Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([I:3])[CH3:2].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2([CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1>CO>[I-:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2([CH2:14][N+:15]3([CH2:1][CH3:2])[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:12][CH2:13]2)=[CH:7][CH:6]=1
Reactant: CCI
Reactant: Clc1ccc(C2(CN3CCCC3)CC2)cc1
Solvent: CO
Product: CC[N+]1(CC2(c3ccc(Cl)cc3)CC2)CCCC1
Product: [I-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 93 %

Procedure:
1-[1-(4-chloro-phenyl)-cyclopropylmethyl]-1-ethyl-pyrrolidinium iodide is prepared from the reaction of the parent amine 1-[1-(4-chloro-phenyl)-cyclopropylmethyl]-pyrrolidine with ethyl iodide. A 100 gm (0.42 mole) of the amine, 1-[1-(4-chloro-phenyl)-cyclopropylmethyl]-pyrrolidine, is dissolved in 1000 ml anhydrous methanol in a 3-liter 3-necked reaction flask (equipped with a mechanical stirrer and a reflux condenser). To this solution, 98 gm (0.62 mole) of ethyl iodide is added, and the mixture is stirred at room temperature for 72 hours. Then, 39 gm (0.25 mol.) of ethyl iodide is added and the mixture is heated at reflux for 3 hours. The reaction mixture is cooled down and excess ethyl iodide and the solvent are removed at reduced pressure on a rotary evaporator. The obtained dark tan-colored solids (162 gm) are further purified by dissolving in acetone (500 ml) followed by precipitation by adding diethyl ether. Filtration and air-drying the obtained solids gives 153 gm (93% yield) of the desired 1-[1-(4-chloro-phenyl)-cyclopropylmethyl]-1-ethyl-pyrrolidinium iodide as a white powder. The product is pure by 1H and 13C-NMR analysis.
Reaction SMILES: C(=O)(OC(C)(C)C)N.[F:9][CH:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[C@@H:12]([C:23](=[O:38])[NH:24][C:25]2([C:28]3[CH:33]=[CH:32][C:31]([C:34]([O:36][CH3:37])=[O:35])=[CH:30][CH:29]=3)[CH2:27][CH2:26]2)[CH2:11]1>>[F:9][CH:10]1[CH2:15][CH2:14][NH:13][C@@H:12]([C:23]([NH:24][C:25]2([C:28]3[CH:29]=[CH:30][C:31]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:33]=3)[CH2:26][CH2:27]2)=[O:38])[CH2:11]1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC(F)CCN3C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)(C)OC(N)=O
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC(F)CCN3)CC2)cc1
Yield: 87.5 %

Procedure:
The title compound (D96) (26 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (2R)-tert-butyl 4-fluoro-2-((1-(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)piperidine-1-carboxylate (D65) (39 mg).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.C(N1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])(OCC)=O.C(N(CC)CC)C>C(Cl)Cl.O>[OH:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([N:2]2[C:19](=[O:20])[C:18]3[C:17](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:16]2=[O:25])[CH2:4][CH2:5]1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of trans-4-aminocyclohexanol hydrochloride (1.0 g, 6.6 mmol) (Aldrich, Cat. #263761), N-carbethoxyphthalimide (1.4 g, 6.6 mmol) (Aldrich, Cat. #C5459), and triethylamine (2.0 mL, 14 mmol) in methylene chloride (10 mL) was stirred at r.t. overnight. The mixture was diluted with water, and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes to afford the desired product (1.2 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.CN.C[CH2:26][N:27](C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:27][CH3:26])[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)nc(Cl)nc32)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: CCCCO
Product: CNc1nc(Cl)nc2c1c(I)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To a mixture of 2,4-dichloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (0.6 g, 1.28 mmol) in nBuOH (2 mL) was added methylamine (2M THF, 0.77 mL, 1.54 mmol) and DIPEA (0.274 mL, 1.54 mmol). After stirring at ambient temperature for 1 h, the resulting precipitate was collected by filtration to give 2-chloro-N-methyl-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.275 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3([N:23]4[CH2:32][C@H:31]([OH:33])[CH2:30][C@H:24]4[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=4)[NH:12][C:11]3=[O:22])[C:4]=2[O:3][CH2:2]1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[C:38]([O:46][C:47]([F:50])([F:49])[F:48])[CH:37]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3([N:23]4[CH2:32][C@H:31]([OH:33])[CH2:30][C@H:24]4[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=4)[N:12]([S:42]([C:39]4[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[CH:37][C:38]=4[O:46][C:47]([F:48])([F:49])[F:50])(=[O:44])=[O:43])[C:11]3=[O:22])[C:4]=2[O:3][CH2:2]1
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C1(c2cccc3c2OCO3)C(=O)Nc2ccc([N+](=O)[O-])cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cccc4c3OCO4)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc([N+](=O)[O-])ccc32)c(OC(F)(F)F)c1
Yield: 37.5 %

Procedure:
With 279 mg of the compound obtained in Step 94-2 (Isomer B) and 214 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 163 mg of the title compound (pale yellow solid) was obtained by a similar method to Example 2.
Reaction SMILES: [CH3:1][C:2]([C:6]1([OH:21])[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7]1)([CH3:5])[CH:3]=[CH2:4]>CO.[Pd]>[CH3:5][C:2]([C:6]1([OH:21])[CH2:10][CH2:9][NH:8][CH2:7]1)([CH3:1])[CH2:3][CH3:4]
Reactant: C=CC(C)(C)C1(O)CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CCC(C)(C)C1(O)CCNC1
Reaction time: 3 h

Procedure:
Benzyl 3-(1,1-dimethylprop-2-en-1-yl)-3-hydroxypyrrolidine-1-carboxylate (56 mg, 0.00019 mol) was dissolved in methanol and to this solution was added Pd/C (10% dry, 10 mg). The reaction vessel was purged with hydrogen and allowed to stir for 3 h with a hydrogen balloon. The catalyst was filtered off and the filtrate was concentrated in-vauo to afford the desired product. LCMS (M+H)=158.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][NH2:24])[CH3:20]>CN(C)C=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:24][CH2:23][CH2:22][N:21]([CH2:25][CH3:26])[CH2:19][CH3:20])=[N:7][N:6]=[CH:5]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: CCN(CC)CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)CCNc1nncc2cc(Br)ccc12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
6-Bromo-1-chlorophthalazine (0.22 g, 0.91 mmol) was dissolved in N,N-dimethylformamide (3 mL) and potassium carbonate (0.25 g, 1.81 mmol) and N1,N1-diethylethane-1,2-diamine (0.25 mL, 1.81 mmol) were added. The reaction mixture was heated to 80° C. for 5 h, cooled to ambient temperature and stirred for 16 h. The reaction mixture was diluted with 20 mL of EtOAc, added to an addition funnel and partitioned with sodium bicarbonate (saturated, aqueous). The organic layer was washed 3× with 20 mL of sodium bicarbonate (saturated, aqueous) and once with aqueous brine, separated, dried over sodium sulfate, and concentrated via rotovap to give crude product. The crude was purified by chromatography to obtain the title compound. Found MS (ES+): 323(M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>C(O)CCC.CN1C(=O)N(C)CCC1>[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH:21][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]c(-c3ccccc3)cc12
Reactant: Nc1cccc(Cl)c1
Solvent: CCCCO
Solvent: CN1CCCN(C)C1=O
Product: Clc1cccc(Nc2ncnc3[nH]c(-c4ccccc4)cc23)c1
Reaction time: 2 h

Procedure:
A suspension of 1.251 g (5.45 mmol) of 4-chloro-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine and 1.15 ml (10.9 mmol) of 3-chloro-aniline in 20 ml of n-butanol and 0.5 ml of DMPU is heated at boiling for 2 hours. The reaction mixture is cooled and filtered. Stirring of the residue in hot THF/methanol yields the title compound; m.p. 285-286° C.; FAB-MS: (M+H)+ =321.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN(C=O)C>C(OCC)(=O)C.O>[CH2:11]([N:5]1[CH:4]=[C:3]2[C:7]([CH:8]=[CH:9][CH:10]=[C:2]2[Br:1])=[N:6]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Brc1cccc2[nH]ncc12
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cccc2nn(Cc3ccccc3)cc12
Temperature: 25 °C
Yield: 65.1 %

Procedure:
4-Bromoindazole of Example 2 (17.4 g, 0.088 M), benzyl bromide (22.7 g, 0.132 M) and DMF (35 mL) were heated to about 50° C. for 25 hours (HPLC: 15:1 ratio of 2-N and 1-N isomers). The mixture was cooled to ambient temperature and diluted with ethyl acetate (160 mL) and water (100 mL). The organic layer was separated, washed with aqueous sodium bicarbonate (5%, 100 mL). The organic layer was separated and concentrated under reduced pressure. The residue was diluted with isopropanol (160 mL) and concentrated under reduced pressure to a volume of about 120 mL. The mixture was heated to 50° C. to dissolve the solid and diluted with water (70 mL) to precipitate the product. The slurry was cooled to 0° C. and the precipitate was filtered off. The solid was washed with a mixture of IPA and Water (1:1, 50 mL), and dried at 50° C. to provide the titled compound (16.5 g, 77%, which contained less than 2% of 1-N-isomer by HPLC): 1H NMR (CDCl3, δ, ppm) 5.56 (s, 2H), 7.11 (m, 1H), 7.21 (d, J=7.2 Hz, 1H), 7.24-7.39 (m, 5H), 7.65 (d, J=8.6 Hz, 1H), 7.88 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9](Br)[C:8]([Cl:12])=[CH:7][C:6]=1[O:13][CH2:14][CH3:15])[CH3:2].[Cu][C:18]#[N:19]>CN(C)C=O.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([C:18]#[N:19])[C:8]([Cl:12])=[CH:7][C:6]=1[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: CCOC(=O)c1cc(Br)c(Cl)cc1OCC
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(C#N)c(Cl)cc1OCC
Yield: 47.2 %

Procedure:
To a solution of 5-bromo-4-chloro-2-ethoxy-benzoic acid ethyl ester (940 mg, 3.0 mmol) in 20 mL of dimethylformamide was added copper(I) cyanide (327 mg, 3.65 mmol). The reaction was stirred at reflux overnight. The reaction was diluted with methylene chloride. It was washed twice with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes) gave 4-chloro-5-cyano-2-ethoxy-benzoic acid ethyl ester (359 mg, 47%). LC-MS: 254.1 [(M+H)+].
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.[CH3:12][C:13]([CH3:21])([CH:16]([OH:20])[CH:17]([CH3:19])[CH3:18])[CH2:14]O>C1(C)C(C)=CC=CC=1>[CH:17]([CH:16]1[C:13]([CH3:21])([CH3:14])[CH2:12][O:6][C:1](=[O:11])[C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:5])[O:20]1)([CH3:19])[CH3:18]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)C(O)C(C)(C)CO
Solvent: Cc1ccccc1C
Product: CC(C)C1OC(=O)c2ccccc2C(=O)OCC1(C)C
Temperature: 1 °C
Yield: 57.5 %

Procedure:
A solution of 114.82 g (0.10 mole) of phthalic anhydride and 16.31 g (0.11 mole) of 2,2,4-trimethyl-1,3-pentanediol (TMPD) in 250 mL of xylene was heated for 96 hr as described in Examples 1-3. Xylene was removed on a rotary evaporator at 20 torr, at a base temperature of 68° C. The residue (30.0 g) was diluted with 30 mL of methanol and the resulting slurry cooled to 1° C., filtered, and washed with methanol which had been chilled to -20° C. to give 15.9 g (58% yield) of 7-Isopropyl-8,8-dimethyl-8,9-dihydro-7H-6,10-dioxabenzocyclononene-5,11-dione, which was 99.9% pure by vapor phase chromatography (vpc). The methanol washing from recovery of 7-Isopropyl-8,8-dimethyl-8,9-dihydro-7H-6,10-dioxabenzocyclononene-5,11-dione contained, on a methanol-free basis, 16.4% of 7-Isopropyl-8,8-dimethyl-8,9-dihydro-7H-6,10-dioxabenzocyclononene-5,11-dione, while the residue from stripping xylene from the original reaction mixture contained 41.2% of 7-Isopropyl-8,8-dimethyl-8,9-dihydro-7H-6,10-dioxabenzocyclononene-5,11-dione.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C@@H:26]([NH2:28])[CH3:27]>>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C@@H:26]([NH:28][CH2:16][CH2:15][C:2]1([OH:1])[CH2:3][CH2:4][C:5]2([O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][O:10]2)[CH2:13][CH2:14]1)[CH3:27]
Reactant: Cc1ccc(C)c([C@H](C)N)c1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Product: Cc1ccc(C)c([C@H](C)NCCC2(O)CCC3(CC2)OCC(C)(C)CO3)c1
Yield: 77 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(2,5-dimethyl-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 77% of theory; LC (method 5): tR=1.12 min; Mass spectrum (ESI+): m/z=376 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])[C:5]([Cl:20])=[CH:4][C:3]=1[CH2:21][OH:22].[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27]>CN(C=O)C>[CH2:27]([O:22][CH2:21][C:3]1[C:2]([Br:1])=[CH:7][C:6]([CH2:8][O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:11]([CH3:12])[CH3:13])[CH:14]([CH3:15])[CH3:16])=[C:5]([Cl:20])[CH:4]=1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: CC(C)[Si](OCc1cc(Br)c(CO)cc1Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCc1cc(Cl)c(CO[Si](C(C)C)(C(C)C)C(C)C)cc1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.9 %

Procedure:
To a solution of alcohol 30 (31 g, 75.5 mmol) in DMF (300 mL) were added NaH (60% dispersion in mineral oil, 4.0 g, 98.2 mmol) at 0° C. The mixture was stirred at 0° C. for 15 min and allyl bromide (23 mL, 264 mmol) was added to the mixture at 0° C. The mixture was warmed up to room temperature and stirred at room temperature for 2 h. After dilution with water, the mixture was extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography to provide the titled compound 31 (32.1 g, 95%).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH2:22][C:23]1[N:28]2[N:29]=[CH:30][C:31]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([OH:41])([CH3:40])[CH3:39])=[N:36][CH:37]=3)=[C:27]2[N:26]=[C:25]([CH:42]2[CH2:48][CH:47]3[NH:49][CH:44]([CH2:45][CH2:46]3)[CH2:43]2)[C:24]=1I.[CH3:51][S:52]([O-:54])=[O:53].[Na+].CS(C)=O>[Cu]I>[NH2:22][C:23]1[N:28]2[N:29]=[CH:30][C:31]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([OH:41])([CH3:40])[CH3:39])=[N:36][CH:37]=3)=[C:27]2[N:26]=[C:25]([CH:42]2[CH2:48][CH:47]3[NH:49][CH:44]([CH2:45][CH2:46]3)[CH2:43]2)[C:24]=1[S:52]([CH3:51])(=[O:54])=[O:53]
Reactant: CS(=O)[O-]
Reactant: CC(C)(O)c1ccc(-c2cnn3c(N)c(I)c(C4CC5CCC(C4)N5)nc23)cn1
Agent: [Cu]I
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CC(C)(O)c1ccc(-c2cnn3c(N)c(S(C)(=O)=O)c(C4CC5CCC(C4)N5)nc23)cn1
Yield: 82.1 %

Procedure:
2-{5-[7-amino-5-(8-azabicyclo[3.2.1]oct-3-yl)-6-iodopyrazolo[1,5-a]pyrimidin-3-yl]pyridin-2-yl}propan-2-ol tris(trifluoroacetate) (salt) (0.720 g, 0.851 mmol), sodium methanesulfinate (306 mg, 2.55 mmol), and Copper(I) iodide (486 mg, 2.55 mmol) were dissolved/suspended in dry dimethyl sulfoxide (18 mL, 250 mmol) under a nitrogen atmosphere. The reaction was placed in an oil bath at 90° C. After mixing 15 min, HPLC showed the starting material to have been consumed and a mixture of the desired material:des-iodo material was observed. The reaction mixture was poured into a 7:3 mixture of sat'd NH4Cl:20% NH4OH (200 ml) and extracted 3×75 ml with 10% IPA in DCM. The combined organics were washed with brine, dried, filtered and evaporated to provide a yellow oil, which was purified by silica gel chromatography, eluted with 0-15% (10% NH4OH in MeOH) in chloroform to provide the desired material as a yellow solid (319 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:8]([CH3:11])=[CH:9][N:10]=1)=[O:5])C.[OH-].[K+:21]>CCO>[K+:21].[CH3:11][C:8]1[N:7]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:18])[CH3:19])[C:6]([C:4]([O-:5])=[O:3])=[N:10][CH:9]=1
Reactant: CCOC(=O)c1ncc(C)n1COCC[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cnc(C(=O)[O-])n1COCC[Si](C)(C)C
Reaction time: 1 h

Procedure:
To a solution of 5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid ethyl ester (as prepared in the previous step, 0.090 g, 0.32 mmol) in 2 mL of ethyl achohol (EtOH) at RT was added 0.16 mL of 2N KOH. The mixture was stirred for 1 h and then concentrated and dried under vacuum to afford the title compound as a solid that was used without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C:13]1[N:14]=[C:15]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[O:16][C:17]=1[CH2:18][OH:19])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([C:13]1[N:14]=[C:15]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[O:16][C:17]=1[CH:18]=[O:19])[CH3:12]
Reactant: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1C=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of oxalyl chloride (2.0M/DCM, 3.52 mL, 7.04 mmloe) in DCM (50 mL), is injected DMSO (0.998 mL, 14.1 mmole) and stirred for 15 minute at −78° C. A solution of [4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol (1.59 g, 5.86 mmole) in DCM (10 mL) is then added. After stirred for 30 minutes, triethyl amine (4.08 mL, 29.3 mmole) is added. The reaction is kept at −78° C. for another 30 minutes, then warmed up to room temperature for 2 hours, washed with brine (3×50 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography (silica gel, 10% ethyl acetate in hexane) and concentrated to provide the titled compound as a white solid. Mass [EI+] 270 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([N:25]5[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]5)[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[N:13][N:14]=[C:8]2[CH:7]=1.Cl.[OH-].[Na+]>C1COCC1.CO.O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[N:13][N:14]=[C:8]2[CH:7]=1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(N5CCN(C(=O)OC(C)(C)C)CC5)c4n3)nnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: COCCOc1ccn2c(-c3ccc4cccc(N5CCNCC5)c4n3)nnc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.7 %

Procedure:
To a solution of tert-butyl 4-(2-(7-(2-methoxyethoxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yl)piperazine-1-carboxylate (0.022 g, 0.0436 mmol) in THF/MeOH (1 mL) was added 4 M HCl (0.109 mL, 0.436 mmol) in dioxane. The reaction mixture was stirred at ambient temperature for 16 hours then neutralized with 1 M NaOH and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified via flash column chromatography (40:1 DCM/MeOH followed by 10:1 DCM/MeOH) to provide 4 mg (23%) of desired product as a yellow solid. MS APCI (+) m/z 405.4 (M+1) detected.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH2:16]([O:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH:17]([CH3:19])[CH3:18].O>CC(C)=O>[CH3:18][CH:17]([CH3:19])[CH2:16][O:20][CH2:21][CH2:22][CH2:23][NH:24][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9]
Reactant: CC(C)COCCCN
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC(C)COCCCNC(c1ccccc1)C(O)c1ccccc1
Temperature: 140 °C
Reaction time: 18 h
Yield: 29.4 %

Procedure:
A mixture of trans-stilbene oxide (91.96 g, 0.10 mole) and 3-isobutoxy-1-propylamine (3.93 g, 0.030 mole) was heated at 140° C. for 5 hrs. After standing at ambient temperature for 18 hrs the mixture was dissolved in acetone (20 ml) and the solution poured into water (120 ml). A solid formed rapidly which was collected by filtration and dried under ambient conditions to obtain 2.89 g (88%) of the desired product. Recrystallization from tolueneisooctone gave 2.44 g of an off-white solid, m.p. 90°-92° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3](B(O)O)=[N:2]1.COCCOC.I[C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][CH2:22][CH2:21][C:20]=2[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[O:24]1[C:19]2[CH:18]=[CH:17][C:16]([C:3]3[CH:4]=[CH:5][NH:1][N:2]=3)=[CH:25][C:20]=2[CH2:21][CH2:22][CH2:23]1
Reactant: Ic1ccc2c(c1)CCCO2
Reactant: OB(O)c1cc[nH]n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: COCCOC
Product: c1cc(-c2ccc3c(c2)CCCO3)n[nH]1
Temperature: 90 °C
Yield: 14 %

Procedure:
To a solution of B-(1H-pyrazol-3-yl)boronic acid (400 mg, 3.57 mmol) in a mixture of tetrahydrofuran (THF), 1,2-dimethoxyethane and water (1:2:1), was added 3,4-dihydro-6-iodo-2H-1-benzopyran (1.53 g, 5.88 mmol; prepared according to Muraki et al., Tetrahedron Lett. 1996, 37, 2441) under nitrogen atmosphere. Then potassium carbonate (980 mg, 7.14 mmol) and bis(triphenylphosphine)palladium(II) dichloride (120 mg, 0.017 mmol) were added, and the reaction mixture was heated at 90° C. for 3 h. The reaction mixture was concentrated and purified by silica gel column chromatography using 30% ethyl acetate in petroleum ether as eluant to provide the title product as solid (100 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[N:5]=[C:4]([S:17][CH3:18])[N:3]=1.[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([S:17][CH3:18])=[N:5][C:6]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16]
Reactant: CSc1nc(Cl)c(C)c(-c2ccc(F)cc2F)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1nc(Cl)c(CBr)c(-c2ccc(F)cc2F)n1
Reaction time: 6 h

Procedure:
A suspension of 5.4 g of 4-chloro-6-(2,4-difluorophenyl)-5-methyl-2-(methylthio)pyrimidine. 3.69 g of N-bromosuccinimide, and 460 mg of benzoyl peroxide in 75 mL of CCl4 was heated to reflux and stirred at this temperature for 6 h, then cooled in the freezer for 1 h. The solids were filtered and washed liberally with cold CCl4, and the filtrate was concentrated. The residue was purified by flash chromatography on a Biotage 40M column, eluting with a gradient system of 99:1 to 97:3 hexanes-acetone to yield the title compound. Mass spectrum (ESI) 367 (M+1).