Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[O:5][C:6]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:2].[CH2:20]=O.Cl.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(O)(=O)C>[CH2:1]([NH:3][C:4]1[O:5][C:6]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]3[O:16][C:17]([CH2:20][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:18][CH:19]=3)[CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:2]
Reactant: C1CCNCC1
Reactant: C=O
Reactant: CCNc1nc2ccc(CCc3ccco3)cc2o1
Agent: Cl
Solvent: CC(=O)O
Product: CCNc1nc2ccc(CCc3ccc(CN4CCCCC4)o3)cc2o1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 2-ethylamino-6-[2-(2-furyl)ethyl]benzoxazole (0.93 g), 37% formalin (0.30 ml), concentrated hydrochloric acid (0.35 ml) and piperidine (0.34 g) in acetic acid (10 ml) was stirred at 70° C. for 2 hours. After the solvent was evaporated in vacuo, saturated aqueous sodium bicarbonate was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel by eluting with ethyl acetate-toluene (2:8, V/V). The free base was converted to the maleate in a usual way and recrystallized from a mixture of ethanol and diethyl ether to give 2-ethylamino-6-[2-(5-piperidinomethylfuran-2-yl)ethyl]benzoxazole 5/4 maleate (0.45 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:21]1[C:22]2[C:9]3([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:31](=[O:32])[CH2:30][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:3][CH2:4]4)[CH2:23][CH:16]([C:15]4[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: O=C(Cl)Cc1ccccc1
Product: O=C(Cc1ccccc1)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1

Procedure:
Using a procedure similar to that described in Example 27 except starting with 4-amino-1-[9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]piperidine (described in Example 8b) and phenylacetyl chloride, the title compound was obtained as a white solid (70%), mp 199.8°-202.1° C.; MS(CI): 423 (M+H); NMR (300 MHz,DMSO-d6): 1.37(m, 2H), 1.67(m, 2H), 2.26(m, 2H), 2.45(s, 2H), 2.93(m, 2H), 3.36(s, 2H), 3.53(m, 1H), 4.30(s, 1H), 6.91(m, 4H), 7.17-7.28(m, 9H), 7.95(d, 1H, J=8.4 Hz).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])[CH2:14][CH2:13]1)=O)(C)(C)C.[ClH:26]>C(OCC)(=O)C>[ClH:26].[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:13][CH2:14][CH:15]([C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NCCCN1CCC(c2ccccc2C#N)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1C1CCN(CCCN)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-[1-(3-tert-butoxycarbonylamino-propyl)piperidin-4-yl] benzonitrile (0.73 g, 2.1 mmol) in ethyl acetate (100 ml), cooled to 0° C. was added hydrogen chloride gas, bubbled vigorously for 5 minutes. The reaction mixture was stirred for 10 minutes at 0° C., purged with argon and concentrated. Flushing with ethyl acetate×2 and concentration gave 2-[1-(3-aminopropyl)-piperidin-4-yl]benzonitrile hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].N1C=CC=CC=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1.Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH3:16])[CH:19]=1)(=[O:26])=[O:25]
Reactant: Nc1ccc(F)cc1F
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(S(=O)(=O)Nc2ccc(F)cc2F)c1
Reaction time: 12 h

Procedure:
To 2,4-difluoro-phenylamine(42, 0.44 mL, 4.4 mmol) in methylene chloride (10.0 mL), under an atmosphere of nitrogen, were added pyridine (1.00 mL, 12.4 mmol) and 3-methoxy-benzenesulfonyl chloride (1.00 g, 4.84 mmol). After 12 hours, the reaction was poured into cold 1 M HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give light yellow solid (91, 0.90 g, 69%). MS (ESI) [M+H+]+=300.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:14][CH2:15][O:16][CH2:17][CH2:18]Cl>CS(C)=O.O.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: ClCCOCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2ccc(Cl)cc2)CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.1 %

Procedure:
To a stirred suspension of 2-(4-chlorophenyl)acetonitrile (3.06 g, 20.3 mmol) at 0° C. in DMSO (200 mL) was added NaH (1.79 g, 60% in mineral oil, 44.6 mmol). The reaction was stirred at 0° C. for 15 min then at room temperature for 30 min, resulting in a dark purple solution. To this solution was added 1-chloro-2-(2-chloroethoxy)ethane (3.18 g, 22.33 mmol) dropwise. The resulting mixture was stirred at room temperature overnight before diluting with 50 mL water and neutralizing to pH˜7.0 with 1.0 M aq. HCl. The reaction was extracted with Et2O (3×200 mL) and the combined organics were washed with brine (200 mL), dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (10-30% EtOAc/hexane eluent) to provide 4-(4-chlorophenyl)tetrahydro-2H-pyran-4-carbonitrile as a yellow crystalline solid (4.01 g, 89% yield) (Note: This compound does not ionize well on LC/MS. It does not have intense UV absorption at 220 nM. The TLC Rf is 0.6 in 30% EA/Hexane).
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:26])=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1(SC)C=CC=CC=1.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[NH2:26][C:20]1[C:19]([C:17]2[O:16][N:15]=[C:14]([CH2:13][C:12]3[CH:27]=[CH:28][C:9]([OH:8])=[CH:10][CH:11]=3)[CH:18]=2)=[CH:24][CH:23]=[C:22]([NH2:25])[N:21]=1
Reactant: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)cc3)no2)c(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 3-(3-(4-benzyloxy-benzyl)-isoxazol-5-yl)-pyridin-2,6-diamine (100 mg, 0.27 mmol) described in Example 13 in trifluoroacetic acid (3 mL) was added thioanisole (126 μl) at room temperature, which was stirred for 2 hours at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution at 0° C., which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (72.4 mg, 95%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C@@H:12]([O:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[C:26](=[O:35])[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.C(N(C(C)C)CC)(C)C.[N:45]1[CH:50]=[CH:49][C:48]([N:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)=[CH:47][CH:46]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.ClCCl>[O:35]=[C:26]1[C:25]([CH:22]2[CH2:21][CH2:20][N:19]([C:17]([O:16][C@H:12]([CH2:11][C:4]3[CH:5]=[C:6]4[C:10](=[C:2]([CH3:1])[CH:3]=3)[NH:9][N:8]=[CH:7]4)[C:13](=[O:14])[N:54]3[CH2:55][CH2:56][N:51]([C:48]4[CH:49]=[CH:50][N:45]=[CH:46][CH:47]=4)[CH2:52][CH2:53]3)=[O:18])[CH2:24][CH2:23]2)=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)O)cc2cn[nH]c12
Reactant: c1cc(N2CCNCC2)ccn1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N2CCN(c3ccncc3)CC2)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carbonyloxy)propanoic acid (50 mg, 0.11 mmol), diisopropylethylamine (37 μL, 0.21 mmol), and 1-(4-pyridyl)piperazine (34.4 mg, 2.0 equiv) in dimethylformamide (0.50 mL) and dichloromethane (0.50 mL) at 0° C. was added PyBOP® (57.6 mg, 0.11 mmol). The reaction was stirred at 0° C. for 4 h, was concentrated, and purified by column chromatography (95:5:1 to 90:10:1 dichloromethane/methanol/triethylamine). The resulting residue was dissolved in 5% methanol/dichloromethane and passed through a basic alumina column to give 53.8 mg (80%) as a white powder. 1H-NMR (CD3OD, 500 MHz) δ 1.25-2.00 (m, 4H), 2.51 (s, 3H), 2.67 (bs, 1H), 2.80-3.31 (m, 7H), 3.35-3.83 (m, 5H), 4.05-4.49 (m, 2H), 5.52 (dd, J=7.6, 7.3, 1H), 6.64 (bs, 2H), 7.12 (s, 11H), 7.22 (dd, J=7.0, 7.0, 1H), 7.32 (d, J=8.2, 1H), 7.47 (m, 1H), 7.52 (m, 1.5H), 7.62 (d, J=7.0, 11H), 7.69 (bs, 0.5H), 7.99 (s, 1H), 8.10 (m, 2H). Mass spec.: 620.28 (MH)+.
Reaction SMILES: [C:1]12([C:11]([OH:13])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([N:16](C(F)(F)C(F)C(F)(F)F)CC)C>N>[C:1]12([C:11]([NH2:16])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: CCN(CC)C(F)(F)C(F)C(F)(F)F
Agent: *CC*
Agent: N
Product: NC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
1-Adamantanecarboxylic acid (10.8 g, 0.06 mole) was added to N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine (13.4 g, 0.06 mole) contained in a wide mouth polyethylene bottle with magnetic stirring. The acid dissolved immediately during which time a highly exothermic reaction occurred. The reaction mixture was allowed to cool to room temperature and cold aqueous ammonia (250 ml) was added slowly. A heavy precipitate of the amide appeared almost immediately. After the addition was complete, the reaction mixture was stirred for about fifteen minutes. The 1-adamantanecarboxamide was collected and washed copiously with water followed by ethyl ether and dried. Yield: 10.7 g, 100%; mp 189.4-190.2° C. (Lit. mp 189° C., Stetter, et. al., Chem. Ber., 1960, 226-230). The analytical sample was recrystallized from cyclohexane and sublimed. Anal. Calcd. for C11H17NO: C, 73.76; H, 9.49; N, 7.82. Found: C, 73.67; H. 9.60; N, 7.78.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][N:10]=[C:11]3[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:18][CH2:17][C:16]1[C:11]2[C:12](=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:9][N:10]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc2c(-c3ccc(F)cc3)onc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(-c2onc3c(CBr)cccc23)cc1
Yield: 79.6 %

Procedure:
A mixture of 9.7 g (0.0427 mole) of 3-(4-fluorophenyl)-7-methyl-2,1-benzisoxazole, 7.7 g (0.0431 mole) of N-bromosuccinimide and 0.2 g of dibenzoyl peroxide in 300 ml of carbon tetrachloride was heated at reflux under floodlight illumination and under an argon atmosphere for 3.5 hr. The cooled reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 10.4 g of solid. The solid was recrystallized twice from 2-propanol to give 9.0 g (69%) of light-yellow, fluffy needles, m.p. 145°-148° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=2)[OH:24])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=1.C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40].O>C(Cl)(Cl)Cl>[C:39]([O:24][CH:23]([C:17]1[C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=[C:19]([CH3:22])[N:18]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2nccc(Oc3ccc(C)nc3C(O)c3cccc(C)n3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3C(OC(C)=O)c3cccc(C)n3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-(6-methyl-pyridin-2-yl)-methanol (43 mg) was dissolved in chloroform (6 ml) to prepare a solution. Triethylamine (0.9 ml) and acetic anhydride (0.45 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (28 mg, yield 61%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8][CH2:7]1)[CH3:2].Cl[C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([NH:12][C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)C[C@H]1CC[C@H](N)CC1
Reactant: Clc1ncccn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@H]1CC[C@H](Nc2ncccn2)CC1

Procedure:
A solution of trans-(4-Amino-cyclohexyl)-acetic acid ethyl ester (Karapavicius K., Palaima A. I., Knunyants I. L., Izv. Akad. Nauk SSSR, Ser. Khim., 1980;10;2374-9) (3.46 g, 18.7 mmol), 2-chloropyrimidine (2.14 g, 18.7 mmol) and triethylamine (5.21 mL) is refluxed in ethanol (EtOH) (10 mL) for 48 hours. The reaction is cooled, and the solvents are removed under reduced pressure. The residue is partitioned between chloroform and 2N aqueous sodium carbonate solution. The organic layer is separated, dried over sodium sulfate, and the solvents are removed under reduced pressure. The residue is chromatographed over silica gel using a mixture of chloroform and methanol to give trans-[4-(pyrimidin-2-ylamino)-cyclohexyl]-acetic acid ethyl ester.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[CH2:10][O:11][C:12](=[O:14])[CH3:13].O.CCOCC>CS(C)=O>[C:1]([CH2:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[CH2:10][O:11][C:12](=[O:14])[CH3:13])#[N:2]
Reactant: [C-]#N
Reactant: CC(=O)OCc1ccccc1CCCCl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(=O)OCc1ccccc1CCCC#N

Procedure:
With exclusion of humidity 12.5 g (0.25 mol) of dry NaCN were heated in 65 ml of anhydrous DMSO to 90°C and at this temperature 44.8 g (0.2 mol) of acetic acid-2-(3-chloropropyl)-benzyl ester were added dropwise. Then the mixture was heated for 50 minutes to 120°C and distributed after cooling between water and ether. The aqueous phase was extracted three times with ether, the organic phase was washed three times with a saturated sodium chloride solution, dried and concentrated under reduced pressure. The product boiled at 128°C/0.2 mm mercury.
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]=[CH2:21])=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:22])[NH:13]2.[H-].[Na+].[H][H].[CH2:27](Cl)[CH:28]=[C:29]([CH3:31])[CH3:30].Cl>CN(C=O)C.O>[OH:7][C:8]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]=[CH2:21])=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:22])[N:13]2[CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30]
Reactant: C=CCOc1ccc(OC2CCCCO2)c2c1NC(=O)CC2
Reactant: [H][H]
Reactant: CC(C)=CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(O)c2c1N(CC=C(C)C)C(=O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7 Grams of 5-tetrahydropyranyloxy-8-allyloxy-3,4-dihydro-2(1H)-quinolinone was dissolved in 50 ml of DMF, then 1 g of 60%-sodium hydride was added gradually in limited amounts to this solution, the reaction mixture was stirred at room temperature until generation of hydrogen gas ceased. To this reaction mixture was added 2.7 g of prenyl chloride, stirred at room temperature for 8 hours. To this mixture was added 100 ml of water and stirred, the mixture was acidified by adding concentrated hydrochloric acid, stirred at 60° C. for 1 hour to remove the tetrahydropyranyl group at 5-position. The mixture was extracted with ethyl acetate, and washed with water, dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The oily product thus obtained was purified by a silica gel column chromatography, there was obtained 4.2 g of 5-hydroxy-8-allyloxy-3,4-dihydro-1-prenyl-2(1H)-quinolinone as pale yellow oily product.
Reaction SMILES: N[CH2:2]/[CH:3]=[CH:4]/[CH:5]=[CH2:6].[CH3:7][C:8]([O:11]C)(C)[CH3:9]>>[CH2:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:7][C:8]([CH3:9])=[O:11]
Reactant: C=C/C=C/CN
Reactant: COC(C)(C)C
Product: C1CCCCC1
Product: CC(C)=O

Procedure:
Initially introduce 83.2 g (1.0 mol) of (E)-1-amino-2,4-pentadiene (title compound from Example B.2.) in 250 ml of MTBE, and add 0.1 g of 4-hydroxyanisole. Subsequently, at an internal temperature of 20-30° C., add 229.2 g (1.05 mol) of di-tert-butyl dicarbonate dissolved in 250 ml of MTBE dropwise. After addition is complete, stir at room temperature for 20 h. Concentrate the reaction 10 mixture and take up in 1 l of toluene. Add 103.0 g (1.05 mol) of maleic anhydride, and stir at an internal temperature of 60° C. for 24 h. Filter off the precipitate with suction, wash it with toluene and dry it at 50° C. to constant weight.
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([C:28]([NH:30][CH3:31])=[O:29])[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)Cl>[NH2:18][C@@H:19]([C:28]([NH:30][CH3:31])=[O:29])[CH2:20][C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22]
Reactant: CNC(=O)[C@@H](CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CNC(=O)[C@H](N)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 233.2 %

Procedure:
To a stirring solution of tert-butyl (R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(methylamino)-4-oxobutanoate (226 mg, 0.53 mmol), in DCM (1.05 mL) was added piperidine (263 μL, 2.7 mmol). The reaction mixture was stirred for 1 h at room temperature. The solvent was evaporated to afford 250 mg (100%) of tert-butyl (R)-3-amino-4-(methylamino)-4-oxobutanoate as a mixture with 1-((9H-fluoren-9-yl)methyl)piperidine. The mixture was used without purification in the next reaction. LCMS-ESI (m/z) calculated for C9H18N2O3: 202.1. found 225.1 [M+Na]+, tR=0.50 min. (Method 15).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[CH2:17]([Mg]Cl)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:8][CH2:7][C:6]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:9])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: Cl[Mg]CCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(O)(CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.83 g 4-dimethylamino-4-phenylcyclohexanone dissolved in 10 ml tetrahydrofuran were added dropwise to 21 ml 1.0 molar phenethyl magnesium chloride solution in tetrahydrofuran and the mixture was stirred overnight at ambient temperature. To work up the mixture with ice cooling, 15 ml ammonium chloride solution (20% by weight) were added, the mixture was extracted three times with 15 ml ethylacetate in each case, the extracts were combined, dried over sodium sulfate, filtered, concentrated and substantially freed of solvent residues under vacuum. The crude 4-dimethylamino-1-phenethyl-4-phenylcyclohexanol (5.75 g) obtained was obtained as a brown oil which was chromatographed with diethylether/hexane (V:V=1:1) over silica gel. 1.71 g 4-dimethylamino-1-phenethyl-4-phenylcylcohexanol were obtained in the form of yellow crystals which were dissolved in 6.8 ml 2-butanone and converted by reaction with 26 μl water and 366 μl chlorotrimethylsilane, stirring overnight with subsequent filtration into 838 mg of the corresponding hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:20]3[O:21][CH:22]=[CH:23][N:24]=3)[N:10](S(C3C=CC=CC=3)(=O)=O)[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CCO.O>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:20]3[O:21][CH:22]=[CH:23][N:24]=3)[NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1c(-c2ncco2)cc2nc(Cl)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Clc1ccc2[nH]c(-c3ncco3)cc2n1
Reaction time: 1 h

Procedure:
A solution of 5-chloro-2-(1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine (2.09 g, 5.81 mmol, from Step 2) in THF (30 mL) and EtOH (10 mL) was treated with 1.0 M NaOH in water (30 mL, 30 mmol). After stirring for 1 hour, the reaction mixture was diluted with water, and the volatile components were removed in vacuo. The aqueous mixture was extracted with three portions of EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The product was triturated in EtOAc/DCM/MeOH, and the yellow solid was isolated by filtration and air dried. Yield: (0.78 g, 61%).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:9]([CH3:22])[CH2:8]2)([O-])=O>C(O)(=O)C.O.[Zn]>[ClH:1].[ClH:1].[NH2:2][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:9]([CH3:22])[CH2:8]2
Reactant: CC1Cc2cc([N+](=O)[O-])ccc2C1NCc1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CC1Cc2cc(N)ccc2C1NCc1ccccc1
Reaction time: 0.02 h

Procedure:
To 5-nitro-2-(methyl)(phenylmethyl)aminoindane hydrochloride (1.08 g, 3.39 mmol) in 85% acetic acid/water was added zinc powder (3.0 g). The mixture was stirred for 1 minute, filtered through celite and concentrated. The concentrate was neutralized with 2N NaOH and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water, dried over magnesium sulfate, and reduced to a syrup. The oil was treated with IPA/HCl, concentrated and used immediately in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]([O:14]C)=[O:13].O[Li].O>CO.C1COCC1.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]([OH:14])=[O:13]
Reactant: COC(=O)C1OCCc2c(Br)cccc21
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1OCCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 5-bromo-3,4-dihydro-1H-isochromene-1-carboxylate (12.1 g, 42.4 mmol) in 200 mL of MeOH/THF/H2O (2/2/1) was added LiOH.H2O (5.34 g, 0.127 mol), and the mixture was stirred at ambient temperature for 30 min. The solvents were removed under vacuum, and the residue was added 100 mL of water and extracted with ether. The aqueous layer was then acidified with 4 N HCl to pH=4˜5 in ice bath, and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to afford 5-bromo-3,4-dihydro-1H-isochromene-1-carboxylic acid.