Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.CC(O)=O.CS(O)(=O)=O.CCOC(C)=O>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[NH:7][C:1]3[C:6]([C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:14][CH:15]=1
Reactant: NNc1ccccc1
Reactant: CS(=O)(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
A solution of phenylhydrazine (203 uL, 1.73 mmol) and 1-(4-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)ethanone (510 mg, 1.73 mmol) (Step 2) in a mixture of toluene/HOAc (2:1; 5 mL) containing 1 drop of methanesulfonic acid was stirred at r.t. overnight. The reaction mixture was diluted with EtOAc and was washed successively with H2O, 1M NaOH, H2O and dried. Evaporation of the solvent gave a residue which was purified by silica gel chromatography using EtOAc/hexane (1:3+10% CH2Cl2) as eluent to afford 339 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:17]1[S:25][C:24]2[C:19](=[N:20][CH:21]=[CH:22][C:23]=2[NH:26][C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][C:31]([CH3:36])=[CH:30]3)[CH:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:17]1[S:25][C:24]2[C:19](=[N:20][CH:21]=[CH:22][C:23]=2[NH:26][C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][C:31]([CH3:36])=[CH:30]3)[CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2cc(Nc3ccnc4cc(Br)sc34)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Product: Cc1cc2cc(Nc3ccnc4cc(-c5cccn5C(=O)OC(C)(C)C)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from N-tert-butoxycarbonylpyrrole-2-boronic acid and (2-bromothieno[3,2-b]pyridin-7-yl)-(2-methyl-1H-indol-5-yl)-amine by the procedure analogous to example 2 above. 1H NMR (400 MHz, CD3OD) δ8.08 (d, 1H), 7.36 (m, 2H), 7.28, s, 1H), 7.27 (d, 1H), 6.94 (dd, 1H), 6.60 (d, 1H), 6.40 (m, 1H), 6.22 (dd, 1H), 6.10 (s, 1H), 2.40 (s, 3H), 1.90 (s, 9H); RP18-HPLC RT: 6.73 minutes; API MS: 445 (M+1).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[N:4]([CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[N:3]=1.C([Mg]Cl)(C)C.[CH2:23]([Sn:27]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:29][CH2:30][CH2:31][CH3:32])Cl)[CH2:24][CH2:25][CH3:26]>C1COCC1>[CH3:16][N:15]([CH3:17])[CH2:14][CH2:13][CH2:12][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=2)[C:2]([Sn:27]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:23][CH2:24][CH2:25][CH3:26])=[N:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1ccc2c(I)nn(CCCN(C)C)c2c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(CCCN(C)C)c2cc(C)ccc12
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 197.5 %

Procedure:
A solution of 3-(3-Iodo-6-methyl-1H-indazol-1-yl)-N,N-dimethylpropan-1-amine (480 mg, 1.4 mmol) in 20 mL of dry THF was cooled to −20° C. under nitrogen atmosphere, isopropylmagnesium chloride (1.4 mL, 2.8 mmol, 2M in THF) was added and stirred for 15 min at −20° C. Then tributylchlorostannane (0.8 mL, 2.8 mmol) was added and allowed to warm to room temperature. The reaction was cooled in an ice bath and quenched with saturated ammonium chloride solution, product extracted with ethyl acetate (3×50 mL), combined organics dried with sodium sulfate and concentrated to give 1.4 g of crude N,N-dimethyl-3-(6-methyl-3-(tributylstannyl)-1H-indazol-1-yl)propan-1-amine as an oil which was used in the next step directly without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]1[C:11](=[O:12])[CH2:10][C:9]1(C(OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:5])[CH3:2].[Cl-].[Na+].O>CS(C)=O>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]1[C:11](=[O:12])[CH2:10][CH:9]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)CCN1C(=O)CC1(C(=O)OCC)C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CCN1C(=O)CC1C(=O)OCC
Temperature: 180 °C
Reaction time: 9 h

Procedure:
To a solution of 9.5 g. (30 mmoles) of crude diethyl 1-(2-ethoxycarbonylethyl)-4-oxo-2,2-azetidine-dicarboxylate in 10 ml. of dimethyl sulfoxide 2.11 g. (36 mmoles) of sodium chloride and 1.1 ml. (60 mmoles) of water are added and the mixture is stirred for 9 hours at an oil bath of 180° C. The reaction mixture is poured on 200 ml. saturated aqueous hydrochloric acid solution and extracted with five 60-ml. portions of ether. The ethereal extract is dried with magnesium sulfate, filtered and the filtrate is evaporated in vacuo.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C@H:25]([NH2:27])[CH3:26].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Si:6]([O:5][C:4]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:2]([CH:3]=1)[NH:27][C@@H:25]([C:19]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=1[Cl:17])[CH3:26])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Cl)c(Br)c1
Reactant: C[C@@H](N)c1ccc(Cl)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: C[C@@H](Nc1cc(O[Si](C)(C)C(C)(C)C)ccc1Cl)c1ccc(Cl)cc1Cl
Temperature: 110 °C
Yield: 91.7 %

Procedure:
To a mixture of (3-bromo-4-chlorophenoxy)-t-butyldimethylsilane (15.0 g, 46.8 mmol) and (1R)-1-(2,4-dichlorophenyl)ethanamine (9.7 g, 51.5 mmol) in anhydrous toluene (250 mL) were added palladium(II) acetate (Pd(OAc)2) (0.42 g, 1.9 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (1.74 g, 2.80 mmol), and sodium t-butoxide (NaO-tBu) (6.3 g, 65.52 mmol). The resulting mixture was heated at 110° C. under nitrogen for 3 h. After cooling to room temperature, the suspension was filtered through a plug of Celite, and washed with ethyl acetate (EtOAc) (100 mL). The filtrate was concentrated in vacuo. The resulting residue was diluted with deionized water, and extracted with ethyl acetate (500 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 0-15% ethyl acetate in hexanes) to afford (R)-5-(t-butyldimethylsilyloxy)-2-chloro-N-(1-(2,4-dichlorophenyl)ethyl)aniline as a viscous oil (18.5 g, 42.9 mmol, 92%). 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=1.6 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.19 (dd, J=1.6, 8.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.13 (dd, J=2.2, 8.4 Hz, 1H), 5.71 (d, J=2.4 Hz, 1H), 4.87-4.84 (m, 1H), 4.67 (d, J=4.8 Hz, 1H), 1.58 (d, J=6.8 Hz, 3H), 0.98 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].COCCOC.[F:19][C:20]([F:26])([F:25])[S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[F:19][C:20]([F:26])([F:25])[S:21]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])(=[O:23])=[O:22]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: COCCOC
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 84.2 %

Procedure:
N-Trifluoromethanesulfonyloxyphthalimide was prepared by the following procedure. To a dried flask equipped with a stirrer, under nitrogen, were added N-hydroxyphthalimide (3.04 g, 18.7 mmol), 60 mL of dried DME, and trifluoromethanesulfonyl chloride (2.00 mL, 18.7 mmol). The mixture was cooled to -15° and triethylamine (3.00 mL, 22 mmol) was added dropwise by syringe. After warming to room temperature, 100 mL of methylene chloride was added and the resulting mixture was washed with 100 mL of 2% aqueous sodium bicarbonate and dried. Evaporation of the solvent gave 4.65 g of crude N-trifluoromethanesulfonyloxyphthalimide: mp 90°-93°. Recrystallization from methylene chloride-hexane gave 2.65 g (48%) of product as shiny white flakes: mp 99°-102°; uv (CH3CN) 220 (47,000), 249 (2090), 297 nm (2290); ir (KBr) 1810 (m), 1750 (vs), 1440 (s), 1240 (s), 1230 (s), 1220 (s), 1115 (m), 940 (m), 860 (m), 695 (s), 585 (m); nmr (CDCl3) 8.10-7.85 (m); 19F nmr (CDCl3) -71.42 ppm (s); mass spectrum 294.9782 (calcd for C9H4NO5F3S: 294.9762).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[OH:16])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:23][CH2:24][CH2:25]Br>CC#N>[Br:23][CH2:24][CH2:25][O:16][C:8]1[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=1[N:4]1[CH:5]=[N:6][C:2]([CH3:1])=[N:3]1
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2O)n1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCBr)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
To a stirred mixture of 2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenol (3 g, 13.63 mmol) and K2CO3 (2.4 g, 17.79 mmol) in MeCN (30 mL) was added 1,2-dibromoethane (3.3 g, 17.71 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (100 mL) and washed with brine (2×25 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo to give 1-(2-(2-bromoethoxy)-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (2.2 g, 49.5%) as a light orange solid. LC-MS (M+H)+=327.13. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.15 (1H, s), 8.09-8.04 (3H, m), 4.70-4.69 (2H, m), 3.99-3.97 (2H, m), 2.40 (3H, s).
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5]1>O.CO>[CH3:3][N:4]1[CH2:9][CH2:8][C@H:7]([OH:10])[C@H:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5]1
Reactant: CN1CCC(=O)C(c2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CC[C@H](O)[C@H](c2ccccc2)C1
Reaction time: 0.5 h

Procedure:
Sodium borohydride (9.46 g) is added portionwise to a solution of the compound of formula IV, (-methyl-3-phenyl-4-piperidone (94.6 g, described by A. A. Patchett and F. F. Gianuso, supra), in water-methanol 1:9 (250 ml). The mixture is stirred for 30 minutes and the methanol is evaporated. The aqueous residue is diluted with water, 6N hydrochloric acid and washed with ether. The aqueous phase is made alkaline and extracted with chloroform. The chloroform extract is evaporated and crystallized from ether to give cis-1-methyl-3-phenyl-4-piperidinol, mp 131-133° C. Anhydrous hydrogen chloride is added to the mother liquors and the precipitate is crystallized from methanol-ether to give trans-1-methyl-3-phenyl-4-piperidnol hydrochloride, mp 131-133° C.
Reaction SMILES: [ClH:1].[CH2:2]([NH:9][CH:10]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[CH2:12][CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:32][C:33]([O:35]CC)=[O:34]>C(O)C>[ClH:1].[CH2:2]([N:9]([CH:10]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[CH2:12][CH2:11]1)[CH2:32][C:33]([OH:35])=[O:34])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cc2c(cc1OC)C(NCc1ccccc1)CC2
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCO
Product: COc1cc2c(cc1OC)C(N(CC(=O)O)Cc1ccccc1)CC2
Yield: 69.7 %

Procedure:
To a solution of 17 g of 1-benzylamino-5,6-dimethoxyindane hydrochloride in 300 ml of ethanol are added 10 g of potassium carbonate, 3.0 g of potassium iodide and 17 g of ethyl bromoacetate, and the mixture is refluxed for 8 hours. The ethanol is distilled off under reduced pressure, 500 ml of ice-water is added to the residue, and extraction with 500 ml of ethyl acetate is carried out. After the extract is washed with water and dried, the ethyl acetate is distilled off under reduced pressure. The residue is dissolved in 200 ml of ethanol. To the solution are added 5.0 g of sodium hydroxide and 10 ml of water, and the mixture is refluxed for 2 hours. Thereafter, the ethanol is evaporated under reduced pressure, and the residue is dissolved in 300 ml of water. The mixture is neutralized with acetic acid, and subjected to extraction with 300 ml of chloroform. After the extract is washed with water and dried, the chloroform is distilled off. To the residue are added 20 ml of 20% alcoholic hydrochloric acid and 200 ml of ethyl ether, and the mixture is allowed to stand. Collection of the crystalline precipitates by filtration gives 14 g of N-benzyl-N-(5,6-dimethoxy-1-indanyl)glycine hydrochloride as colorless needles. Melting point: 174°-177° C.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3].[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:30][CH2:31][CH:32]2[CH2:33][CH2:34]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][N:27]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3]
Reactant: CCC(=O)Cl
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C(C)=O)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[5-acetyl-2-(cyclopropylmethoxy)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f55) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[C:13]([O:23][CH2:24][CH2:25][CH3:26])[CH:14]=[C:15]4[CH2:22][CH2:21][CH2:20][C:16]4=3)[NH:11][CH:10]=2)=[CH:5][CH:4]=1.[I-].[Na+].[H-].[Na+].[P:31]([O:43][CH2:44]Cl)([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>CN(C=O)C>[P:31]([O:43][CH2:44][N:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:18](=[O:19])[C:17]2[C:12]1=[C:13]([O:23][CH2:24][CH2:25][CH3:26])[CH:14]=[C:15]1[CH2:22][CH2:21][CH2:20][C:16]1=2)([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:32]
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Reactant: CCCOc1cc2c(c3c(=O)c(-c4ccc(OC)cc4)c[nH]c13)CCC2
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1cc2c(c3c(=O)c(-c4ccc(OC)cc4)cn(COP(=O)(OC(C)(C)C)OC(C)(C)C)c13)CCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
To a DMF solution (10 ml) of 8-(4-methoxyphenyl)-5-propoxy-1,2,3,6-tetrahydro-6-aza-cyclopenta[a]naphthalen-9-one (400 mg, 1.15 mmol) and sodium iodide (343 mg, 2.29 mmol) was added sodium hydride (60% oil base, 74.9 mg, 1.72 mmol), and the mixture was then stirred for 10 minutes at room temperature. To the resulting mixture was added a DMF solution (20 ml) of di-tert-butyl chloromethyl phosphate (888 mg, 3.43 mmol), and the mixture was then stirred at 40° C. for 4 hours. The reaction mixture was ice-cooled, ice water was added thereto, and then the reaction mixture was subjected to extraction using ethyl acetate. The thus-obtained organic layer was washed with an aqueous saturated sodium chloride solution twice, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified using medium pressure liquid chromatography (NH silica gel, n-hexane:ethyl acetate=100:0→0:100). The purified product was concentrated under reduced pressure, giving a white powder of di-tert-butyl 8-(4-methoxyphenyl)-9-oxo-5-propoxy-1,2,3,9-tetrahydro-6-aza-cyclopenta[a]naphthalen-6-ylmethyl phosphate (263 mg, yield: 40%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])[N:3]=1.O.[NH2:23][NH2:24].C(#N)C>CCO>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=3)=[CH:15][CH:14]=2)[NH:24][N:23]=1
Reactant: CC(C)(C)Nc1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: CCO
Solvent: O
Solvent: CC#N
Product: CC(C)(C)Nc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 95 °C
Reaction time: 22 h

Procedure:
Into a 25 mL sealable tube under nitrogen were combined 4-{2-amino-6-[(1,1-dimethylethyl)amino]-4-pyrimidinyl}-2-fluorobenzonitrile (500 mg, 1.25 mmol) and hydrazine monohydrate (1.22 mL) in EtOH (8 mL). The vial was sealed, and the reaction mixture was stirred at 95° C. for 22 hours. The solution was concentrated, partitioned between EtOAc and water, and extracted with EtOAC (2×) and CH2Cl2. The organic layer was separated, washed with NaHCO3 and brine, dried (MgSO4), filtered and concentrated. The resulting solid was dissolved in a mixture of CH3CN/water/CH3OH/DMSO and purified on a Gilson RPHPLC (CH3CN/H2O w/0.1% TFA). Fractions were evaporated, aqueous potassium carbonate was added to the residue and the solution was stirred at room temperature for 2 hrs. The aqueous mixture was extracted with EtOAc (×2) and DCM (×2). The organic layer was separated, washed with brine, dried (MgSO4), filtered, concentrated and azeotroped with CH3CN to give a brown solid. Minimum amount of acetonitrile was added to the solids, and the resulting mixture was sonicated. A white precipitate crashed out which was filtered and washed with hexanes and Et2O to afford the title compound (102 mg) as a white solid. LC-MS (ES) m/z=298 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.42 (s, 9H), 5.36 (s, 2H), 5.90 (s, 2H), 6.31 (s, 1H), 6.53 (s, 1H), 7.36 (dd, J=8.6, 1.3 Hz, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.80 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:16])=[CH:13][C:12]([O:17]C)=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br.[OH-].[Na+]>ClCCl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:16])=[CH:13][C:12]([OH:17])=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2ccc(OC)cc2c1Cl
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCC(=O)c1cnc2ccc(O)cc2c1Cl
Reaction time: 8 h
Yield: 20.1 %

Procedure:
3-Butyryl-4-chloro-6-methoxyquinoline (7.9 g) was stirred in dry dichloromethane (150 ml) under nitrogen and boron tribromide (8.5 ml) was added via a syringe. The mixture was stirred overnight then cautiously added to a large volume of ice. The mixture was taken to pH 14 with sodium hydroxide solution, washed with dichloromethane, neutralized with hydrochloric acid and extracted several times with dichloromethane. The combined extracts were washed with brine, dried, filtered and evaporated to give 3-butyryl-4-chloro-6-hydroxyquinoline as a yellow powder (1.5 g, 20%) m.p. 157°-160°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9]2)[CH:2]=1.[CH:20]1([CH2:26][N:27]=[C:28]=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([CH2:26][NH:27][C:28](=[O:29])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:9][C:10]3([CH3:19])[CH3:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC1(C)CN(Cc2cccnc2)c2ccc(O)cc21
Reactant: O=C=NCC1CCCCC1
Product: CC1(C)CN(Cc2cccnc2)c2ccc(OC(=O)NCC3CCCCC3)cc21

Procedure:
The title compound was synthesized from 1-(3-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with cyclohexylmethylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (11.6 mg, 38%) having the following characteristics.
Reaction SMILES: [OH:1][C:2]1[CH2:3][C:4]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][C:6](=[O:8])[CH:7]=1.C1C(=O)N([Br:29])C(=O)C1>>[Br:29][C:7]1[C:6](=[O:8])[O:5][C:4]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3][C:2]=1[OH:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)CCCCC1(c2ccccc2)CC(O)=CC(=O)O1
Product: O=C(O)CCCCC1(c2ccccc2)CC(O)=C(Br)C(=O)O1

Procedure:
The title compound was prepared as described in General Method 3 using 1.4 mmol of 5-[4-hydroxy-6-oxo-2-phenyl-3,6-dihydro-2H-pyran-2-yl]pentanoic acid (prepared in Example J1) and 1.4 mmol of NBS. 1H NMR (DMSO-d6) δ 0.94 (m, 1 H), 1.22-1.40 (m, 3 H), 1.92 (m, 2 H), 2.13 (t, 2 H), 3.28 (q, 2 H), 7.16-7.52 (m, 5 H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][N:8]([CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:9]1[N:14]=[CH:13][N:12]=[C:11]2[NH:15][N:16]=[CH:17][C:10]=12.C1(C)C=CC(S([O:35][CH2:36][CH:37]2[CH2:41]OC(C)(C)[O:38]2)(=O)=O)=CC=1>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][N:8]([CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:9]1[N:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:41][CH:37]([OH:38])[CH2:36][OH:35])[N:16]=[CH:17][C:10]=12
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Reactant: Clc1cccc(CN(c2ncnc3[nH]ncc23)C2CCCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCC(O)Cn1ncc2c(N(Cc3cccc(Cl)c3)C3CCCC3)ncnc21
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a suspension of 1.5 g (30 mmole) 50% sodium hydride in 50 ml. N,N-dimethylformamide are added dropwise 9.6 g. (30 mmole) 4-[N-(3-chlorobenzyl)-cyclopentylamino]-1H-pyrazolo[3,4-d]pyrimidine (compound of Example 1) in 25 ml. N,N-dimethylformamide. The reaction mixture is stirred for 1 hour at 80° C., 10.0 g. (35 mmole) 4-(4-toluenesulphonyloxymethyl)-2,2-dimethyl-1,3-dioxolan in 25 ml. N,N-dimethylformamide are added thereto, the reaction mixture is further stirred for 3 hours at 80° C. and evaporated in a vacuum. The residue is taken up in water, extracted with dichloromethane and the extract evaporated. The residue is mixed with 300 ml. 0.1N hydrochloric acid, heated under reflux for 10 hours, allowed to cool, washed with diethyl ether and the aqueous phase rendered alkaline with aqueous sodium hydroxide solution. After extraction with dichloromethane and evaporation of the extract, there are obtained 8.2 g. of crude product which is purified by chromatography on silica gel (elution agent: dichloromethane/methanol; 9:1 v/v). 4.1 g. (34% of theory) of the title compound are eluted which, after trituration with diethyl ether, melts at 98°-100° C.