Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[C:12]1[C:16]1[C:17]([C:36]2[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=2)=[N:18][C:19]([NH:22][CH2:23][CH2:24][NH:25]C2C=CC(C(F)(F)F)=CN=2)=[N:20][CH:21]=1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:25][CH2:24][CH2:23][NH:22][C:19]2[N:18]=[C:17]([C:36]3[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=3)[C:16]([C:12]3[NH:11][CH:15]=[CH:14][N:13]=3)=[CH:21][N:20]=2)[N:3]=1
Reactant: N#Cc1ccc(-c2nc(NCCNc3ccc(C(F)(F)F)cn3)ncc2-c2ncc[nH]2)cc1
Reactant: N#Cc1cnc(Cl)nc1N
Product: N#Cc1ccc(-c2nc(NCCNc3ncc(C#N)c(N)n3)ncc2-c2ncc[nH]2)cc1

Procedure:
4-amino-2-[(2-{[4-(4-cyanophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)amino]pyrimidine-5-carbonitrile was prepared from 4-amino-2-chloropyrimidine-5-carbonitrile using the general method for 4-{5-imidazolyl-2-[(2-{[5-(trifluoromethyl)(2-pyridyl)]amino}ethyl)amino]pyrimidin-4-yl}benzenecarbonitrile.
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:8]=[C:9]([C:13](=O)[CH3:14])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@:21]([NH:23][CH:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:2]([F:16])([F:1])[CH:3]([F:5])[F:4])[CH:8]=1)[CH3:14])=[O:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cccc(OC(F)(F)C(F)F)c1
Product: CC(N[S@](=O)C(C)(C)C)c1cccc(OC(F)(F)C(F)F)c1
Yield: 81 %

Procedure:
The title compound is prepared in 81% yield (0.92 g, colorless oil) from 1-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanone (0.79 g, 3.36 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[O:12]1[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13]1>O>[O:12]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])[CH2:13]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: OCC1CCOC1
Solvent: O
Product: O=C(O)c1ccccc1C(=O)OCC1CCOC1
Temperature: 130 °C
Reaction time: 1.5 h

Procedure:
A mixture of phthalic anhydride (7.41 gm) and tetrahydro-3-furanmethanol were heated with stirring at 130° C. under nitrogen. After 1.5 h, the clear liquid was allowed to cool, treated with water and extracted with EtOAc (×3). The combined organics were dried by passing through a hydrophobic frit and evaporated to a clear oil which crystallised on trituration with light petrol. The solid was filtered, washed and dried, yield 11.93 gm.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][CH2:12][CH3:13])=[N:8]2)=[C:4]([CH3:14])[N:3]=1.[CH3:15][NH:16][CH3:17]>C(O)C>[CH3:15][N:16]([CH3:17])[C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][CH2:12][CH3:13])=[N:8]2)=[C:4]([CH3:14])[N:3]=1
Reactant: CNC
Reactant: CCCc1nc2nc(Cl)nc(C)c2[nH]1
Solvent: CCO
Product: CCCc1nc2nc(N(C)C)nc(C)c2[nH]1
Temperature: 110 °C

Procedure:
To a solution of 2-Chloro-6-methyl-8-propylpurine (from Step 1 of Example 32) (0.1 g,0.47 mmol) in ethanol (2 ml) was added condensed dimethylamine (1 ml) at 0° C. The mixture was then placed in a steel-bomb and heated at 110° C. for 7 hours. The reaction was cooled and the mixture was concentrated inn vacuo. The residue was partitioned between CHCl3 and water, and the organic was separated and dried over MgSO4. The crude product obtained after removal of the solvent was purified by flash-chromatography on silica-gel using 5% MeOH in CHCl3 giving the titled compound as an amorphous solid (0.065 g, 64%). NMR(CDCl3): δ 1.01 (t, J=8Hz, 3H), 1.8 (q, J=8Hz, 2H), 2.65 (s, 3H), 2.8 (t, J=8Hz, 2H), 3.2 (s, 6H). FAB-MS: m/e 220 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11](O)[CH2:12][CH:13]([CH3:15])[CH3:14])=[C:8]([CH3:17])[C:7]=2[CH:18]=1.N1C=CC=CC=1.S(Cl)([Cl:27])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:27][CH:11]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][C:7]=2[C:8]=1[CH3:17])[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2oc(C(O)CC(C)C)c(C)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc2oc(C(Cl)CC(C)C)c(C)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a solution (10 mL) of 1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-3-methylbutan-1-ol (761 mg) synthesized above in toluene were added pyridine (297 μL) and thionyl chloride (268 μL), and the mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (769 mg, 94%) as a brown oil.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:23]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1/[CH:33]=[CH:34]\[C:35]([OH:37])=O)(=[O:25])[CH3:24].ClC(Cl)C.[NH2:42][C@H:43]1[CH2:48][CH2:47][CH2:46][CH2:45][C@H:44]1[NH:49][C:50]1[N:55]=[C:54]([NH:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([CH3:63])[CH:58]=2)[C:53]([C:64]([NH2:66])=[O:65])=[CH:52][N:51]=1>O.CN(C=O)C>[C:23]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1/[CH:33]=[CH:34]\[C:35](=[O:37])[NH:42][C@@H:43]1[CH2:48][CH2:47][CH2:46][CH2:45][C@@H:44]1[NH:49][C:50]1[N:55]=[C:54]([NH:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([CH3:63])[CH:58]=2)[C:53]([C:64](=[O:65])[NH2:66])=[CH:52][N:51]=1)(=[O:25])[CH3:24]
Reactant: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)ncc2C(N)=O)c1
Reactant: CC(=O)Oc1ccccc1/C=C\C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccccc1/C=C\C(=O)N[C@@H]1CCCC[C@@H]1Nc1ncc(C(N)=O)c(Nc2cccc(C)c2)n1
Reaction time: 0.33 h
Yield: 19.6 %

Procedure:
A 135 mg portion of HOBt and 192 mg of WSC·HCl were added to a mixture of 195 mg of (Z)-3-[2-(acetoxy)phenyl]acrylic acid and 10 ml of dichloroethane, followed by stirring for 20 minutes under ice-cooling. Then, 2 ml of DMF solution containing 340 mg of 2-(cis-2-aminocyclohexylamino)-4-(3-methylanilino)pyrimidine-5-carboxamide was added, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent; chloroform:methanel) and then the thus obtained colorless solid was recrystallized from ethyl acetate, thereby obtaining 98 mg of 2-{(Z)-2-[(cis-2-{[5-carbamoyl-4-(3-methylanilino)pyrimidin-2-yl]amino}cyclohexyl)carbamoyl]vinyl}phenyl acetate (colorless crystals).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:16]2[CH:9]([CH2:10][CH:11]=[CH:12][CH2:13][CH:14]([NH:18][C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][N:22]=3)=[O:20])[C:15]2=[O:17])[CH2:8][N:7](S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:6]1)=[O:4].SC1C=CC(O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]([CH:5]1[N:16]2[CH:9]([CH2:10][CH:11]=[CH:12][CH2:13][CH:14]([NH:18][C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][N:22]=3)=[O:20])[C:15]2=[O:17])[CH2:8][NH:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC2CC=CCC(NC(=O)c3nccc4ccccc34)C(=O)N21
Agent: O=C([O-])[O-]
Agent: Oc1ccc(S)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1CNCC2CC=CCC(NC(=O)c3nccc4ccccc34)C(=O)N21
Temperature: 25 °C
Reaction time: 12 h
Yield: 112.3 %

Procedure:
To a solution of 6-[(isoquinoline-1-carbonyl)-amino]-2-(2-nitro-benzenesulfonyl)-5-oxo-1,3,4,5,6,7,10,10a-octahydro-2H-2,4a-diaza-benzocyclooctene-4-carboxylic acid methyl ester (1.5 g, 2.53 mmol) in DMF (55 mL) is added 4-mercaptophenol (1.28 g, 10.1 mmol) and K2CO3 (1.4 g, 10.1 mmol). The solution is stirred at rt for 12 hrs, diluted with EtOAc, washed with water and brine, dried (MgSO4), filtered, and concentrated. The crude residue is purified by preparative reverse phase HPLC (CH3CN/H2O with 0.1% TFA) to yield 1.16 g of product as a TFA salt.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:10]([CH2:20][OH:21])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:29])C(=O)C1.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>CC#N.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C@H:10]([CH2:20][OH:21])[CH2:9]2)=[CH:4][C:3]=1[Br:29]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2ccc(N)nc2)C[C@H]1CO
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C[C@@H](c2cnc(N)c(Br)c2)C[C@H]1CO
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
A solution of (2S,4R)-tert-butyl 4-(6-aminopyridin-3-yl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (230 mg, 0.784 mmol) in MeCN (10 mL) was treated with NBS (147 mg, 0.823 mmol). After 10 min, the reaction was complete. The reaction was treated with 10 mL 1:1 sat. aq. NaHCO3:sat.aq. Na2S2O3 and the mixture was stirred vigorously for 10 min. The mixture was diluted with ethyl acetate (30 mL) and the layers were separated. The organics were washed with brine, dried over magnesium sulfate and concentrated to provide (2S,4R)-tert-butyl 4-(6-amino-5-bromopyridin-3-yl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (290 mg, 100% yield). LCMS (m/z): 372.1/374.0 (MH+), 0.55 min.
Reaction SMILES: [C:1]([OH:5])(=[S:4])[CH2:2][CH3:3].[C:6]([OH:11])(=[O:10])[C:7]([CH3:9])=[CH2:8]>>[C:1]([S:4][CH2:8][CH:7]([CH3:9])[C:6]([OH:11])=[O:10])(=[O:5])[CH2:2][CH3:3]
Reactant: CCC(O)=S
Reactant: C=C(C)C(=O)O
Product: CCC(=O)SCC(C)C(=O)O
Reaction time: 8 h

Procedure:
A mixture of thiopropanoic acid (50 g) and methacrylic acid (34.1 g) was heated on a steam bath for 3 hours and allowed to stand at room temperature overnight. The reaction mixture was distilled under reduced pressure to give the title compound, b.p. 135°-138° C. (2 mmHg).
Reaction SMILES: Cl[CH:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][SH:26])=[CH:23][CH:22]=1)([O-:20])=[O:19].[H-].[Na+]>O1CCCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][CH:2]([S:26][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:28][CH:27]=2)[CH2:3][N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)=[CH:12][CH:13]=1
Reactant: Clc1ccc(CCC(Cl)Cn2ccnc2)cc1
Reactant: O=[N+]([O-])c1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CSC(CCc2ccc(Cl)cc2)Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.35 g of 1-[2-chloro-4-(4-chlorophenyl)butyl]imidazole and 1.60 g of 4-nitrobenzyl mercaptan in 40 ml tetrahydrofuran was treated with 380 mg of 50% sodium hydride dispersion in mineral oil. After stirring at room temperature for 1 hour and under reflux for 12 hours the solvent was evaporated under vacuum and 50 ml of ether added. The resulting mixture was washed twice with water and the ethereal solution dried (MgSO4) and evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in methylene chloride to give 1-[4-(4-chlorophenyl)-2-(4-nitrobenzylthio)-n-butyl]imidazole.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:16])=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=2)[CH2:6][CH2:5]1)(=O)C.Cl.O1CCOCC1>O1CCCC1.CO>[F:16][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[N+:13]([O-:15])=[O:14])[NH:4][CH2:5][CH2:6]2
Reactant: CC(=O)N1CCc2cc(F)c([N+](=O)[O-])cc21
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc2c(cc1F)CCN2
Yield: 90.8 %

Procedure:
A solution of 1-acetyl-5-fluoro-6-nitro-2,3-dihydro-1H-indole (1.22 g, 5.44 mmol) and 4.0 M HCl/dioxane (6.80 ml, 27.2 mmol) in tetrahydrofuran (50 ml) and methanol (100 ml) was heated overnight at 50 C. The reaction was quenched with saturated NaHCO3 (200 ml), solvent removed, aqueous layer extracted with dichloromethane (250 ml), organic layer adsorbed to silica gel and purified by LC (20-75% ethyl acetate/hexanes) to afford the indoline (0.9 g, 91%). ESIMS (M+H)+=183.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31]([OH:33])=O)[CH:20]=[C:19]1[CH3:34])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].[Cl-].[NH4+].C[N:38](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C@H:21]([C:31](=[O:33])[NH2:38])[CH:20]=[C:19]1[CH3:34])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 52 %

Procedure:
To a solution of (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)-4-methyl-1,2,5,6-tetrahydropyridine-2-carboxylic acid (Intermediate 19, 4.16 g, 8.36 mmol) in DMF (35 mL) at room temperature was added ammonium chloride (0.895 g, 16.72 mmol), HATU (4.77 g, 12.54 mmol) and DIEA (5.84 mL, 33.45 mmol). After 15 minutes the reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and twice with 1:1 brine:water. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-80% ethyl acetate/hexanes) was run twice to afforded the desired product (2.16 g, 52%) as a yellow foam.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])([O:3][CH3:4])=[O:2].[C:13](C1C=CC=CC=1C=O)(O)=O.ICC.C([O-])([O-])=O.[K+].[K+]>>[C:1]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])([O:3][CH2:4][CH3:13])=[O:2]
Reactant: COC(=O)c1ccccc1C=O
Reactant: O=Cc1ccccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Product: CCOC(=O)c1ccccc1C=O

Procedure:
Using the same procedure as for the preparation of 2-carbomethoxybenzaldehyde (Compound 43), but instead using 5.0 g (33 mmol) of 2-carboxybenzaldehyde, 23.4 g (150 mmol) of iodoethane and 13.8 g (100 mmol) of K2CO3 gave the title compound as a clear colorless oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=CC=CC=2)[CH:4]=[CH:3][C:2]=1CO.N1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(Br)(Br)[Br:20]>C1(C)C=CC=CC=1>[Br:20][CH2:14][C:15]1[C:10]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: BrP(Br)Br
Reactant: c1ccncc1
Reactant: OCc1ccc2ccccc2c1
Solvent: Cc1ccccc1
Product: BrCc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Naphthalen-2-ylmethanol (2.0 g, 12.7 mmol) was dissolved in toluene (30 mL) and pyridine (1.02 mL, 12.7 mmol) was added. The solution was cooled to 0° C. PBr3 (1.19 mL, 12.7 mmol) was added dropwise over 15 min. The mixture was then brought up to room temperature and stirred for 1 h. The mixture was washed with K2CO3 solution and extracted with EtOAc (3×30 mL). The EtOAc layer was washed with brine and dried (MgSO4). The solvent was evaporated off in-vacuo to give crude 1-(bromomethyl)naphthalene. This intermediate was used in the following reactions. Sodium ethoxide (169 mg, 2.49 mmol) was added to DMF (5 mL) at 0° C., and the suspension was stirred for 10 min. 7-hydroxy-4-methylcoumarin (438 mg, 2.49 mmol) was slowly added and resulting mixture was stirred at this temp for 0.5 h, then allowed to reach room temp. To this mixture 1-(bromomethyl)naphthalene (500 mg, 2.26 mmol) was added portionwise. Resulting reaction mixture was stirred at room temperature for 16 h. DMF was evaporated off in-vacuo and the residue was taken up in EtOAc, and washed with brine (2×50 mL), water (2×50 mL) and 1M NaOH (2×30 mL). The organic layer was dried (MgSO4) and product was purified by flash chromatography, eluting with hexane:EtOAc (2:1) to give 44 (1.44 g, 36%) as a white solid. m/z=317.12 (M+H), 633.24 (2M+H). H1 NMR (500 MHz, CDCl3): δ=7.93-7.87 (4H, m, ArH), 7.58-7.52 (4H, m, Ar), 6.97 (1H, t, J=2.43 Hz, ArH), 6.16 (1H, s, ArH), 5.32 (2H, s, CH2), 2.41 (3H, s, CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[C:14]([O-])([O-])=O.[Na+].[Na+].IC>O>[ClH:1].[ClH:1].[CH3:14][N:12]1[CH2:11][CH2:10][NH:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:13]1
Reactant: Clc1ccc(C2CNCCN2)cc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN1CCNC(c2ccc(Cl)cc2)C1
Product: Cl
Yield: 20.8 %

Procedure:
A mixture of 10 g (0.051 mol) of 2-(4-chlorophenyl)piperazine (comparison product CP 1 of Table IV below; M.p=124° C.) 10.80 g (0.102 mol) of Na2CO3, 7.24 g (0.051 mol) of ICH3 and 100 ml of water is heated under reflux for 6 hours. It is cooled, extraction is carried out with CHCl3 and the chloroform phase is washed with water and dried over MgSO4. It is filtered, the filtrate is evaporated to dryness, the evaporation residue is taken up with CH3OH and the mixture is acidified with a solution of hydrochloric acid in ethanol. It is evaporated to dryness; recrystallization of the evaporation residue from a methanol/ethyl acetate mixture (1:1 v/v) gives 3 g (yield: 20.8%) of CRL 41 202. M.p.inst. =200° C. (decomposition).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=O)[C:2]1=[O:11].[F:12][C:13]1[CH:14]=[C:15]([C:20](=O)[CH3:21])[CH:16]=[CH:17][C:18]=1[F:19].[OH-:23].[K+]>O1CCOCC1>[F:12][C:13]1[CH:14]=[C:15]([C:20]2[CH:21]=[C:3]([C:2]([OH:11])=[O:23])[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:1]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: [OH-]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CC(=O)c1ccc(F)c(F)c1
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2ccc(F)c(F)c2)nc2ccccc12
Temperature: 105 °C
Yield: 5.3 %

Procedure:
A mixture of 2,3-indolinedione (5 g, 0.03 mole), 3′,4′-difluoroacetophenone (5 g, 0.03 mole) and potassium hydroxide (3 g, 0.05 mole) in 1,4-dioxane (50 mL) is heated at 105° C. for 48 hours. The reaction solution is then cooled to room temperature and concentrated under reduced pressure. The residue is treated with EtOAc and extracted with water. The pH of the aqueous layer is adjusted to 5-6 with 1N HCl, the resulting solid is collected by vacuum filtration, washed with water, and dried to give the titled compound (450 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:25][C:26]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(=O)(O)[O-].[Na+]>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:11][N:29]2[CH2:30][CH2:31][C:26]([OH:25])([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:27][CH2:28]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: O=CCC(Cn1ccnc1-c1ccccc1)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cl
Product: OC1(c2ccccc2)CCN(CCC(Cn2ccnc2-c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 0.08 h
Yield: 138 %

Procedure:
3-(3,4-Dichlorophenyl)-4-(2-phenylimidazol-1-yl)butyraldehyde (1.0 g) in methanol (7 mL) was added to a solution of 4-hydroxy-4-phenylpiperidine (0.741 g) and acetic acid (0.24 mL) in methanol (7 mL). After 5 minutes, sodium cyanoborohydride (0.263 g) in methanol (7 mL) was added in a single portion. After being stirred for 2 hours, the reaction mixture was diluted with aqueous sodium bicarbonate, stirred for 30 minutes, and extracted with dichloromethane. The organic extracts were dried, evaporated, and chromatographed, with dichloromethane:methanol (gradient 98:2, 90:10) as eluent. The purified material was dissolved in dichloromethane, precipitated out as the hydrochloride salt with ethereal hydrogen chloride, evaporated, and placed under high vacuum overnight to give the title compound as a white solid (0.760 g); NMR: 7.92 (m,1), 7.69 (m,2), 7.59 (m,2), 7.50 (m,2), 7.36 (m,2), 7.28 (m,4), 7.10 (d,1, J=2.1), 6.85 (dd,1, J=2.1, 8.3), 4.70 (dd,1, J=4.5, 14.0), 4.57 (dd,1, J=10.5, 13.9), 3.47 (m,3), 3.27 (m,2), 3.14 (m,1), 2.84 (m,1), 2.47-2.20 (m,4), 1.93 (m,2); MS: m/z=520(M+1) Analysis for C30H31Cl2N3O.02.80 HCl.0.15 Et2O: Calculated: C, 58.00; H, 5.61; N, 6.63; Found: C, 57.99; H, 5.80; N, 6.77.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].[N:13]#[C:14][Br:15]>CO>[BrH:15].[N:3]1[CH2:4][CH2:5][N:1]2[C:2]=1[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[N:8]=[C:14]2[NH2:13]
Reactant: N#CBr
Reactant: Nc1ccccc1C1=NCCN1
Solvent: CO
Product: Br
Product: NC1=Nc2ccccc2C2=NCCN12
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
To a suspension of 2-(4,5-dihydro-1H-imidazol-2-yl)aniline (5.00 g, 31.0 mmol) in 85% methanol (60 ml) at 0° C. was added cyanogen bromide (3.61 g, 34.1 mmol) by portions. This mixture was stirred at room temperature overnight. After the mixture was concentrated under reduced pressure, the resulting precipitate was collected by filtration. This pale green solid was washed with water, methanol and diethyl ether successively, and dried under reduced pressure to give 2,3-dihydroimidazo[1,2-c]quinazolin-5-ylamine hydrobromide (4.94 g, 60% yield).
Reaction SMILES: O.[OH-].[Li+:3].[F:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:6]=1[N:17]1[CH2:22][CH2:21][CH2:20][C@H:19]([C:23]([O:25]CC)=[O:24])[CH2:18]1.CO.O1CCCC1.[ClH:35]>O>[F:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:6]=1[N:17]1[CH2:22][CH2:21][CH2:20][C@H:19]([C:23]([OH:25])=[O:24])[CH2:18]1.[Li+:3].[Cl-:35]
Reactant: Cl
Reactant: CCOC(=O)[C@H]1CCCN(c2ccc(-c3ccncc3)cc2F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)[C@H]1CCCN(c2ccc(-c3ccncc3)cc2F)C1
Product: [Cl-]

Procedure:
Lithium hydroxide, monohydrate (0.013 g, 0.00030 mol) was added to ethyl (3S)-1-(2-fluoro-4-pyridin-4-ylphenyl)piperidine-3-carboxylate (0.050 g, 0.00015 mol) in methanol (0.5 mL, 0.01 mol), tetrahydrofuran (0.5 mL, 0.006 mol) and water (0.5 mL, 0.03 mol). The mixture was irradiated under microwave at 100° C. for 30 min. The reaction mixture was diluted with water and adjusted to pH=5 by adding 1N HCl. The volatiles were removed in-vacuo to afford the desired product and LiCl, which was used as a mixture in the next step.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[S:25][C:26]([Cl:40])=[C:27]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36]C(=O)C)=[CH:32][CH:31]=2)[CH:28]=1)(=O)C.C[O-].[Na+].CC(O)=O>CO>[Cl:40][C:26]1[S:25][C:24]([C@H:6]2[C@H:5]([OH:4])[C@@H:10]([OH:11])[C@H:9]([OH:15])[C@@H:8]([CH2:19][OH:20])[O:7]2)=[CH:28][C:27]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cc(Cc3ccc(OC(C)=O)cc3)c(Cl)s2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: OC[C@H]1O[C@@H](c2cc(Cc3ccc(O)cc3)c(Cl)s2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
To a suspension of acetate 28 (413 mg, 0.617 mmol) in MeOH (15 mL) was added NaOMe (25 wt % in MeOH, 0.2 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. Glacial AcOH was added to the mixture to acidify the mixture. The mixture was concentrated under reduced pressure. The residue was purified by prep HPLC (C18) to provide the title compound 29 (130 mg, 55%).