Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:7](S(C)(=O)=O)[N:6]=1)(=[O:4])=[O:3].[C-]#N.[K+].CN(C=[O:37])C>>[CH3:1][S:2]([C:5]1[N:6]=[C:7]([OH:37])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(S(C)(=O)=O)n1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [K+]
Product: CS(=O)(=O)c1nc(O)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
To a round bottom flask fitted with a magnetic stir bar and rubber septum was added 2 mL DMF, 6-[2,4-dichlorophenyl]-5-[4-chlorophenyl]-2,4-bis(methylsulfonyl)pyrimidine (Reference Example 5) (98 mg, 0.2 mmol) and potassium cyanide (15 mg, 0.22 mmol). The mixture was heated for 30 min at 80°. By LC, all starting material was consumed (Rt=3.59 min) and a new peak appeared (Rt=3.50 min). The molecular weight corresponded not to the cyano derivative, but to 2-methylsulfonyl-4-hydroxy-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine. (HPLC/MS: m/e=430 (M+)) probably due to the fact that the solvent was not anhydrous.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>C(O)C>[ClH:10].[Cl:10][CH2:11][C:12]1[N:1]=[C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][N:9]2[CH:14]=1
Reactant: N#Cc1ccnc(N)c1
Reactant: O=C(CCl)CCl
Solvent: CCO
Product: Cl
Product: N#Cc1ccn2cc(CCl)nc2c1
Temperature: 25 °C
Yield: 115.6 %

Procedure:
To an ethanol 50 mL solution of 2-amino-isonicotinonitrile (5.0 g, 42 mmol) was added 1,3-dichloroacetone (6.93 g, 54.6 mmol). The mixture was heated to reflux for 1.5 hr and cooled to room temperature to give a suspension. The precipitate was collected by suction filtration, washed with dichloromethane and dried to give the title compound (7.2 g). LC/MS: m/z 192(M+H).
Reaction SMILES: COC[O:4][C:5]1[C:10]2[C:11]3([CH2:14][O:15][CH2:16][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH2:13][CH2:12]3.O>CO>[C:11]12([C:10]3=[C:5]([OH:4])[CH:6]=[CH:7][CH:8]=[C:9]3[CH2:16][O:15][CH2:14]1)[CH2:13][CH2:12]2
Reactant: COCOc1cccc2c1C1(CC1)COC2
Solvent: O
Solvent: CO
Product: Oc1cccc2c1C1(CC1)COC2
Temperature: 50 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of 5-{[(methyloxy)methyl]oxy}-1H-spiro[2-benzopyran-4,1′-cyclopropane] (Intermediate 135, 380 mg) in methanol (10 mL) HCl 10% in water (1.048 mL, 3.45 mmol) was added and the reaction mixture was stirred overnight at 50° C. The combined solvents were evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 25 g SNAP column and cyclohexane/ethyl acetate as eluents from 100:0 to 8:2. This afforded the title compound as a white solid (260 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[C:23]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[CH:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cccc(N3CCOCC3)c21
Product: CC1c2c(cccc2N2CCOCC2)CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-8-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:24]#[N:25])([CH2:18][CH2:19][C:20]([O:22]C)=O)[CH2:12][CH2:13]C(OC)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].CO>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([C:24]#[N:25])[CH2:12][CH2:13][C:20](=[O:22])[CH2:19][CH2:18]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of dimethyl 4-(3,4-dimethoxyphenyl)-4-cyanopimelate (11.2 g, 32.1 mmol), sodium hydride (2.31 g, 48.1 mmol) and methanol (1 ml) in 250 ml anhydrous toluene was heated at reflux for 10 hours, cooled to 25° C., quenched with 4 ml acetic acid, washed with H2O, alkali, and brine and dried with MgSO4. The volatiles were removed in vacuo. The residue was recrystallized with hexanes-ethyl acetate. This intermediate was heated at reflux in ethanol, concentrated HCl and 25% aqueous H2SO4 for 10 hours. The volatiles were removed in vacuo. The residue was diluted with water and extracted with ether. The combined organic extracts were washed with water, brine and dried (MgSO4). The volatiles were removed in vacuo. The residue was recrystallized with toluene and then with hexanes-ethyl acetate, mp 111°-12° C. ##STR5##
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[OH-].[K+].C(O)C>O>[CH2:16]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCOc1ccc2cc(C(=O)O)ccc2c1
Reaction time: 2 h

Procedure:
6-Hydroxynaphthalene-2-carboxylic acid (39.8 g), 1-bromooctane (61.3 g), potassium hydroxide (23.7 g), ethanol (900 ml) and water (120 ml) were stirred and refluxed for 16 hours. 10% Aqueous potassium hydroxide (200 ml) was added and refluxing was continued for a further 2 hours, when the solution was poured into water (5 liter) and acidified to ph 1. The solid was filtered, washed with water, dried and recrystallised from acetic acid to give the product (49.0 g, 77.2% theory) as a white crystalline solid, mpt 150°-153° C. (98.2% pure by hplc).
Reaction SMILES: C([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]2[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=23)=[N:10]1)#N.S(=O)(=O)(O)O.[C:36](=[O:39])(O)[O-:37].[Na+]>>[C:36]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]2[C:17]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=23)=[N:10]1)([OH:37])=[O:39]
Reactant: N#CC1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)C1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 3-[2-(2-cyanocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (130 mg) and conc. sulfuric acid (1.5 ml) was stirred at room temperature for 45 minutes. Then, the mixture was cooled in an ice-bath and treated with saturated aqueous sodium bicarbonate to make pH of the mixture to 2.0. The mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The organic extract was dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was crystallized from diethyl ether to give colorless crystals of 3-[2-(2-carboxycyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.10 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[N+:16]([O-:18])=[O:17])[CH2:3][CH2:2]1.[CH3:19][Si](C=[N+]=[N-])(C)C>CO.CCCCCC>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:19])=[O:12])=[CH:9][C:8]=2[N+:16]([O-:18])=[O:17])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(N2CCOCC2)c([N+](=O)[O-])c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)c1ccc(N2CCOCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Morpholino-3-nitrobenzoic acid prepared in the same manner as in Example 10(1) (3.0 g) is dissolved in methanol (15 ml), and thereto is added dropwise a 10% solution of trimethylsilyldiazomethane in n-hexane in an equimolar amount, and the mixture is stirred at room temperature for one hour. Methanol is distilled off under reduced pressure, and the residue is extracted with ethyl acetate. The extract is washed with 5% aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution in this order, dried over anhydrous sodium sulfate, and ethyl acetate is distilled off under reduced pressure to give methyl 4-morpholino-3-nitrobenzoate (3.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4](OC)=[O:5].[BH4-].[Na+].CO.O>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: COC(=O)c1cc(F)ccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-bromo-5-fluorobenzoate (10, 21.30 g, 91.4 mmol) in dry THF (150 mL) was added NaBH4 (6.95 g, 183 mmol). Methanol (20 mL) was added dropwise at RT. After the addition, the mixture was stirred at RT for 1 h. Water (200 mL) was slowly added. The mixture was extracted with CH2Cl2 (100 mL×2). The combined extracts were washed with saturated NaHCO3 and brine, dried over MgSO4 and concentrated to give (2-bromo-5-fluorophenyl)methanol (11).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:12][C:11](=O)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:14])[CH:9]=2)[N:4]=1.P(Cl)(Cl)([Cl:17])=O>C(Cl)(Cl)Cl.CN(C)C1C=CC(C)=CC=1>[Cl:17][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:14])[CH:9]=2)[N:4]=[C:3]([CH2:2][Cl:1])[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2nc(CCl)[nH]c(=O)c2c1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccc(N(C)C)cc1
Product: Cc1ccc2nc(CCl)nc(Cl)c2c1

Procedure:
2. 114.1 g of 2-chloromethyl-6-methyl-3H-quina-zolin-4-one are dissolved in 1.11 of chloroform and 120 ml of N,N,4-trimethylaniline, treated with 53 ml of phosphorus oxychloride and heated at reflux temperature for 20 h. The reaction mixture is evaporated in a vacuum. The residue is dissolved in 1.0 l of ethyl acetate and washed in succession with 2N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. The organic extracts are concentrated to about 0.51 in a vacuum. The mixture is left to crystallize at -25° C. overnight. The crystal slurry is filtered, the crystals are washed with ethyl acetate (-25° C.) and dried in a vacuum. 89.9 g of 4-chloro-2-(chloromethyl)-6-methylquinazoline of m.p. 111°-112° C. are obtained. A further 11.1 g of 4-chloro-2-(chloromethyl)-6-methylquinazoline of m.p. 114°-116° C. can be obtained from the mother liquor.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:27][C:26]=2[O:37][CH3:38])[C:21]([Cl:39])=[CH:20][N:19]=1>>[Cl:39][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:27][C:26]=2[O:37][CH3:38])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)cc2CC1

Procedure:
5-Chloro-N*2*-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 308c. Product isolated as an off-white solid (137 mg, 75%). m.p.=144-146° C.; LCMS (m/e) 539 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.25 (d, 1H, J=8.8 Hz), 8.00 (s, 1H), 7.59 (s, 1H), 7.39 (s, 1H), 7.22-7.16 (m, 1H), 7.01 (d, 1H, J=8.0 Hz), 6.84 (s, 1H), 6.54 (bs, 1H), 6.52-6.46 (m, 1H), 3.92 (s, 3H), 3.92-3.86 (m, 4H), 3.54 (t, 2H, J=5.6 Hz), 3.36 (s, 3H), 3.19-3.13 (m, 4H), 2.94-2.87 (m, 4H), 2.78-2.68 (m, 6H).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=3[F:29])=[C:19]([F:30])[C:15]3[N:16]=[N:17][S:18][C:14]=3[CH:13]=2)=[O:11])[CH2:4][O:3]1.Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[C:19]([F:30])[C:15]2[N:16]=[N:17][S:18][C:14]=2[CH:13]=1)=[O:11]
Reactant: CC1(C)OCC(CONC(=O)c2cc3snnc3c(F)c2Nc2ccc(I)cc2F)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NOCC(O)CO)c1cc2snnc2c(F)c1Nc1ccc(I)cc1F
Yield: 79.4 %

Procedure:
To a solution of N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxamide (229 mg, 0.41 mmol) in CH2Cl2 (10 mL) was added 1.0 N HCl (aq., 1.5 mL, 1.5 mmol). The mixture was stirred for 1 h and neutralized with saturated sodium bicarbonate (aq.). The aqueous layer was extracted by CH2Cl2 (10 mL×2). The combined organic layers were washed by water (30 mL×2) and brine (30 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 20:1, v/v) to afford the desired product (yellow solid, 170 mg, 67.9% yield for two steps). 1H NMR (400 MHz, DMSO-d6): δ 11.98 (s, 1H), 8.40 (s, 1H), 8.20 (s, 1H), 7.58 (d, 1H), 7.33 (d, 1H), 6.64 (m, 1H), 4.86 (m, 1H), 4.62 (m, 1H), 3.87 (m, 1H), 3.72 (m, 2H), 3.33 (m, 2H, covered by the peak of water). MS APCI (+) m/z: 522.9 [M+H].
Reaction SMILES: [CH2:1]([O:5][P:6]([O:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH2:8]/[CH:9]=[CH:10]/[CH2:11][C:12]1([C:27]([NH:29][CH2:30][CH2:31][CH3:32])=[O:28])[C:24]2[CH:23]=[C:22]([F:25])[CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][C:15]([F:26])=[CH:16][CH:17]=2)=[O:7])[CH2:2][CH2:3][CH3:4]>[Pd]>[CH2:34]([O:33][P:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])([CH2:8][CH2:9][CH2:10][CH2:11][C:12]1([C:27]([NH:29][CH2:30][CH2:31][CH3:32])=[O:28])[C:13]2[CH:14]=[C:15]([F:26])[CH:16]=[CH:17][C:18]=2[C:19]2[C:24]1=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:7])[CH2:35][CH2:36][CH3:37]
Reactant: CCCCOP(=O)(C/C=C/CC1(C(=O)NCCC)c2cc(F)ccc2-c2ccc(F)cc21)OCCCC
Agent: [Pd]
Product: CCCCOP(=O)(CCCCC1(C(=O)NCCC)c2cc(F)ccc2-c2ccc(F)cc21)OCCCC
Reaction time: 14 h
Yield: 90 %

Procedure:
An ethanol solution of Example 195 compound (260 mg, 0.49 mmol) containing 50 mg of 10% palladium on carbon was stirred under a hydrogen atmosphere (balloon) for 14 hrs. The reaction was filtered through a 0.2 μm nylon filter to remove the catalyst and the solvent evaporated yielding 235 mg (90%) of title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH2:10][C:4]=2[C:3]=1[C:19]1[NH:20][N:21]=[N:22][C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N.CO>[ClH:1].[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:19]1[NH:20][N:21]=[N:22][C:23]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(N1CCc2ccc(Cl)c(-c3[nH]nnc3-c3ccccc3)c2CC1)C(F)(F)F
Agent: N
Solvent: CO
Product: Cl
Product: Clc1ccc2c(c1-c1[nH]nnc1-c1ccccc1)CCNCC2
Yield: 193.8 %

Procedure:
Stir 7-chloro-6-(5-phenyl-3H-[1,2,3]triazol-4-yl)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (43 mg, 0.1 mmol) in 7M ammonia in methanol (10 mL) for 16 h. Concentrate the mixture in vacuo, and purify the residue by SCX chromatography. Use a method similar to the General Procedure 2-2 to obtain the desired intermediate (35 mg, 97%). MS (ES+) m/z: 325 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:42]1[CH:43]=[C:44]2[C:61](=[N:62][CH:63]=1)[NH:60][C:59](=[O:64])[C:46]1([CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]1)[CH2:45]2>C(#N)CC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:6]([O:5][C:1](=[O:4])/[CH:2]=[CH:3]/[C:42]1[CH:43]=[C:44]2[C:61](=[N:62][CH:63]=1)[NH:60][C:59](=[O:64])[C:46]1([CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:56])([CH3:57])[CH3:58])=[O:53])[CH2:48][CH2:47]1)[CH2:45]2)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Cc1cc(Br)cnc1NC2=O
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CC1(CCN(C(=O)OC(C)(C)C)CC1)C(=O)N2

Procedure:
Tert-Butyl acrylate (3.9 mL, 26.8 mmol), diisopropylethylamine (2.46 mL, 14.1 mmol) and P(o-tolyl)3 (409 mg, 1.34 mmol) were successively added to a suspension of tert-butyl 6-bromo-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-1′-carboxylate (2.66 g, 6.7 mmol) in propionitrile (107 mL) and dimethylformamide (40 mL) in a sealed tube. The resulting mixture was then purged with argon prior to the addition of palladium acetate (151 mg, 0.673 mmol). The mixture was purged with argon again and refluxed overnight. The reaction mixture was then filtered on Celite® and the cake was washed with DCM (50 mL). The filtrate was concentrated to dryness and the residue was triturated with dichloromethane. The title product was obtained as a light grey solid (1.83 g, 61%, py 79.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:18](O)(=O)[CH3:19].[C:22]([BH3-])#N.[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][N:12]([CH:18]([CH3:19])[CH3:22])[CH2:11][CH2:10]1
Reactant: [BH3-]C#N
Reactant: O=[N+]([O-])c1ccc(OC2CCNCC2)c(Cl)c1
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)N1CCC(Oc2ccc([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 78 %

Procedure:
To a suspension of 3-chloro-4-(piperidin-4-yloxy)nitrobenzene (1.50 g) obtained in reference example 8 in acetone (20 ml) were successively added acetic acid (0.33 ml) and sodium cyanoborohydride (0.18 g) under ice-cooling, and the resulting mixture was stirred at room temperature for 4.5 hours. After stirring, to the reaction mixture was added sodium cyanoborohydride (0.18 g) and the resulting mixture was stirred at room temperature for 3 hours. After stirring, to the reaction mixture were furthermore added successively acetic acid (0.33 ml) and sodium cyanoborohydride (0.18 g), and the resulting mixture was stirred at room temperature overnight and then evaporated in vacuo. The residue obtained was neutralized with an aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to afford the title compound (1.36 g, yield: 78%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([OH:14])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15].[C:16](O)(=[O:18])[CH3:17]>[C].[Pd]>[CH3:1][C:2]1[CH:10]=[C:9]([NH:11][C:16](=[O:18])[CH3:17])[C:8]([OH:14])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15]
Reactant: CC(=O)O
Reactant: Cc1cc([N+](=O)[O-])c(O)c2c1CCC2=O
Agent: [Pd]
Product: CC(=O)Nc1cc(C)c2c(c1O)C(=O)CC2

Procedure:
Into a solution of 11.5 g of 4-methyl-6-nitro-7-hydroxy-1-indanone in 500 ml of acetic acid was added 1.5 g of 5% palladium carbon, then the mixture was subjected to a catalytic hydrogenation under an atmospheric pressure at a room temperature. The catalyst was removed by filtration and the solvent was removed by evaporation. The residue obtained was washed with ether and was recrystallized from methanol to obtain 6.34 g of 4-methyl-6-acetamido-7-hydroxy-1-indanone.
Reaction SMILES: [C:1]([O:4][CH:5]([C@H:8]1[O:12][C@@H:11]([N:13]2[C:17]3[N:18]=[C:19]([NH2:23])[NH:20][C:21](=[O:22])[C:16]=3[S:15][C:14]2=[O:24])[C@@H:10](CC([O-])=O)[CH2:9]1)[CH2:6][CH3:7])(=[O:3])[CH3:2].C([O-])([O-])=[O:30].[K+].[K+].CC(O)=O>CO>[C:1]([O:4][CH:5]([C@@H:8]1[CH2:9][C@@H:10]([OH:30])[C@H:11]([N:13]2[C:17]3[N:18]=[C:19]([NH2:23])[NH:20][C:21](=[O:22])[C:16]=3[S:15][C:14]2=[O:24])[O:12]1)[CH2:6][CH3:7])(=[O:3])[CH3:2]
Reactant: CCC(OC(C)=O)[C@@H]1C[C@H](CC(=O)[O-])[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CCC(OC(C)=O)[C@@H]1C[C@@H](O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.9 %

Procedure:
To a solution of [(2R,3R,5S)-5-(1-acetoxypropyl)-2-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-3-yl]acetate (compound 1g, 7.0 g, 16.9 mmol) in methanol (200 mL) was added K2CO3 (1.18 g, 8.5 mmol). After being stirred at room temperature for 12 hours, the reaction mixture was adjusted to pH 6.0 by addition of HOAc (1.2 g, 17 mmol), concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1:2 EtOAc in petroleum ether) to afford 2.8 g of 1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl acetate (compound 22a) as a yellow solid. MS obsd. (ESI−) [(M−H)+]: 369.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][CH2:31][CH:30]([CH2:33][C:34]([O:36]CC)=[O:35])[CH2:29][CH2:28]2)[C:9]=1[Br:39].C1COCC1.[Li+].[OH-]>O>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:28][CH2:29][CH:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:31][CH2:32]2)[C:9]=1[Br:39]
Reactant: CCOC(=O)CC1CCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(Br)c(C2CCC(CC(=O)O)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 20 mL scintillation vial was charged ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)-methyl)amino)-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate (100 mg, 130 μmol) and 2:1 THF:H2O (10 mL). To this solution was added 1N LiOH(aq) (200 μL). The resulting reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in TFA and stirred at room temperature for 1 hour. This solution was concentrated in vacuo and the residue was dissolved in 3:1 DMSO:MeCN. The crude product was purified via reverse-phase preparatory HPLC to yield 2-(4-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetic acid (m+H=480.1, retention time=3.95 min (isomer 1) and 4.03 min (isomer 2))
Reaction SMILES: [N+:1]([CH2:4][C:5]1([CH2:11][CH2:12][NH2:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([O-:3])=[O:2].[C:14](Cl)(=[O:16])[CH3:15].C(N(CC)CC)C>O1CCCC1>[N+:1]([CH2:4][C:5]1([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([O-:3])=[O:2]
Reactant: NCCC1(C[N+](=O)[O-])CCCCC1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCCC1(C[N+](=O)[O-])CCCCC1
Yield: 68.1 %

Procedure:
The amine hydrochloride salt (compound 4, 0.50 g, 2.25 mmol) was reacted with acetyl chloride (0.20 g, 2.55 mmol) and triethylamine (0.45 g, 4.45 mmol) in tetrahydrofuran following the procedure described in Example 1, Step 4. Purification by chromatography on silica eluting with ethyl acetate gave the required product as a crystalline solid (0.35 g, 69%); mp 68–70° C.