Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[N:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.C1C(=O)N([I:19])C(=O)C1>C(Cl)(Cl)Cl>[I:19][C:5]1[C:4]2[C:8](=[CH:9][N:10]=[CH:11][C:3]=2[O:2][CH3:1])[NH:7][CH:6]=1
Reactant: COc1cncc2[nH]ccc12
Reactant: O=C1CCC(=O)N1I
Solvent: ClC(Cl)Cl
Product: COc1cncc2[nH]cc(I)c12
Reaction time: 18 h
Yield: 91.4 %

Procedure:
4-Methoxy-6-azaindole (662 mg, 4.47 mmol) was dissolved in CHCl3 (20 mL), NIS (1.06 g, 4.69 mmol) was added and the reaction mixture was stirred for 18 h. The precipitate was collected by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (50 mL), washed with 10% aq sodium thiosulfate (50 mL), sat aq NaHCO3 (50 mL) and water (50 mL), dried (MgSO4), concentrated in vacuo and combined with the precipitate to give the title compound as a red solid (1.12 g, 91%). LCMS (ES+): 274.9 [MH]+. HPLC: Rf 3.98 min, 96% purity.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].[NH2:23][NH2:24]>ClCCl.O1CCOCC1.C(OCC)(=O)C>[Si:15]([O:9][CH2:8][C:7]1[C:2]([NH:23][NH2:24])=[N:3][CH:4]=[CH:5][CH:6]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccnc1Cl
Reactant: NN
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OCc1cccnc1NN
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
To a solution of (2-chloropyridin-3-yl)methanol (3.4 g, 23.7 mmol) in 50 mL of dichloromethane was added imidazole (2.4 g, 35.3 mmol) and tert-butyldimethylsilyl chloride (4.3 g, 28.5 mmol) at RT. The mixture was stirred at RT for 60 min, and then diluted with 100 mL of hexanes. The white solid was filtered off, and the filtrate was concentrated under reduced pressure. Additional solid was removed by triturating with 5% ethyl acetate in hexanes to provide a pale yellow oil. The pale yellow oil was dissolved in 40 mL of dioxane and then hydrazine (7.5 mL, 238.7 mmol) was added. The resulting mixture was heated to reflux for 36 h. After this time, the mixture was cooled to RT, and the solvent was removed in vacuo to provide a residue. The residue was diluted with ethyl acetate, washed with water, dried over Na2SO4 and concentrated under reduced pressure to give the title compound (4.7 g, 78%) as a brown oil. HPLC Rt (Method A): 2.42 min. LC/MS (m/z)=254 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]#[N:14])[CH2:9][CH2:8]1.[NH2:15][OH:16]>C(O)C>[OH:16][NH:15][C:13]([N:10]1[CH2:11][CH2:12][CH:7]([C@H:5]2[CH2:6][C@H:4]2[CH2:3][CH2:2][OH:1])[CH2:8][CH2:9]1)=[NH:14]
Reactant: NO
Reactant: N#CN1CCC([C@H]2C[C@H]2CCO)CC1
Solvent: CCO
Product: N=C(NO)N1CCC([C@H]2C[C@H]2CCO)CC1
Temperature: 65 °C

Procedure:
4-((1R,2S)-2-(2-hydroxyethyl)cyclopropyl)piperidine-1-carbonitrile (4.1 g, 21.10 mmol) was dissolved in Ethanol (60 ml) and hydroxylamine (5.17 ml, 84 mmol) (50% water solution) was added dropwise. The mixture was heated at 65° C. for 1 h. The mixture was evaporated to afford the desired product which was used for the next step without further purification. Rf was 0 @ 70% EtOAc in hexanes (blue spot on CAM stain)
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[CH2:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18](O)=O)[CH:16]=2)[N:11]=[C:10]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)[N:9]1[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[OH2:49].O[N:51]1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(NC(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[NH2:51][C:18]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([N:21]1[CH2:22][CH2:23][N:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:25][CH2:26]1)[N:9]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:41])([F:43])[F:42])[CH:35]=1)[CH:8]2[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:44])=[O:49]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)CC1c2cc(C(=O)O)ccc2N=C(N2CCN(c3ccc(F)cc3)CC2)N1c1cccc(C(F)(F)F)c1
Reactant: O
Agent: CCN=C=NCCCN(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC1c2cc(C(N)=O)ccc2N=C(N2CCN(c3ccc(F)cc3)CC2)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
560 mg (0.9 mmol) of the carboxylic acid from Example 48A, 2.6 mmol of aluminium chloride, 1.1 mmol of 1-hydroxy-1H-benzotriazole hydrate and 1.1 mmol of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide are suspended in DMF. 2.6 mmol of N,N-diisopropylamine are added, and the mixture is stirred at room temperature for 16 hours. 20 ml of ethyl acetate are added to the reaction mixture, which is then washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The combined aqueous phases are adjusted to pH=8 and extracted with ethyl acetate. The combined organic phases are finally washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated. This gives 548 mg (97% of theory) of product.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]([C:14]([O:16]CC)=[O:15])[N:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8][CH2:7]2.C1COCC1.O.[OH-].[Li+]>CO>[C:22]([O:21][C:19]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([CH2:3][O:2][CH3:1])[CH:5]=2)[CH:10]1[C:14]([OH:16])=[O:15])=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(=O)C1c2ccc(COC)cc2CCN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COCc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)O
Temperature: 60 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a solution of 1-ethyl 2-tert-butyl 6-(methoxymethyl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (160 mg, 0.0.46 mmol) in a mixture of MeOH (5 mL), THF (5.00 mL) and water (5.00 mL) was added lithium hydroxide (65.8 mg, 2.75 mmol), and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in water, and the solution was washed with ethyl acetate. The pH of the aqueous layer was adjusted to 3 with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2-(tert-butoxycarbonyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (148 mg, 0.461 mmol, 101%) as a colorless amorphous solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]5[CH2:34][O:33][CH2:32]5)[CH2:27][C@@H:26]4[CH3:35])=[CH:21][N:20]=3)[C:15](=[O:36])[N:14]([CH3:37])[CH:13]=2)=[CH:10][C:9]([F:38])=[CH:8][C:7]=1[N:39]1[CH2:53][CH2:52][N:42]2[C:43]3[CH2:44][C:45]([F:51])([F:50])[CH2:46][CH2:47][C:48]=3[CH:49]=[C:41]2[C:40]1=[O:54])(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[F:51][C:45]1([F:50])[CH2:44][C:43]2[N:42]3[CH2:52][CH2:53][N:39]([C:7]4[CH:8]=[C:9]([F:38])[CH:10]=[C:11]([C:12]5[CH:17]=[C:16]([NH:18][C:19]6[CH:24]=[CH:23][C:22]([N:25]7[CH2:30][CH2:29][N:28]([CH:31]8[CH2:32][O:33][CH2:34]8)[CH2:27][C@@H:26]7[CH3:35])=[CH:21][N:20]=6)[C:15](=[O:36])[N:14]([CH3:37])[CH:13]=5)[C:6]=4[CH2:5][OH:4])[C:40](=[O:54])[C:41]3=[CH:49][C:48]=2[CH2:47][CH2:46]1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CC(F)(F)CC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCn5c(cc6c5CC(F)(F)CC6)C4=O)c3CO)cn(C)c2=O)nc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
A mixture of 113q (37 mg, 0.05 mmol) and lithium hydroxide (12 mg, 0.5 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure. Water (10 mL) was added to the residue and the resulting mixture was extracted with ethyl acetate (2×10 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 113 (20 mg, 57%) as a white solid. MS: [M+H]+ 704.3. 1H NMR (500 MHz, CDCl3) δ 8.57-8.54 (m, 1H), 7.95 (d, J=3.0 Hz, 1H), 7.82 (d, J=3.5 Hz, 1H), 7.45-7.41 (m, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.19-7.16 (m, 1H), 6.99-6.95 (m, 1H), 6.88 (d, J=6.5 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 5.97 (d, J=11.5 Hz, 1H), 4.71-4.64 (m, 4H), 4.54 (d, J=12.0 Hz, 1H), 4.35-4.18 (m, 5H), 3.99-3.95 (m, 1H), 3.71 (s, 3H), 3.53 (t, J=6.0 Hz, 1H), 3.47-3.45 (m, 1H), 3.17 (t, J=12.0 Hz, 1H), 3.08 (t, J=5.0 Hz, 2H), 2.90 (t, J=8.5 Hz, 1H), 2.79 (t, J=6.0 Hz, 1H), 2.66-2.63 (m, 1H), 2.56 (d, J=11.0 Hz, 1H), 2.49-2.47 (m, 2H), 2.30-2.20 (m, 2H), 0.99 (d, J=6.0 Hz, 3H).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13](=[O:38])[N:14]([CH:21]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH3:37])[CH:28]=1)[CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:15]2=[O:20].[Cl:39][CH2:40][C:41](Cl)=[O:42]>>[Cl:39][CH2:40][C:41]([NH:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13](=[O:38])[N:14]([CH:21]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH3:37])[CH:28]=1)[CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:15]2=[O:20])=[O:42]
Reactant: O=C(Cl)CCl
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(CN)c3C2=O)ccc1OC
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(CNC(=O)CCl)c3C2=O)ccc1OC
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
Triethylamine (0.52 g, 5.11 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindoline-1,3-dione hydrochloride (1.0 g, 2.13 mmol). The clear solution was cooled in an ice bath to 5° C. Chloroacetyl chloride (0.30 g, 2.56 mmol) was added keeping the temperature between 5-9° C. The mixture was stirred at 5° C. for 30 min and then warmed to room temperature for 2 hours. The mixture was washed with water (2×30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (silica gel, methylene chloride:ethyl acetate 7:3) to give 2-chloro-N-({2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}methyl)acetamide (1.0 g, 92%): 1H NMR (CDCl3) δ 7.84-7.65 (m, 4H), 7.14-7.12 (m, 2H), 6.86 (d, J=8.9 Hz, 1H), 5.94-5.88 (dd, J=4.6, 10.3 Hz, 1H), 4.79 (d, J=6.5 Hz, 2H), 4.61-4.51 (dd, J=10.4, 14.4 Hz, 1H), 4.10 (q, J=7.2 Hz, 2H), 4.02 (s, 2H), 3.85 (s, 3H), 3.80-3.72 (dd, J=4.6, 14.4 Hz, 1H), 2.86 (s, 3H), 1.47 (t, J=7.0 Hz, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]([C:19](=[O:25])[CH:20](OCC)O)=[CH:15][C:10]=1[C:11]([O:13]C)=O)C1C=CC=CC=1.[CH3:26][O:27][C:28]1[CH:38]=[CH:37][C:31]([CH2:32][C:33]2([NH2:36])[CH2:35][CH2:34]2)=[CH:30][CH:29]=1.FC(F)(F)C([O-])=O>>[OH:25][CH:19]([C:16]1[CH:17]=[CH:18][C:9]([OH:8])=[C:10]([CH2:11][OH:13])[CH:15]=1)[CH2:20][NH:36][C:33]1([CH2:32][C:31]2[CH:37]=[CH:38][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[CH2:35][CH2:34]1
Reactant: COc1ccc(CC2(N)CC2)cc1
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(C(=O)OC)c1
Agent: O=C([O-])C(F)(F)F
Product: COc1ccc(CC2(NCC(O)c3ccc(O)c(CO)c3)CC2)cc1

Procedure:
Prepared according to general method 5 from 344 mg (1 mmol) methyl 2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 177 mg (1 mmol) 1-(4-methoxy-benzyl)-cyclopropylamine. Yield: 123 mg (27%, trifluoroacetate); mass spectroscopy: [M+H]+=344.
Reaction SMILES: [S:1]1[C:5]2=[C:6]([C:13]([OH:15])=[O:14])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:2]1.C(O[CH2:20][CH3:21])(=O)C>>[CH2:5]([N:4]1[CH2:12][CH2:11][CH:20]([CH2:21][O:14][C:13]([C:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]3[CH2:3][CH2:2][S:1][C:5]=23)=[O:15])[CH2:2][CH2:3]1)[CH2:6][CH2:7][CH3:8]
Reactant: CCOC(C)=O
Reactant: O=C(O)c1c2n(c3ccccc13)CCS2
Product: CCCCN1CCC(COC(=O)c2c3n(c4ccccc24)CCS3)CC1
Yield: 31 %

Procedure:
The title compound was prepared from 2,3-dihydrothiazolo[3,2-a]indole-9carboxylic acid (D15) using the method of Example 10. The crude product was purified by chromatography on silica gel eluting with 5% methanol/chloroform to give a yellow oil. This was passed through a plug of basic alumina eluting with ethyl acetate to afford the title compound as a pale yellow oil (31%) which was converted to its oxalate salt and was crystallised from acetone as an off-white solid mp 212°-215° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[CH:30]=[C:29]([CH2:31][CH3:32])[C:28](=[O:33])[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)(Cl)[Cl:40].CO>>[ClH:40].[CH:34]1([N:27]2[C:25]3[N:26]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:15][N:16]=4)[N:22]=[CH:23][C:24]=3[CH:30]=[C:29]([CH2:31][CH3:32])[C:28]2=[O:33])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CCc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Reactant: ClC(Cl)Cl
Solvent: CO
Product: CCc1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O
Product: Cl
Reaction time: 3.5 h

Procedure:
4-[6-(8-Cyclopentyl-6-ethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.204 g, 0.39 mmol) prepared as in Example 4 was dissolved in 1:1 chloroform/methanol (16 ml) and purged with anhydrous hydrogen chloride gas. After stirring for 3.5 hours, addition of diethyl ether (8 ml) gave a solid precipitate. The solid was filtered, washed with diethyl ether and dried in vacuo yielding 0.180 g of 8-cyclopentyl-6-ethyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride as a yellow solid. MS (APCI); M++1: Calc'd, 420.52, Found, 420.2. Analyses for C34H29N7O.1.2 H2O.2.1HCl: Calc'd: C, 53.36; H, 6.52; N, 18.93, Cl (ionic), 14.38; H2O, 4.17. Found: C, 53.25; H, 6.43; N, 18.80; Cl (ionic), 14.36; H2O, 3.87
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[C:20](=[O:21])[C:19]2[N:18]([CH2:22][C:23]#[C:24][CH3:25])[C:17](Br)=[N:16][C:15]=2[N:14]([CH3:27])[C:12]1=[O:13].[C:28]([O:32][C:33]([C@@H:35]1[CH2:40][CH2:39][CH2:38][N:37](N)[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].O.C[N:50](C)C=O>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[C:20](=[O:21])[C:19]2[N:18]([CH2:22][C:23]#[C:24][CH3:25])[C:17]([N:37]3[CH2:38][CH2:39][CH2:40][CH:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[C@@H:36]3[NH2:50])=[N:16][C:15]=2[N:14]([CH3:27])[C:12]1=[O:13]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN(N)C1
Reactant: CN(C)C=O
Reactant: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc3ccccc3s1)c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC#CCn1c(N2CCCC(C(=O)OC(C)(C)C)[C@@H]2N)nc2c1c(=O)n(Cc1nc3ccccc3s1)c(=O)n2C
Temperature: 25 °C
Yield: 90.8 %

Procedure:
By utilizing the well known method, 1-[(1,3-benzothiazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine 2b (400 mg, 0.9 mmol) was dissolved in N,N-dimethylformamide (6 ml). (R)-3-tert-butoxycarbonyl-aminopiperidine (180 mg, 0.9 mmol) and potassium carbonate (186.5 mg, 1.35 mmol) were added to give a reaction mixture. The reaction mixture was reacted at 75° C. for 2 hours, and TLC was used to monitor the reaction progress. After the reaction was completed, the obtained reaction mixture was cooled to room temperature. The cooled reaction solution was poured into water, suction filtered, and the obtained solid was washed with water, dried to give 1-[(1,3-benzothiazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-tert-butoxycarbonyl-amino-piperidin-1-yl]-xanthine 2c (460 mg, yellow solid), yield: 90.8%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][C:28]=1[N+:29]([O-])=O)[CH2:12][CH:13]1[NH:19][C:18](=[O:20])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[NH:15][C:14]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.CO.[Pt]=O>[NH2:29][C:28]1[CH:27]=[CH:26][C:11]([CH2:12][CH:13]2[NH:19][C:18](=[O:20])[C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[NH:15][C:14]2=[O:25])=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(Cc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)C(=O)Nc2ccccc21
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(CC2NC(=O)c3ccccc3NC2=O)cc1OCc1ccccc1

Procedure:
A solution of the title J compound, 3-(3-benzyloxy-4-nitro-benzyl)-3,4-dihydro-1H-benzo[1,4]diazepine-2,5-dione (196 mg, 0.47 mmol) in EtOAc-methanol (1:1, 44 mL) is hydrogenated over platinum oxide (22 mg) at atmospheric pressure for 1 h. The catalyst is filtered off and the filtrate is evaporated to dryness to give 3-(4-amino-3-benzyloxy-benzyl)-3,4-dihydro-1H-benzo[1,4]diazepine-2,5-dione as a foam: [M+1]+=388.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:5][C@H:4]([C:6]([OH:8])=[O:7])[CH2:3]1.O=S(Cl)[Cl:11].[CH3:13]O>>[ClH:11].[NH2:1][C@H:2]1[CH2:5][C@H:4]([C:6]([O:8][CH3:13])=[O:7])[CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: N[C@H]1C[C@H](C(=O)O)C1
Product: COC(=O)[C@H]1C[C@H](N)C1
Product: Cl
Temperature: 100 °C

Procedure:
To a solution of trans-3-aminocyclobutanecarboxylic acid (500 mg, 3.3 mmol) in MeOH (20 mL) was added SOCl2 dropwise at 0° C. The resulting mixture was heated at 100° C. for 4 hours and then concentrated in vacuo to afford the crude methyl trans-3-aminocyclobutanecarboxylate hydrochloride which was used in the next step directly.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>ClCCl.CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:24])=[O:23])[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1cncc(Br)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 5-bromo-3-pyridinamine (2 g, 11.56 mmol), triethylamine (6.6 mL, 47.39 mmol) in dichloromethane (40 mL) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred for 15 min and then benzenesulfonyl chloride (3.21 mL, 23.69 mmol) was added slowly to give a brown solution. The reaction mixture was stirred for 2 h at room temperature. Diluted with dichloromethane and then washed with saturated aqueous sodium chloride solution, separated the organic layer, dried over sodium sulphate, concentrated under high vacuum, light yellow solid obtained. The solid was dissolved in methanol (20 mL), cooled to 0° C., added 10N aqueous sodium hydroxide (20 mL) solution. The reaction mixture was stirred for 1 h and then distilled out methanol completely, extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to obtain the title compound MS (M+1): 315.2.
Reaction SMILES: [CH3:1][S:2][CH2:3][O:4][N:5]=[C:6]([C:12]1[N:13]=[C:14]([NH:17][CH:18]=[O:19])[S:15][CH:16]=1)[C:7]([O:9]CC)=[O:8].[OH-].[Na+].Cl>CO>[CH3:1][S:2][CH2:3][O:4][N:5]=[C:6]([C:12]1[N:13]=[C:14]([NH:17][CH:18]=[O:19])[S:15][CH:16]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(=NOCSC)c1csc(NC=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 30 °C
Reaction time: 2.5 h
Yield: 51.9 %

Procedure:
A mixture of ethyl 2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)acetate (syn isomer) (2.4 g.), 1 N aqueous sodium hydroxide (23.8 ml.) and methanol (19.8 ml.) was stirred at 30° C. for 2.5 hours. The resultant solution was adjusted to pH 7 with 10% hydrochloric acid and methanol was distilled off in vacuo. The aqueous solution was adjusted to pH 1 with 10% hydrochloric acid under ice-cooling, and extracted with ethyl acetate three times. The extracts were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give 2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (1.13 g.), mp. 157° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH2:22])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.C1N=CN([C:28]([N:30]2[CH:34]=N[CH:32]=[CH:31]2)=[O:29])C=1.Cl.N1CC([OH:40])C1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH:22][C:28]([N:30]4[CH2:31][CH:32]([OH:40])[CH2:34]4)=[O:29])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC1CNC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12)N1CC(O)C1
Reaction time: 2 h
Yield: 95 %

Procedure:
To a DCM (0.8 mL) solution of (R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Example 6, Step A; 50 mg, 0.17 mmol) was added CDI (41 mg, 0.25 mmol) at ambient temperature in one portion. After stirring two hours, azetidin-3-ol hydrochloride (28 mg, 0.25 mmol) was added in one portion, followed by addition of DIEA (0.059 mL, 0.34 mmol). The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 5 to 55% acetonitrile/water to yield the final product as a yellowish foamy powder (64 mg, 96% yield). MS (apci) m/z=397.2 (M+H).
Reaction SMILES: [C:1]1([Sb:7](=O)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1>>[OH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([O-:28])=[O:27])=[CH:24][CH:23]=1.[OH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([O-:28])=[O:27])=[CH:24][CH:23]=1.[C:14]1([Sb+2:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=[Sb](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Product: O=C([O-])c1ccc(O)cc1
Product: c1ccc([Sb+2](c2ccccc2)c2ccccc2)cc1

Procedure:
Triphenyl antimony oxide was reacted with p-hydroxybenzoic acid to yield triphenyl antimony di(p-hydroxybenzoate). ##SPC6##
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:29])[C@H:15]([CH2:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([F:27])=[C:22]([CH3:28])[CH:21]=1)[CH2:16]C=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][NH:40][CH3:41])=[CH:33][CH:32]=1.[C:42](O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:29])[C@@H:15]([CH2:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([F:27])=[C:22]([CH3:28])[CH:21]=1)[CH2:16][CH2:41][N:40]([CH2:39][CH2:38][CH2:37][C:34]1[CH:33]=[CH:32][C:31]([F:30])=[CH:36][CH:35]=1)[CH3:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[C@@H](Cc1cc(C)c(F)c(C)c1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CNCCCc1ccc(F)cc1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Cc1cc(C[C@@H](CCN(C)CCCc2ccc(F)cc2)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc(C)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
To a solution of (R)-4-benzyl-3-[(S)-2-(4-fluoro-3,5-dimethyl-benzyl)-pent-4-enoyl]-oxazolidin-2-one (0.045 g, 0.113 mmol), [3-(4-fluoro-phenyl)-propyl]-methyl-amine (C6, 0.023 g, 0.136 mmol), and acetic acid (0.014 g, 0.226 mmol) in 3 mL of dichloroethane, was added NaBH(OAc)3 (0.034 g, 0.158 mmol). After stirring at room temperature overnight, the reaction was quenched with 20 mL of saturated aqueous NaHCO3 solution and the reaction mixture extracted with ethyl acetate (20 mL×3). The combined organic extracts were dried, filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel) eluting with 0-10% methanol/dichloromethane to give the title compound as colorless oil (0.046 g, 75% yield). LC-MS: tR=7.7 min; m/z 549 (M+H)+.