Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9].C(=O)(O)[O-].[Na+].CC(C)=O.O.[CH2:23]([O:30][C:31](Cl)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[CH2:23]([O:30][C:31](=[O:32])[NH:9][C:8]1[CH:10]=[CH:11][CH:12]=[C:6]([C:2]2[O:1][CH:5]=[N:4][N:3]=2)[CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1cccc(-c2nnco2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1cccc(-c2nnco2)c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
A solution of 3-(1,3,4-oxadiazol-2-yl)aniline (1 g, 6.2 mmol) and sodium bicarbonate (1.1 g, 13 mmol) in a 2:1 mixture of acetone/water (10 mL) was cooled to 0° C. Benzylchloroformate (0.92 mL, 6.5 mmol) was added dropwise over 5 minutes. The reaction mixture was brought to room temperature and stirred for 30 minutes at which point LCMS indicated completion of the reaction. The reaction mixture was diluted with water and filtered on a glass frit to give (3-[1,3,4]Oxadiazol-2-yl-phenyl)-carbamic acid benzyl ester as a white powder (1.7 g, 93%). M+1=296.4
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:19])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[OH-].[Li+].Cl>O1CCCC1.O>[I:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[O:6][C:7]=2[CH3:19])=[CH:13][CH:14]=1
Reactant: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(C(=O)O)cc1COc1ccc(I)cc1
Yield: 70.4 %

Procedure:
A stirred solution of 4-(4-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (20) (2.7 g) in tetrahydrofuran (25 mL) was treated with a solution of lithium hydroxide (1.5 g) in water (2 mL). After 3 hours the reaction mixture was diluted with water and acidified to pH 2 with 1.0 M hydrochloric acid. The white precipitate was filtered off and dried in vacuo. The solid was triturated with ethyl acetate at 0° C. then collected by filtration to give compound 26 as a white solid (1.83 g). LC/MS system A: Rt=1.74 min.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[C:7]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]>C(OCC)C>[C:7]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][O:16][C:1](=[O:5])[C:2]([Cl:4])=[O:3])=[CH:17][CH:18]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1ccc(CO)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: CC(C)(C)c1ccc(COC(=O)C(=O)Cl)cc1

Procedure:
To a stirred solution of oxalyl dichloride (100ml) in diethylether (500 ml) at -10° under nitrogen a solution of 4-t-butylbenzyl alcohol (200 ml) in diethylether (100 ml) was added dropwise so as to maintain the temperature between -10° and -5°. The solvent was then evaporated under vacuum to give the title compound (289 g,) as a clear oil (b.p. 120°-122° at 2 mbar).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[N+:16]([O-])=O.C1(C)C=CC=CC=1.[H][H]>[Pd].O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[NH2:16]
Reactant: [H][H]
Reactant: O=C(OCCCCl)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)OCCCCl)c(N)c1
Yield: 100.4 %

Procedure:
A two liter autoclave was charged with 142 g of (3-chloropropyl)-2,4-dinitrobenzoate, 1275 ml of toluene and 4.5 g of a 5% palladium on carbon/50% water catalyst. The mixture was hydrogenated at 800 psi hydrogen pressure while maintaining the temperature below 100° C. with cooling. The mixture was cooled and 350 ml of tetrahydrofuran was added to dissolve the solid that had precipitated from the toluene. The resulting solution was filtered to remove the catalyst and the solvents removed at reduced pressure to give 113 g of (3-chloropropyl)-2,4-diaminobenzoate, a white solid, mp 97° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]2[CH3:24])[C:5]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.[CH:25]1([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)=[O:30])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:29](=[O:30])[NH:31][C:32]2[CH:33]=[CH:34][C:35]([C:2]3[N:3]=[C:4]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]4[CH3:24])[C:5]4[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=4[N:7]=3)=[CH:36][CH:37]=2)[CH2:27][CH2:26]1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C(=O)OC(C)(C)C)C2
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CN(C(=O)OC(C)(C)C)C2

Procedure:
(S)-tert-butyl 2-(4-(3-cyclopropylureido)phenyl)-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate was prepared by the method described for intermediate 5 using intermediate 1 and 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea as starting materials
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:19]O)[N:10]=1.S(Cl)([Cl:34])=O>O1CCCC1>[Cl:21][C:6]1[CH:5]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:19][Cl:34])[N:10]=1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(CO)c1=O
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(CCl)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-[3,5-dichloro-4-(1-hydroxymethyl-5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (600 mg, 1.29 mmol) in tetrahydrofuran (9.0 mL, 0.14 M) cooled to 0° C. was treated with thionyl chloride (0.28 mL, 3.84 mmol). The reaction mixture was allowed to slowly warm to 25° C. The reaction mixture was stirred at 25° C. overnight. At this time, the reaction mixture was concentrated in vacuo. The residue was taken up in benzene and was re-concentrated twice to afford 2-[3,5-dichloro-4-(1-chloromethyl-5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile as a yellow solid. The material was used without further purification.
Reaction SMILES: C(OC(=O)[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:29])[NH2:28])=[C:23]([OH:30])[CH:22]=2)=[C:16]([F:31])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.[ClH:33]>ClCCl.O1CCOCC1>[ClH:33].[F:31][C:16]1[CH:15]=[C:14]([CH2:13][NH:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:19]=[CH:18][C:17]=1[O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH2:28])=[O:29])=[C:23]([OH:30])[CH:22]=1
Reactant: CC(C)CCN(Cc1ccc(Oc2ccc(C(N)=O)c(O)c2)c(F)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)CCNCc1ccc(Oc2ccc(C(N)=O)c(O)c2)c(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
[4-(4-Carbamoyl-3-hydroxy-phenoxy)-3-fluoro-benzyl]-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-1e-1: 15 g) was dissolved in 150 mL of dichloromethane and treated with 50 mL of a 4.0 M hydrogen chloride solution in dioxane. After stirring 24 hours at room temperature, the volatiles were removed under reduced pressure and the resulting crude material was suspended in methanol, heated at reflux for 20 minutes, and stirred overnight at room temperature. The resulting slurry was collect via filtration, rinsed with chilled methanol, and dried under vacuum to provide the title compound (1A).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:44])[O:14][CH2:15][C@@H:16]([N:30]([CH3:43])[C:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=1[Cl:42])=[O:32])[CH2:17][NH:18][C:19](=[O:29])[CH2:20][NH:21]C(OC(C)(C)C)=O)=[CH:5]2.C(O)(C(F)(F)F)=O.Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:44])[O:14][CH2:15][C@@H:16]([N:30]([CH3:43])[C:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=1[Cl:42])=[O:32])[CH2:17][NH:18][C:19](=[O:29])[CH2:20][NH2:21])=[CH:5]2
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CNC(=O)CNC(=O)OC(C)(C)C)COC(=O)Nc1cc2cc(F)ccc2cn1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CNC(=O)CN)COC(=O)Nc1cc2cc(F)ccc2cn1
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of (S)-3-(2-tert-butoxycarbonylaminoacetamido)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)propyl 6-fluoroisoquinolin-3-ylcarbamate (0.87 g, 1.37 mmol) in DCM (30.0 mL) was added TFA (3.0 mL). The mixture was stirred for 1 h. The mixture was concentrated and dissolved in EtOAc. The EtOAc solution was washed with Na2CO3, brine, dried over Na2SO4, and filtered. To the filtrate was added HCl (4 M in dioxane, 0.7 mL, 2.8 mmol,). The organic solvent was removed under reduced pressure to give (S)-3-(2-aminoacetamido)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)propyl 6-fluoroisoquinolin-3-ylcarbamate (730 mg, 93%) as a HCl salt. LRMS (M+H+) m/z 535.2.
Reaction SMILES: CC[N:3](C(C)C)C(C)C.[CH3:10][C:11]([C:15]1[N:19]([CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:18]2[CH:27]=[CH:28][C:29]([S:31]([N:34]3[CH:38]=[CH:37][C:36]([C:39]([OH:41])=O)=[CH:35]3)(=[O:33])=[O:32])=[CH:30][C:17]=2[N:16]=1)([CH3:14])[CH2:12][CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N>CN(C=O)C>[CH3:14][C:11]([C:15]1[N:19]([CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:18]2[CH:27]=[CH:28][C:29]([S:31]([N:34]3[CH:38]=[CH:37][C:36]([C:39]([NH2:3])=[O:41])=[CH:35]3)(=[O:33])=[O:32])=[CH:30][C:17]=2[N:16]=1)([CH3:10])[CH2:12][CH3:13]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(N)=O)c3)ccc2n1CC1CCOCC1
Yield: 56.7 %

Procedure:
Following the same procedure in Example 24, Step A, using DIPEA (105 uL, 78 mg, 0.60 mmol), 1-{[2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carboxylic acid (0.20 mmol) (see following Steps B and C for preparation), HATU (114 mg, 0.30 mmol) and saturated ammonia in DMF (5 mL). The crude product was purified by reversed HPLC using CH3CN/H2O (30-60%) to give 52 mg (45%) of a white solid as the title compound. 1H NMR (400 MHz, CD3OD) δ 0.78 (t, J=7.52 Hz, 3 H), 1.41-1.57 (m, 4 H), 1.59 (s, 6 H), 1.95 (q, J=7.42 Hz, 2 H), 2.20-2.37 (m, 1 H), 3.22-3.38 (m, 2 H), 3.90 (dd, J=11.82, 3.22 Hz, 2 H), 4.42 (d, J=7.42 Hz, 2 H), 7.94 (d, J=8.8 Hz, 1 H), 8.01 (dd, J=8.8, 1.8 Hz, 1 H), 8.05 (s, 1 H), 8.36 (d, J=1.56 Hz, 1 H), 8.79 (d, J=0.59 Hz, 1 H); MS (ESI) (M+H)+=460.3.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=[O:3])C.[F:8][C:9]1[CH:10]=C2[C:15](=[CH:16][CH:17]=1)[NH:14]C(=O)C2=O>[O-2].[Cr+6].[O-2].[O-2].C(O)(=O)C>[F:8][C:9]1[CH:10]=[C:6]2[C:5]([O:4][C:1](=[O:3])[NH:14][C:15]2=[CH:16][CH:17]=1)=[O:7]
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: CC(=O)OC(C)=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(F)cc2c(=O)o1
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
Acetic anhydride (90.0 mL), 5-fluoroisatin (20.62 g, 0.125 mmol, 1.00 eq), and acetic acid (90 mL) were added to a 250 mL, three neck flask fitted with a magnetic stir bar and a condenser. The flask was placed in a water bath and heated to 85° C. Chromium (VI) oxide (20.36 g, 0.204 mol, 1.63 eq) was added in small portions (0.5 g size) over 40 min to the red solution. The reaction mixture was stirred for an additional 15 min and cooled to 10° C. in an ice bath. The solid that formed was isolated by filtration. Washing with 400 mL of water removed most of the green color. The solid was taken up in 300 mL of 2:1 acetic acid/water, refiltered, and dried overnight in a 50° C. vacuum oven. The 5-fluoroisatoic anhydride was isolated as a bright yellow solid (14.45 g, 64%). ##STR5##
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[F:8][C:9]([F:27])([F:26])[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:17]=[C:16]([I:24])[C:15]=1[OH:25])=[O:11].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]([CH3:7])[S:3](=[O:5])(=[O:4])[O:25][C:15]1[C:16]([I:24])=[CH:17][C:18]([C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:19][C:14]=1[CH2:13][NH:12][C:10](=[O:11])[C:9]([F:8])([F:26])[F:27]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(I)c(O)c(CNC(=O)C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)Oc1c(I)cc(C(C)(C)C)cc1CNC(=O)C(F)(F)F
Reaction time: 72 h

Procedure:
To a solution of N,N-dimethylsulfamoyl chloride (17.4 g., 0.12 mole) in dry methylene chloride (75 ml.) maintained under a nitrogen atmosphere is added slowly and with good stirring a solution of 2,2,2-trifluoro-N-[2-hydroxy-3-iodo-5-(1,1-dimethylethyl)phenylmethyl]acetamide (8 g., 0.02 mole) and triethylamine (12.12 g., 0.12 mole) in dry methylene chloride (200 ml.) at 20°-25° C. The resulting reaction mixture is stirred at 20°-25° C. under nitrogen for 72 hours. Removal of the solvent in vacuo leaves a tacky residue which is partitioned between ether and water. The phases are separated and the organic phase is washed successively with 2N hydrochloric acid, water and saturated brine, dried over sodium sulfate and filtered. Evaporation of the filtrate leaves the intermediate 2-(2,2,2-trifluoroacetamidomethyl)-4-(1,1-dimethylethyl)-6-iodophenyl N,N-dimethylsulfamate as a tan oil (10.3 g., 100%).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])=[O:5].[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1>[C:17]([O:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[O:5])(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(c1ccccc1O)c1ccccc1O
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccccc1C(=O)c1ccccc1OC(=O)C(C)(C)C

Procedure:
2 g (0.01 mole) of 2,2'-dihydroxybenzophenone was dissolved in 30 mls of dry pyridine and 3 g (0.03 mole) of pivaloyl chloride added and contents warmed for 3 hrs. at 50° C. Solvent was removed by rotary evaporator and H2O added and crystals filtered. Recrystallized from ethanol, 3.2 g (83%) yield, M.P.~106°-108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[C:4]([F:10])[CH:3]=1.S(Cl)([Cl:13])=O>O1CCCC1.N1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Cl:13])=[C:4]([F:10])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Cl)cc1F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Fc1cc(Cl)ccc1CCl

Procedure:
Then, 16.5 g of 4-chloro-2-fluorobenzylalcohol was dissolved in 150 ml of tetrahydrofuran and 1 ml of pyridine, to which 10 ml of thionyl chloride was added dropwise at 5° C., and the mixture was stirred for 2⅚ hours. After completion of the reaction, the reaction mixture was concentrated, and the precipitated crystals were collected by filtration. The filtrate was subjected to silica gel column chromatography, which afforded 18.5 g of 4-chloro-2-fluorobenzyl chloride.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH:15]2[CH2:17][CH2:16]2)[N:3]=1.C(N(C(C)C)C(C)C)C.[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCOCC1>[CH:15]1([NH:14][C:4]2[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:36]3[CH2:37][CH2:38][N:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:34][CH2:35]3)[N:3]=2)[CH2:17][CH2:16]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NC2CC2)nc1NCCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCO)nc(NC2CC2)nc1N1CCN(c2ccccc2)CC1
Temperature: 100 °C
Yield: 59.3 %

Procedure:
A mixture of 70 mg (0.27 mmol) of 4-chloro-2-cyclopropylamino-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile and 0.047 ml (0.27 mmol) of N-ethyl-diisopropylamine in 5 ml of dioxane was treated with 49 mg (0.3 mg) of 1-phenyl-piperazine. The solution was heated to 100° C. during 18 hours, thereafter, for the working-up, evaporated under reduced pressure. For purification, the residue obtained was chromatographed by preparative HPLC on RP18-silica gel using a gradient of a mixture of acetonitrile and water (plus 0.1% of formic acid) as the eluent to give 60 mg (0.16 mmol, 58% of theory) of the 2-cyclopropylamino-4-(2-hydroxy-ethylamino)-6-(4-phenyl-piperazin-1-yl)-pyrimidine-5-carbonitrile as a white powder after lyophilization; MS: [M+H]+=380.
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:10]([Mg]Br)[CH:11]([CH3:13])[CH3:12].[Cl-].[NH4+]>O1CCCC1>[CH2:10]([C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: OCc1cccnc1Br
Reactant: CC(C)C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)Cc1ncccc1CO
Reaction time: 4 h

Procedure:
To a solution of (2-bromopyridin-3-yl)methanol (100 mg) in tetrahydrofuran (1 ml), 36 mg of dichloro(1,1′-bis(diphenylphosphino)ferrocene)nickel(II) and 0.8 ml of isobutyl magnesium bromide (2.0M diethyl ether solution) were added under ice-cooling, and the reaction solution was stirred at the same temperature for 4 hours. To the reaction solution was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (98:2-50:50)) to afford the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([C:14]1[N:18]([CH3:19])[C:17]2[C:20]([Cl:24])=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]=1)[CH2:11][C:12]#[CH:13]>>[Cl:24][C:20]1[C:17]2[N:18]([CH3:19])[C:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)=[N:15][C:16]=2[CH:23]=[CH:22][CH:21]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCc1nc2cccc(Cl)c2n1C
Product: Cn1c(CCC#Cc2cccc(CF)n2)nc2cccc(Cl)c21

Procedure:
The title compound was prepared in accordance with the general method of Example 190(F), from 2-bromo-6-(fluoromethyl)pyridine (30 mg, 0.16 mmol) and 2-(but-3-ynyl)-7-chloro-1-methyl-1H-benzo[d]imidazole (35 mg, 0.16 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 99/1 as eluent) to afford 43 mg of a light brown solid. The resulting solid was triturated into isopropyl ether to give 6 mg of 7-chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-1-methyl-1H-benzo[d]imidazole (Yield: 10%) as white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].C(=O)(O)[O-].[Na+].[NH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>C(OCC)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=[O:8])([O-:3])=[O:2]
Reactant: NCc1cccnc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=C(NCc1cccnc1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a stirred two-phase solution of 3-nitrobenzoyl chloride (9.3 g) in a mixture of diethyl ether (50 ml) and saturated sodium bicarbonate solution (50 ml) was added 3-aminomethylpyridine (5.4 g) in an ice-cooled bath. The mixture was stirred vigorously at ambient temperature for 30 minutes. The reaction mixture was filtered, and the resulting solid was washed with water. The solid was further solidified with diisopropyl alcohol-water to afford 3-nitro-N-(3-pyridylmethyl)benzamide (5.91 g) as a pale yellow amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]=[C:6]2[C:14]=1[CH2:13][C@H:12]1[C@@H:7]2[CH2:8][NH:9][CH2:10][CH2:11]1.CCN(CC)CC.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(Cl)Cl>[CH2:32]([O:31][C:29]([N:9]1[CH2:8][C@H:7]2[C@H:12]([CH2:13][C:14]3[C:6]2=[CH:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3][C:2]=3[CH3:1])[CH2:11][CH2:10]1)=[O:30])[CH3:33]
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(-c2ccccc2)cc2c1C[C@@H]1CCNC[C@H]21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CC[C@H]2Cc3c(C)cc(-c4ccccc4)cc3[C@H]2C1
Temperature: 20 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a solution of cis-8-methyl-6-phenyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene (22 mg, 0.084) in CH2Cl2 was added Et3N (43 mg, 0.42 mmol) followed by ethyl chloroformate (18 mg, 0.17 mmol). The reaction mixture was stirred at 20° C. for 2 h and concentrated in vacuo. The residue was chromatographed in silica gel column (Hex/EtOAc 9/1) to give cis-8-methyl-6-phenyl-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylic acid ethyl ester (20 mg, 0.060 mmol).
Reaction SMILES: C(O)(C(F)(F)F)=[O:2].[OH:8][C:9]1[C:22]2[C:21](=[O:23])[C:20]3[C:15](=[C:16]([O:24][CH3:25])[CH:17]=[CH:18][CH:19]=3)[O:14][C:13]=2[CH:12]=[C:11]([O:26][CH2:27][CH:28]2[CH2:30][O:29]2)[CH:10]=1>>[OH:29][CH:28]([CH2:30][OH:2])[CH2:27][O:26][C:11]1[CH:10]=[C:9]([OH:8])[C:22]2[C:21](=[O:23])[C:20]3[C:15]([O:14][C:13]=2[CH:12]=1)=[C:16]([O:24][CH3:25])[CH:17]=[CH:18][CH:19]=3
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cccc2c(=O)c3c(O)cc(OCC4CO4)cc3oc12
Product: COc1cccc2c(=O)c3c(O)cc(OCC(O)CO)cc3oc12
Temperature: 50 °C
Reaction time: 4 h
Yield: 47.3 %

Procedure:
50% TFA (5 mL) was added to 1-hydroxy-5-methoxy-3-(oxiran-2-ylmethoxy)-9H-xanthen-9-one (20 mg, 0.06 mmol) synthesized in Step 2 of Example 1, and the reaction mixture was stirred at 50° C. for 4 hours. The solvent was removed, and the resulting residue was dried under reduced pressure to give the title compound (10 mg, 47.3%) as a white solid.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([NH:7]N)=[CH:3][CH:2]=1.Cl.[CH2:11]([C:14]1([CH3:22])[C:19](=O)[CH2:18][CH2:17][N:16]([CH3:21])[CH2:15]1)[CH:12]=[CH2:13].OS(O)(=O)=O>O1CCOCC1>[CH2:11]([C:14]1([CH3:22])[C:19]2[NH:7][C:4]3[CH:3]=[CH:2][C:1]([CH3:9])=[CH:6][C:5]=3[C:18]=2[CH2:17][N:16]([CH3:21])[CH2:15]1)[CH:12]=[CH2:13]
Reactant: Cc1ccc(NN)cc1
Reactant: C=CCC1(C)CN(C)CCC1=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: C=CCC1(C)CN(C)Cc2c1[nH]c1ccc(C)cc21

Procedure:
To a stirred solution of p-tolylhydrazine.HCl (1.2 g, 7.56 mmol) and 3-allyl-1,3-dimethyl-piperidin-4-one (1.5 g, 9.077 mmol) in 1,4-dioxane (12 mL) at 25° C. was added conc. H2SO4 (1 mL). The reaction mixture was heated at 100° C. for 30 min after which the dioxane layer was decanted and residue was basified with saturated aqueous NaHCO3 solution. The product was extracted with EtOAc (3×50 mL), organic layer dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1.7 g of 4-allyl-2,4,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as a solid.