Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9](C(OCC)=O)[C:10](=[O:12])[NH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH-].[K+].IC[CH2:22][CH2:23][C:24]([CH3:29])([N+:26]([O-:28])=[O:27])[CH3:25]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[C:8]2[NH:9][C:10](=[O:12])[N:11]([CH2:22][CH2:23][C:24]([CH3:29])([N+:26]([O-:28])=[O:27])[CH3:25])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)n1c(=O)[nH]c2cccc(OC)c21
Reactant: CC(C)(CCCI)[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1[nH]c(=O)n2CCC(C)(C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.0 g (17 mmol) ethyl 7-methoxy-2-oxo-2,3-dihydro-benzimidazol-1-carboxylate in DMF are combined with 85% potassium hydroxide solution (3.3 g, 51 mmol) while being cooled with the ice bath. After 30 minutes a solution of 5.2 g (21 mmol) 1-iodo-4-methyl-4-nitro-pentane in DMF is added and the mixture is stirred overnight at ambient temperature. The reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic phases are washed with water, dried and freed from the solvent. The oil remaining is purified by chromatography on a silica gel column (cyclohexane/ethyl acetate gradient). Yield: 0.5 g (8%); mass spectroscopy: [M+H]+=366.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C:12]2([CH3:15])[CH2:14][O:13]2)(=O)=O)=CC=1.[N:17]1([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C.[I-].[K+]>CN(C=O)C.O>[C:26]([O:25][C:24](=[O:30])[NH:23][N:17]1[CH2:22][CH2:21][N:20]([CH2:11][C:12]2([CH3:15])[CH2:14][O:13]2)[CH2:19][CH2:18]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NN1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)CO2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NN1CCN(CC2(C)CO2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
A mixture of (2-methyl-2-oxiranylmethyl) toluene-4-sufonate (9.75 g, 40.3 mmol), tert-butyl piperazin-1-yl-carbamate (6.75 g, 33.5 mmol) prepared in Reference Example 36, triethylamine (7 ml, 50.3 mmol) and potassium iodide (6.68 g, 33.5 mmol) in DMF (70 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/acetone=4/1) to afford tert-butyl[4-(2-methyl-2-oxiranylmethyl)piperazin-1-yl]carbamate (4.66 g, yield 51%) as a colorless crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:20]#[N:21])=[C:10]([NH2:19])[N:11]([C:13]3C=CC=CC=3)[CH:12]=2)[CH:5]=[CH:6][CH:7]=1.CN([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27]N=1)C.O.[CH:32]([NH2:34])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:10]([NH2:19])=[N:11][CH:13]=[N:21][C:20]=3[N:34]([C:32]3[CH:25]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1c(-c2cccc(Cl)c2)cn(-c2ccccc2)c1N
Reactant: NC=O
Reactant: CN(C)c1ccccn1
Solvent: O
Product: Nc1ncnc2c1c(-c1cccc(Cl)c1)cn2-c1ccccc1
Temperature: 25 °C

Procedure:
1 g of 4-(3-chlorophenyl)-1-phenyl-2-amino-3-cyanopyrrole is heated at 180° C. with a spatula tipful of dimethylaminopyridine for 14 h in 10 ml of formamide under a nitrogen atmosphere. After cooling to RT, the mixture is treated with water and the crystals obtained are filtered off, washed with water and dried. After chromatography on silica gel (methylene chloride/methanol 15:1), the product-containing fractions are concentrated, slurried in ether and filtered. 5-(3-Chlorophenyl)-7-phenyl-4-aminopyrrolo[2,3-d]pyrimidine having a melting point of 173°-175° C. is obtained. 1H--NMR (d6 -DMSO): delta (ppm)=6.3 (br. s, 2H), 7.3-7.55 (m, 6H), 7.65(s, 1H), 7.8 (s, 1H), 7.85 (d, 2H), 8.2 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([N:35]4[CH:39]=[N:38][NH:37][C:36]4=[O:40])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:37]1[C:36](=[O:40])[N:35]([C:32]2[CH:33]=[CH:34][C:29]([N:26]3[CH2:27][CH2:28][N:23]([C:20]4[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=4)[CH2:24][CH2:25]3)=[CH:30][CH:31]=2)[CH:39]=[N:38]1)[CH3:13]
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: COc1ccc(N2CCN(c3ccc(-n4cnn([C@H](C)[C@@]5(c6ccc(F)cc6F)CO5)c4=O)cc3)CC2)cc1
Yield: 30.4 %

Procedure:
In the same manner as in Reference Example 5, starting from 543 mg of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 809 mg of 4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3(2H,4H)-1,2,4-triazolone prepared by a method described in Journal of Medicinal Chemistry, vol. 27, page 894 (1984), 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3(2H,4H)-1,2,4-triazolone (373 mg) was obtained as colorless prisms.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.Cl.[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH2:34]([N:36]([CH2:37][CH3:38])[C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:32])([F:1])[F:31])=[CH:4][CH:5]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:29])[CH3:35]
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with diethylamine hydrochloride (15 mg, 0.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 30 ml of ethyl acetate, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 46 mg of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]=[N+:16]=[N-:17])[O:11][C:10]2=[O:18])[CH:5]=[CH:6][C:7]=1[I:8].[Cl:19][C:20](S(Cl)(=O)=O)=[CH2:21]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:21]=[C:20]([Cl:19])[N:17]=[N:16]3)[O:11][C:10]2=[O:18])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: C=C(Cl)S(=O)(=O)Cl
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Solvent: ClC(Cl)Cl
Product: O=C1O[C@@H](Cn2cc(Cl)nn2)CN1c1ccc(I)c(F)c1
Temperature: 80 °C
Yield: 27.7 %

Procedure:
A stirred mixture of (5R)-3-(3-fluoro-4-iodophenyl)-5-azidomethyl-1,3-oxazolidin-2-one (1 g, 28 mmol) and 1-chloro-1-ethenesulfonyl chloride (1 g, 6.2 mmol) was heated in a pressure tube at 80° C. for one hour. The reaction mixture was cooled to room temperature, diluted with chloroform (15 mL), and heated at 80° C. for an additional 4 hours. The reaction mixture was cooled to room temperature and the precipitate was collected by filtration and washed with little dichloromethane to yield the title compound as a colorless amorphous solid (725 mg, 62%).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:4]=1[Cl:11].[CH3:12][N:13]1[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[N:15]=[C:14]1[SH:21].C(N(CC)CC)C>C(O)C>[CH3:12][N:13]1[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[N:15]=[C:14]1[S:21][CH2:2][C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9]
Reactant: Clc1ccc(Cl)c(CBr)c1Cl
Reactant: Cc1cc(=O)n(C)c(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(=O)n(C)c(SCc2c(Cl)ccc(Cl)c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
A mixture of 2-(bromomethyl)-1,3,4-trichlorobenzene (576 mg, 2.1 mmol), 3,6-dimethyl-2-sulfanyl-3,4-dihydropyrimidin-4-one (300 mg, 1.9 mmol), and triethylamine (280 μl, 2.0 mmol) in absolute ethanol (10 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The solid product was suspended in water (30 mL). The solid material was recovered by filtration, washed with water (2×10 mL) and hexanes (2×20 mL), and dried in vacuo, affording the title compound (475 mg, 72% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 3.31 (s, 3H), 4.77 (s, 2H), 6.08 (s, 1H), 7.57 (d, 1H, J=8.8 Hz), 7.68 (d, 1H, J=8.8 Hz); M+350; HPLC purity: 95.8%.
Reaction SMILES: [Na].[CH3:2][C@H:3]([NH:11][C:12]1[N:17]=[C:16](Cl)[N:15]=[C:14]2[N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:21][C:13]=12)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:28]([OH:31])[CH2:29][CH3:30]>[Na+].[Cl-]>[CH3:2][C@H:3]([NH:11][C:12]1[N:17]=[C:16]([O:31][CH2:28][CH2:29][CH3:30])[N:15]=[C:14]2[N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:21][C:13]=12)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[C@@H](Cc1ccccc1)Nc1nc(Cl)nc2c1cnn2-c1ccccc1
Reactant: CCCO
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Product: CCCOc1nc(N[C@@H](C)Cc2ccccc2)c2cnn(-c3ccccc3)c2n1
Temperature: 90 °C

Procedure:
Next, 324 mg sodium was reacted with 10 ml of n-propanol. To this, 640 mg of (S)-N-(1-methyl-2-phenylethyl)-1-phenyl-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine in 5 ml of n-propanol was added with stirring and the reaction was heated to 90° C. for 2 hours. It was then cooled, diluted with 200 ml saturated NaCl, and extracted with 200 ml CHCl3. The organic layer was dried over MgSO4, filtered, and concentrated to yield an oil which was purified by radial chromatography (30-50% Et2O/hexane) to yield after recrystallization from 30% Et2O/hexane 382 mg of product (m.p. 134-136° C.). Proton NMR indicated ether was still present. The compound was then oven dried under vacuum for 6 hours to yield 318 mg of (S)-N-(1-methyl-2-phenylethyl)1-phenyl-6-propoxy-1H-pyrazolo[3,4-d]pyrimidin-4-amine (m.p. 134-136° C.).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1)=O.[CH3:11][NH:12][CH3:13].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[Br:10][C:6]1[CH:5]=[C:4]([CH:2]([CH3:1])[N:12]([CH3:13])[CH3:11])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(c1cccc(Br)c1)N(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
60 g (0.30 mols) of 3-bromoacetophenone are dissolved in 800 ml of ethanol and mixed with 250 ml of dimethylamine. The pH of the solution is adjusted to 6.5 with acetic acid. The reaction mixture is then cooled to 0° and mixed with 19 g of sodium cyanoborohydride. After stirring for 2 days at room temperature, the reaction mixture is concentrated. The residue is mixed with 800 ml of water and acidified. The solution is then extracted twice with 400 ml of ether, the aqueous phase is rendered basic and extraction follows 3× with 400 ml of ether. The combined organic extracts are dried and concentrated. After distillation of the residue, the 3-bromo-N,N,α-trimethylbenzenemethanamine is obtained; b.p.: 98°-100°/10 mmHg.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32]>C(Cl)Cl>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:31]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:32])=[CH:7][CH:8]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Oc1ccccc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1
Yield: 78 %

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.36 mmol, example 9 (step 3) and DIEA (62.8 μL, 0.36 mmol) in DCM (2 mL) was added phenyl chloroformate (45.2 μL, 0.36 mmol). The resulting mixture was reacted under the same conditions as described for example 10 to give 112 mg (78% yield) of the title compound as an off-white oil. MS (ESI, positive ion) m/z: 398 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=CC(I)=C[C:3]=1CO.[H-].[Na+].C([Li])CCC.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[CH:27][C:28]([F:31])([F:30])[F:29])=[CH:22][CH:21]=1.[CH2:32]1[CH2:36][O:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:9]=[CH:34][C:33]([CH:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[C:28]([F:29])([F:30])[F:31])=[C:32]([CH2:36][OH:35])[CH:3]=1.[Cl:1][C:2]1[CH:3]=[C:32]([CH:33]=[CH:34][CH:9]=1)[CH2:36][OH:35]
Reactant: COc1ccc(N=CC(F)(F)F)cc1
Reactant: C1CCOC1
Reactant: OCc1cc(I)ccc1Cl
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Product: COc1ccc(NC(c2ccc(Cl)cc2CO)C(F)(F)F)cc1
Product: OCc1cccc(Cl)c1
Temperature: -78 °C

Procedure:
A solution of 2-chloro-5-iodobenzyl alcohol (0.537 g, 2.0 mmol) in THF (10 mL) was added to sodium hydride (88 mg of a 60% dispersion in mineral oil, 2.2 mmol) at 0° C. with stirring under nitrogen. After 5 min the mixture was cooled to −78° C. and n-butyl-lithium (2.5 M in hexanes, 1.66 mL, 4.15 mmol) was added over 6 min. After a further 5 min a solution of N-(4-methoxyphenyl)-N-(-2,2,2-trifluoroethylidene)amine (0.406 g, 2.0 mmol) in THF (2 mL) was added over 5 min. After a further 5 min the reaction was quenched with saturated ammonium chloride solution and the mixture was warmed to ambient temperature and partitioned between ethyl acetate and brine. The organic layer was dried (Na2SO4) and evaporated to a gum which was purified by chromatography on silica (eluting with 2% methanol/chloroform) to give N-{1-[4-chloro-2-(hydroxymethyl)phenyl]-2,2,2-trifluoroethyl}-N-(4-methoxyphenyl)amine as a 1:1.7 mixture with 3-chlorobenzyl alcohol (0.38 g) as a gum: MS 346.4 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:24])[S:18][CH:19]=2)=[CH:13][CH:14]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)CNc1nc(-c2ccc(F)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1nc(-c2ccc(F)cc2)cs1)Nc1ccccc1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt and 50.8 mg (0.54 mmol) of aniline. Yield: 4.7 mg.
Reaction SMILES: CNC.[CH3:4][C:5](=[O:10])[CH2:6][C:7](=[O:9])[CH3:8].Cl.Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>O>[OH:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH:6]([C:5](=[O:10])[CH3:4])[C:7](=[O:9])[CH3:8])=[CH:15][CH:16]=1
Reactant: Oc1ccc(CCl)cc1
Reactant: CC(=O)CC(C)=O
Agent: CNC
Agent: Cl
Solvent: O
Product: CC(=O)C(Cc1ccc(O)cc1)C(C)=O
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of p-chloromethyl phenol in acetonitrile (Example 12) was reacted with equimolar dimethyl amine and equimolar 2,4-pentanedione by stirring together for one hour. The reactive mixture was diluted with water, acidified with hydrochloric acid, extracted with ether, and then the ether extract was dried with sodium sulfate. The residual oil was triturated with benzene to yield 78% of 3(4' hydroxybenzyl)-2,4-pentanedione, M.P. 93°-94.5°C. Infrared and nuclear magnetic resonance spectra confirmed the identity of the product.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:49]([Cl:51])[Cl:50]>C(O)(=O)C>[NH3:1].[CH2:49]([Cl:51])[Cl:50].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([OH:32])[CH2:27][CH2:28][N:29]([CH2:15][C:14]3[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:12][CH:13]=3)[CH2:30][CH2:31]2)=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: N
Product: OC1(c2ccc(Cl)cc2)CCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1
Reaction time: 16 h

Procedure:
A solution of the product of Example 9 (200 mg), 4-(4-chloro-phenyl)-piperidin-4-ol (170 mg), and acetic acid (0.05 mL) in DCM (3 mL) was treated with sodium triacetoxyborohydride (300 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (5 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Chromatography of the residue (1-5% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (203 mg). 1H NMR (400 MHz, CDCl3): 7.46-7.42 (m, 2H), 7.32-7.28 (m, 2H), 7.25-7.22 (m, 2H), 6.87-6.84 (m, 2H), 3.99 (t, J=6.3 Hz, 2H), 3.51 (s, 2H), 2.78 (m, 2H), 2.51-2.36 (m, 8H), 2.11 (m, 2H), 1.98 (m, 2H), 1.69 (m, 2H), 1.63-1.56 (m, 4H), 1.48-1.40 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[C:3]1=[O:12].C(O)C.[N+](=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N-]>CN(C=O)C>[OH:11][C:4]1[C:3](=[O:12])[N:2]([CH3:1])[C:10]2[C:5]([C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CN1C(=O)C(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1c(O)c(=O)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.9 %

Procedure:
1-Methylindoline-2,3-dione (5.0 g, 31.0 mmol) was stirred in DMF (15 mL) and Ethanol (85 mL) at 0° C. Ethyl 2-diazoacetate (4.51 mL, 43.4 mmol) was added. The ice bath was removed and the mixture was stirred at rt for two days. The mixture was evaporated to remove most of the EtOH. 1N HCl (ca. 100 mL) was added. It was stirred at rt for 3 h. LC-MS showed the desired ring expansion product. The precipitate was filtered and rinsed with H2O (2×) and dried under vacuum to give Intermediate 16 (5.05 g, 20.42 mmol, 94% yield) as slightly tan solids. LC-MS (ESI) 248.0 (M+H), RT=2.91 min (Method A).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[H-].[Na+].[Cl:11][CH2:12][CH2:13][CH2:14]I.[Na+].[Cl-]>CN(C)C=O.O>[Cl:11][CH2:12][CH2:13][CH2:14][O:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)cn1
Reactant: ClCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(OCCCCl)cn1
Temperature: 25 °C
Yield: 134.5 %

Procedure:
Under a nitrogen atmosphere, a solution of 5-hydroxy-2-methylpyridine (2.00 g, 18.3 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added drop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.825 g of an 80% dispersion in mineral oil, 27.5 mmol) in DMF (15 mL). The mixture was allowed to stir and warm to ambient temperature over 1 h. Next, 1-chloro-3-iodopropane (4.49 g, 22.0 mmol) was added drop-wise over 5 min. The resulting dark-brown mixture was stirred at ambient temperature for 4 h. Water (25 mL) was added, followed by saturated NaCl solution (25 mL), and the mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 4.57 g of an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:32]([CH2:33][CH3:34])=[N:31][NH:30][C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([F:29])[CH:23]=3)[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)C>C(O)(C)C.O1CCOCC1>[CH2:33]([C:32]1[C:17]2[C:18](=[N:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([F:29])[CH:23]=3)=[CH:21][C:16]=2[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])[NH:30][N:31]=1)[CH3:34]
Reactant: CCc1n[nH]c2nc(-c3ccc(O)c(F)c3)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CC(C)O
Product: CCc1n[nH]c2nc(-c3ccc(O)c(F)c3)cc(C(=O)N3CCNCC3)c12
Yield: 102.9 %

Procedure:
To a solution of 4-[3-ethyl-6-(3-fluoro-4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (0.23 g, 0.50 mmol) in iso-propanol (7 ml) was added 4N HCl in dioxane (1.3 ml). The reaction mixture was heated for 4 hours, diethyl ether was then added, the resulting precipitate was filtered off and washed once with diethyl ether to afford the hydrochloride salt of the title compound (0.19 g, 97%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[NH:13][NH2:14].[F:15][C:16]([F:20])([F:19])[C:17]#[N:18]>CO.CCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[NH:13][NH:14][C:17](=[NH:18])[C:16]([F:20])([F:19])[F:15]
Reactant: N#CC(F)(F)F
Reactant: CC(C)Oc1cc(NN)c(Cl)cc1Cl
Solvent: CCCCC
Solvent: CO
Product: CC(C)Oc1cc(NNC(=N)C(F)(F)F)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
Under a dry nitrogen atmosphere a stirred solution of 2.4 g (0.01 mole) of 2,4-dichloro-5-(1-methylethoxy)phenylhydrazine in 140 mL of methanol was cooled to -60° C. in a dry ice-isopropanol bath. Trifluoroacetonitrile (23.2 g, 0.24 mole) was bubbled into the cold solution during a two minute period. After complete addition the cold solution was stirred for 30 minutes, then allowed to warm slowly to room temperature during the next three hours. A stream of nitrogen gas was bubbled into the room temperature solution to aid in the vaporization and removal of trifluoroacetonitrile, leaving a liquid residue. This residue was evaporated further under reduced pressure to leave a resinous material. This material was stirred in cold pentane to produce a solid. The pentane was decanted and the solid triturated in fresh cold pentane. The pentane was decanted and the solid dried under reduced pressure to yield 2.9 g of N-[2,4-dichloro-5-(1-methylethoxy)anilino]trifluoroacetamidine (mp 80.5°-81° C.).
Reaction SMILES: CN1C[CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH:16][C:17]4[C:22]([N+]([O-])=O)=[CH:21][CH:20]=[CH:19][N:18]=4)[CH:14]=3)[NH:9][CH:8]=2)C1.CO[CH:28](OC)[N:29]([CH3:31])[CH3:30].C(OCC)(=O)C.CO.[CH2:42]([N:44](CC)CC)C>>[CH3:30][N:29]1[CH2:31][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N:16]4[C:20]5[C:19](=[N:44][CH:42]=[CH:22][CH:21]=5)[NH:18][CH2:17]4)[CH:14]=3)[NH:9][CH:8]=2)[CH2:28]1
Reactant: COC(OC)N(C)C
Reactant: CN1CCC(c2c[nH]c3ccc(Nc4ncccc4[N+](=O)[O-])cc23)C1
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCC(c2c[nH]c3ccc(N4CNc5ncccc54)cc23)C1
Yield: 24 %

Procedure:
3-(N-Methylpyrrolidin-3-yl)-5-(3-nitropyrid-2-ylamino)-1H-indole was used. Reduction was by catalytic hydrogenation, the cyclization reaction used dimethylformamide dimethylacetal, and the cyclization reaction was heated for 24 hours. Chromatography using 9:1:1 [ethyl acetate/methanol/triethylamine] afforded the title compound (24%) as a white solid: mp, 110.0°-112.0° C.; 13C NMR (CDCl3) δ 147.7, 144.8, 144.3, 136.2, 135.7, 128.3, 127.3, 126.8, 122.4, 119.0, 118.7,115.6, 112.4, 62.3, 56.2, 42.2, 34.9, 32.1. HRMS calculated for C19H19N5 317.1643, found 317.1665. Anal. calcd for C19H19N5.0.5 C4H8O4 [ethyl acetate].0.5 H2O: C, 68.08; H, 6.53; N, 18.90. Found: C, 67.93; H, 6.51; N, 19.17.