=S
Reactant: Nc1ccnc(CSCCN2C(=O)c3ccccc3C2=O)n1
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCSCc1nccc(NC(=S)NCC(F)(F)F)n1
Reaction time: 72 h
Yield: 62.6 %

Procedure:
A mixture of 4-amino-2-[(2-phthalimidoethyl)thiomethyl]pyrimidine (5.9 g.), 2,2,2-trifluoroethylisothiocyanate (3.9 g.) and acetonitrile (20 ml.) was stirred at 70° for 72 hours. The reaction mixture was cooled and the crystalline precipitate collected to give 4-[3-(2,2,2-trifluoroethyl)thioureido]-2-[(2-phthalimidoethyl)thiomethyl]pyrimidine (5.35 g.), m.p. 178°-179°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].Br[CH2:11][CH2:12][CH2:13][Cl:14]>>[CH3:1][C:2]1[CH:3]=[C:4]([S:9][CH2:11][CH2:12][CH2:13][Cl:14])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: ClCCCBr
Reactant: Cc1ccc(S)cc1C
Product: Cc1ccc(SCCCCl)cc1C

Procedure:
Prepared by Procedure R and Scheme Z using 3,4-dimethylbenzenethiol and 1-bromo-3-chloropropane.