Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[OH-].[Na+].[C:8]([C:10]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)([CH2:13][CH3:14])[CH2:11]Br)#[N:9].O>CS(C)=O>[C:8]([C:10]([C:15]1[CH:16]=[CH:17][C:18]([Br:21])=[CH:19][CH:20]=1)([CH2:13][CH3:14])[CH2:11][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)#[N:9]
Reactant: c1nc[nH]n1
Reactant: CCC(C#N)(CBr)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCC(C#N)(Cn1cncn1)c1ccc(Br)cc1
Reaction time: 1.5 h

Procedure:
2.2 g (0.032 Mol ) of 1,2,4-triazole and 1.3 g (0.032 mol) pulverised NaOH in 30 ml of dimethylsulfoxide are heated at 110°. To this mixture are added, within a few minutes, at 110° a solution of 2-cyano-2-(4-bromophenyl)butylbromide in 10 mol of dimethylsulfoxide. The reaction mixture is stirred at 110° for another 90 minutes, poured into 600 ml of water and extracted several times with diethylether. The united ether phases are washed with water and dried with magnesiumsulfate. Thereafter the ether is evaporated at the water jet and residues of dimethylsulfoxide at high vacuum to give the title compound (solid; m.p. 68°-70°, Rf=0.45 employing CH2Cl2 /CH3OH 95:5 as eluant).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([C@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[CH2:15][OH:16])[C:7]2[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:6]=2[N:5]=1.I[CH2:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH:37]=[CH:38][CH:39]=1)[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].[C:40]([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[C:33]([O:32][C:30](=[O:31])[NH:29][C:28]1[CH:27]=[C:26]2[C:39](=[CH:38][CH:37]=1)[CH2:23][CH:24]([CH2:40][N:12]1[CH2:13][CH2:14][CH:9]([N:8]3[C:7]4[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:6]=4[N:5]=[C:4]3[CH3:3])[CH:10]([CH2:15][OH:16])[CH2:11]1)[CH2:25]2)([CH3:36])([CH3:35])[CH3:34]
Reactant: Cc1ccc2c(c1)nc(C)n2[C@H]1CCNC[C@H]1CO
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCCI)c1
Agent: Cl
Agent: [Cs+]
Solvent: CC#N
Product: Cc1ccc2c(c1)nc(C)n2C1CCN(CC2Cc3ccc(NC(=O)OC(C)(C)C)cc3C2)CC1CO
Temperature: 25 °C

Procedure:
cis-4-(2,5-Dimethylbenzimidazol-1-yl)-3-hydroxymethylpiperidine dihydrochloride (313 mg; 0.94 mmol), 3-[3-iodopropyl]-N-Boc aniline (361 mg. 1 mmol) and Cs2CO3 (1625 mg; 5 mmol) were added to CH3CN (10 mL) and the reaction mixture was heated to reflux for 14 h. After cooling to rt, the reaction mixture was filtered through Celite® and all volatiles were removed under reduced pressure to yield a brown oil from which {2-[4-(2,5-dimethyl-benzoimidazol-1-yl)-3-hydroxymethyl-piperidin-1-ylmethyl]-indan-5-yl}-carbamic acid tert-butyl ester was isolated by flash chromatography (0-10% CH3OH in EtOAc) as a heavy oil (191 mg; 39%).
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH2:10][Cl:11])([CH3:9])[CH3:8])=[CH:3][CH:2]=1.[CH:18]([Li])(CC)C.CN(C)CCN(C)C.CI.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:1]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH3:8])([CH3:9])[CH:10]([Cl:11])[CH3:18])=[CH:3][CH:2]=1
Reactant: [Li]C(C)CC
Reactant: C[Si](C)(CCl)c1ccc(-c2ccccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(Cl)[Si](C)(C)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
A solution of 4.0 g (15.3 mmol) of (1,1'-biphenyl-4-yl)chloromethyldimethylsilane in 20 ml of tetrahydrofuran was cooled to -78°, and 12.5 ml (16.8 mmol) of 1.35 molar sec-butyllithium in hexane was slowly dripped in followed by addition of 2.42 ml (16.1 mmol) of tetramethylethylenediamine. After stirring for one hour at -78°, the solution was warmed to -55° and 1.43 ml (22.9 mmol) of methyl iodide in 5 ml of tetrahydrofuran was added dropwise. The mixture was stirred another 30 minutes at -50°, warmed to room temperature, poured into saturated aqueous ammonium chloride, and extracted with ether. The ether extracts were washed with water and brine, dried over magnesium sulfate, and evaporated to give 3.33 g (65%) of the title compound contaminated by about 18% of an impurity: nmr (CDCl3) 0.3 (s, 2.7H, impurity), 0.4 (6H, s), 1.5 (3H, d, J=7 Hz), 3.5 (1H, q, J=7 Hz) and 7.3-7.7 (m, 13H).
Reaction SMILES: CC[N:3]([CH2:6][CH3:7])[CH2:4][CH3:5].BrC1C=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:10]=1C#N.[C]=[O:20]>[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].CO>[CH3:18][O:17][C:14]1[CH:15]=[C:7]2[C:5](=[CH:10][CH:13]=1)[C:4](=[O:20])[NH:3][CH2:6]2
Reactant: COc1ccc(Br)c(C#N)c1
Reactant: CCN(CC)CC
Reactant: [C]=O
Agent: [Fe+2]
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Product: COc1ccc2c(c1)CNC2=O

Procedure:
Methanol (53 mL) and NEt3 (6.90 mL, 49.5 mmol) were added to 2-bromo-5-methoxybenzonitrile (5.25 g, 24.76 mmol) and Pd-dppf (Heraeus) (0.362 g, 0.495 mmol) in a pressure tube. The mixture was stirred under 60 psi of Carbon Monoxide at 80° C. for 8 hr. HPLC analysis (starting material retention time 3.24 min., product retention time 2.82 min.) indicated clean and complete conversion. The obtained solution was concentrated down to a light orange color solid, 6.66 g.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:15]([CH3:16])=[N:14][N:13]=[N:12]1)(=[O:4])=[O:3].[CH3:17][O:18][C:19]1[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH:26][C:27](=O)[O:28]C2C=CC=CC=2)[N:20]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C>[CH3:17][O:18][C:19]1[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH:26][C:27]([NH:1][S:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]2[C:15]([CH3:16])=[N:14][N:13]=[N:12]2)(=[O:4])=[O:3])=[O:28])[N:20]=1
Reactant: COc1nc(C)nc(NC(=O)Oc2ccccc2)n1
Reactant: Cc1nnnn1-c1ccccc1S(N)(=O)=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2-n2nnnc2C)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
To 0.48 g of 1-(2-aminosulfonylphenyl)-5-methyl-1H-tetrazole and 0.52 g of phenyl N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)carbamate in 25 mL of acetonitrile at ambient temperature and pressure was added 0.3 mL of DBU. The mixture was stirred for three hours and then added to 25 g of ice and acidified with hydrochloric acid. The precipitate thus obtained was filtered, washed with water and dried in vacuo to yield 0.65 g of the desired product melting at 207°-209° C. Infrared absorption spectra showed absorption at 1700, 1600 and 1550 cm-1 consistent for the desired structure.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[CH:14][C:15]3[C:21]([CH2:23][O:24][CH3:25])([CH3:22])[CH2:20][CH2:19][CH2:18][O:17][C:16]=3[CH:26]=2)=[CH:6][CH:5]=1.[OH-].[Na+].Cl>C1COCC1.C(O)C.O>[CH3:25][O:24][CH2:23][C:21]1([CH3:22])[CH2:20][CH2:19][CH2:18][O:17][C:16]2[CH:26]=[C:12]([C:11]#[C:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:27])=[O:2])=[CH:9][CH:8]=3)[CH:13]=[CH:14][C:15]1=2
Reactant: COCC1(C)CCCOc2cc(C#Cc3ccc(C(=O)OC)cc3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COCC1(C)CCCOc2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 0 °C
Reaction time: 42 h
Yield: 98 %

Procedure:
20.06 g (55.04 mmol) of 4-(5-methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo[b]oxepin-8-ylethynyl)-benzoic acid methyl ester was dissolved in 100 ml of THF/ethanol (1/1) and treated with 8.81 g (4 eq.) of NaOH, dissolved in 50 ml of water. The reaction flask was kept in the dark and stirring continued for 42 h at room temperature. The mixture was then poured onto crushed ice/60 ml of 25% HCl, extracted twice with ethylacetate; the organic phase was washed with a small amount of water, dried over sodium sulfate, filtrated, and evaporated to dryness. Crystallization from hexane/ethylacetate yielded 18.90 g of the title product as pale yellow crystals of m.p. 205-206° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-ethoxy-phenyl)-carbamic acid tert-butyl ester (Example J25) (215 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (142 mg, 37%).
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[S:7][C:8]([CH2:11]Cl)=[CH:9][CH:10]=1.C(Cl)(Cl)Cl.[Na+].[Cl-].C[N:20]([CH:22]=O)C>>[C:1]([CH2:5][C:6]1[S:7][C:8]([CH2:11][C:22]#[N:20])=[CH:9][CH:10]=1)#[N:2]
Reactant: [C-]#N
Reactant: ClCc1ccc(CCl)s1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: N#CCc1ccc(CC#N)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 25.3 %

Procedure:
An solution of sodium cyanide (97.7 g, 1.99 mol) in anhydrous DMF (650 mL) is cooled to 0° C. and treated with 2,5-bis-chloromethyl-thiophene (84.7 g, 468 mmol) in one portion. The reaction mixture is allowed to warm to room temperature with stirring for 24 h, then heated to 40° C. for an additional 0.5 h. After cooling to room temperature, chloroform (300 mL) is added and the mixture is poured into saturated aq NaCl. After separation, the aq layer is extracted with chloroform (3×). The combined organic layers are washed with saturated aq NaCl, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is purified by distillation to give (5-cyanomethyl-thiophen-2-yl)-acetonitrile (19.2 g, 25.3%) as a light brown oil: (bp 160-165° C., 0.75 mm Hg; Rf 0.26 (15% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 6.93 (s, 2 H), 3.85 (s, 4 H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[S:11][C:12]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:13]=2[N:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.CCOC(C)=O>[CH2:1]([O:19][C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([Cl:9])[S:11][C:12]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2nc(Cl)sc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Clc1nc2ccc(OCc3ccccc3)cc2s1
Temperature: 70 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
Benzyl bromide (0.921 g, 5.39 mmol) was added to a mixture of 2-chlorobenzo[d]thiazol-6-ol (1.00 g, 5.39 mmol) and cesium carbonate (1.76 g, 5.39 mmol) in CH3CN (15 mL). After 2 h at rt, the reaction mixture was heated to 70° C. overnight. Upon cooling to rt, the reaction mixture was diluted with EtOAc (100 mL) and washed with water (3×75 mL) and brine (75 mL). The EtOAc layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by column chromatography (0 to 8% EtOAc in Hexanes gradient), yielding 1.396 g (94%) of the title compound as a reddish, waxy solid. LC-MS: RT=10.51 min., [M+H]+=275.9. Rf=0.41 in 10% EtOAc/Hexanes.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.[Cl-].[CH3:16][O:17][C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[CH:20]=[N+:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[OH:1][C:2]1[C:3]([CH:20]([C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[O:17][CH3:16])[N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2
Reactant: COc1ccccc1C=[N+]1CCOCC1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: [Cl-]
Product: COc1ccccc1C(c1c(O)ccc2c(C(=O)O)cccc12)N1CCOCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 6-hydroxy-1-naphthoic acid and 4-(2-methoxy-benzylidene)-morpholin-4-ium chloride, which had been prepared in accordance with example 28.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][C:37]([O:39]CC2C=CC=CC=2)=[O:38])[CH:31]=1)([O:27][CH3:28])=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.[H][H]>CO.O.[C].[Pd]>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][C:37]([OH:39])=[O:38])[CH:31]=1)([O:27][CH3:28])=[O:26])[C:13]([OH:15])=[O:14]
Reactant: [H][H]
Reactant: COP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1cccc(CC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COP(=O)(CCC(N)C(=O)O)Oc1cccc(CC(=O)O)c1
Yield: 51.2 %

Procedure:
Next, 0.72 g (1.12 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-{[3-(benzyloxycarbonylmethyl)phenyl](methyl)phosphono}butanoate was dissolved in 24 mL of a solvent mixture of methanol and water at 5:1 and mixed with 200 mg of 5% palladium-carbon, and hydrogen gas was introduced at room temperature for 2.5 hours. Thereafter, the palladium-carbon was removed by Celite filtration and the filtrate was vacuum-concentrated and the residue was freeze-dried from water to obtain 2-amino-4-{[3-(carboxymethyl)phenyl] (methyl)phosphono}butanoic acid (0.19 g, yield 51%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:20]([O-:22])=O)[C:5]([NH:12][C:13]([C:15](OCC)=[O:16])=[O:14])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN(C)C=O.N.[H][H]>O1CCCC1.[Pt]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([NH:12][C:13](=[O:14])[C:15](=[O:16])[N:20]2[OH:22])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: [H][H]
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(Cl)cc1C(F)(F)F
Agent: [Pt]
Agent: N
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=c1[nH]c2c(C(F)(F)F)cc(Cl)cc2n(O)c1=O
Yield: 80 %

Procedure:
To a solution of 1.0 g (2.94 mmol) 5-chloro-2-ethoxalylamino-3-nitrobenzotrifluoride in 75 ml tetrahydrofuran was added 25 ml dimethylformamide and 1.0 ml 25% aqueous ammonia. The mixture was hydrogenated at atm. pressure by using 100 mg 5% Pt-C as a catalyst. When the hydrogen uptake was completed, the catalyst was filtered off, and the filtrate was evaporated in vacuo. The residue was stirred with 1N aqueous hydrochloric acid to give 0.66 g (80%) of 7-chloro-1-hydroxy-5-trifluoromethylquinoxaline -2,3(1H,4H)-dione. M.P. 275° C. decomp. 1H-NMR (DMSO-d6): 11.7 (2H, m), 7.60 (1H, d), 7.43 (1H, d).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[N:26]12[CH2:33][CH2:32][CH:29]([CH2:30][CH2:31]1)[C@@H:28]([NH2:34])[CH2:27]2>>[N:26]12[CH2:33][CH2:32][CH:29]([CH2:30][CH2:31]1)[C@@H:28]([NH:34][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=1)(=[O:10])=[O:9])[CH2:27]2
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Reactant: N[C@H]1CN2CCC1CC2
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2N[C@H]2CN3CCC2CC3)ccc2c1OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Example 73, starting from (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67) and (R)-1-azabicyclo[2.2.2]oct-3-ylamine.
Reaction SMILES: [H][H].CC(O)=O.[OH:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:12]3[CH2:11][C:10]=2[CH:9]=1>C1COCC1.CCO.[OH-].[OH-].[Pd+2]>[OH:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:12]3=[CH:11][C:10]=2[CH:9]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)CC1CCN2c3ccc(O)cc3CC12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Temperature: 50 °C

Procedure:
tert-Butyl-2-(7-(benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ylidene)acetate (1.391 g, 3.70 mmol) was dissolved in THF (25 mL) and 10% palladium on carbon (50% in water, 217 mg) was added. The reaction mixture was placed under 225 psi of hydrogen in a hydrogenation reactor for 24 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide tert-butyl 2-(7-(benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate. The above material was taken up in a mixture of THF (20 mL) and EtOH (20 mL) and Pd(OH)2/C (250 mg) was added. The reaction mixture was placed under 200 psi of hydrogen in a hydrogenation reactor for 2 days. Additional Pd(OH)2/C (250 mg) was added and the reaction mixture was placed under 300 psi of hydrogen in a hydrogenation reactor for 24 h. Pd(OH)2/C (250 mg) was again added and the vessel placed under 500 psi of hydrogen in a hydrogenation reactor for 24 h. The hydrogenation reactor was warmed to 50° C. for 8 h. The reaction mixture was cooled to room temperature and AcOH (5 mL) was added. The reaction mixture was placed under 500 psi of hydrogen for 16 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to provide a mixture of the title compound and tert-butyl 2-(7-hydroxy-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate. The title compound (150 mg) was isolated by silica gel column chromatography. tert-Butyl 2-(7-hydroxy-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (600 mg) was dissolved in toluene (100 mL) and Pd/C (1.0 g) was added. The reaction mixture was warmed to 80° C. and stirred for 2 days. The reaction mixture was filtered through Celite® and the title compound (250 mg) was isolated as a white solid resulting from precipitation during concentration of the filtrate. LCMS m/z=288.3 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1[N:6]=[CH:7][N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=3)[C:9]=12.Cl.[CH3:24][NH:25][O:26][CH3:27].C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[CH:5]1[N:6]=[CH:7][N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([N:25]([O:26][CH3:27])[CH3:24])=[O:20])=[CH:21][CH:22]=3)[C:9]=12
Reactant: CNOC
Reactant: O=C(O)c1ccc(C2OCCn3cncc32)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CON(C)C(=O)c1ccc(C2OCCn3cncc32)cc1
Temperature: 2.5 °C
Reaction time: 16 h

Procedure:
9.30 mmol of thionyl chloride are added to a solution of 3.10 mmol of 4-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)benzoic acid in 5 ml of chloroform. The reaction mixture is heated to reflux for 3 hours and then evaporated. The residue is stripped with toluene and then taken up in 10 ml of dichloromethane. The reaction solution is cooled to 0-5° C., and 3.10 mmol of N,O-dimethylhydroxylamine hydrochloride, followed by 15.5 mmol of diisopropylethylamine, are added. The reaction mixture is stirred at room temperature for 16 hours and filtered through Hyflo, and the filtrate is evaporated. The title compound is obtained as a yellowish oil from the residue by flash chromatography (SiO2 60F). Rf=0.13 (dichloromethane-2M ammonia in ethanol 97:3); Rt=4.00.
Reaction SMILES: CC1(C)CO[C:5]2([CH2:27][CH2:26][C:10]3[N:11]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]4[N:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:18](=[O:19])[C:9]=3[CH2:8]2)[O:4]C1.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(=O)CC>[C:20]1([N:11]2[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18](=[O:19])[C:9]3[CH2:8][C:5](=[O:4])[CH2:27][CH2:26][C:10]2=3)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1(C)COC2(CCc3c(c(=O)c4cccnc4n3-c3ccccc3)C2)OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCC(C)=O
Solvent: O
Product: O=C1CCc2c(c(=O)c3cccnc3n2-c2ccccc2)C1

Procedure:
Reflux 6,8,9,10-tetrahydro-5',5'-dimethyl-10-phenyl-spiro[benzo[b][1,8]naphthyridin-7-(5H),2'-[1,3]dioxan]-5-one (32 mmoles) with water (6 ml) and p-toluenesulfonic acid monohydrate (3.2 g) dissolved in 2-butanone (319 ml) for 3 days. Monitor the progress of hydrolysis by thin-layer chromatography. When hydrolysis is complete, cool the solution and evaporate the 2-butanone. Wash a CH2Cl2 solution of the residue with aqueous NaHCO3 solution and with water. Evaporate the CH2Cl2 after drying the organic solution, and crystallize the residue from C2H5OH--CHCl3 to obtain 6,8,9,10-tetrahydro-10-phenyl-benzo[b][1,8]naphthyridin-5,7-dione, m.p. 244°-247° C. (d).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.S(C1C=CC(C)=CC=1)(O)(=O)=O.O[CH2:25][CH2:26][CH2:27][C:28]1[C:36]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:35][C:31]2[CH2:32][CH2:33][O:34][C:30]=2[CH:29]=1.CS(C)=O>O1CCCC1.O>[C:2]1([NH:1][CH2:25][CH2:26][CH2:27][C:28]2[C:36]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:35][C:31]3[CH2:32][CH2:33][O:34][C:30]=3[CH:29]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: OCCCc1cc2c(cc1OCc1ccccc1)CCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li]CCCC
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(COc2cc3c(cc2CCCNc2ccccc2)OCC3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a -78° solution of lithium anilide, prepared from aniline (0.217 g, 2.33 mmol) and n-butyllithium (1.6 M in hexane, 1.46 mL, 2.33 mmol), in tetrahydrofuran (2 mL) was added a solution of 8a (0.980 g, 2.23 mmol). Dimethyl sulfoxide (0.1 mL) was added and the mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ether (2 X). The extracts were dried (MgSO4) and concentrated to afford 12.
Reaction SMILES: NCCCN(C1C=C(C)N=C(N2C=CN=C2)N=1)[CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:8].O.[O-]C#N.[K+]>N1C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][NH:9][C:7](=[O:8])[CH3:6])=[CH:17][CH:16]=1
Reactant: COc1ccc(CCNC(=O)CN(CCCN)c2cc(C)nc(-n3ccnc3)n2)cc1
Agent: N#C[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(CCNC(C)=O)cc1
Temperature: 80 °C

Procedure:
To 2-[(3-aminopropyl)[2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide (135 mg, 0.32 mmol) (a compound of formula (Yc6)) in pyridine (1.5 mL) was added water (1.5 mL) solution of potassium cyanate (64 mg, 0.76 mmol). The mixture was stirred and heated in an oil bath at 80° C. overnight. The mixture was poured into water and extracted with ethyl acetate (3×20 mL). The combined ethyl acetate fractions were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (9:1 CH3CN/NH4OH) to afford 2-[[3-ureido)propyl][2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]-N-[2-(4-methoxyphenyl)ethyl]acetamide, a compound of formula (Yc9); as a white solid; NMR (DMSO-d6, 90° C.) 8.4 (s, 1), 7.8 (s, 1), 7.05 (d, 2), 7.0 (s, 1), 6.75 (d, 2), 6.4 (s, 1), 4.1 (s, 2), 3.7 (s, 3), 3.5 (m, 2), 3.25 (m, 2), 3.05 (m, 2), 2.65 (t, 2), 2.3 (s, 3), 1.7 (m, 2) ppm.