Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[C:6]([OH:8])=[O:7])=[O:2].O=S(Cl)Cl.[CH3:17]O>>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[C:6]([O:8][CH3:17])=[O:7])=[O:2]
Reactant: CO
Reactant: O=Cc1cc(C(=O)O)ccc1O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)c(C=O)c1
Temperature: 7.599999904632568 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
3-formyl-4-hydroxybenzoic acid (Aldrich 633488, 20 g; 120.39 mmol; 1 eq.) was dissolved in MeOH (400 mL). The solution was cooled down to 0°. SOCl2 (26.20 mL; 361.16 mmol; 3 eq.) was added dropwise (addition took 60 min and the temperature of the reaction mixture increased to 7.6° C.). The reaction mixture was stirred at RT for 24 hours. The reaction mixture was concentrated and the crude mixture was dissolved in EtOAc (500 mL) and washed with a saturated aqueous solution of NaHCO3 (300 mL), HCl 1N (300 mL) and brine (300 mL), dried over MgSO4 and concentrated affording the title compound as a beige solid (19.86 g, 91%). 1H NMR (DMSO-d6, 300 MHz) δ 8.25-8.24 (d, J=2.33 Hz, 1H), 8.08-8.03 (dd, J=8.79 Hz, 2.33 Hz, 1H), 7.12-7.09 (d, J=8.75 Hz, 1H), 3.83 (s, 3H). LC/MS (Method B): 179.1 (M−H)−. HPLC (Method A) Rt 3.04 min (Purity: 91.6%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH:8](C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.CS(C)=O.[Cl-].[Na+]>O>[F:1][C:2]1[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncccc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1ncccc1F
Temperature: 148.5 °C
Reaction time: 0.67 h
Yield: 81.7 %

Procedure:
5.10 g of diethyl (3-fluoro-2-pyridyl)malonate and 25 ml of dimethyl sulfoxide were mixed. To the mixture was added 1.29 g of sodium chloride and 0.72 g of water. The mixture was stirred for about 40 minutes at an inner temperature of 145 to 152° C. The reaction mixture was allowed to cool to room temperature, then, to the reaction mixture was added water, and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure, to obtain 2.99 g of ethyl (3-fluoro-2-pyridyl)acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH3:13])[CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[CH3:21][C:22]1[C:26](B(O)O)=[C:25]([CH3:30])[O:24][N:23]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd]Cl>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:26]4[C:22]([CH3:21])=[N:23][O:24][C:25]=4[CH3:30])[CH:3]=3)[NH:8][C:7](=[O:12])[N:6]2[CH3:13])=[CH:15][CH:16]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: CN1C(=O)Nc2ccc(Br)cc2C1c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccc(Cl)cc1)N(C)C(=O)N2
Temperature: 120 °C

Procedure:
To a solution of 6-Bromo-4-(4-chloro-phenyl)-3-methyl-3,4-dihydro-1H-quinazolin-2-one (0.2 g, 0.57 mmol) dissolved in dioxane (50 mL) is added 3,5-dimethylisoxazole-4-boronic acid (0.1 g, 0.74 mmol), PdCl2 (0.048 g, 0.057 mmol) and Na2CO3 aq. The mixture is stirred at 120° C. to reflux for 5 hours. Then cooled to RT, concentrated and purified by column chromatography on silica gel to give the desired compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:7]([C:8](OCC)=[O:9])=[CH:6][NH:5][N:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:14][C:2]([F:1])([F:13])[C:3]1[C:7]([CH2:8][OH:9])=[CH:6][NH:5][N:4]=1
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1c[nH]nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
Ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (95.00 g, 0.456 mol) was dissolved in dry THF (1 L) and the resulting solution cooled in an acetone/ice bath. A 1M solution of LiAlH4 in THF (550 mL, 0.550 mol) was added over 30 min, keeping the temperature <10° C. Cooling was then removed and the reaction mixture was stirred at RT for 4 h. The reaction was again cooled and a 1:1 THF:water solution (250 mL) was added with cooling (maintaining the temperature <20° C.), followed by 5M HCl (160 mL) to neutrality/pH 6. EtOAc (1.5 L) was added and the mixture stirred for 30 min then left to settle overnight. The resulting grey granular solid was removed by filtration through dicalite and washed with EtOAc. The combined filtrates were washed with brine and dried over MgSO4, before concentrating in vacuo to give a white solid (76.00 g, 0.457 mol, 100%).
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[Br:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[C:49]([N+:50]([O-])=O)=[C:48]([NH2:53])[CH:47]=[CH:46][C:45]=2[S:54]([C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[C:58]([N+:63]([O-])=O)[C:57]=2[C:66]2[CH:71]=[CH:70][C:69]([Br:72])=[CH:68][CH:67]=2)=[O:55])=[CH:40][CH:39]=1>>[Br:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]2[C:49]([NH2:50])=[C:48]([NH2:53])[CH:47]=[CH:46][C:45]=2[S:54]([C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[C:58]([NH2:63])[C:57]=2[C:66]2[CH:71]=[CH:70][C:69]([Br:72])=[CH:68][CH:67]=2)=[O:55])=[CH:42][CH:43]=1
Reactant: Nc1ccc(S(=O)c2ccc(N)c([N+](=O)[O-])c2-c2ccc(Br)cc2)c(-c2ccc(Br)cc2)c1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: Nc1ccc(S(=O)c2ccc(N)c(N)c2-c2ccc(Br)cc2)c(-c2ccc(Br)cc2)c1N

Procedure:
Following the procedure described in Example 40 but using as a starting material instead of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide a corresponding amount of 4-bromophenyl-(4-amino-3-nitrophenyl) sulfoxide, the title compound is obtained.
Reaction SMILES: C(O[C:4](=[O:18])[C:5]([C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)=[CH:6]O)C.[NH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[NH2:20].C([O-])C.[Na+].Cl>C(O)C>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:19]1[C:4](=[O:18])[C:5]([C:8]2[CH:9]=[N:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=2)=[CH:6][NH:20]1
Reactant: NNc1ccccn1
Reactant: CCOC(=O)C(=CO)c1ccc(C(F)(F)F)nc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=c1c(-c2ccc(C(F)(F)F)nc2)c[nH]n1-c1ccccn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
261 mg (1.00 mmol) of the compound from Example 41A and 115 mg (1.05 mmol) 2-hydrazinopyridine are dissolved in 5 ml anhydrous ethanol under argon and the mixture is stirred at RT for 20 h. 68 mg (1.00 mmol) sodium ethanolate are added, the mixture is stirred at RT for 30 min and 1 M hydrochloric acid and a little ethanol are then added, a precipitate separating out. This is filtered off, washed with a little ethanol and dried in vacuo.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[C:27]([CH3:32])=[N:28][O:29][C:30]=4[CH3:31])=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:40]1([NH2:44])[CH2:43][CH2:42]C1>C1COCC1>[N:44]1([C:22]2[N:21]=[C:20]([CH2:19][N:15]3[C@@H:14]([CH3:37])[C@@H:13]([C:5]4[CH:4]=[C:3]([C:2]([F:39])([F:38])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=4)[O:17][C:16]3=[O:18])[C:25]([C:26]3[C:27]([CH3:32])=[N:28][O:29][C:30]=3[CH3:31])=[CH:24][N:23]=2)[CH2:40][CH2:43][CH2:42]1
Reactant: NC1CCC1
Reactant: Cc1noc(C)c1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cnc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 150 °C

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-(3,5-dimethylisoxazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one was dissolved in an excess amount of cyclobutylamine in THF, then heated to 150° C. for 2 hours in a microwave reactor. The reaction mixture was evaporated, then reconstituted in methanol and purified by preparative reverse phase HPLC to give the title compound. LCMS (M+H)+: 556.1. 1H NMR (CDCl3, 500 MHz): δ 8.15 (s, 1H), 7.91 (s, 1H), 7.74 (s, 2H), 5.77 (d, 1H), 4.50-4.30 (m, 6H), 3.92 (t, 1H), 2.53 (m, 2H), 2.32 (d, 3H), 2.16 (d, 3H), 0.77 (d, 3H). RTA IC50: 271 nM.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[C:3]=1[Cl:13].[Cu][C:15]#[N:16].O>CN(C)C=O>[Cl:13][C:3]1[C:4]([F:12])=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][C:2]=1[C:15]#[N:16]
Reactant: CC(=O)Nc1ccc(Br)c(Cl)c1F
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C#N)c(Cl)c1F
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A mixture of N-(4-bromo-3-chloro-2-fluorophenyl)acetamide (17.0 g) and copper(I) cyanide (5.88 g) in N,N-dimethylformamide was stirred at 150° C. overnight. After warming to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give N-(3-chloro-4-cyano-2-fluorophenyl)acetamide. Ethanol (250 ml)-concentrated hydrogen chloride (26.6 mL) was added to N-(3-chloro-4-cyano-2-fluorophenyl)acetamide, and the mixture was refluxed overnight. The mixture was ice-cooled, and neutralized with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column, and the obtained solid was washed with hexane to give the title compound as a pale-yellow solid (yield: 7.0 g, 64%).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1([O:14][CH3:15])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[N:12][OH:13].Cl.[Br:17]Br.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)C>[Br:17][CH:11]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5](=[N:12][OH:13])[C:4]1([O:3][CH3:2])[O:14][CH3:15]
Reactant: COC1(OC)CCCCCCC1=NO
Reactant: BrBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOCC
Product: COC1(OC)C(=NO)CCCCCC1Br
Yield: 50 %

Procedure:
Following the general procedure of Example 1, but using diethyl ether as a solvent in place of methylane chloride, to a solution of 5.025 parts of 2,2-dimethoxycyclooctanone oxime in 28 parts of diethyl ether was added 1.7 parts anhydrous hydrogen chloride at about 32° C. The mixture was stirred and to this was added about 4 parts bromine dissolved in 7 parts diethyl ether over a 5 minute period. After the addition the mixture was allowed to stir for about 0.5 hour. The mixture was then treated with aqueous sodium carbonate to remove dissolved acids in the ether layer and then worked with water. The ether phase was then dried and then distilled under vacuum to yield 50 percent of theory of 3-bromo-2,2-dimethoxycyclooctanone oxime as determined by nuclear magnetic resonance spectroscopy.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([S:12](Cl)(=[O:14])=[O:13])[CH2:9][CH2:10][CH3:11].I.[CH:17]12[CH2:28][CH2:27][CH:20]([CH2:21][CH:22]1[C:23]([O:25][CH3:26])=[O:24])[CH2:19][NH:18]2>C(Cl)(Cl)Cl>[CH2:8]([S:12]([N:18]1[CH2:19][C@H:20]2[CH2:27][CH2:28][C@@H:17]1[C@H:22]([C:23]([O:25][CH3:26])=[O:24])[CH2:21]2)(=[O:14])=[O:13])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCS(=O)(=O)Cl
Reactant: COC(=O)C1CC2CCC1NC2
Agent: I
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCS(=O)(=O)N1C[C@H]2CC[C@@H]1[C@H](C(=O)OC)C2
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Triethylamine (0.51 mL, 3.7 mmol) and 1-butanesulfonyl chloride (0.233 mL, 1.84 mmol) were added to a chloroform (5 mL) solution of methyl 2-azabicyclo[2.2.2]octane-6-carboxylate hydroiodide (298 mg, 0.989 mmol) synthesized according to the method described in literature (Chem. Pharm. Bull. 53(1) 81-85 (2005)), and the mixture was stirred at room temperature for 13 hours. The reaction mixture was washed once with distilled water, and once with a saturated sodium hydrogen carbonate aqueous solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was then purified using silica gel column chromatography to obtain the target (157 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([CH3:13])[CH:8]([CH3:14])[N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[CH3:21]N(C)C(=O)C.IC.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:21])[C:10](=[O:12])[CH:9]([CH3:13])[CH:8]([CH3:14])[N:7]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)[C:6]=2[N:20]=1
Reactant: CC(=O)N(C)C
Reactant: CC1C(=O)Nc2cnc(Cl)nc2N(C2CCCC2)C1C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC1C(=O)N(C)c2cnc(Cl)nc2N(C2CCCC2)C1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.09 g (0.0003 mole) of (rac)-2-chloro-9-cyclopentyl-7,8-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-41), 1 mL of N,N-dimethylacetamide and 0.028 mL (0.00045 mole) of iodomethane at 0 degrees was added 0.027 g (0.00045 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.092 g of (rac)-2-chloro-9-cyclopentyl-5,7,8-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-41) as an yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].Cl.[CH:22]([N:25]([CH2:29][CH2:30]Cl)[CH2:26][CH2:27]Cl)([CH3:24])[CH3:23]>>[CH2:16]([O:15][C:12]1[CH:11]=[CH:10][C:9]([S:6]([C:5]2([C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH2:30][CH2:29][N:25]([CH:22]([CH3:24])[CH3:23])[CH2:26][CH2:27]2)(=[O:7])=[O:8])=[CH:14][CH:13]=1)[C:17]#[C:18][CH3:19]
Reactant: CC(C)N(CCCl)CCCl
Reactant: CC#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Agent: Cl
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(C(C)C)CC2)cc1
Yield: 64 %

Procedure:
Ethyl 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-isopropyl-4-piperidine carboxylate was prepared according to the general method as outlined in example 1 (step 6), starting from (4-but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (6 g, 20.3 mmol) and isopropyl [bis(2-chloroethyl)]amine hydrochloride (4.88 g, 22.3 mmol); 5.28 g brown oil. Yield 64%; MS: 408.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:17]([CH3:19])[CH3:18]>CC(C)=O>[CH:17]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2])([CH3:19])[CH3:18]
Reactant: N#Cc1ccccc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)Oc1ccccc1C#N
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 97.5 %

Procedure:
A mixture of 2-cyanophenol (5.0 g, 42 mmol), cesium carbonate (27.1 g, 82.9 mmol) and 2-iodopropane (7.63 mL, 76 mmol) in acetone (80 mL) was heated at 60° C. with vigorous stirring. After 45 min, the gray brown mixture was decanted and the acetone layer was concentrated in vacuo. Water was added to dissolve the solid, and the mixture was extracted with diethyl ether (3×200 mL). The organic layers were washed with water, 1 N ammonium hydroxide and brine, and dried over anhydrous sodium sulfate. The solids were then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 5% ethyl acetate in hexanes yielded 2-isopropoxy-benzonitrile (6.6 g, 97%) as a colorless liquid.
Reaction SMILES: C(OC[N:10]1[N:14]=[N:13][C:12]([C:15]2[N:20]=[C:19]([NH:21][C@H:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH3:23])[N:18]=[C:17]([NH:31][C:32]3[CH:37]=[N:36][CH:35]=[CH:34][N:33]=3)[CH:16]=2)=[N:11]1)C1C=CC=CC=1.Cl.C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C@@H:22]([NH:21][C:19]2[N:18]=[C:17]([NH:31][C:32]3[CH:37]=[N:36][CH:35]=[CH:34][N:33]=3)[CH:16]=[C:15]([C:12]3[N:11]=[N:10][NH:14][N:13]=3)[N:20]=2)[CH3:23])=[CH:29][CH:28]=1
Reactant: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2nnn(COCc3ccccc3)n2)n1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2nn[nH]n2)n1)c1ccc(F)cc1
Temperature: 80 °C
Yield: 39.5 %

Procedure:
50 mg of (S)-6-[2-(Benzyloxymethyl)-2H-tetrazol-5-yl]-N2-[1-(4-fluoro phenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine was dissolved in 1.5 ml of methanol, and 1.5 ml of 10% hydrochloric acid was added thereto, and the mixture was stirred at 80° C. for hours. The reaction solution was air-cooled to room temperature, and then diluted with ethyl acetate, and the pH of the mixture was adjusted to 4 by using saturated sodium bicarbonate aqueous solution. The organic layer was subjected to extraction, and washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was washed with methanol and filtered and dried under reduced pressure to obtain 15 mg of the objective compound as white powder.
Reaction SMILES: C([N:4]1[C:8](=[O:9])[CH2:7][C:6]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:5]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C>[O:9]=[C:8]1[CH2:7][C:6]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:5][NH:4]1
Reactant: CC(=O)N1CC2(CCCCCC2)CC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1CC2(CCCCCC2)CN1

Procedure:
38 g. N-acetyl-3-oxo-2-azaspiro[4,6]undecane are heated to 60° C. for 6 hours in a solution of 40 g. potassium carbonate in 400 ml. 80% aqueous ethanol. The reaction mixture is then acidified with dilute hydrochloric acid, the ethanol is stripped off in a vacuum and the aqueous residue is extracted with methylene chloride. The residue obtained after evaporation of the solvent gives, upon vacuum distillation, 3-oxo-2-azaspiro[4,6]undecane in the form of a colourless syrup; b.p. 125°-135° C./10-3 mm.Hg. After crystallisation from diisopropyl ether, the compound melts at 70°-74° C.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S:7]([O-:9])=[O:8])=[CH:3][CH:2]=1.[Na+].O.Br[CH2:14][CH2:15][CH2:16][CH2:17][Sn:18]([CH3:21])([CH3:20])[CH3:19]>[Br-].C([P+](CCCC)(CCCC)CCCCCCCCCCCCCCCC)CCC.C1(C)C=CC=CC=1>[C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S:7]([CH2:14][CH2:15][CH2:16][CH2:17][Sn:18]([CH3:21])([CH3:20])[CH3:19])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: C[Sn](C)(C)CCCCBr
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)CCCC[Sn](C)(C)C)cc1
Yield: 37.7 %

Procedure:
Into a 125 ml single-necked round bottom flask fitted with a teflon coated magnetic stir bar and a reflux condenser was charged 4.45 g of sodium p-toluenesulfinate, 20 ml water, 10 ml toluene, 7 g of 75% 4-bromobutyltrimethylstannane and 0.44 g of tri-n-butylhexadecylphosphonium bromide. The mixture was refluxed for 2.5 hours with rapid stirring. On cooling, the organic phase was separated, dried over anhydrous magnesium sulfate and stripped of solvent on a rotary evaporator. The oil residue was distilled two times through a short path distillation head. The second distillation afforded 3.3 g of 4-(p-tolylsulfonyl)butyltrimethylstannane, b.p. 136°-140° C. (1×10-3 mm Hg). The presence of both the sulfonyl and trimethyltin moieties was indicated by strong infrared absorption bands at 1315 cm-1, 1300 cm-1, 1142 cm-1 (--SO2 --) and 765 cm-1 ([(CH3)3Sn--]. NMR spectroscopy showed the following:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[C:11]4[C:16](=[CH:17][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4.C1C2C3=CC4C(C(C=O)=C3[O:23][C:22]=2C=CC=1)=CC=CC=4>C1(C)C=CC=CC=1.CCCCCC>[CH:1]1[C:9]2[C:8]3[C:10]([CH:22]=[O:23])=[C:11]4[C:16](=[CH:17][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4
Reactant: c1ccc2cc3c(cc2c1)oc1ccccc13
Reactant: O=Cc1c2ccccc2cc2c1oc1ccccc12
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=Cc1c2ccccc2cc2oc3ccccc3c12
Yield: 58 %

Procedure:
Benzo[b]naphtho[2,3-d]furan (H. G. Pars Pharmaceutical Laboratories, Inc.) was formylated using the procedure of A. Rieche et al., Chem. Ber. 93, 88 (1960). The crude aldehyde appeared to be mainly one isomer accompanied by a small amount of a second aldehyde by TLC. Purification by chromatography (SiO2, PhCH3) followed by recrystallization (CH2Cl2 /hexane) gave the main component in 58% yield identified using NMR techniques to be benzo[b]naphtho[2,3-d]furan-6-carbaldehyde, (2A) mp 169°-171.5°, (C,H). The minor component, obtained in 3.4% yield was shown by NMR to be benzo[b]naphtho2,3-d]-furan-11-carbaldehyde, mp 128°-132°, (C,H), (PhCH3 /hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[Cl:17][C:18]1[C:23]([S:24](Cl)(=[O:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1>N1C=CC=CC=1>[Cl:17][C:18]1[C:23]([S:24]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]3[C:10]=2[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]3)(=[O:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CCOC(=O)c1cc2c(C)ccc(N)c2[nH]1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2c(C)ccc(NS(=O)(=O)c3cccnc3Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a solution of ethyl 7-amino-4-methyl-1H-indole-2-carboxylate (1.00 g) in pyridine (10 mL) was added 2-chloropyridine-3-sulfonyl chloride (1.99 g) at 0° C., and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with 10% aqueous citric acid solution and saturated brine, dried (MgSO4), and concentrated to give ethyl 7-{[(2-chloropyridin-3-yl)sulfonyl]amino}-4-methyl-1H-indole-2-carboxylate (1.32 g) as a crude oil.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5](=[O:7])[N:6]=1.[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]N>>[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][NH:1][C:2]1[O:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5](=[O:7])[N:6]=1
Reactant: NCc1ccccc1Cl
Reactant: CC(C)C1OC(N)=NC1=O
Product: CC(C)C1OC(NCc2ccccc2Cl)=NC1=O

Procedure:
Synthesis was performed from 2-amino-5-isopropyl-1,3-oxazol-4(5H)-one and 2-Chlorobenzylamine according to Method G+H.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[NH:14])=[CH:8][C:7]=2[O:16][CH3:17])=[CH:4][N:3]=[CH:2]1.[CH2:18](Br)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>CN(C)C=O>[CH3:17][O:16][C:7]1[CH:8]=[C:9]([NH:12][C:13]2[NH:15][C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:18][N:14]=2)[CH:10]=[CH:11][C:6]=1[C:5]1[O:1][CH:2]=[N:3][CH:4]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: COc1cc(NC(=N)N)ccc1-c1cnco1
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(-c3ccccc3)[nH]2)ccc1-c1cnco1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The product of Example 243, Part A, 4-Oxazol-5-yl-3-methoxyphenylguanidine, 243A (150 mg, 0.65 mmol) and phenacylbromide (128 mg, 0.65 mmol) were dissolved in N,N-dimethylformamide (0.25 mL) and stirred at room temperature for 3 days. The reaction mixture was evaporated and purified by prep RPHPLC to yield 5 mg (2%, a significant portion of the product was spilled during isolation) of the title compound. LCMS conditions J, retention time=1.62 min, (90%), M+H+=333.17. (100%).