Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[Cl:31][C:32]1[CH:37]=[C:36]([C:7]2[NH:6][C:5]([CH:9]=[O:10])=[C:4]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[C:3]=2[CH2:1][CH3:2])[CH:35]=[CH:34][CH:33]=1
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Reactant: OB(O)c1cccc(Cl)c1
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2cccc(Cl)c2)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 3-chloro phenylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C21H19ClNO3 (M+H): 368.1048. Found 368.1018
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[CH:17]([CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25](OCC2C=CC=CC=2)=O)[CH2:20]1)=O.C1([SiH3])C=CC=CC=1>C1COCC1.CCOC(C)=O.C([Sn](Cl)(Cl)CCCC)CCC>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][CH2:17][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH3:25])[CH2:20]1)=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Reactant: O=CC1CCCN(C(=O)OCc2ccccc2)C1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(-c2ccccc2)cc1NCC1CCCN(C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.7 %

Procedure:
A suspension of 3-amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (0.268 g, 1.15 mmol) and 3-formyl N-Cbz-piperidine (0.284 g, 1.15 mmol) in THF (0.5 mL) was treated with dibutyltin dichloride (17 mg, 0.057 mmol). After 5 min, phenylsilane (156 □L, 1.26 mmol) was added and the mixture was stirred for 6 days at room temperature. The solvent was then evaporated and the residue was purified by silica gel column chromatography using CH2Cl2:hexanes:EtOAc as eluent to provide 3-[(1-Methyl-piperidin-3-ylmethyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester as an oil (0.2723 g, 51% yield). 1H NMR (CDCl3, 400 MHz): 7.63-7.59 (m, 2H), 7.40-7.28 (m, 9H), 7.18-6.84 (br s, 1H), 5.20 (d, 1H), 5.10 (d, 1H), 4.55 (m, 1H), 4.15 (m, 1H), 3.82 (s, 3H), 3.58-3.40 (m, 2H), 2.90 (t, 1H), 1.88-1.40 (m, 6H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[CH:16][CH:15]=1.CN(C)C1C=CC=CC=1.C(OCC)C>O1CCCC1>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=2)=[CH:16][CH:15]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: OCCCCCCOc1ccc(CCc2ccc(O)cc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)c1ccccc1
Solvent: CCOCC
Product: C=CC(=O)OCCCCCCOc1ccc(CCc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
0.8 ml of acryloyl chloride was added to a solution of 2.2 g of 4-{2-[4-(6-Hydroxy-hexyloxy)-phenyl]-ethyl}-phenol (L) and 1.23 ml of N,N-dimethylaniline in 20 ml of tetrahydrofuran, cooled in an icebath. The mixture was stirred for 3 hours at room temperature. 40 ml of diethylether was added which was extracted twice with 20 ml of 2.4N hydrochloric acid and once with 20 ml of brine. It was dried over magnesium sulphate and evaporated. 1.65 g of 4-{2-[4-(6-acryloyloxy-hexyloxy)-phenyl]-ethyl}-phenol (N, 64%) was obtained after washing with 15 ml of pentane.
Reaction SMILES: [Na].[C:2]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:6])[CH2:3][CH2:4][CH3:5].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH2:23]Br>C(O)C.C1COCC1>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([C:2](=[O:6])[CH2:3][CH2:4][CH3:5])[CH2:23][C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1)[CH3:12]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: BrCc1ccc2ccccc2c1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCC(=O)C(Cc1ccc2ccccc2c1)C(=O)OCC

Procedure:
Ethyl-α-(2-naphthalenylmethyl)-butyrylacetate was prepared following the procedure of Example 2 from 2.18 g of sodium, 15 g of ethyl butyrylacetate and 21 g of 2-naphthalenylmethyl bromide in 300 mL ethanol-THF (10:1). The crude product was purified by removal of excess starting β-keto ester using a kugelrohr apparatus (oven ≤100° C./0.50 mm).
Reaction SMILES: [CH2:1]([P:3]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[F:24])[CH:10]=[CH:9][C:8]=1[N+:25]([O-:27])=[O:26])(=[O:6])[O:4]C)[CH3:2].Cl>>[CH2:1]([P:3]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][C:15]=2[F:24])[CH:10]=[CH:9][C:8]=1[N+:25]([O-:27])=[O:26])(=[O:4])[OH:6])[CH3:2]
Reactant: CCP(=O)(OC)c1cc(Oc2ccc(C(F)(F)F)cc2F)ccc1[N+](=O)[O-]
Agent: Cl
Product: CCP(=O)(O)c1cc(Oc2ccc(C(F)(F)F)cc2F)ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 13, methyl P-ethyl-2-nitro-5-(2-fluoro-4-trifluoromethylphenoxy)phenylphosphinate is reacted with 6N HCl to give P-ethyl-2-nitro-5-(2-fluoro-4-trifluoromethylphenoxy)phenylphosphinic acid.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH:9]=[CH:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[N+:15]([C:18](=[C:23]1[NH:28][CH2:27][CH2:26][CH2:25][S:24]1)[C:19](OC)=[O:20])([O-:17])=[O:16]>CN(C)C=O>[N+:15]([C:18](=[C:23]1[NH:28][CH2:27][CH2:26][CH2:25][S:24]1)[C:19]([O:12][CH2:11][CH:10]=[CH:9][CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:20])([O-:17])=[O:16]
Reactant: COC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Reactant: OCC=CC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCC=CC=Cc1ccccc1)C(=C1NCCCS1)[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 8.0 g of 5-phenyl-2,4-pentadien-1-ol in 30 ml of dimethylformamide (DMF) was added dropwise over a 30-minute period to a mixture of 1.5 g of sodium hydride and 20 ml of DMF, at 5°. The mixture was stirred for 1 hour at 5°. Then 3.3 g of 1A was added to the stirred mixture at 5° and the resulting mixture was stirred for three hours. The mixture then was poured into ice water and extracted with ether, and the aqueous phase was separated, acidified with acetic acid and extracted with methylene chloride. The methylene chloride extracts were washed with water, dried (MgSO4), and stripped of solvent. The residue was triturated in water and then ether, to give a solid which on recrystallization from ethanol gave 1, as a yellow solid, m.p.: 123°-125°.
Reaction SMILES: [F:1][C:2]1([CH2:9][OH:10])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[H-].[Na+].F[C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][C:15]=1[S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25].O>O1CCCC1.ClCCl>[F:1][C:2]1([CH2:9][O:10][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][C:15]=2[S:24]([C:27]([F:28])([F:30])[F:29])(=[O:26])=[O:25])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1
Reactant: NS(=O)(=O)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Reactant: CN1CCC(F)(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CN1CCC(F)(COc2ccc(S(N)(=O)=O)cc2S(=O)(=O)C(F)(F)F)CC1
Reaction time: 0.25 h

Procedure:
To a solution of (4-fluoro-1-methylpiperidin-4-yl)methanol (0.315 g) in tetrahydrofuran (5 mL) was added sodium hydride (0.342 g). After stirring for 15 minutes, 4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (0.658 g) was added as a solution in tetrahydrofuran (2 mL) followed by additional tetrahydrofuran (5 mL). After stirring for 1 hour, the reaction was poured in dichloromethane (50 mL) and water (25 mL) and the pH of the water layer was adjusted to 8. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The resulting oil was chromatographed over silica gel (Reveleris 40 g) eluting with a gradient of 1.0% to 10% 7N NH3 in methanol/dichloromethane over 20 minutes then maintaining 10% 7N NH3 in methanol/dichloromethane for 5 minutes (flow=30 mL/min) to provide the title compound.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][OH:13]>>[C:4]([O:13][CH3:12])(=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:1]([OH:6])=[O:11]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CO
Product: COC(=O)c1ccccc1C(=O)O

Procedure:
Methanol (300 ml) was added in a single portion to 148 g (1.00 mole) of phthalic anhydride and the resulting suspension was stirred and heated at reflux for 36 hours; solution occurred during heating. The solvent was removed and the product was recrystallized from a mixture of ethyl acetate and hexane to afford 114.6 g of the title compound (Lit. Beilstein, 9,797-mp 82.5°, 84°).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]([CH3:19])([CH3:18])[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[CH3:18][C:9]([CH3:19])([CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:31]2[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)=[CH:3][CH:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:10]([NH:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[O:11]
Reactant: CC(C)(C(=O)Nc1nccs1)C(c1ccccc1)c1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(C(c3ccccc3)C(C)(C)C(=O)Nc3nccs3)cc2)cc1
Yield: 40.3 %

Procedure:
An Emry™ process vial was charged with 3-(4-bromo-phenyl)-2,2-dimethyl-3-phenyl-N-thiazol-2-yl-propionamide (70 mg, 0.168 mmol) and 4-methoxy-phenylboronic acid (77 mg, 0.50 mmol), tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol), 2.0 mL of 2M K2CO3, and 1.5 mL of DMF. The reaction mixture was degassed by bubbling nitrogen through for 15 min, then sealed and exposed to microwave irradiation for 30 min at 150° C. The reaction mixture was cooled, filtered, and diluted with ethyl acetate. The organic solution was washed, dried and concentrated. The crude product was purified by preparative HPLC to give the title compound of Example 374 as a white solid (30 mg, 40%). LC/MS (m/z) 444.37 [(M+H)+]; HPLC Rt: 3.770 min. 1H NMR (400 MHz, MeOD) δ ppm 7.34-7.54 (9H, m) 7.23 (2H, t, J=7.38 Hz) 7.16 (1H, t, J=7.12 Hz) 7.02 (1H, d, J=3.56 Hz) 6.93 (2H, d, J=8.65 Hz) 4.63 (1H, s) 3.78 (3H, s) 1.40 (6H, s).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Cl:14])[N:6]=1.[Cl-].[NH4+]>C1COCC1>[Cl:14][C:7]1[N:6]=[C:5]([O:2][CH3:1])[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
Sodium methoxide (1.40 g) was gradually added to a THF (50 mL) solution of 2,6-dichloro-3-nitropyridine (5.00 g) over 30 minutes under ice-cooling. Then, the reaction solution was agitated at 0° C. for 1 hour, and agitated at room temperature for further 12 hours. The reaction solution was poured into a saturated ammonium chloride solution (50 mL), and extracted with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate 2:1), and 2.90 g (58%) of 6-chloro-2-methoxy-3-nitropyridine was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [F:1][C:2]([F:27])([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH2:18][F:19])([CH2:16][F:17])[CH:13]=[C:12]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=S)[C:11]=2[CH:26]=1)[C:3]([F:6])([F:5])[F:4].IC.[N:30]#[C:31][NH2:32].[H-].[Na+]>O1CCCC1>[C:31]([N:32]=[C:21]1[CH2:22][CH2:23][CH2:24][N:20]1[C:12]1[C:11]2[CH:26]=[C:7]([C:2]([F:27])([F:1])[C:3]([F:6])([F:5])[F:4])[CH:8]=[CH:9][C:10]=2[O:15][C:14]([CH2:18][F:19])([CH2:16][F:17])[CH:13]=1)#[N:30]
Reactant: N#CN
Reactant: FCC1(CF)C=C(N2CCCC2=S)c2cc(C(F)(F)C(F)(F)F)ccc2O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: N#CN=C1CCCN1C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc21
Temperature: 0 °C
Yield: 96.1 %

Procedure:
To a mixture of 0.05 g of 6-pentafluoroethyl-2,2-bisfluoromethyl-4-(2-thioxo-1-pyrrolidinyl)-2H-1-benzopyran, 0.20 g of iodomethane, 0.05 g of cyanamide and 3 ml of tetrahydrofuran was added 0.06 g of sodium hydride (60%) under ice-cooling with stirring. The mixture was stirred under ice-cooling for 30 minutes and then stirred at room temperature for 17 hours. After addition of ice water, the mixture was extracted with methylene chloride. The organic layer was washed with water and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 49 mg of 4-(2-cyanoimino-1-pyrrolidinyl)-6-pentafluoroethyl-2,2-bisfluoromethyl-2H-1-benzopyran represented by the following formula having a melting point of 207°-210° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[C:10]([CH2:16][CH3:17])[C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH3:18][N:19]([CH3:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>>[CH3:18][N:19]([CH3:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[C:10]([CH2:16][CH3:17])[C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1)=[O:24]
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Reactant: CCc1cc(-c2ccc(CN)o2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(CNC(=O)c3cccc(N(C)C)c3)o2)c(C)[nH]c1=O

Procedure:
Example 269 is substantially repeated except for utilizing 5-(5-aminomethylfuran-2-yl)-3-ethyl-6-methyl-1H-pyridin-2-one and 3-dimethylamino-benzoyl chloride to afford the title compound. MS: m/e=380 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:22])[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: O=C(CBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (301 mg) in DMF (5 mL) was added sodium hydride (67 mg of 60% in oil dispersion). The resulting mixture was stirred at room temperature for 5 min. To the dark green solution was added 2-bromo-acetophenone (273 mg) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([Br:4])[CH2:2][OH:3].[CH2:5]=[C:6]1[O:10][C:8](=[O:9])[CH2:7]1>C(N(CC)CC)C.ClCCl>[C:8]([O:3][CH2:2][CH2:1][Br:4])(=[O:9])[CH2:7][C:6]([CH3:5])=[O:10]
Reactant: C=C1CC(=O)O1
Reactant: OCCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)CC(=O)OCCBr
Reaction time: 3 h
Yield: 90.3 %

Procedure:
To 30 g of ethylene bromohydrin in ice bath were added by turns 22 g of diketene and 1.5 g of triethylamine with stirring while the reaction temperature was controlled at 30°-40° C. The reaction was continued at room temperature for 3 hours. To the reaction solution was added dichloromethane, the mixture was washed successively with diluted hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and water and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by distillation to obtain 45.3 g of 2-bromoethyl acetoacetate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Br)C.[CH3:30][C:31]1([CH3:39])[C:33]([CH3:35])([CH3:34])[CH:32]1[C:36](Cl)=[O:37]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:14][CH:13]=[C:12]2[C:36]([CH:32]1[C:33]([CH3:35])([CH3:34])[C:31]1([CH3:39])[CH3:30])=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2cc3cc[nH]c3cc2OCc2ccccc2)cc1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3cc(OCc4ccccc4)c(OCc4ccccc4)cc23)C1(C)C
Yield: 55 %

Procedure:
The 5,6-dibenzyloxyindole (Sigma, 0.60 g, 1.8 mmol), ethylmagnesium bromide (1.0 M solution in THF, 2.2 mL, 2.2 mmol), zinc chloride (1.0 M solution in Et2O, 2.2 mL, 2.2 mmol) and the product of Example 1A (2.7 mmol) in 20 mL of dichloromethane were processed as described in Example 1B to provide the title compound (0.45 g, 0.99 mmol, 55% yield). MS (DCI/NH3) m/z 454 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:14]=[CH:13][C:12]2[CH2:11][CH2:10][C:9]3[N:15]=[C:16]([NH2:18])[S:17][C:8]=3[C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:19]1[N:23]=[CH:22][N:21]([C:24](N2C=NC=C2)=[O:25])[CH:20]=1.C(Cl)Cl>CN(C=O)C>[C:1]([C:5]1[N:14]=[CH:13][C:12]2[CH2:11][CH2:10][C:9]3[N:15]=[C:16]([NH:18][C:24]([N:21]4[CH:20]=[CH:19][N:23]=[CH:22]4)=[O:25])[S:17][C:8]=3[C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ncc2c(n1)-c1sc(N)nc1CC2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1ncc2c(n1)-c1sc(NC(=O)n3ccnc3)nc1CC2
Temperature: 4 °C

Procedure:
8-tert-Butyl-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-ylamine (Stage A.1, 0.319 g, 1.225 mmol) and CDI (278 mg, 1.715 mmol) were added to DCM (5 ml) and DMF (0.25 ml) under an argon atm. After 18 h the residue was cooled to 4° C. and the precipitate was collected by filtration. The solid was dried at 50° C. in high vacuo to give the title compound as a pale yellow solid. LCMS: tR 0.95 min and M+H 319.0 (method A2) for (8-tert-butyl-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl)-carbamic acid methyl ester; the product of the reaction of the title compound with MeOH during the preparation of the sample as MeOH solution.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]1([CH3:27])[CH:22]([CH2:23][CH2:24][OH:25])[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:26])[CH:19]=2)[O:14]1>N1C=CC=CC=1>[CH3:12][C:13]1([CH3:27])[CH:22]([CH2:23][CH2:24][O:25][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:26])[CH:19]=2)[O:14]1
Reactant: CC1(C)Oc2ccc(F)cc2CC1CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2Cc3cc(F)ccc3OC2(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.01 g (21 mmol) of 4-toluenesulfonyl chloride are added while stirring at room temperature to a solution of 4.48 g (20 mmol) of 2,2-dimethyl-6-fluoro-3-(2-hydroxyethyl)-chroman in 30 ml of absolute pyridine, the slightly exothermic reaction being maintained at room temperature with an ice bath. The reaction mixture is then stirred at room temperature for 2 hours, then poured onto ice-water and the mixture is extracted with diethyl ether. The combined organic phases are washed while cold with 2N hydrochloric acid and then with water, dried over sodium sulfate and concentrated by evaporation in vacuo, yielding 6.5 g (85.8% of the theoretical yield) of 2,2-dimethyl-6-fluoro-3-[2-(4-toluenesulfonyloxy)-ethyl]-chroman in the form of a light-yellow oil.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=O)[N:6]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:16]([N:6]1[CH:5]([CH2:4][CH2:3][OH:2])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)CC1Cc2ccccc2C(=O)N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC1Cc2ccccc2CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a well-stirred ice-bath-chilled solution of the racemic mixture of Step C (650 mg, 2.0 mmol) in anhydrous tetrahydrofuran (10 ml), a solution of lithium aluminum hydride in tetrahydrofuran (6.11 ml of a 1.0M solution, 6.11 mmol of lithium aluminum hydride) was added dropwise over 5 minutes. The reaction mixture was then stirred for 24 hours at ambient temperature before being ice-bath-chilled and cautiously quenched with 15% aqueous sodium hydroxide (2 ml). Anhydrous sodium sulfate was added to dry the mixture, which was then filtered. The filtrate was concentrated in vacuo to afford the title compound as a colorless oil in quantitative yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=O)=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1)([O-:14])=[O:13].C(OCC)(=O)C>CCOCC>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][N:22]=[CH:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:19][CH:20]=1)([O-:14])=[O:13]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: O=CCCc1ccc(F)cc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(NN=CCCc2ccc(F)cc2)cc1
Yield: 41.7 %

Procedure:
A solution of 3-(4-fluorophenyl)propanal (7.0 g) in ether (50 ml) was addedto a stirred suspension of 4-nitrophenylhydrazine (7.0 g) in ether (1 50 ml), followed by sufficient ethyl acetate to achieve a clear solution. Thesolution was filtered and evaporated and the residue was crystallised from ethyl acetate/hexane to give the title compound (5.48 g), m.p. 125°-127° C. Found: C,62.81; H,4.87; N,14.44. C15 H14FN3O2 requires: C,62.71; H,4.91; N,14.63%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH:5]=O.[CH3:12][O:13][CH:14]([O:25][CH3:26])[CH2:15][NH:16]CC1C=CC(F)=CC=1>>[CH3:12][O:13][CH:14]([O:25][CH3:26])[CH2:15][NH:16][CH2:5][C:4]1[CH:3]=[C:2]([F:1])[C:9]([F:10])=[C:8]([F:11])[CH:7]=1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: COC(CNCc1ccc(F)cc1)OC
Product: COC(CNCc1cc(F)c(F)c(F)c1)OC

Procedure:
Starting from 3,4,5-trifluorobenzaldehyde, the title compound was prepared following the method described for 2,2-dimethoxy-ethyl)-(4-fluoro-benzyl)-amine (3). Rt=0.79 min (Method #4). Detected mass: 250.1 (M+H+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][CH:7]2[CH:9]([NH2:10])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[Cl:11][C:12]1[S:16][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:1][CH:2]1[CH2:3][CH:4]2[CH:9]([NH:10][S:17]([C:15]3[S:16][C:12]([Cl:11])=[CH:13][CH:14]=3)(=[O:19])=[O:18])[CH:7]([CH2:6][CH2:5]2)[CH2:8]1
Reactant: CC1CC2CCC(C1)C2N
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1CC2CCC(C1)C2NS(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 66 h
Yield: 10 %

Procedure:
3-Methyl-bicyclo[3.2.1]oct-8-ylamine (prepared in Step 2, 0.165 mmol) was dissolved in DCM (1.5 mL) and treated with 5-chlorothiophenesulphonyl chloride (53.7 mg, 0.248 mmol) followed by pyridine (100 μL). The reaction was stirred at room temperature for 66 h, followed by heating at 60° C. for 18 h. The reaction mixture was evaporated and purified by mass-directed preparative HPLC to give the desired product (5.3 mg, 10%) as a mixture of four isomers. m/z 320 (M+H+).