Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6]C[CH2:4][CH2:3]1.[CH2:8]([N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C-]#N.[Na+]>CO.O.O>[ClH:1].[ClH:1].[C:9]1([C:8]2([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:6][CH2:7][NH:2][CH2:3][CH2:4]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C1CCNCC1
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: c1ccc(C2(N3CCCCC3)CCNCC2)cc1
Reaction time: 48 h
Yield: 170.2 %

Procedure:
12.16 g of piperidine hydrochloride and 18.9 g of 1-benzylpiperid-4-one are dissolved in 50 ml of an MeOH/H2O mixture (50/50; v/v). 5.3 g of NaCN dissolved in 20 ml of water are added dropwise. After stirring for 48 hours, the precipitate formed is filtered, rinsed with water and dried to give 27 g of the expected product.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[C:46]([O:45][C:44](=[O:50])[NH:43][C@H:40]1[CH2:39][CH2:38][C@@H:37]([NH:36][C:33]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[C:22]=2[CH3:32])=[O:34])[CH2:42][CH2:41]1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(C(C)C)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c2ncnc(-c3cc(C(C)C)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c15) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Cl>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:18])[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[N:6][CH:7]=1
Reactant: OC1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Product: O=C1CCC(O)(c2ccc(Br)cn2)CC1

Procedure:
The title compound was prepared by treating the ketal of step A with HCl in water following the procedure described in step B of Example 2. MS (M+H)+ 271.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].[BrH:8].[CH2:9](O)[CH3:10]>>[CH2:9]([O:5][C:3](=[O:4])[CH:2]([OH:1])[CH2:7][CH2:6][Br:8])[CH3:10]
Reactant: O=C1OCCC1O
Reactant: CCO
Reactant: Br
Product: CCOC(=O)C(O)CCBr
Reaction time: 66 h

Procedure:
2-hydroxybutyrolactone, Brit. Pat. No. 688.253 [C A 48, p.3996 (1954)], (5.1 g) was dissolved in 10 ml ethanol and the solution was saturated with hydrogenbromide at 0° C. After standing at room temperature during 66 hours, the solvent was evaporated at a low pressure. The residue was mixed with ice-water and the mixture neutralized with 10% aqueous sodium carbonate. The mixture was then extracted several times with diethyl ether and the combined ether extracts washed with saturated, aqueous sodium sulphate and dried over anhydrous sodium sulphate. After evaporation of the solvent, the residue was distilled at 12 mm Hg. The fraction boiling at 109°-112° C. weighing 3,79 g was used in example 2 below.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:34]5[NH:35][C:36]([CH:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44](=[O:54])[CH:45]([NH:49][C:50]([O:52][CH3:53])=[O:51])[CH:46]([CH3:48])[CH3:47])=[N:37][CH:38]=5)[CH:30]=4)[CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.Cl.[CH3:56][O:57][C:58]([NH:60][C:61]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)([CH3:65])[C:62](O)=[O:63])=[O:59].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH3:53][O:52][C:50](=[O:51])[NH:49][CH:45]([C:44]([N:40]1[CH2:41][CH2:42][CH2:43][CH:39]1[C:36]1[NH:35][C:34]([C:29]2[CH:28]=[CH:27][C:26]3[C:31](=[CH:32][CH:33]=[C:24]([C:21]4[CH:20]=[CH:19][C:18]([C:15]5[NH:14][C:13]([CH:9]6[CH2:10][CH2:11][CH2:12][N:8]6[C:62](=[O:63])[C:61]([NH:60][C:58]([O:57][CH3:56])=[O:59])([C:66]6[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=6)[CH3:65])=[N:17][CH:16]=5)=[CH:23][CH:22]=4)[CH:25]=3)[CH:30]=2)=[CH:38][N:37]=1)=[O:54])[CH:46]([CH3:47])[CH3:48]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)NC(C)(C(=O)O)c1ccccc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(C)(NC(=O)OC)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.205 mmol) in CH2Cl2 (2 mL) and MeOH (0.2 mL) was added HCl (in dioxanes, 4 M, 1.0 mL, 4.1 mmol). The solution was stirred at room temperature for 1 h and concentrated to dryness. The resulting solid was dissolved in DMF (2.3 mL). 2-Methoxycarbonylamino-2-phenyl-propionic acid (0.06 g, 0.29 mmol), COMU (0.12 g, 0.27 mmol) and DIPEA (0.2 mL, 1.15 mmol) were added. The reaction was stirred at room temperature for 18 h before HCl (6M, 0.1 mL) was added. The solution was purified by preparative HPLC (Gemini, 15→40% MeCN in H2O (0.1% formic acid)) and lyophilized to provide [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.072 g, 42%). LCMS-ESI+: calc'd for C48H52N8O6: 836.40 (M+); Found: 837.87 (M+H+).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.O>CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(O)CC1
Reactant: Fc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(OCc2ccc(F)cc2)CC1
Reaction time: 3 h
Yield: 57.4 %

Procedure:
1-Acetylpiperidin-4-ol (Preparation 193, 10 g, 70 mmol) in N,N-dimethylformamide (50 ml) was added dropwise to a stirred suspension of sodium hydride (50% wt dispersion in oil, 3.8 g, 80 mmol) in N,N-dimethylformamide (50 ml) at room temperature under nitrogen. After stirring the reaction mixture for 3 hours, 4-fluorobenzyl chloride (10.1 g, 70 mmol) in N,N-dimethylformamide (50 ml) was added dropwise and the reaction mixture was stirred for a further 4 h. The reaction mixture was filtered and the filtrate was evaporated to give an orange oil. Water was added and the mixture was extracted with petroleum ether (3×100 ml) and then with diethyl ether (3×100 ml). The combined organic extracts were washed with sodium hydroxide solution (1 M, 3×100 ml), before drying (Na2SO4) and concentrating to give the title compound as an oil (10.1 g, 99%).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[NH:13][C:12](=[O:14])[CH2:11][N:10]1[CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1>ClCCl>[NH:18]1[CH2:17][CH2:16][CH:15]([N:10]2[CH2:11][C:12](=[O:14])[NH:13][C:9]2=[O:8])[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC(=O)NC2=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CN(C2CCNCC2)C(=O)N1
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (0.300 mL) was added to a solution of tert-butyl 4-(2,4-dioxoimidazolidin-1-yl)piperidine-1-carboxylate (32 mg, 0.113 mmol) in dichloromethane (1 mL). After 4 h, the reaction was concentrated to give the title compound. MS 184.04 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH:12]=[CH2:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>[O-]S([O-])(=O)=O.[Ba+2].[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH2:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=Cc1ccc(C(=O)OC)c(Cl)c1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CCOC(C)=O
Product: CCc1ccc(C(=O)OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
Charged methyl 2-chloro-4-ethenylbenzoate (437 mg, 2.23 mmol), BaSO4/Pd (100 mg, 5%) and ethyl acetate (9 mL) to a flask, the mixture was then purged with H2, and stirred at room temperature for 4 h. The reaction mixture was then filtered, concentrated to give 424 mg of the title compound (96%). 1H NMR (400 MHz, CDCl3): δ 1.24 (3H, t, J=7.6 Hz), 2.65 (2H, q, J=7.6 Hz), 3.91 (3H, s), 7.12 (1H, dd, J=1.2 Hz, 8.4 Hz), 7.28 (1H, d, J=1.6 Hz), 7.77 (1H, d, J=8.0 Hz).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([O:26]C(=O)C)=[C:8]2[C:16]([Cl:17])=[CH:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+].CO>>[Cl:17][C:16]1[C:8]2[C:9](=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:5])[C:7]=2[OH:26])[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH:15]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2cccc(F)c2)c1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)cn(Cc3cccc(F)c3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 4-acetoxy-3-chloro-7-cyano-1-(3-fluoro-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 403 (M+H)+.
Reaction SMILES: CON(C)[C:4](=[O:21])[CH:5]([C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][N:14]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH:23]([Mg]Br)=[CH2:24].Cl>O1CCCC1>[CH3:20][S:19][C:16]1[CH:17]=[CH:18][C:13]([CH:5]([CH2:6][CH:7]2[CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)[C:4](=[O:21])[CH:23]=[CH2:24])=[N:14][CH:15]=1
Reactant: CON(C)C(=O)C(CC1CCOCC1)c1ccc(SC)cn1
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)C(CC1CCOCC1)c1ccc(SC)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A solution of N-methoxy-N-methyl-2-[5-(methylsulfanyl)pyridin-2-yl]-3-(tetrahydro-2H-pyran-4-yl)propanamide (404 mg) in tetrahydrofuran (5 mL) was cooled to 0° C., and vinylmagnesium bromide (1.0M tetrahydrofuran solution, 5.0 mL) was added dropwise thereto. The reaction mixture was stirred at room temperature for 2 hr, and poured into 1M hydrochloric acid, and the mixture was stirred for 30 min. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (168 mg, yield 46%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [OH-:1].[Na+].[C:3]1([N:9]2[C:13]3([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:12][NH:11][CH:10]2CC(OCC)=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.Cl.[O:27]1[CH2:31][CH2:30]CC1>>[C:3]1([N:9]2[C:13]3([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:12][N:11]([CH2:30][C:31]([OH:27])=[O:1])[CH2:10]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)CC1NCC2(CCCCC2)N1c1ccccc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)CN1CN(c2ccccc2)C2(CCCCC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41 %

Procedure:
200 mg (5 mmol) of sodium hydroxide are added to a solution of 510 mg (1.68 mmol) of ethyl (1-phenyl-1,3-diazaspiro[4.5]decyl)acetate in 10 ml of tetrahydrofuran. The solution is stirred for 4 h at room temperature. The medium is then poured into water, acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phases are collected and washed with water. They are dried over sodium sulfate. The solvents are evaporated. The product is triturated in heptane. 190 mg of (1-phenyl-1,3-diazaspiro[4.5]dec-3-yl)acetic acid are obtained in the form of a yellowish solid. M.p. 162-4° C., yield=41%.
Reaction SMILES: [OH:1][CH:2]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:3][NH:4][C:5]1[N:10]([CH3:11])[C:9](=[O:12])[C:8]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[C:7]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[N:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.ClCCl.CO.[2H]C([2H])([2H])C#N.[2H]O[2H]>C(#N)C.ClCCl>[CH3:11][N:10]1[C:9](=[O:12])[C:8]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[C:7]([C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)[N:6]=[C:5]1[NH:4][CH2:3][C:2](=[O:1])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cn1c(NCC(O)Cc2ccccc2)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [2H]C([2H])([2H])C#N
Agent: [2H]O[2H]
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: Cn1c(NCC(=O)Cc2ccccc2)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Reaction time: 0.05 h

Procedure:
To a striring suspension of 2-(2-hydroxy-3-phenyl-propylamino)-3-methyl-5-naphthalen-2-yl-6-pyridin-4-yl-3H-pyrimidin-4-one (150 mg, 0.32 mmol) in 5 mL dry acetonitrile and 5 mL dichloromethane was added Dess-Martin Periodinane (206 mg, 0.49 mmol). The reaction mixture turned to an orange color within 3 min. After 30 min, TLC (95:5 dichloromethane/methanol) showed approximately 15% of the starting material remained. More Dess-Martin Periodinane (50 mg, 0.12 mmol) was added and the reaction was stirred for and additional 30 min. The curde product was purified on 10 g silica eluting with 0 to 3% methanol/dichloromethane to give a clear film. The material was further purified on reverse phase high performance chromatography eluting with water/acetonitrile (0.1% TFA) gradient. The final material was lyophilized from 50% acetonitrile/water to give a pale yellow powder. M+1=461.3. NMR (CD3CN/D2O 3:1) s (3H; 3.5 ppm), s (2H; 3.8 ppm), s (2H; 4.3 ppm), dd (2H; 7.15 ppm), m (4H, 7.2-7.3 ppm), m (3H, 7.45-7.55 ppm), d (2H, 7.62 ppm), d (1H, 7.72 ppm), d (1H, 7.84 ppm), d (1H, 7.88 ppm), d (2H, 8.39 ppm). M+1=461.2.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([O:30][CH2:31][C:32]#[N:33])=[C:26]([N+:27]([O-])=O)[C:20]=4[S:19](=[O:35])(=[O:34])[N:18]=3)[C:7]2=[O:36])[CH2:3][CH2:2]1.[Cl-].[NH4+]>CO.O1CCCC1.O.[Fe]>[NH2:27][C:26]1[C:20]2[S:19](=[O:35])(=[O:34])[N:18]=[C:17]([C:8]3[C:7](=[O:36])[N:6]([NH:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:15]4[C:10]([C:9]=3[OH:16])=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:22][C:21]=2[CH:23]=[CH:24][C:25]=1[O:30][CH2:31][C:32]#[N:33]
Reactant: N#CCOc1ccc2c(c1[N+](=O)[O-])S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N#CCOc1ccc2c(c1N)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 60 °C
Yield: 41.6 %

Procedure:
A mixture of the product of Example 388A (13 mg, 0.025 mmol), iron powder (6.0 mg, 0.107 mmol), and ammonium chloride (1.5 mg, 0.028 mmol) in methanol:tetrahydrofuran:water (2:2:1, 2 mL) was heated at 60° C. for 1 hour. The solution filtered through Celite® and washed with tetrahydrofuran. The solution was evaporated under reduced pressure and the residue was triturated with ethyl acetate, filtered washed with water and dried to give title compound (5 mg, 41%). 1H NMR (300 MHz, DMSO-d6) δ 0.14 (d, J=1.11 Hz, 2 H) 0.41 (d, J=5.88 Hz, 2 H) 1.01 (m, 1 H) 2.85 (d, J=5.40 Hz, 2 H) 5.23 (s, 2 H) 5.80 (s, 2 H) 6.45 (s, 1 H) 6.83 (d, J=8.46 Hz, 1 H) 7.38 (d, J=8.46 Hz, 1 H) 7.44 (t, J=7.02 Hz, 1 H) 7.90 (t, J=7.02 Hz, 1 H) 8.10 (d, J=8.46 Hz, 1 H) 8.16 (d, J=7.74 Hz, 1 H) 13.93 (s, 1 H) 14.94 (s, 1 H). MS (ESI−) m/z 479 (M−H)−.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])[CH:9]=[CH:10][CH:11]=1)(=[O:5])[CH3:4]>O1CCOCC1.CCOCC>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])[CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: BrBr
Reactant: CCOC(=O)Nc1cccc(C(C)=O)c1
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOC(=O)Nc1cccc(C(=O)CBr)c1
Reaction time: 2 h
Yield: 97.8 %

Procedure:
24.1 gm of bromine were added slowly over a period of 30 minutes to a stirred suspension of 28.5 gm of ethyl N-(3-acetyl-phenyl)-carbamate in 13.3 gm of dry dioxane and 245 ml of dry ether. After stirring the reaction solution for 2 hours more, it was cooled, and the product which crystallized out was collected and washed with ether, yielding 38.5 gm of the title compound, m.p. 108°-110° C.
Reaction SMILES: [OH:1][C:2]1[N:11]=[C:10]([N:12]([NH2:18])C(OCC)=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:19][CH3:20])[N:3]=1.CN(C)[CH:23]=[O:24]>>[CH3:20][O:19][C:8]1[C:9]2[C:10]3[N:11]([C:23](=[O:24])[NH:18][N:12]=3)[C:2](=[O:1])[NH:3][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)N(N)c1nc(O)nc2cccc(OC)c12
Product: COc1cccc2[nH]c(=O)n3c(=O)[nH]nc3c12
Temperature: 25 °C

Procedure:
2.4 g (0.0086 mol) of ethyl 2-hydroxy-5-methoxy-quinazolin-4-yl-carbazate in 50 ml of dimethylformamide were boiled under reflux for 3 hrs. The reaction mixture was cooled to room temperature and then poured on to ice-water. The precipitate was filtered off, washed with methanol and dried in a vacuum. There were obtained white crystals which were recrystallized from dimethylformamide. Yield: 0.32 g (16%) of 10-methoxy-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione as white crystals; m.p. >350° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][S:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.O.O.[Sn](Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.C(OCC)(=O)C>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([S:11][CH2:10][CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:17][CH:16]=1
Reactant: CC1CCN(CCCSc2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1CCN(CCCSc2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve 15.5 g (0.0520 mol) of 4-methyl-1-[3-[(4-nitrophenyl)thio]propyl]piperidine in 150 mL of ethanol. Add 59.3 g (0.26 mol) of tin(II) chloride dihydrate and heat mixture to reflux for 5 h. After 5 h, cool the reaction mixture to room temperature. Pour reaction mixture over 100 g of potassium carbonate and dilute with 500 mL of water and 500 mL of ethyl acetate. Filter this suspension through celite and separate the layers. Extract the aqueous layer with 3×300 mL of ethyl acetate. Combine organic layers and dry over anhydrous sodium sulfate. Filter the drying agent and remove the solvent in vacuo to provide the title compound.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:21][CH2:22][NH2:23].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:21][CH2:22][NH:23][C:25](=[O:26])[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.2 %

Procedure:
N,N-diisopropylethylamine (0.745; 4.33 mmol) was added to a mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.500 g; 2.16 mmol), and phenyl chloroformate (0.406 mL; 3.25 mmol) in dichloromethane (20 mL). The solution was stirred at room temperature for 20 minutes, diluted in dichloromethane, washed with sodium hydrogen sulfate (1M, water), sodium carbonate (1M, water) and brine. The organic layer was dried and concentrated under reduced pressure to furnish 0.60 g (88%) of phenyl 2-(5-chloro-1H-indol-3-yl)ethylcarbamate as a yellow oil.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:45])[CH2:30][CH2:31][N:32]([C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1)[C:33](=[O:37])[CH2:34][CH2:35][CH3:36]>>[CH3:45][N:29]([CH3:28])[CH2:30][CH2:31][N:32]([C:38]1[CH:44]=[CH:43][C:41]([NH:42]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:8]3[C:7]\2=[CH:12][CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:40][CH:39]=1)[C:33](=[O:37])[CH2:34][CH2:35][CH3:36]
Reactant: CCCC(=O)N(CCN(C)C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: CCCC(=O)N(CCN(C)C)c1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-(2-dimethylamino-ethyl)-N-butyryl-amino)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C31H34N4O4
Reaction SMILES: C([O:4][N:5]1[C:10](=[O:11])[C:9]2[S:12][CH:13]=[CH:14][C:8]=2[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=2)[C:6]1=[O:23])C=C.BrCC1O[C:30]2[CH:32]=CC=[CH:35][C:29]=2OC1>>[OH:4][N:5]1[C:10](=[O:11])[C:9]2[S:12][CH:13]=[CH:14][C:8]=2[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]3[C:18](=[CH:35][CH:29]=[CH:30][CH:32]=3)[CH:17]=2)[C:6]1=[O:23]
Reactant: C=CCOn1c(=O)c2sccc2n(Cc2cccc(Br)c2)c1=O
Reactant: BrCC1COc2ccccc2O1
Product: O=c1c2sccc2n(Cc2ccc3ccccc3c2)c(=O)n1O

Procedure:
3-Allyloxy-1-(3-bromo-benzyl)-1H-thieno[3,2-d]pyrimidine-2,4-dione was alkylated with 2-bromomethyl-2,3-dihydro-benzo[1,4]dioxine via general procedure B2. The crude intermediate was deprotected via general procedure D2. The final product was purified by mass triggered preparative HPLC. Electrospray MS: 333 (M+H); retention time: 2.05 min.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@H:37]1[C@H:41]([OH:42])[CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][C@H:37]4[C@H:41]([OH:42])[CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](O)C1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)N[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2O)c2ncnc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c1) and commercially available tert-butyl (3R*,4R*)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate the title compound is obtained as pale yellow foam.