Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH2:34]([N:37]=[C:38]=[O:39])[CH2:35][CH3:36]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:38]([NH:37][CH2:34][CH2:35][CH3:36])=[O:39])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: CCCN=C=O
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCNC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 18.9 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, propyl isocyanate (0.24 g, 2.77 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2: CH3OH 100:3) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(propylamino)carboxamide (0.13 g, 20%) as a white solid: mp 160-162° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 7.86-7.69 (m, 3H), 6.44 (t, J=5.9 Hz, 1H), 6.16 (t, J=1H), 5.18-5.11 (dd, J=5.3 and 12.4 Hz, 1H), 4.63 (d, J=5.9 Hz, 2H), 2.99-2.83 (m, 3H), 2.64-2.50 (m, 2H), 2.08-2.04 (m, 1H), 1.42-1.32 (m, 2H), 0.83 (t, J=7.3 Hz, 3H); 13C NMR (DMSO-d6) δ 172.78, 169.84, 167.59, 167.05, 158.03, 141.16, 134.62, 133.34, 131.51, 126.96, 121.63, 48.82, 41.18, 30.94, 23.15, 21.99, 11.33; Anal. Calcd. For C18H20N4O5: C, 58.06; H, 5.41; N, 15.05. Found: C, 57.94; H, 5.31; N, 14.90.
Reaction SMILES: [C:1]([C:3]1[N:7]([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)[CH:6]=[N:5][C:4]=1[C:17]([NH2:19])=[O:18])#[CH:2].[OH-].[Na+]>Cl>[C:1]([C:3]1[NH:7][CH:6]=[N:5][C:4]=1[C:17]([NH2:19])=[O:18])#[CH:2]
Reactant: C#Cc1c(C(N)=O)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C#Cc1[nH]cnc1C(N)=O
Temperature: 100 °C
Yield: 37.6 %

Procedure:
A solution of 200 mg (0.75 mmol) of 5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide in 5 ml of 1N hydrochloric acid solution was heated under reflux at 100° C. for 4 hours. After the reaction, the reaction solution was neutralized with lN sodium hydroxide solution, silica gel powder was added, and the solvent was evaporated. The residue was adsorbed onto a silica gel column (2.7×11 cm), eluted with a 0-16% ethanol-chloroform solvent mixture, and crystallized from an ethanol-hexane solvent mixture to obtain 38 mg of pale yellow crystals of 5-ethynylimidazole-4-carboxamide (yield: 37.6%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][O:44][CH3:45])=[CH:38][CH:37]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH2:25][CH2:24]2)=[O:22])=[CH:7][CH:6]=1.Cl.[O:47]1[CH2:52][CH2:51][N:50]([CH2:53][CH2:54]Cl)[CH2:49][CH2:48]1>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:36]2[CH:37]=[CH:38][C:39]([O:42][CH2:43][O:44][CH3:45])=[CH:40][CH:41]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:54][CH2:53][N:50]3[CH2:51][CH2:52][O:47][CH2:48][CH2:49]3)[C:13]=2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH2:25][CH2:24]2)=[O:22])=[CH:9][CH:10]=1
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)N3CCN(c4ccccc4Cl)CC3)[nH]c3ccccc23)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)N3CCN(c4ccccc4Cl)CC3)n(CCN3CCOCC3)c3ccccc23)cc1
Yield: 89 %

Procedure:
Substantially the same procedure as in Example 2 was repeated using Compound 1 (2.0 g, 3.19 mmol) obtained in Example 1 and 2-morpholinoethylchloride hydrochloride (600 mg, 3.19 mmol) to give 2.1 g (yield: 89%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=O.O.[NH2:18][NH2:19]>C(O)CO>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[N:18][NH2:19]
Reactant: COc1ccc(C(=O)c2sccc2Br)cc1
Reactant: NN
Solvent: O
Solvent: OCCO
Product: COc1ccc(C(=NN)c2sccc2Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture prepared form 18 g of (3-bromothien-2-yl) (4-methoxyphenyl)methanone, 12 ml of hydrazine hydrate (99%) and 120 ml of ethylene glycol was stirred at 120° for 2 hours. Thereafter, the mixture was cooled and diluted with 1000 g of ice water and quickly extracted with ether (3×500 ml). The combined ether solution was washed four times with water to remove unreacted hydrazine and dried over anhydrous magnesium PG,54 sulfate overnight.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl[CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[CH:33]([S:34]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:36])=[O:35])=[CH2:32]
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3)c12
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CS(=O)(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Reaction time: 15 h

Procedure:
To ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (60 mg, 0.21 mmol) was added DCM (1.1 mL) and DIPEA (45 μL, 0.26 mmol) at 0° C. Then 2-chloroethanesulfonyl chloride (68 mg, 0.42 mmol) was added and the reaction was stirred vigorously for 15 hours before being quenched by pouring into a separatory funnel containing aqueous sodium hydrogen carbonate (20%). The aqueous layer was then extracted with ethyl acetate (×3) and the organic layers were combined, dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was then purified using a silica column, eluting with DCM with a 10-80% of a 2% methanol/EtOAc modifying co-solvents. The product was collected and concentrated in vacuo to afford the desired product as a yellow solid. LRMS (ESI) calc'd for C17H17N4O4S [M+H]+: 373, found 373. 1H NMR (600 MHz, CDCl3) δ 10.74 (bs, 1H), 9.04 (s, 1H), 8.12 (s, 1H), 7.38-7.54 (m, 5H), 6.61 (dd, 1H, J=17.4, 10.8 Hz), 6.33 (d, 1H, J=16.2 Hz), 5.96 (d, 1H, J=10.2 Hz), 4.04 (q, 2H, J=7.2 Hz), 1.01 (t, 3H, J=7.2 Hz).
Reaction SMILES: Br[C:2]1[C:3]([O:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][N:33]([CH:35]3[CH2:40][CH2:39][N:38]([C:41](OC(C)(C)C)=O)[CH2:37][CH2:36]3)[CH:34]=2)O1>>[CH:18]1([O:17][C:3]2[C:2]([C:30]3[CH:31]=[N:32][N:33]([CH:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)[CH:34]=3)=[CH:11][CH:10]=[C:9]3[C:4]=2[CH2:5][CH2:6][C@H:7]([CH3:16])[N:8]3[C:12]([O:14][CH3:15])=[O:13])[CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)N1c2ccc(Br)c(OC3CCC3)c2CC[C@@H]1C
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: COC(=O)N1c2ccc(-c3cnn(C4CCN(C)CC4)c3)c(OC3CCC3)c2CC[C@@H]1C

Procedure:
Methyl (S)-5-cyclobutoxy-2-methyl-6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate was synthesized from methyl (S)-6-bromo-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate according to the procedure outlined above for Example 60. 1H NMR (300 MHz, CDCl3) δ ppm 0.64-0.99 (m, 1H), 1.12-1.26 (m, 4H), 1.39-1.52 (m, 1H), 1.55-1.67 (m, 1H), 1.97-2.14 (m, 5H), 2.14-2.27 (m, 1H), 2.30-2.58 (m, 2H), 2.63 (br s, 1H), 2.73-2.78 (m, 1H), 2.79 (s, 3H), 2.84-3.09 (m, 1H), 3.15 (br s, 1H), 3.37-3.63 (m, 4H), 3.64-3.92 (m, 3H), 4.54 (s, 1H), 7.14-7.39 (m, 2H), 7.81 (d, J=8.21 Hz, 2H). MS (ESI, pos. ion) m/z 439 [M+H]+.
Reaction SMILES: [CH:1]1([C@@H:4]2[O:14][CH2:13][C:7]3=[N:8][O:9][C@@H:10]([CH2:11][F:12])[C@@H:6]3[CH2:5]2)[CH2:3][CH2:2]1.C1([C@@H]2OC[C@]3([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])NOC[C@@H]3C2)CC1>>[CH:1]1([C@@H:4]2[O:14][CH2:13][C@:7]3([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])[NH:8][O:9][C@@H:10]([CH2:11][F:12])[C@@H:6]3[CH2:5]2)[CH2:2][CH2:3]1
Reactant: FC[C@@H]1ON=C2CO[C@@H](C3CC3)C[C@H]21
Reactant: Fc1ccc([C@]23CO[C@@H](C4CC4)C[C@H]2CON3)c(F)c1
Product: FC[C@@H]1ON[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CC3)C[C@@H]12

Procedure:
Conversion of rel-(3R,3aR,5R)-5-cyclopropyl-3-(fluoromethyl)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C43) to the product was carried out using the method described for synthesis of rel-(3aR,5R,7aS)-5-cyclopropyl-7a-(2,4-difluorophenyl)hexahydro-1H-pyrano[3,4-c][1,2]oxazole (C19) in Example 2. The product was obtained as an oil. Yield: 0.10 g, 0.32 mmol, 64%. 1H NMR (400 MHz, CDCl3) δ 7.93 (ddd, J=9, 9, 7 Hz, 1H), 6.90 (br ddd, J=9, 8, 2 Hz, 1H), 6.80 (ddd, J=12, 8.6, 2.5 Hz, 1H), 6.45 (s, 1H), 4.12-4.21 (m, 1H), 3.60-3.95 (m, 4H), 3.09 (br dd, J=9, 9 Hz, 1H), 2.88 (br dd, J=10, 9 Hz, 1H), 2.18 (br dd, J=14, 7.5 Hz, 1H), 1.63-1.75 (m, 1H), 0.88-0.98 (m, 1H), 0.52-0.64 (m, 2H), 0.37-0.46 (m, 1H), 0.24-0.33 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[C:11](=[O:19])[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[C:28]([C:21]1[CH:22]=[CH:23][C:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11](=[O:19])[C:10]=2[CH:20]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: O=C1c2ccccc2CN(Cc2ccccc2)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)C(=O)c1ccccc1CN2Cc1ccccc1
Yield: 14.6 %

Procedure:
5,6-Dihydro-5-benzyl-11-oxodibenz[b,e]azepine (6.2 g), anhydrous aluminum chloride (6.07 g), acetyl chloride (4.87 g) and methylene chloride (60 ml) were treated in the same manner as described in Example 25 to obtain the desired compound (1.03 g).
Reaction SMILES: [NH:1]([CH3:18])[C@H:2]([C:15]([NH2:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[NH:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:20]([C:24]([OH:26])=O)[CH:21]([CH3:23])[CH3:22].C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>CN(C=O)C.C(OCC)(=O)C>[NH:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:20]([C:24]([N:1]([CH3:18])[C@H:2]([C:15]([NH2:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:5]=1)=[O:26])[CH:21]([CH3:22])[CH3:23]
Reactant: CN[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 120 mg (0.480 mmol) of N-Me-Tyr(3-tBu)-NH2,156 mg (0.718 mmol) of Boc-Val-OH and 110 mg (0.718 mmol) of HOBT in 2 ml of DMF, 0.111 ml (0.718 mmol) of DIC was added under cooling with ice and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed first with saturated aqueous NaHCO3, then with water, and finally with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane=2:1) to give Boc-Val-N-Me-Tyr(3-tBu)-NH2 in the amount of 147 mg (68%).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH2:16]([O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:22]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[CH:24]=[C:25](O)[CH:26]=1)[CH3:17].N1C=CC=CC=1>C(Cl)Cl>[CH2:16]([O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:22]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=2)[CH:24]=[C:25]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[CH:26]=1)[CH3:17]
Reactant: CCOC(=O)Cc1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Trifluoromethanesulphonic anhydride (570 mg, 2.0 mmol) was added drop wise to a solution of (5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (546 mg, 1.69 mmol) and pyridine (0.41 mL, 5.0 mmol) in DCM (10 mL) at 0° C. The temperature was maintained at 0° C. for 15 mins before warming to room temperature and the mixture stirred for 18 hrs. The reaction was diluted with DCM, washed with H2O, Na2CO3, dil. HCl, brine, dried (MgSO4) and evaporated under reduced pressure to give a yellow oil. The residue was purified by flash column chromatography (EtOAc:petroleum ether), yield 695 mg (96%). 1H NMR (CDCl3) δ 7.72 (d, 2H), 7.66 (d, 2H), 7.54 (t, 1H), 7.39 (t, 1H), 7.28 (t, 1H), 4.19 (q, 2H), 3.73 (s, 2H), 1.28 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10](#[N:14])[CH2:11][C:12]#[N:13]>C(O)(C)C.N1CCCCC1>[C:12]([C:11]([C:10]#[N:14])=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)#[N:13]
Reactant: N#CCC#N
Reactant: O=Cc1ccc(O)cc1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: N#CC(C#N)=Cc1ccc(O)cc1
Temperature: 25 °C
Yield: 69.8 %

Procedure:
3.7 g of p-hydroxybenzaldehyde and 2.3 g of malononitrile were dissolved in 10 ml of isopropanol followed by adding 1 drop of piperidine and reacted at 80° C. for 1 hour. Crystals were precipitated after cooling to the room temperature, collected by filtration and recrystallized from isopropanol to obtain 3.6 g of 4-(2,2'-dicyanovinyl)phenol as yellow crystals. Melting point=188-189.5° C.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])=[CH:17]3)[CH2:9]1)C1C=CC=CC=1>[Pd].C(OCC)(=O)C.CO>[N:25]1([C:23]([C:18]2[NH:19][C:20]3[C:16]([CH:17]=2)=[CH:15][C:14]([O:13][C@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[CH:22][CH:21]=3)=[O:24])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: O=C(c1cc2cc(O[C@H]3CCN(Cc4ccccc4)C3)ccc2[nH]1)N1CCOCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(c1cc2cc(O[C@H]3CCNC3)ccc2[nH]1)N1CCOCC1
Reaction time: 4 h
Yield: 77 %

Procedure:
A mixture of 4.6 (0.016 mol) [5-((S)-1-Benzyl-pyrrolidin-3-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone and 480 mg of 10% palladium on charcoal in 250 ml ethyl actetate/acetic acid 9/1 was hydrogenated at room temperature during 4 h. After filtration the filtrate was evaporated to dryness and the residue was taken up in 250 ml DCM and 150 ml 10% Na2CO3. The aqueous phase was extracted with 2×100 ml DCM and the combined organic phases were dried with Na2SO4 and evaporated to dryness to yield 2.77 g (77% of the title compound as off white solid. MS (m/e): 316.1 (MH+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:18]([O-])=O)[C:5]2[O:17][CH2:16][CH2:15][C:8]3([S:12][C:11](=[O:13])[NH:10][C:9]3=[O:14])[C:6]=2[CH:7]=1.C(Cl)(Cl)Cl>C(O)C.[Pt]=O>[F:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]2[O:17][CH2:16][CH2:15][C:8]3([S:12][C:11](=[O:13])[NH:10][C:9]3=[O:14])[C:6]=2[CH:7]=1
Reactant: O=C1NC(=O)C2(CCOc3c([N+](=O)[O-])cc(F)cc32)S1
Agent: O=[Pt]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Nc1cc(F)cc2c1OCCC21SC(=O)NC1=O
Reaction time: 2.5 h

Procedure:
755 mg of (±)-6-fluoro-8-nitro-2,3-dihydrospiro[4H-1-benzopyran-4,5'-thiazolidine]-2',4'-dione were hydrogenated at room temperature and normal pressure in the presence of 50 mg of platinum oxide in 50 ml of ethanol. An additional 100 mg of platinum oxide were added after 30 minutes. After 2.5 hours under hydrogen, some chloroform was added, the catalyst was filtered, the filtrate was concentrated and the residue was chromatographed on silica gel 60 with chloroform/methanol (19:1). (±)-6-Fluoro-8-amino-2,3-dihydrospiro[4H-1-benzopyran-4,5'-thiazolidine]-2',4'-dione was obtained in the form of a yellowish foam. The IR spectrum showed amine bands at 3383, 3202 and 2766 cm-1, in the mass spectrum the molecular ion appeared as a basic peak (m/e=268).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:10]2[C:11]3[C:12](=[O:18])[CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[BH4-].[Na+]>C(O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:10]2[C:11]3[CH:12]([OH:18])[CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(=O)CC3
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(O)CC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
To a stirred solution of Intermediate 3 (0.12 g, 0.37 mmol) in ethanol (2 ml) was added NaBH4 (28 gm, 0.74 mmol). The reaction mixture was allowed to stir at RT for 1 hour. The reaction mixture was diluted with water and extracted with DCM (3×). The combined DCM extracts were washed with brine, dried (Na2SO4), and solvent evaporated in vacuo to give the sub-titled compound as a colorless oil (104 mg) which was used as obtained in the next step. MS: ESI (positive): 276 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Reactant: C1COCCN1
Product: COc1ccc(-c2cc(N3CCOCC3)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (125.5 mg, 0.384 mmol) and morpholine were reacted as starting materials at 100° C. for 15 hours and post-treatment was then conducted, whereby the title compound was obtained as a pale yellow crystalline powder (115.2 mg, 79.5%). Melting point: 188.0-190.3° C. (chloroform-diethylether).
Reaction SMILES: [CH2:1]1[C:12]2[C:4](=[CH:5][C:6]3[CH2:7][CH2:8][CH2:9][C:10]=3[CH:11]=2)[CH2:3][CH2:2]1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[CH2:3]1[C:4]2[C:12](=[C:11]([C:13](=[O:15])[CH3:14])[C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[CH:5]=2)[CH2:1][CH2:2]1
Reactant: CC(=O)Cl
Reactant: c1c2c(cc3c1CCC3)CCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CC(=O)c1c2c(cc3c1CCC3)CCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 1,2,3,5,6,7-Hexahydro-s-indacene (30 grams) and acetyl chloride (14.2 mL) in 120 mL of benzene at 0° C. was added 30 grams of aluminum chloride over a period of 1 hour. The cooling bath was removed and the solution was warmed to room temperature and stirred for 4 hours. The deep red mixture was then poured onto a mixture of 270 grams of ice and 50 mL of concentrated hydrochloric acid. The layers were separated and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford an orange solid which was recrystallized from hexane to give 34 grams of the title compound, m.p. 69.1-76.1° C.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[C:15]3[C:20]([CH:21]=[C:22]4[C:27]=2[CH:26]=[CH:25][CH:24]=[CH:23]4)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:6][CH:5]=1>ClCCl.C(O)C>[Br:1][C:21]1[C:22]2[C:27]([C:14]([C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:4]([CH3:3])=[CH:5][CH:6]=3)=[C:15]3[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]3)=[CH:26][CH:25]=[CH:24][CH:23]=2
Reactant: BrBr
Reactant: Cc1ccc(-c2c3ccccc3cc3ccccc23)c2ccccc12
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccc(-c2c3ccccc3c(Br)c3ccccc23)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 18.0 ml (352 mmol) of bromine in 100 ml of dichloromethane is added dropwise with vigorous stirring to a solution of 102.0 g (320 mmol) of 9-(4-methylnaphth-1-yl)anthracene in 2000 ml of dichloromethane at −5° C., and the mixture is stirred at room temperature for 12 h. The suspension is subsequently diluted with 1000 ml of ethanol. The precipitated solid is filtered off with suction, washed with 500 ml of a mixture of water and ethanol (1:1, v:v) and three times with 200 ml of ethanol. After washing twice with 1000 ml of boiling ethanol each time, the solid is dried under reduced pressure. Yield: 108.0 g (84.9% of theory), about 97% according to 1H-NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@:8]2([CH3:21])[C@@H:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:12][O:11][C:10]([NH2:20])=[N:9]2)[CH:7]=1.[F:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[NH2:20][C:10]1[O:11][CH2:12][C@H:13]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:29][N:28]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:22])([CH3:21])[N:9]=1
Reactant: O=C(O)c1ccc(F)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1OCC(F)(F)F
Product: C[C@]1(c2cc(NC(=O)c3ccc(F)cn3)ccc2F)N=C(N)OC[C@@H]1OCC(F)(F)F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.4) and 5-fluoro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=445.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]O)=O.O.Cl[CH2:14]Cl>>[CH2:3]([C@@H:4]([CH2:9][CH2:10][CH2:11][CH3:14])[CH2:5][OH:7])[CH3:2]
Reactant: ClCCl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Product: CCCC[C@H](CC)CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 1000 ml of phosphate buffer (0.1 M, HK2PO4/H2KPO4 with 95/5 in mol/mol, pH˜8.0) was added yeast (200 g, Sigma Aldrich) and sucrose (10 g, Thermo FiSEHr Scientific Inc.), and the mixture was stirred for 2 hrs. Then pentane (1500 ml) was added followed by adding 2-ethylidenehexanal (10.0 g, 79.2 mmol, TCI). The mixture was stirred for 2 days. Then the mixture was divided into batches of 300 ml each, and separated by centrifuging, and the yeast and water phase was extracted with pentane. After volatiles were removed, 12.0 g of yellowish oil was collected, with the crude product yield over 100%. GC and GC/MS analysis indicated an impurity of about 40% (˜4.8 g) while starting materials were less than 2%. The impurity was judged to be 2-ethylidenehexan-1-ol based on GC/MS results (with m/z of 128). The crude product was dissolved in dichloromethane and cooled down to 0° C., meta-chloroperoxybenzoic acid (MCPBA) (6.46 g, 37.5 mmol) was added, and the reaction was stirred at 0° C. for 1 hr. Then the reaction was poured into deionized water, the organic phase was extracted with dichlormethane, and then the organic phase was dried over sodium sulfate. The volatiles of the organic phase were removed under reduced pressure, and the resulted dark oil was separated by flash column chromatography with pentane/dichloromethane (1/1 in v/v). The over all yield was 50%. 1H NMR (500 MHz, CDCl3) δ (ppm): 3.58 (d, J=5.05 Hz, 2H), 1.44-1.24 (m, 10H), 0.92 (t, J=7.15 Hz, 6H). GC/MS: calcd for C8H18O (m/z): 130.14. found 130. [α]D=+3.1° (Concentration of 1.2 g/100 ml in acetone, 25° C.). ([Ref]: [α]D=+ 3.1°, e.e. =96%, C. R. G. Grenier, S. J. George, T. J. Joncheray, E. W. Meijer, and J. R. Reynolds, J. Am. Chem. Soc. 2007, 129, 10694-10699.