Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([NH2:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[N:27]=1)[C:22](O)=[O:23])=[O:18]>>[CH3:28][C:26]1[N:27]=[C:19]([C:17]([O:16][CH3:15])=[O:18])[CH:20]=[C:21]([C:22](=[O:23])[NH:12][CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:13])([F:14])[F:1])[CH:5]=2)[CH3:11])[CH:25]=1
Reactant: CC(N)c1cccc(OC(F)(F)F)c1
Reactant: COC(=O)c1cc(C(=O)O)cc(C)n1
Product: COC(=O)c1cc(C(=O)NC(C)c2cccc(OC(F)(F)F)c2)cc(C)n1

Procedure:
The title compound is prepared from (+)-1-(3-(trifluoromethoxy)phenyl)ethanamine (Amine-9) and 2-(methoxycarbonyl)-6-methylisonicotinic acid by the similar manner in Step-1 of Example 8.
Reaction SMILES: OC1C=C(CNC=C2C3C(=CC=C(I)C=3)C(=O)NC2=O)C=CC=1C1C=CC=CC=1.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[C:41](=[O:45])[NH:40][C:39](=[O:46])[C:38]2=[CH:47]OC.[NH2:50][CH2:51][C:52]1[CH:53]=[C:54]([OH:65])[C:55]([C:58]2[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=2)=[CH:56][CH:57]=1>>[F:64][C:61]1[CH:62]=[CH:63][C:58]([C:55]2[CH:56]=[CH:57][C:52]([CH2:51][NH:50][CH:47]=[C:38]3[C:37]4[C:42](=[CH:43][CH:44]=[C:35]([C:31]5[O:30][CH:34]=[CH:33][CH:32]=5)[CH:36]=4)[C:41](=[O:45])[NH:40][C:39]3=[O:46])=[CH:53][C:54]=2[OH:65])=[CH:59][CH:60]=1
Reactant: NCc1ccc(-c2ccc(F)cc2)c(O)c1
Reactant: COC=C1C(=O)NC(=O)c2ccc(-c3ccco3)cc21
Agent: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Product: O=C1NC(=O)c2ccc(-c3ccco3)cc2C1=CNCc1ccc(-c2ccc(F)cc2)c(O)c1
Yield: 62 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound is prepared from 6-Furan-2-yl-4-methoxymethylene-4H-isoquinoline-1,3-dione (40 mg, 0.15 mmol) and 4-Aminomethyl-4′-fluoro-biphenyl-2-ol (33 mg, 0.15 mmol) in 62% yield: MS (ESI): 453.2 (M−1)−1.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:22]([O:29][C:30](=[O:33])[CH2:31]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30](=[O:33])[CH2:31][N:14]([S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])[C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]2)=[CH:13][CH:12]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Product: CCCCS(=O)(=O)N(CC(=O)OCc1ccccc1)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from butane-1-sulfonic acid [4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example 228) and benzyl-2-bromoacetate according to the procedure of Example 251 as an orange oil; 1H NMR (300 MHz, CDCl3) δ 0.91 (t, J=7.29 Hz, 3H), 1.34–1.47 (m, 2H), 1.75–1.86 (m, 2H), 2.55 (t, J=6.09 Hz, 4H), 3.17–3.23 (m, 2H), 3.62 (t, J=6.00 Hz, 4H), 4.45 (s, 2H), 5.18 (s, 2H), 6.87–6.92 (m, 2H), 7.30–7.40 (m, 7H); MS (ES) m/z: 459.0 (MH+); HRMS found for C24H30N2O5S: 459.1944.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([OH:16])=[O:15])([O-:3])=[O:2].[CH3:17][Si](C=[N+]=[N-])(C)C>>[CH3:17][O:15][C:14](=[O:16])[CH2:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Product: COC(=O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
2,4-diaminophenylacetic acid methyl ester is obtained by reacting 2,4-dinitrophenylacetic acid with trimethylsilyldiazomethane to obtain 2,4-dinitrophenylacetic acid methyl ester, followed by reducing 2,4-dinitrophenylacetic acid methyl ester using a strong reducing agent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[C:25]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])=[C:24]([CH3:34])[NH:23][C:22]=1[CH:35]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:35][C:22]4[NH:23][C:24]([CH3:34])=[C:25]([C:26]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[O:27])[C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCOCC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)c(C)c1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 79.3 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3,5-dimethyl-4-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (70.9 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 98.5 mg (79%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.28 (br s, 1H, NH), 11.68 (br s, 1H, NH), 9.12 (br s, 1H), 8.29 (s, 1H), 7.71 (m, 1H), 7.40 (m, 1H), 7.31-7.36 (m, 2H), 3.56 (m, 4H, 2×CH2), 3.45 (m, 4H,2×CH2), 2.31 (s, 3H, CH3), 2.14 (s, 3H, CH3). MS 497 [M++1].
Reaction SMILES: [CH:1]12[CH2:14][CH:6]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=31)[CH2:5][NH:4][CH2:3][CH2:2]2.C(=O)(O)[O-].[Na+].[CH2:20](Br)[CH:21]=[CH2:22].[ClH:24]>CCOCC.CO>[ClH:24].[CH2:22]([N:4]1[CH2:3][CH2:2][CH:1]2[CH2:14][CH:6]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=32)[CH2:5]1)[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: c1ccc2c(c1)CC1CNCCC2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: C=CCN1CCC2CC(Cc3ccccc32)C1

Procedure:
1.87 g of 2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine, 1.25 g of sodium bicarbonate and 1.33 g of allyl bromide were added into 30 ml of methanol, and the mixture was refluxed for 5 hours and subjected to distillation under reduced pressure. The residue was dissolved in 15 ml of 10% hydrochloric acid. The solution was washed once with 5 ml of benzene, and the water layer was made alkaline with sodium hydroxide and extracted with ether. Ether was distilled from the ether extract and the residue was subjected to vacuum distillation to obtain 2 g of a colorless oily substance as a fraction boiling at 110° to 120° C. (bath temperature) under 0.7 mmHg. The product was dissolved in 15 ml of ether and gaseous hydrochloric acid was blown into the solution to form a white precipitate. The precipitate was recovered by filtration and dried to obtain 4-allyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine hydrochloride. Recrystallization from isopropanol gave a white crystalline powder melting at 212.5° to 214.5° C.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=1>CN(C=O)C.O>[NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][O:4][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(N)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(N)COc1ccc(C#N)cn1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-2-methyl-1-propanol (0.5 ml, 5.60 mmol), in DMF (20 mL) was added NaH 60% (0.67 g, 16.80 mmol) and then 6-chloronicotinonitrile (2.03 g, 11.22 mmol). The mixture heated to 70° C. for 2 hours and then stirred at room temperature overnight. The reaction mixture was taken up in H2O and extracted with EtOAc. The organic phase was washed with water (3×), dried over Na2SO4 and concentrated under reduced pressure to provide the titled compound as a pale yellow solid. MS (DCI) m/z 235 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][CH2:28][CH:29]=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:31]OS([O-])=O.[K+].Cl.C(OC(C)C)(=O)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: Cc1c(C)c(OCc2ccccc2)c(CCCC=O)c(C)c1OCc1ccccc1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)C
Product: Cc1c(C)c(OCc2ccccc2)c(CCCC(=O)O)c(C)c1OCc1ccccc1
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To a solution of 4-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)butanal (450 mg, 1.12 mmol) in DMF (11.5 mL) was added Oxone (350 mg, 1.12 mmol) giving a cloudy white solution. The suspension was stirred vigorously overnight and poured over 10 mL 2.5 M HCl and stirred until the solution clarified. Isopropyl acetate (iPrOAc) (25 mL) was added after the exotherm subsided. The organics were washed 2×10 mL 2.5 M HCl, 1×10 mL saturated aqueous NaCl and dried over Na2SO4. Concentration gave 435 mg of 4-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)butanoic acid as a white solid. MS M++H at 419 m/z; 1H NMR (400 MHz, CDCl3) δ=7.50 (m, 4H), 7.43-7.34 (m, 6H), 4.75 (s, 2H), 4.74 (s, 2H), 2.71 (t, 2H), 2.37 (t, 2H), 2.26 (s, 3H), 2.26 (s, 6H), 1.85 (s, 2H) ppm.
Reaction SMILES: [CH3:1][C@H:2]([C:15]([OH:17])=[O:16])[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][C:11]=2[CH:12]=1.[Cl-:18].O>ClCCl>[CH3:14][O:13][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:12]=[C:3]([C@H:2]([CH3:1])[C:15]([O:17][CH2:1][CH2:2][CH2:3][CH2:12][Cl:18])=[O:16])[CH:4]=[CH:5]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc2cc([C@H](C)C(=O)OCCCCCl)ccc2c1
Temperature: 0 °C
Reaction time: 10 h

Procedure:
Preparation: 30 g of Naproxen chloride are dissolved in 120 g of dichloromethane. This solution is cooled at 0° C. and a solution of 14.5 g of 1-chloro-3-buthanol in 100 g of dichloromethane is added dropwise in 2 hours. After a completion time of 3 hours at 0° C., 60 g of water are added and is the mixture is stirred for 10 hours. After phase separation, 60 g of water are added to organic phase and the mixture is stirred for 10 hours. After phase separation, the organic phase is concentrated to 120 mL and 4.5 g of potassium carbonate are added. The mixture is refluxed at about 40° C. for 4 hours. After filtration and vacuum concentration, an oil is obtained (HPLC purity 90%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[O:5][CH2:6][C:7]([OH:9])=[O:8].O[C:15]([CH3:29])([CH3:28])[C:16]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)=O.C1CCN2C(=NCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[O:5][C:6]1[C:7](=[O:9])[O:8][C:15]([CH3:29])([CH3:28])[C:16]=1[C:18]1[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: O=C(O)COc1ccc(F)c(F)c1
Reactant: CC(C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(Oc2ccc(F)c(F)c2)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
A solution of 3,4-difluorophenoxyacetic acid (0.51 g, 2.73 mmol), 2-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one (0.5g, 2.1 mmol, Step 3), CMC (1.13 g, 2.73 mmol) and DMAP (15 mg, 0.10 mmol) in dichloromethane (12 ml) was stirred at r.t. for 18 hrs. Then, DBU (0.63 ml, 4.2 mmol) was added and the reaction mixture was refluxed for 3 h. After cooling to r.t. the mixture was extracted with ethyl acetate and washed successively with water, 1 N HCl and brine. The organic layer was dried over MgSO4, filtered and the solvent evaporated under vacuum. The residue was triturated in a mixture of ethyl acetate and hexane affording the title compound as a solid. M.P.: 93-95 ° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:14]([CH3:18])([CH3:17])[C:15]#[N:16])[CH:6]=[C:7]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:8]=1.N1C=CC=CC=1.S(Cl)([Cl:27])=O>ClCCl>[Cl:27][CH2:2][C:3]1[CH:4]=[C:5]([C:14]([CH3:18])([CH3:17])[C:15]#[N:16])[CH:6]=[C:7]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C#N)c1cc(CO)cc(C(C)(C)C#N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cc(CCl)cc(C(C)(C)C#N)c1
Reaction time: 2 h

Procedure:
A solution of 2,2'-(5-hydroxymethyl-1,3-phenylene)di-(2-methylpropiononitrile), (3.8 g) and pyridine (1.58 g) in dichloromethane (10 ml) was stirred, and cooled in an ice bath, while thionyl chloride (3 g) was added over 10 minutes. The solution was kept at room temperature for 2 h and then heated under reflux for 1 h and evaporated to dryness under reduced pressure The residue was partitioned between water and ethyl acetate and the organic phase was separated, dried and evaporated to dryness under reduced pressure to give 2,2'-(5-chloromethyl-1,3-phenylene)di(2-methylpropiononitrile), which was used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[NH:17][C:16](=S)[NH:15][C:14](=[O:19])[CH:13]=1.N.[CH3:21][CH2:22]O>[Ni]>[O:2]1[CH2:1][CH2:22][CH2:21][CH:3]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:17]=[CH:16][NH:15][C:14](=[O:19])[CH:13]=1
Reactant: CCO
Reactant: COCCOc1ccccc1-c1cc(=O)[nH]c(=S)[nH]1
Agent: [Ni]
Agent: N
Product: O=c1cc(-c2ccccc2OCC2CCCO2)nc[nH]1

Procedure:
6-[2-(2-methoxy-ethoxy)-phenyl]-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.6 g, 1.97 mmol) is dissolved in EtOH (12 mL) and aqueous solution of ammonia (25%, 4 mL). After addition of Raney-Nickel (0.5 g) the reaction mixture is stirred under reflux for 1 h, filtered from the solid material, which is washed with a mixture of ammonia and EtOH. The combined solutions were evaporated, dissolved in water (10 mL), neutralized with 10% HCl and extracted with ethyl acetate (3×15 mL). Organic layers were combined, washed with water (7 mL) then dried over anhydrous sodium sulfate and concentrated. The residue was triturated with diethyl ether yielding 0.47 g (87%) 6-[2-(tetrahydro-furan-2-ylmethoxy)-phenyl]-3H-pyrimidin-4-one as cream powder.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.[CH2:32]([N:35]=[C:36]=[O:37])[CH2:33][CH3:34]>>[CH2:32]([NH:35][C:36]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:11]2[N:10]=[C:9]([NH2:8])[C:14]([C:15](=[O:16])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[CH:13][N:12]=2)[CH2:27][CH2:28]1)=[O:37])[CH2:33][CH3:34]
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CCCN=C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCNC(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 25 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 11, and propyl isocyanate (Aldrich), to give 4-[4-Amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid propylamide. HRMS, observed:413.2299; Calcd for (M+H)+: 413,2296.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=O.[CH2:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>CO>[CH2:19]([NH:27][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCc1ccccc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3ccccc3)cc2)cc1
Yield: 64.9 %

Procedure:
Combine 4-(4-Formyl-phenoxy)-benzamide (from Example 247, step 2) (0.39 g, 1.6 mmol), phenethylamine (0.15 g, 1.2 mmol), 20 mL of methanol and 2 g of 3 Å molecular sieves, and stir at ambient temperature ambient under nitrogen for 5 h. Add sodium borohydride (0.18 g, 4.8 mmol), and stir at ambient temperature for 18 h at ambient temperature. Filter the reaction mixture through Celite, and adsorb on silica gel. Purify by Biotage Flash 40S, eluting with 95:5:0.5 chloroform/ethanol/ammonium hydroxide to afford 0.27 g (93%) of the title compound: mass spectrum (ion spray): m/z=347.28 (M+1); HPLC retention time: 6.01 min (HPLC method in this experiment and subsequent experiments: 5:95-95:5 ACN/0.1% TFA in water over 10 minutes using a 15 cm Zorbax column, running at 1 mL/minute, ultraviolet detector set at 254 nM).
Reaction SMILES: [N+]([C:4]1[C:13]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)([O-])=O.C1C2C(=CC=CC=2)C=CC=1.[N+:27]([O-])([OH:29])=[O:28].[N+](C1C2C(=CC=CC=2)C=CC=1)([O-])=O>>[N+:14]([C:9]1[C:8]2[C:13](=[CH:4][CH:5]=[CH:6][C:7]=2[N+:27]([O-:29])=[O:28])[CH:12]=[CH:11][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1cccc2c([N+](=O)[O-])cccc12
Agent: O=[N+]([O-])c1cccc2ccccc12
Solvent: c1ccc2ccccc2c1
Product: O=[N+]([O-])c1cccc2cccc([N+](=O)[O-])c12

Procedure:
The process for the production of 1,5-dinitronaphthalene according to the invention is based on the direct nitration of naphthalene by nitric acid having a concentration of 72–87 wt.-% without mononitronaphthalene isolation. The washing of the reaction products with water and acetone leads to 1,5-dinitronaphthalene of high purity [≧98 wt.-%]. The acetone and nitric acid used in the process may be recovered and returned into the process. 1,8-dinitronaphthalene is produced in the process as a by-product.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=1.Cl[C:23]1[C:28]([C:29]([OH:31])=[O:30])=[CH:27][N:26]=[C:25]([Cl:32])[C:24]=1[F:33]>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:23]2[C:28]([C:29]([OH:31])=[O:30])=[CH:27][N:26]=[C:25]([Cl:32])[C:24]=2[F:33])=[C:16]([F:21])[CH:15]=1
Reactant: O=C(O)c1cnc(Cl)c(F)c1Cl
Reactant: Nc1ccc(Br)cc1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)c(F)c1Nc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
nBuLi (14.7 mL, 36.7 mmol, 2.5 M solution in hexanes) was added to a stirred solution of diisopropylamine (5.15 mL, 36.7 mmol) in THF (20 mL) at 0° C. After 20 minutes, the reaction mixture was cooled to −78° C. and a solution of 4-bromo-2-fluorophenylamine (4.65 g, 24.5 mmol) in THF (10 mL) was added. After 20 minutes, a solution of 4,6-dichloro-5-fluoro-nicotinic acid (Sanchez et al J Heterocylc. Chem. 1993, 30 (4), 855-9) (2.57 g, 12.25 mmol) in THF (10 mL) was added. After 10 minutes, the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. After quenching the reaction mixture with 10% HCl (20 mL), it was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Trituration with methylene chloride yielded 3.21 g (72%) of clean desired product.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([NH:15][CH2:16][C@@H:17]([OH:22])[C:18]([O:20][CH3:21])=[O:19])[CH:3]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>>[F:1][C:2]1[C:7]2[N:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([N:15]2[CH2:16][C@H:17]([C:18]([O:20][CH3:21])=[O:19])[O:22][C:23]2=[O:24])[CH:3]=1
Reactant: COC(=O)[C@H](O)CNc1cc(F)c2c(c1)oc(=O)n2C(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Product: COC(=O)[C@H]1CN(c2cc(F)c3c(c2)oc(=O)n3C(C)C)C(=O)O1

Procedure:
Prepared from methyl (2R)-3-[(4-fluoro-3-isopropyl-2-oxo-2,3-dihydro-6-benzoxazolyl)amino]-2-hydroxypropanoate (Step 3, 0.908 g, 2.91 mmol) and 1,1′-carbonyldiimidazole (0.471 g, 2.91 mmol) according to the method of EXAMPLE 86, Step 9 (0.90 g, 92%); MS for C15H15FN2O6 m/z 339 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:31][C:32](=[O:36])[C@H:33]([CH3:35])O>>[CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C@H:33]([CH3:35])[C:32]([OH:36])=[O:31])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Reactant: COC(=O)[C@H](C)O
Product: C[C@@H](Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-biphenyl-4-ol, and (S)-(+)- lactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h, and was obtained as a white solid, mp 112-114° C.; MS m/e 448 (M+);
Reaction SMILES: CC(C)(OC([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:12][S:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28])=O)C.BrC1C=CC2C(NC(=O)C2(C=CCC)C=1)=O.C1(=O)NC(=O)C2=CC=CC=C12.[ClH:57].O1CCOCC1>C(Cl)Cl>[ClH:57].[NH:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:12][S:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CSC/C=C\CN1C(=O)c2ccccc2C1=O
Agent: CCC=CC12C=C(Br)C=CC1C(=O)NC2=O
Agent: Cl
Agent: O=C1NC(=O)c2ccccc21
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1C/C=C\CSC[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of (S,Z)-2-[4-[[[1-[(1,1-dimethylethoxy)carbonyl]-2-pyrrolidinyl]methyl]thio]-2-butenyl]-1H-isoindole-1,3(2H) -dione, (prepared as in Example I, Part A, except substituting 4-bromo-2-butenyl phthalimide for the corresponding phthalimide) (3.60 mmol)) in 2 mL of CH2Cl2 was added 18 mL of 4N HCl/dioxane at 0° C. The ice bath was removed and the reaction was stirred at room temperature for 3 hrs. The reaction mixture was concentrated in vacuo to give title compound (92% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:17](Br)[CH:18]=[CH2:19].O>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)[CH:18]=[CH2:17]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-hydroxyindole (1.23 g, 9.24 mmol) and cesium carbonate (3.01 g, 9.24 mmol) in DMF (40 mL) under nitrogen atmosphere at 0° C. was added allylbromide (879 μl, 10.16 mmol). The reaction mixture was stirred at RT for 2 h and poured into water and extracted with EtOAc (×3). The combined organic layers were washed twice with water, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 9:1) to give the desired compound. TLC, Rf (c-hexane/EtOAc 1:1)=0.76; tR (conditions a): 3.46 min.
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[CH:6][C:5]=2[N:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.C(OC([N:21]1[C@H:25]([CH3:26])[CH2:24]OS1(=O)=O)=O)(C)(C)C>>[CH2:13]1[C:3]2=[C:2]([CH2:24][C@H:25]([NH2:21])[CH3:26])[C:10]3[CH:9]=[N:8][CH:7]=[CH:6][C:5]=3[N:4]2[CH2:11][CH2:12]1
Reactant: C[C@@H]1COS(=O)(=O)N1C(=O)OC(C)(C)C
Reactant: Brc1c2n(c3ccncc13)CCC2
Product: C[C@@H](N)Cc1c2n(c3ccncc13)CCC2

Procedure:
By the same general procedure as in example 3(R)-2-(2,3-Dihydro-1H-3a,6-diaza-cyclopenta[a]inden-8-yl)-1-methyl-ethylamine was obtained from 8-Bromo-2,3-dihydro-1H-3a,6-diaza-cyclopenta[a]indene and (R)-4-Methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester as white solid.