Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]1[CH:24]=[CH:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:29]=1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:50][CH2:51][CH2:52][CH2:53]Br>CN(C=O)C>[CH2:17]([O:16][CH:11]1[CH:12]=[C:13]([O:15][CH2:53][CH2:52][CH2:51][Br:50])[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]1[CH:24]=[CH:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:29]=1)=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc(C(=O)C=CC2C(OCc3ccccc3)=CC(O)=CC2OCc2ccccc2)cc1OCc1ccccc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)C=CC2C(OCc3ccccc3)=CC(OCCCBr)=CC2OCc2ccccc2)cc1OCc1ccccc1
Yield: 83.7 %

Procedure:
A mixture of 2.37 g (5 mmol) of 2,3',6-tris(benzyloxy)-4-hydroxy-4'-methoxydihydrochalcone, 1.38 g (10 mmol) of K2CO3, and 70.1 g (50 mmol) of 1,3-dibromopropane in 75 mL of DMF was reacted for 48 hours, after which standard workup yielded 2.91 g (84%) of 2,3',6-tris(benzyloxy)-4-(3-bromopropoxy)-4'-methoxydihydrochalcone as a white solid. The resulting intermediate bromide (2.91 g, 4.18 mmol) was dissolved in 50 mL of P(OCH3)3 and refluxed for 39 hours. After all solvent was removed in vacuo, standard workup, followed by column chromatography over 200 g of silica gel (CHCl3 --CH3OH), yielded 1.93 g (64%) of 2.3',6-tris(benzyloxy)-4-(dimethyl-3-phosphopropoxy)-4'-methoxydihydrochalcone as an oil, which crystallized on standing. Crystallization from hexane-EtOAc yielded colorless clusters: mp 92°-95.5° C.; IR (film) 5.88 (C=O) μm; UV (MeOH)λmax 278 nm (ε 7600); NMR (CDCl3)δ 2.90 (m, 4H, ArCOCH2CH2Ar'), 3.64 [s, 6H, PO(OCH3)2 ], 3.77 (s, 3H, Ar'OCH3), 3.94 (t, 2H, J=6 Hz, ArOCH2), 5.03 (s, 6H, PhCH2O), 6.17 (s, 2H, ArH), 7.37 (s, 15H, PhH). Anal (C42H45O9P) C, H.
Reaction SMILES: [CH3:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]2[N:6]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=[N:8][C:4]=2[CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH3:28][C:29](N(C)C)=[O:30]>O1CCCC1.CCCCCCC>[CH3:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]2[N:6]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:16])[CH3:15])[C:7]([C:29](=[O:30])[CH3:28])=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2ncn(COCC[Si](C)(C)C)c2cc1C
Reactant: CC(=O)N(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(=O)c1nc2cc(C)c(C)cc2n1COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole [5.01 g, Reference Example 4(a)] in dry tetrahydrofuran (55 mL), at −78° C., was treated with a solution of lithium diisopropylamide in a mixture of tetrahydrofuran and heptane (11.9 mL, 2M) over 10 minutes. The mixture was stirred for 15 minutes then treated dropwise with dimethylacetamide (2.15 mL) over 10 minutes. After stirring at −78° C. for a further 30 minutes the reaction mixture was poured into ice (50 g) and then left until all the ice had melted. This mixture was extracted with dichloromethane and the extracts were washed with brine, then with water, then dried over magnesium sulfate and then evaporated. The residual orange oil (5.91 g) was subjected to column chromatography on silica eluting with a mixture of petroleum ether and ethyl acetate (4:1, v/v) to give 1-[5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-ethanone (3.93 g) as a yellow crystalline solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.I[C:12]1[C:20]2[C:15](=[N:16][CH:17]=[N:18][C:19]=2[NH2:21])[N:14]([CH:22]([CH3:24])[CH3:23])[N:13]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:21][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:14]([CH:22]([CH3:24])[CH3:23])[N:13]=[C:12]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[C:20]=12
Reactant: OB(O)c1ccc(O)cc1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2ccc(O)cc2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 34.3 %

Procedure:
A solution of 4-Hydroxyphenylboronic acid (30 mg, 0.14 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA56 (12 mg, 32% yield). ESI-MS (M+H)+ m/z calcd 270.1, found 270.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]1(=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[O:7]1.CCN(CC)CC>C1(C)C=CC=CC=1>[OH:5][CH2:4][CH2:3][CH2:2][N:1]1[C:6](=[O:7])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:15]
Reactant: NCCCO
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCCO
Yield: 67 %

Procedure:
To a solution of 3-aminopropan-1-ol (1.0 g, 13.1 mmol) and isobenzofuran-1,3-dione (2.0 g, 13.1 mmol) in toluene (25 mL, 3 mL/mmol) was added Et3N (2 mL, 13.1 mmol) and the reaction was heated at reflux for 24 h. Then reaction was quenched with water and extracted with EtOAc (2×40 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford 2-(3-hydroxypropyl)isoindoline-1,3-dione (1.8 g, 87%). Observed mass (M+1): 206.1. This material was taken to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16](N)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[CH2:35]C(N)=O>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][C@@H:15]([CH3:35])[CH2:16][OH:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: NCC(N)=O
Agent: Cl
Product: Cc1ccc(C(=O)N[C@@H](C)CO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting (S)-(+)-2-amino-1-propanol for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.92 (m, 1H), 7.77 (s, 1H), 7.61 (q, 1H, J=8.4 Hz), 7.52 (d, 1H, J=8.0 Hz), 7.02 (m, 2H), 5.60 (m, 2H), 4.16 (m, 1H), 3.58 (m, 2H), 2.20 (s, 3H), 1.22 (d, 3H, J=6.0 Hz). ESHRMS m/z 464.1198 (M+H calculated for C22H21ClF2N3O4 requires 464.1183).
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]([C:8]3[O:12][N:11]=[C:10](N)[N:9]=3)CN(C2)[CH2:2]1.[Cl:14][C:15]1[C:16]([CH3:30])=[C:17](C2C=CC(NO)=CC=2)[CH:18]=[CH:19][C:20]=1N>>[CH2:6]([C:8]1[O:12][N:11]=[C:10]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([Cl:14])[C:16]=2[CH3:30])[N:9]=1)[CH2:5][C:1]#[CH:2]
Reactant: Nc1noc(C2CN3CCC2C3)n1
Reactant: Cc1c(-c2ccc(NO)cc2)ccc(N)c1Cl
Product: C#CCCc1nc(-c2cccc(Cl)c2C)no1
Yield: 46 %

Procedure:
According to the general protocol for oxadiazole synthesis described in Example 40(C) the conversion of 3-chloro-N′-hydroxy-2-methylbenzidine (628 mg, 3.4 mmol) afforded 387 mg of 5-(but-3-ynyl)-3-(3-chloro-2-methylphenyl)-1,2,4-oxadiazole (Yield: 46%) as yellow oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[N:22]3)=[C:17](Cl)[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH2:1]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[N:22]3)=[C:17]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(-c2ccc(N(Cc3ccccc3)Cc3ccccc3)cc2)cc2ncccc12
Reactant: C1COCCN1
Product: c1ccc(CN(Cc2ccccc2)c2ccc(-c3cc4ncccc4c(N4CCOCC4)n3)cc2)cc1

Procedure:
A solution of dibenzyl-[4-(5-chloro-[1,6]naphthyridin-7-yl)-phenyl]amine 3 (350 mg, 0.81 mmol, 1 eq) in morpholine (5.0 mL, 56 mmol, 70 eq) was heated up at 100° C. overnight under Ar(g). Once cooled down, the solution was partitioned and extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with hexane/EtOAc (1:1-1:3) to yield the product, B, as a pale yellow solid (242 mg, 62%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:16]3[CH:15]4[N:11]([CH2:12][CH2:13][CH2:14]4)[CH2:10][CH2:9][C:8]=3[N:7]([CH3:17])[C:6]=2[N:18]=1.[Cl:19][C:20]1[CH:34]=[CH:33][C:23]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][NH:29][C:28](=[O:32])[CH:27]=2)=[C:22]([F:35])[CH:21]=1>>[ClH:19].[Cl:19][C:20]1[CH:34]=[CH:33][C:23]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][N:29]([C:2]3[CH:3]=[CH:4][C:5]4[C:16]5[CH:15]6[N:11]([CH2:12][CH2:13][CH2:14]6)[CH2:10][CH2:9][C:8]=5[N:7]([CH3:17])[C:6]=4[N:18]=3)[C:28](=[O:32])[CH:27]=2)=[C:22]([F:35])[CH:21]=1
Reactant: Cn1c2c(c3ccc(Br)nc31)C1CCCN1CC2
Reactant: O=c1cc(OCc2ccc(Cl)cc2F)cc[nH]1
Product: Cl
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cc5F)cc4=O)nc31)C1CCCN1CC2
Yield: 44 %

Procedure:
9-Bromo-7-methyl-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine (156 mg, 0.511 mmol) and 4-(4-chloro-2-fluorobenzyloxy)pyridin-2(1H)-one (129 mg, 0.511 mmol) were reacted following the procedure for Example 2 (step b) to provide the title compound (58 mg, 22%) as a yellow solid: mp 150-160° C.; 1H NMR (500 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.11-8.09 (d, J=8.2 Hz, 1H), 7.83-7.81 (d, J=7.7 Hz, 1H), 7.65-7.62 (t, J=8.2 Hz, 1H), 7.55-7.53 (d, J=8.5 Hz, 1H), 7.40-7.36 (m, 2H), 6.17-6.15 (dd, J=7.7, 2.5 Hz, 1H), 6.07-6.05 (d, J=2.5 Hz, 1H), 5.20 (s, 2H), 5.02-5.00 (m, 1H), 3.72 (s, 3H), 3.63-3.34 (m, 3H), 3.32-3.28 (m, 1H), 3.25-3.14 (m, 2H), 2.64-2.55 (m, 1H), 2.14-2.10 (m, 2H), 2.09-1.95 (m, 1H); ESI MS m/z 479 [M+H]+; HPLC (Method B) 95.5% (AUC), tR=14.1 min.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]([NH2:13])=[O:12]>CCO>[NH2:13][C:11]1[O:12][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:10]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(N)=O
Solvent: CCO
Product: CCOC(=O)c1coc(N)n1
Yield: 85 %

Procedure:
A stirred solution of ethyl bromopyruvate (50.2 g, 257.2 mmol) in EtOH was treated with urea (23.2 g, 385.8 mmol) refluxed overnight and concentrated under reduced pressure. The resultant residue was dissolved in EtOAC and water. The layers were separated and the aqueous layer washed with EtOAC. The combined organic layers were washed successively with saturated sodium chloride, dried over Mg2SO4 and concentrated under reduced pressure to give the title product in 85% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 157.1 (MH+).
Reaction SMILES: CN(C)[CH2:3][CH2:4]CN=C=O.[CH2:10]([C:17]1[NH:25][C:24]2[C:23](=[O:26])[N:22]([CH2:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:21](=[O:33])[N:20]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)[C:19]=2[N:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:51]([NH:53][CH2:54][CH2:55][OH:56])[CH3:52]>ClCCCl>[CH2:10]([C:17]1[N:25]([CH2:52][CH2:51][N:53]([CH2:3][CH3:4])[CH2:54][CH2:55][OH:56])[C:24]2[C:23](=[O:26])[N:22]([CH2:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:21](=[O:33])[N:20]([CH2:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)[C:19]=2[N:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCNCCO
Reactant: CN(C)CCCn1c(=O)c2[nH]c(Cc3ccccc3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: CN(C)CCCN=C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CCN(CCO)CCn1c(Cc2ccccc2)nc2c1c(=O)n(CCCN(C)C)c(=O)n2CCc1ccc([N+](=O)[O-])cc1

Procedure:
By methods well known in the art 3-dimethylaminopropyl isocyanate is converted into 8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-(3-dimethylaminopropyl)xanthine. By the method of Example 3, this substance is alkylated with a mixture of 1,2-dichloroethane, sodium carbonate and 2-(ethylamino)ethanol to yield 8-benzyl-1-(3-dimethylaminopropyl)-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(4-nitrophenyl)ethyl]xanthine. By the method of Example 4 this substance is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-8-benzyl-1-(3-dimethylaminopropyl)-7-[2-ethyl(2-hydroxyethyl)amino]ethylxanthine free base. The corresponding hydrochloride salt is then made on exposure to an excess of hydrogen chloride in solution.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[S:7][C:8]([S:15]([CH3:17])=O)=[CH:9][C:10]=1[Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:5])[CH3:2].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CC(C)=O.C(Cl)Cl>[CH2:1]([NH:3][C:4]([C:6]1[S:7][C:8]([S:15][CH3:17])=[CH:9][C:10]=1[Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:5])[CH3:2]
Reactant: CCNC(=O)c1sc(S(C)=O)cc1[Si](C)(C)C
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCNC(=O)c1sc(SC)cc1[Si](C)(C)C
Temperature: 0 °C
Yield: 88.2 %

Procedure:
To a solution of the compound of Example 260 (0.6 g) and Nal (0.8 g) in 10 mL acetone was added slowly 0.4 mL trifluoroacetic anhydride at 0° C. and the mixture was stirred at 0° C. for an additional hour. Then CH2Cl2 and aq sat sodium meta-bisulfite were added. The organic layer was separated, washed with brine, dried and concentrated. Flash chromatography of the residue with 10% ethyl acetate-hexane gave 0.5 g of the title compound as a white solid. m.p. 58-61° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:7]2[CH2:14][CH2:13][CH2:12][C:11](=O)[C:8]=2[S:9][CH:10]=1)=[O:5])[CH3:2].[OH2:16].Cl.[NH2:18]O.C([O-])(=O)C.[Na+]>C(O)C>[CH2:1]([NH:3][C:4]([C:6]1[C:7]2[CH2:14][CH2:13][CH2:12]/[C:11](=[N:18]/[OH:16])/[C:8]=2[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1csc2c1CCCC2=O
Reactant: NO
Reactant: O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCNC(=O)c1csc2c1CCC/C2=N/O
Temperature: 50 °C

Procedure:
A solution of 7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ethyl amide (the compound of Preparation Example 115) (96 mg) in ethanol (2 mL) and water (1 mL) was added hydroxylamine.hydrochloride (39 mg) and 46 mg of sodium acetate (46 mg). After heating at 50° C. for 4.5 hours, the reaction solution was cooled to room temperature, the solid that precipitated was collected by filtration, and the title compound (36 mg) was obtained as a colorless solid.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[S:16][C:17]([C:20]#[N:21])=[CH:18][N:19]=2)[CH:9]=1)(C)(C)C.F>C1COCC1>[OH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[S:16][C:17]([C:20]#[N:21])=[CH:18][N:19]=2)[CH:9]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccnc(Nc2ncc(C#N)s2)c1
Agent: F
Solvent: C1CCOC1
Product: N#Cc1cnc(Nc2cc(CO)ccn2)s1
Reaction time: 0.33 h

Procedure:
2-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamino]-thiazole-5-carbonitrile (1.30 g, 3.75 mmol) was dissolved in 10 mL anh THF. Hydrogen-fluoride (Aldrich, 5.0 mL) was added and the reaction was stirred for 20 minutes. The bulk of the solvent was removed in vacuo and the resulting residue was diluted with half-saturated NaHCO3 (aq). A precipitate formed which was filtered and washed with water to afford the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([CH:9]=[N:10][OH:11])=[CH:7][CH:6]=1)=[O:4].[ClH:14].OOS([O-])=O.[K+]>CN(C)C=O.O1CCOCC1>[Cl-:14].[CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([CH:9]=[N:10][OH:11])=[CH:7][CH:6]=1)=[O:4]
Reactant: Cl
Agent: COC(=O)c1ccc(C=NO)cc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: [Cl-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-methoxycarbonylbenzaldehyde oxime (896 mg) in N,N-dimethylformamide (10 ml) was added 4N-hydrochloride acid in 1,4-dioxane (1.38 ml) and oxone® (1.69 g). The suspension was stirred at ambient temperature for 16 hours and poured into ice-water. The object compound was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate. The solvents were removed under reduced pressure to give 4-Methoxycarbonylbenzaldehyde oxime chloride (1.05 g).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH3:17][C:18]1[NH:19][C:20]2[C:25]([C:26]=1[CH:27]=O)=[CH:24][CH:23]=[CH:22][CH:21]=2>>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:27][C:26]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][C:18]=1[CH3:17])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: Cc1[nH]c2ccccc2c1C=O
Product: Cc1[nH]c2ccccc2c1C=C1C(=O)Nc2ccc(S(=O)(=O)N(C)C)cc21

Procedure:
5-Dimethylaminosulfonyl-2-oxindole was condensed with 2-methylindole-3-carboxaldehyde to give the title compound.
Reaction SMILES: [P:1]([O:5][CH2:6][C@:7]([NH:31]C(=O)OC(C)(C)C)([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH:20]3[CH2:25][CH2:24][C:23]4([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:22][CH2:21]3)[CH:15]=2)[CH:10]=1)[CH3:8])([OH:4])([OH:3])=[O:2].C(O)(=O)C.Cl>O>[P:1]([OH:3])([OH:4])([O:5][CH2:6][C@:7]([NH2:31])([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH:20]3[CH2:21][CH2:22][C:23]4([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)[CH2:24][CH2:25]3)[CH:15]=2)[CH:10]=1)[CH3:8])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(COP(=O)(O)O)c1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: C[C@](N)(COP(=O)(O)O)c1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1
Yield: 36 %

Procedure:
tert-Butyl (2R)-1-(phosphonooxy)-2-(6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)propan-2-ylcarbamate (13.6 mg, 0.0000248 mol) was dissolved in acetic acid (0.78 mL, 0.014 mol) and 10 M of hydrogen chloride in water (0.2 mL) was added and the mixture was stirred for Id. Lypholyzing gave (2R)-2-amino-2-(6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)propyl dihydrogen phosphate as a white solid (4.0 mg, 36%). LCMS give a single peak Rf=1.64 min (431.41, [M-16]+, 100%, 895.73, [M+M+1], 20%). 1H NMR (400 MHz, MeOD) δ=7.82-7.89 (m, 3 H), 7.56 (d, J=5.5 Hz, 1 H), 7.27 (s, 1 H), 7.21 (d, J=8.6 Hz, 1 H), 4.54-4.47 (m, 1 H), 4.14-4.17 (m, 2H), 1.99-1.90 (m, 2 H), 1.86 (s, 3 H), 1.78-1.66 (m, 4 H), 1.50 (m, 8 H), 1.42-1.30 (m, 4 H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[S:10][C:9]([CH2:11][CH2:12]C(O)=O)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:31]=2[CH:32]=[N:33][NH:34]3)O1.[C:40](=O)([O-:42])[O-:41].[Na+].[Na+].C(OCC)(=O)C>C(#N)C.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>[NH:34]1[C:35]2[C:31](=[C:30]([C:2]3[N:3]=[C:4]([N:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[C:5]4[S:10][C:9]([CH:11]([CH3:12])[C:40]([OH:42])=[O:41])=[CH:8][C:6]=4[N:7]=3)[CH:38]=[CH:37][CH:36]=2)[CH:32]=[N:33]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: O=C(O)CCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: O=C([O-])[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(C(=O)O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
A mixture of 3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-propionic acid (200 mg), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole (209 mg), 1 M aqueous sodium carbonate solution (1.83 mL) and PdCl2(PPh3)2 (22 mg) in acetonitrile (3 mL) was reacted in the microwave at 140° C. for 15 min. The reaction mixture was then poured into a mixture of ethyl acetate (20 mL) and water (20 mL). The aqueous layer was collected and carefully acidified to pH 6 using 2 M aqueous hydrochloric acid. The product was then filtered and washed with water to give 3-[2-(1H-indazol-4-yl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl]-propionic acid as a grey solid (145 mg).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH2:34]([N:41]=[C:42]=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:42]([NH:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:43])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=NCc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)NCc4ccccc4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 54 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, benzyl isocyanate (0.32 g, 2.41 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:CH3OH 96:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(benzylamino)carboxamide (0.42 g, 54%) as a white solid: mp 192–194° C.; 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 7.86–7.69 (m, 3H), 7.34–7.19 (m, 5H), 6.67 (t, J=5.8 Hz, 1H), 6.60 (t, J=5.9 Hz, 1H) 5.18–5.11 (dd, J=5.3 and 12.5 Hz, 1H, 4.67 (d, J=5.9 Hz, 2H), 4.23 (d, J=5.8 Hz, 2H), 2.97–2.83 (m, 1H), 2.63–2.50 (m, 2H), 2.07–2.03 (m, 1H); 13C NMR (DMSO-d6) δ 175.63, 172.75, 167.56, 167.03, 158.05, 141.01, 140.70, 134.61, 133.31, 131.52, 128.19, 126.98, 126.55, 121.66, 48.83, 42.99, 30.93, 21.98; Anal. Calcd. For C22H20N4O5: C, 62.85; H, 4.79; N, 13.33. Found: C, 62.78; H, 4.53; N, 13.18.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)=[O:5])[CH3:2].Br[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:18][CH:17]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)=[CH:20][CH:21]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Product: CCOC(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cc2)cc1
Yield: 5.6 %

Procedure:
The title compound (2.4 mg, 6%) was prepared from {4-[(ethyloxy)carbonyl]phenyl}boronic acid (19.4 mg, 0.1 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (Example 9, Step 2, 36 mg, 0.10 mmol) in a manner similar to Example 9, Step 3. LRMS (ESI), m/z 448 (M+Na).