Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH2:20]([O:27][C:28](=[O:60])[CH2:29][CH2:30][C:31]([O:33][C:34]1([CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:52][C@H:51]([CH2:53][NH:54][C:55](=[O:57])[CH3:56])[O:50][C:49]3=[O:58])=[CH:44][C:43]=2[F:59])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C[Si](C)(C)Cl>CN1CCCC1=O>[CH2:20]([O:27][C:28](=[O:60])[CH2:29][CH2:30][C:31]([O:33][C:34]1([CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:52][C@H:51]([CH2:53][NH:54][C:55](=[O:57])[CH3:56])[O:50][C:49]3=[O:58])=[CH:44][C:43]=2[F:59])[CH2:39][CH2:38][N:37]([C:2]2[C:3]([F:19])=[CH:4][C:5]3[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]([CH:12]4[CH2:14][CH2:13]4)[C:10]=3[N:11]=2)[CH2:36][CH2:35]1)=[O:32])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)CCC(=O)OCc4ccccc4)CCNCC3)c(F)c2)C(=O)O1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: C[Si](C)(C)Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)CCC(=O)OCc4ccccc4)CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1

Procedure:
In analogy to example 1 step 7, with 113 mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[1,8]naphthyridine-3-carboxylic acid (MW: 282.66, 0.4 mmol), 230 mg succinic acid 4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-piperidin-4-yl ester benzyl ester (MW: 571.60, 0.4 mmol), 161 mg triethylamine (MW: 101.19, 1.6 mmol) and 87 mg trimethylchlorsilan (MW: 108.64, 0.8 mmol) in 2 ml N-methyl-pyrrolidin-2-one. Yield: 25 mg, 7.6%. MS: 819 (M+H)+, 817.8, Method ESI+, ESI−.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=2)[C:5]=1[CH3:21])([O-])=O>O1CCCC1.C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[C:6]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=2)[C:5]=1[CH3:21]
Reactant: COc1ccnc(-c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2C)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccnc(-c2cc(N)cc(N)c2C)c1
Yield: 98.4 %

Procedure:
A suspension of 2,4-dinitro-6-(4-methoxypyridin-2-yl)toluene (132 mg) in tetrahydrofuran (2 ml) and ethanol (2 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 50 mg) under a hydrogen atmosphere for 4 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 2,4-diamino-6-(4-methoxypyridin-2-yl)toluene (103 mg).
Reaction SMILES: Cl.C([O:5][CH2:6][CH2:7][N:8]([CH2:12][CH2:13][N:14]1[C:22]2[CH:21]=[CH:20][C:19]([NH2:23])=[C:18]3[S:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:16]([C:17]=23)=[N:15]1)C(=O)C)(=O)C.[Cl:31][CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][O:36]C1=O>C(Cl)Cl.CO>[ClH:31].[OH:36][CH2:37][CH2:38][NH:34][CH2:33][CH2:32][NH:23][C:19]1[CH:20]=[CH:21][C:22]2[N:14]([CH2:13][CH2:12][NH:8][CH2:7][CH2:6][OH:5])[N:15]=[C:16]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[S:24][C:18]=1[C:17]=23
Reactant: CC(=O)OCCN(CCn1nc2c3c(c(N)ccc31)Sc1ccccc1-2)C(C)=O
Reactant: O=C1OCCN1CCCl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: OCCNCCNc1ccc2c3c(nn2CCNCCO)-c2ccccc2Sc13
Temperature: 150 °C
Reaction time: 2 h
Yield: 111.1 %

Procedure:
A mixture of 5.1 g (0.012 mol) of N-[2-(acetyloxy)ethyl]-N-[2-(5-amino-2H[1]benzothiopyrano[4,3,2-cd]indazol-2-yl)ethyl]acetamide, hydrochloride salt and 11.6 g (0.077 mol) of 3-(β-chloroethyl)-2-oxazolidinone was stirred at 150° C. for 2 hours, dissolved in 20 ml of a CH2Cl2 /MeOH (20/1) mixture, and flash chromatographed over silica gel, eluting with a CH2Cl2 /MeOH (20/1) mixture. The appropriate fractions were combined and concentrated to dryness in vacuo. The residue was treated with 20 ml of 2N KOH in MeOH, 10 ml of H2O, and 10 ml of THF, and the mixture was heated under reflux under a N2 atmosphere for 16 hours. The mixture was treated with 100 ml of H2O and 100 ml of CH2Cl2 and the layers were separated. The aqueous phase was extracted twice with CH2Cl2 and the Ch2Cl2 extracts were combined, dried (MgSO4), and concentrated to dryness in vacuo. The residue was dissolved in 50 ml of EtOH and treated with an excess of i-PrOH saturated with gaseous HCl. The precipitate was collected and recrystallized from MeOH to give 6.0 g of product, mp 222°-225° C.
Reaction SMILES: [OH-].[K+].[CH3:3][CH2:4][CH2:5][C:6]([C:8]([OH:10])=[O:9])=[O:7].[C:11]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)(=[O:13])[CH3:12]>O.C(O)C>[OH:7][C:6]([CH2:5][CH2:4][CH3:3])([CH2:12][C:11](=[O:13])[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[C:8]([OH:10])=[O:9]
Reactant: CC(=O)c1cccs1
Reactant: CCCC(=O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCC(O)(CC(=O)c1cccs1)C(=O)O
Reaction time: 48 h
Yield: 41.3 %

Procedure:
11.2 g (200 mmol) of potassium hydroxide in 75 ml of water are added at 0° dropwise to a suspension of 11.6 g (100 mmol) of 2-oxo-n-valeric acid and 12.6 g (100 mmol) of 2-acetylthiophene in 75 ml of ethanol and the suspension is held at 0° for 48 hours. After evaporation of the ethanol the residue is made acidic with 25% hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate extracts are dried, filtered and evaporated. After chromatography on silica gel using a 5:1 mixture of methylene chloride and methanol as the eluent and crystallisation from ether there are obtained 10.0 g (41%) of rac-α-hydroxy-α-propyl-γ-oxo-2-thiophenebutyric acid as a colorless powder, melting point 128°-131°, MS: 197 (M-COOH)+.
Reaction SMILES: O=[C:2]([CH3:9])[CH2:3][C:4]([O:6]CC)=O.Cl.[C:11](=[NH:14])([NH2:13])[CH3:12].C([O-])C.[Na+].O>C(O)C>[CH3:12][C:11]1[N:14]=[C:4]([OH:6])[CH:3]=[C:2]([CH3:9])[N:13]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)CC(C)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(O)nc(C)n1
Yield: 35.9 %

Procedure:
Ethyl 3-oxobutanoate (10.0 g, 77 mmol) and acetimidamide hydrochloride (7.23 g, 77 mmol) were added to the solution of sodium ethanolate (10.5 g, 154 mmol) in ethanol (200 mL). And the mixture was refluxed for 20 hours. Water (10 mL) was added to the mixture. The resultant mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to give 2,6-dimethylpyrimidin-4-ol as a yellow solid (3.43 g, 36%). LRMS (M+H) m/z: calcd 124.06. found 124.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH2:13][NH:12][CH2:11][CH2:10]3)[CH2:5][C@H:4]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[O:3]1.C(N(CC)CC)C.[CH2:33]([O:40][CH2:41][C:42](Cl)=[O:43])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH2:13][N:12]([C:42](=[O:43])[CH2:41][O:40][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:11][CH2:10]3)[CH2:5][C@H:4]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[O:3]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc3c(c2)CCNC3)C(=O)O1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc3c(c2)CCN(C(=O)COCc2ccccc2)C3)C(=O)O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
A solution of 1,1-dimethylethyl [[(5S)-2-oxo-3-[1,2,3,4-tetrahydro-6-isoquinolinyl]-5-oxazolidinyl]methyl]carbamate (Example 6, Step 2, 347 mg, 0.999 mmol) and triethylamine (0.21 mL, 1.50 mmol) in dry CH2Cl2 at 0° C. under N2 is treated with benzyloxyacetyl chloride (0.19 mL, 1.20 mmol), and the resulting mixture is stirred at 0° C. for 1 hr and then allowed to warm to ambient temperature. The reaction mixture is then diluted with CH2Cl2 (20 mL), washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue is chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with a gradient of MeOH/CH2Cl2 (1/99-2/98), and those fractions with an Rf=0.72 by TLC (MeOH/CHCl3, 10/90) are pooled and concentrated to give 425 mg (86%) of the title compound as an amorphous, glassy solid. MS (ESI+) for C27H33N3O6 m/z 496 (M+H)+.
Reaction SMILES: CO[C:3](=[O:22])[CH2:4][CH:5]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1.[NH:23]1C2C(=CC=C(C(C3C=CC=CC=3OC)CC(NC)=O)C=2)C=[CH:24]1>>[NH:19]1[C:20]2[C:16](=[CH:15][CH:14]=[C:13]([CH:5]([C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=3)[CH2:4][C:3]([NH:23][CH3:24])=[O:22])[CH:21]=2)[CH:17]=[CH:18]1
Reactant: CNC(=O)CC(c1ccc2cc[nH]c2c1)c1ccccc1OC
Reactant: COC(=O)CC(c1cccc(Cl)c1)c1ccc2cc[nH]c2c1
Product: CNC(=O)CC(c1cccc(Cl)c1)c1ccc2cc[nH]c2c1
Yield: 89 %

Procedure:
3-(1H-Indol-6-yl)-3-(3-chloro-phenyl)-N-methyl-propionamide XLI (340 mg, 89% yield) was prepared from 3-(1H-indol-6-yl)-3-(3-chloro-phenyl)-propionic acid methyl ester using the procedure described above for 3-(1H-Indol-6-yl)-3-(2-methoxy-phenyl)-N-methyl-propionamide XXXVIII (see Example 9).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17].S(Cl)([Cl:24])=O>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([Cl:24])=[O:17]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(OCc2ccc3ccccc3n2)c1
Product: O=C(Cl)c1cccc(OCc2ccc3ccccc3n2)c1

Procedure:
A mixture of 15.6 g (0.1 mol) of 3-(2-quinolinylmethyloxy)benzoic acid and 11.9 g (0.1 mol) of thionyl chloride is refluxed for 4 hours. The reaction mixture is then evaporated to dryness at room temperature and used directly in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][S:9]([OH:12])(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-])=O.CO>[Pd].O>[NH2:1][C:4]1[CH:14]=[CH:13][C:7]([CH2:8][S:9]([OH:12])(=[O:10])=[O:11])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)O)cc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: Nc1ccc(CS(=O)(=O)O)cc1
Yield: 90.3 %

Procedure:
A 250 ml of Par hydrogenation bottle was charged 4-Nitrobenzyl Sulfonic Acid (6.80 g, 31.34 mmol), 10% Pd/C (0.4 g), CH3OH (150 ml) with few drop of water, and purged with hydrogen. The reaction mixture was shaken with 20 psi H2 over night. The catalyst was removed by filtration through celite and the solvent was evaporated. The crude compound was co-evaporated three times with 3×50 ml of water and crystallized with water/THF/EtAc/Toluene (1:10:10:100) to give 5.3 g (91%) of the title compound. 1H NMR (D2O), 7.28 (dd, 2H, J=2.2, 4.3 Hz), 6.95 (dd, 2H, J=2.2, 4.3 Hz), 4.10 (s, 2H); 13C NMR 134.30, 127.10, 121.04, 120.42, 59.14; MS m/z−186.35 (M−H).
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].[H-].[Na+].[CH3:18][S-:19].[Na+].O>CN(C)C=O>[CH3:15][C:3]1[C:2]([S:19][CH3:18])=[C:10]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: Cc1c(C(=O)O)ccc(C(F)(F)F)c1F
Reactant: C[S-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1c(C(F)(F)F)ccc(C(=O)O)c1C
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
300 mg (1.35 mmol) of 3-fluoro-2-methyl-4-trifluoromethylbenzoic acid were initially charged in 5 ml of N,N-dimethylformamide, and 59 mg (purity 60% by weight, 1.49 mmol) of NaH were added. The mixture was stirred for 10 min, and 199 mg (purity 95% by weight, 2.70 mmol) of sodium thiomethoxide were then added. The mixture was stirred at RT for 1.5 h and then heated at 80° C. for 16 h. The reaction mixture was cooled and, for workup, poured into water and extracted with ethyl acetate, and the aqueous phase was then acidified with concentrated HCl. The mixture was extracted twice with t-butyl methyl ether, dried and concentrated. This gave 310 mg of the product.
Reaction SMILES: [OH-].[K+].[C:3]([N:6]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([O:29]C)=[O:28])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:5])[CH3:4]>CO>[C:3]([N:6]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([OH:29])=[O:28])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:5])[CH3:4]
Reactant: COC(=O)c1ccccc1CN(C(C)=O)c1ccccc1Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N(Cc1ccccc1C(=O)O)c1ccccc1Oc1ccccc1
Temperature: 60 °C
Yield: 92.4 %

Procedure:
To a mixture of 23 ml of methanol and 3.6 ml of 2 N aqueous potassium hydroxide solution was added 2.26 g of N-acetyl-N-(2-methoxycarbonylbenzyl)-2-phenoxyaniline synthesized in the same manner as in Example 2, followed by stirring at 60° C. for an hour. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was made acidic with 2 N hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:1) to give 2.01 g of N-acetyl-N-(2-carboxybenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.[CH2:9]([O:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=1)[CH3:10]>CS(C)=O>[CH3:8][C@H:4]1[NH:3][C@@H:2]([CH3:1])[CH2:7][N:6]([C:16]2[CH:17]=[CH:18][C:13]([C:12]([O:11][CH2:9][CH3:10])=[O:20])=[CH:14][CH:15]=2)[CH2:5]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CCOC(=O)c1ccc(F)cc1
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1
Temperature: 120 °C
Reaction time: 20 h
Yield: 71.9 %

Procedure:
(2S,6R)-2,6-dimethylpiperazine (6.85 g, 60.00 mmol) was added to ethyl-4-fluorobenzoate (2.20 mL, 15 mmol), in DMSO (40 mL) and warmed to 120° C. under nitrogen. The resulting solution was stirred at 120° C. for 20 h. The reaction mixture was cooled and the solvent evaporated. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 10% methanol in dichloromethane containing 1% 0.880 ammonia. Pure fractions were evaporated to dryness to afford ethyl 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate (2.83 g, 71.9%) as a brown oil, which solidified on standing.
Reaction SMILES: C(O[CH:4]=[C:5]([C:21](=[O:23])[CH3:22])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19])=[O:7])C.Cl.[NH2:25]O>C(O)C>[N+:18]([C:9]1[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=1[C:6]([C:5]1[CH:4]=[N:25][O:23][C:21]=1[CH3:22])=[O:7])([O-:20])=[O:19]
Reactant: CCOC=C(C(C)=O)C(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: NO
Agent: Cl
Solvent: CCO
Product: Cc1oncc1C(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 5 h
Yield: 37.5 %

Procedure:
A mixture of crude 2-ethoxymethylene- 1-(2-nitro-4-trifluoromethylphenyl)butan-1,3-dione (13.25g) and hydroxylamine hydrochloride (3.7 g) in ethanol (80 ml) was stirred for 5 hours. The solution was evaporated almost to dryness and the resultant solution was diluted with ethyl acetate (100 ml). The solution was washed with water (3×40 ml), dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was triturated with a mixture of ether and petroleum spirit (bp 60°-80° C.) (1:1) and the resultant buff solid was filtered off. The solid was dissolved in dichloromethane (100 ml) and filtered through silica. The silica was washed with dichloromethane (100 ml) and the combined filtrates were evaporated to dryness to give 4-(2-nitro-4-trifluoromethylbenzoyl)-5-methylisoxazole (Compound 1,4.5 g) as an off-white solid mp 85°-86° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([N:19]=O)=[C:15]2[OH:18])=[CH:10][CH:9]=1>CCCCCC>[Cl:7][C:8]1[CH:9]=[CH:10][C:11](/[CH:12]=[CH:13]\[C:14]#[N:19])=[C:16]([C:15]([Cl:2])=[O:18])[CH:17]=1
Reactant: O=Nc1ccc2ccc(Cl)cc2c1O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCCCCC
Product: N#C/C=C\c1ccc(Cl)cc1C(=O)Cl

Procedure:
To a rapidly stirring suspension of phosphorus pentachloride (150.0 g) in dry hexane (2.6 liters) is added 156.4 g (0.72 mole) of 7-chloro-2-nitroso-1-naphthol (VI). The mixture is stirred at room temperature for 1 hour after which it is refluxed for 2 hours. The hexane solution is decanted while hot, 2.0 liters of dry hexane are added to the residue in the flask, and refluxed for another hour. The hexane solution is decanted, combined with the first hexane extract and evaporated to dryness. Yield: 100 g, semi-solid dark brown residue. The crude product is extracted with 2.0 liters of hot dry hexane. The hot supernatant solution is decanted from the tarry residue at the bottom of the flask, concentrated to a volume of 700 ml and cooled in an ice bath. Repeated extractions of the original residue and tarry material are done with a total of 3.0 liters of hexane. All of the extracts are concentrated, cooled in an ice bath, and the product filtered off and dried. Total yield: 51.1 g (31.4%), mp 71°-74°.
Reaction SMILES: [CH2:1]([N:6]([C:10]1[CH:19]=[CH:18][C:17]2[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=2[CH:11]=1)[C:7](Cl)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1>N1C=CC=CC=1.O>[CH2:1]([N:6]([C:10]1[CH:19]=[CH:18][C:17]2[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=2[CH:11]=1)[C:7](=[O:8])[NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:34][CH:35]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN(C(=O)Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCN(C(=O)Nc1ccc(C(=O)OCC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 40 °C
Reaction time: 15 h
Yield: 21.5 %

Procedure:
A solution of pentyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-carbamoyl chloride (35) (900 mg, 2.6 mmole) in 20 mL pyridine was treated with 481 mg of ethyl p-aminobenzoate (3 eq.) and stirred at 40° C. for 15 hours. The reaction mixture was diluted with 100 mL of cold water and extracted with two 100 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give an orange oil, which was purified by flash chromatography (SiO2, 5% ethyl acetate/hexanes) to provide 260 mg of ethyl 4-[3-pentyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoate (37) as a pale yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[BH4-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH:18](O)[C:19]1[C:20]2[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:21]=2[O:22][C:23]=1[CH3:24].[OH-].[Na+]>C(Cl)Cl>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][C:19]1[C:20]2[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:21]=2[O:22][C:23]=1[CH3:24]
Reactant: COC(=O)c1ccc2oc(C)c(C(O)c3ccc(Cl)cc3Cl)c2c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2oc(C)c(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Trifluoroacetic acid (50 ml) was ice-cooled and sodium borohydride (873 mg, 23.1 mmol) was gradually added over 20 min under a nitrogen atmosphere at 5-7° C. Thereto was dropwise added a solution of 3-((2,4-dichlorophenyl)-hydroxymethyl)-5-(methoxycarbonyl)-2-methylbenzo[b]furan in methylene chloride over 20 min, and the mixture was stirred at room temperature for 45 min. After the completion of the reaction, the reaction mixture was poured into ice water and a 25% aqueous sodium hydroxide solution was added to make an alkali solution. The solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The crystalline residue was purified by silica gel column chromatography to give the objective compound (0.58 g, 72% in 2 steps) as colorless crystals.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:28][C:18]2=[C:19]3[N:24]([N:25]=[C:17]2[CH2:16]1)[C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=[N:20]3)=O)(C)(C)C>CO>[ClH:1].[ClH:1].[CH3:27][C:22]1[CH:21]=[N:20][C:19]2[N:24]([N:25]=[C:17]3[CH2:16][NH:15][CH2:28][C:18]3=2)[C:23]=1[CH3:26]
Reactant: Cc1cnc2c3c(nn2c1C)CN(C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cnc2c3c(nn2c1C)CNC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
A 4M solution of HCl in 1,4-dioxane (10 mL; 40 mmol; 82.4 eq.) was added to a solution 6,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carboxylic acid tert-butyl ester (140 mg; 0.49 mmol; 1 eq.) in MeOH (2 mL) and the resulting mixture was stirred at room temperature for 18 hours then concentrated in vacuo. The residue was triturated in EtOH and the precipitate filtered off and dried to afford the title compound (78 mg, 62%) as a pale yellow solid. 1H NMR (DMSO-d6) δ 10.39 (br s, 2H), 8.91 (d, J=0.9 Hz, 1H), 6.24 (br s, 1H), 4.51-4.48 (m, 4H), 2.49 (s, 3H), 2.26 (s, 3H). HPLC (max plot) 99.9%; Rt 1.03 min. UPLC/MS: (MS+) 189.0 ([M+H]+).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[NH:25][N:24]=[C:23]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])[S:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:40]([N:48]=[C:49]=[S:50])(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[Si:1]([O:18][CH2:19][CH2:20][C:21]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:25]([C:49]([NH:48][C:40](=[O:47])[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[S:50])[N:24]=[C:23]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])[S:22]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](OCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1)(c1ccccc1)c1ccccc1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=S)NC(=O)c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole (1.00 g, 1.79 mmol) in 20 mL of anhydrous THF was added benzoyl isothiocyanate (0.29 mL, 2.15 mmol). The reaction was allowed to stir overnight at reflux then cooled and concentrated in vacuo. The residue was purified by flash column chromatography (5-10% ethyl acetate/hexanes) to afford the desired product as a yellow foam, 0.677 g, 52%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](O)=[N:8][C:9]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:10]2)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=[C:9]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=1
Reactant: COc1ccc2c(O)nc(N3CCCC3)nc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(N3CCCC3)nc2c1
Yield: 84 %

Procedure:
A solution of 7-methoxy-2-(pyrrolidin-1-yl)quinazolin-4-ol (155 mg, 0.632 mmol) in POCl3 (2 ml, 21.46 mmol) was refluxed at 90° C. for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM and the pH was adjusted to 7 with 4N NaOH. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using 50% DCM in hexanes. The product fractions were collected and the solvent was removed under vacuum to give 4-chloro-7-methoxy-2-(pyrrolidin-1-yl)quinazoline (140 mg, 84% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.86 (d, J=9.0 Hz, 1H), 6.91 (d, J=2.3 Hz, 1H), 6.82 (dd, J=9.0, 2.5 Hz, 1H), 3.92 (s, 3H), 3.69 (br. s., 4H), 2.03 (t, J=6.8 Hz, 4H); MS: MS m/z 264.1 (M++1).