Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][C@@H:33]([CH2:51][C@H:52]([CH2:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[C:59]([O:65][CH2:66][CH2:67][CH2:68][O:69][CH3:70])[CH:58]=1)[CH:53]([CH3:55])[CH3:54])[C@@H:34]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:35][C@@H:36]([CH:40]([CH3:42])[CH3:41])[C:37](O)=[O:38])=[O:31])([CH3:28])([CH3:27])[CH3:26].[CH2:71]([NH2:78])[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1.CCOC(C)=O>C(#N)C.CN(C=O)C>[C:25]([O:29][C:30](=[O:31])[NH:32][C@@H:33]([CH2:51][C@H:52]([CH2:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[C:59]([O:65][CH2:66][CH2:67][CH2:68][O:69][CH3:70])[CH:58]=1)[CH:53]([CH3:54])[CH3:55])[C@@H:34]([O:43][Si:44]([C:47]([CH3:48])([CH3:50])[CH3:49])([CH3:45])[CH3:46])[CH2:35][C@H:36]([C:37](=[O:38])[NH:78][CH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[CH:40]([CH3:41])[CH3:42])([CH3:26])([CH3:28])[CH3:27]
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@H](C[C@H](C(=O)O)C(C)C)O[Si](C)(C)C(C)(C)C)C(C)C)ccc1OC
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@H](C[C@H](C(=O)NCc2ccccc2)C(C)C)O[Si](C)(C)C(C)(C)C)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
HBTU (400 mg, 1.03 mmol, 1.2 equiv.) is added to a solution of (2S,4S,5S,7S)-5-tert-butoxycarbonylamino-4-(tert-butyl-dimethyl-silanyloxy)-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoic acid (575 mg, 0.86 mmol, 1.0 equiv.) in acetonitrile (CH3CN) (15 mL) and DMF (1 mL) at 0° C. After 5 minutes, a solution of benzylamine (94 μL, 0.86 mmol, 1.0 equiv.) and Net3 (1.2 mL, 8.6 mmol, 10 equiv.) in CH3CN (3 mL) is added and the reaction mixture is stirred at room temperature for 5 minutes. For workup EtOAc is added and the organic layer is washed with 1 N HCl, a saturated solution of sodium bicarbonate (NaHCO3) and brine. Drying (Na2SO4) of the organic phase and evaporation of the solvent affords the crude product which is purified by flash column chromatography [50 g SiO2, hexane:EtOAc (4:1)] to afford the desired product as a colorless foam. MS (LC-MS): 780.4 [M+Na]+; Rf [hexane:EtOAc (1:1)]: 0.65 minutes.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][CH2:9][CH2:10][CH2:11]O)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[I:33]C>C(#N)C.C(OCC)C>[CH2:13]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:20])[CH2:8][CH2:9][CH2:10][CH2:11][I:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N(CCCCO)Cc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N(CCCCI)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
To a solution of benzyl-(4-hydroxy-butyl)-carbamic acid tert butyl ester (6.06 g 21.7 mmol) in acetonitrile (25 mL), carbonyldiimidazole (3.52 g 21.7 mmol) and iodomethane (6.8 mL 109 mmole) were added. The reaction mixture became lukewarm and was stirred for an hour at room temperature followed by another 2 h under reflux. The reaction mixture was allowed to cool to room temperature and additional iodomethane (6.8 mL) was added and the reaction was refluxed for an additional hour. The reaction mixture was allowed to cool to room temperature and was diluted with diethyl ether (150 mL) resulting in a white suspension that was washed with of water (100 mL). The organic layer was washed successively with, 1N HCl (50 mL), saturated NaHCO3 (50 mL), 5% Na2S2O3 (50 mL), and brine. The organic layer was dried on Na2SO4 and the resulting yellow oil crude was purified by flash chromatography using a 95:5 mixture of ethyl acetate-petroleum ether as eluent to give N-benzyl-N-(t-butoxycarbonyl)-4-amino-1-iodobutane (4.49 g, 53%) as colorless, viscous oil. 1H NMR (CDCl3) δ 7.24-7.35 (m, 5H); 4.42 (bs, 2H); 3.19 (bs, 4H); 1.76 (bs, 2H); 1.6 (bs, 2H); 1.51 (s, 9H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])(OCC)=O.Cl.NC1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]1>O>[OH:31][C@H:28]1[CH2:29][CH2:30][C@H:7]([N:12]2[C:13](=[O:22])[C:14]3[C:15](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:17])[CH2:26][CH2:27]1
Reactant: NC1CCC(O)CC1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](O)CC1
Reaction time: 0.5 h

Procedure:
Potassium carbonate (1.64 g, 11.9 mmol) and N-carboethoxyphthalimide (1.59 g, 7.25 mmol) were added to a solution of 4-aminocyclohexanol hydrochloride (1.0 g, 6.59 mmol) in water (15 ml) at room temperature and stirred for 30 minutes. The reaction solution was filtered and the resulting precipitate was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=2/1) to obtain trans-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (823 mg, 51%).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:41][CH2:42][CH2:43][O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1>CN(C)C=O>[CH3:1][N:2]([CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)[CH2:41][CH2:42][CH2:43][O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1
Reactant: BrCCCOC1CCCCO1
Reactant: CNC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)CCCOC3CCCCO3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a solution of 5-methylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.5 g) in dimethyformamide (20 ml) are added potassium carbonate (0.6 g), potassium iodide (0.72 g) and 2-(3-bromopropyloxy)-3,4,5,6-tetrahydro-2H-pyrane (0.97 g) and the mixture is stirred at room temperature overnight. The reaction solution is concentrated and to the resulting residue is added water. The mixture is extracted three times with dichloromethane. The extract is washed with saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane→dichloromethane:methanol=50:1) to give 5-{N-methyl-N-[3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propyl]amino}-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.3 g) as colorless amorphous.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8]Br)(=O)C.[CH2:10]([NH:17][C:18](=[O:40])[N:19]([C:21]1[CH:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:29][C:28]=2[OH:39])[CH:24]=[CH:25][CH:26]=1)[CH3:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:10]([NH:17][C:18](=[O:40])[N:19]([C:21]1[CH:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:29][C:28]=2[O:39][CH2:8][CH2:7][CH2:6][CH2:5][OH:4])[CH:24]=[CH:25][CH:26]=1)[CH3:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(=O)OCCCCBr
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCCO)c1
Yield: 87.4 %

Procedure:
In a manner similar to that of Example (25a), by reaction of 500 μL (3.45 mmol, 4.9 eq) of 4-bromobutyl acetate and 300 mg (0.7 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f) in 6 ml of methyl ethyl ketone in the presence of 500 mg (3.61 mmol, 5.1 eq) of potassium carbonate at 80° C. for 15 hours, 305 mg of methyl 3-[3′-(3-heptyl-1-methylureido)-2-(4-hydroxybutoxy)biphenyl-4-yl]propanoate are obtained in oil form. Yield=80%
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=3)=[CH:24][N:23]=2)=[CH:18][CH:17]=1)[C:3]([NH:5][C@H:6]([CH3:14])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4].[C:42]([C:46]1[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][CH:47]=1)([CH3:45])([CH3:44])[CH3:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[C:42]([C:46]1[CH:47]=[CH:48][C:49]([C:50]([NH:1][C@@H:2]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=4)=[CH:24][N:23]=3)=[CH:18][CH:17]=2)[C:3]([NH:5][C@H:6]([CH3:14])[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])=[O:4])=[O:51])=[CH:53][CH:54]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](N)C(=O)N[C@H](C)C(=O)OC(C)(C)C)cc3)nc2)cc1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)N[C@H](C)C(=O)OC(C)(C)C)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
Prepared using General Procedure 7. A stirred solution of (R)-tert-butyl 2-((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)propanoate (122 mg, 0.218 mmol), 4-(tert-butyl)benzoic acid (38.8 mg, 0.218 mmol) and TEA (60.7 μl, 0.435 mmol) in DMF (4 mL) was cooled to 0° C. and HATU (87 mg, 0.228 mmol) was slowly added over 5 minutes. The reaction was stirred at room temperature for 2 h, then diluted with EA (100 mL), washed with saturated aqueous NaHCO3 (100 mL) and brine (100 mL). The solvent was dried over MgSO4 and removed. The crude product was purified by chromatography 0-30% ACN in DCM to afford 123 mg (78%) of (R)-tert-butyl 2-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)propanoate as a white solid. LCMS-ESI (m/z) calculated for C44H56N4O5: 720.4; no m/z observed, tR=3.47 min (Method 11).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2].[OH:14]OS([O-])=O.[K+].O.Cl>CN(C=O)C.CCOC(C)=O>[CH3:11][O:10][C:8]([C:7]1[CH:12]=[C:3]([CH:4]=[CH:5][C:6]=1[CH3:13])[C:1]([OH:14])=[O:2])=[O:9]
Reactant: COC(=O)c1cc(C=O)ccc1C
Reactant: O=S([O-])OO
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(=O)O)ccc1C
Temperature: 25 °C
Reaction time: 16.75 h

Procedure:
A mixture of 268 mg of the methyl 5-formyl-2-methylbenzoate and 1.08 g (1.76 mmol) of Oxone in 6 mL of DMF was stirred at r.t. for 16.75 h. Water, 1N HCl, and EtOAc were added, and the aqueous layer was extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated, and 3-(methoxycarbonyl)-4-methylbenzoic acid, which was used for the next reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:22]([C:13]1[CH:14]=[C:15]([C:18]([F:19])([F:20])[F:21])[CH:16]=[CH:17][C:12]=1[O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])#[N:23]
Reactant: N#Cc1cc(C(F)(F)F)ccc1Cl
Reactant: O=C(O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(F)(F)F)ccc1Oc1cccc(C(=O)O)c1
Reaction time: 65 h
Yield: 39.1 %

Procedure:
3-Hydroxybenzoic acid (27.6 g), 4-chloro-3-cyanobenzotrifluoride (41.1 g) and anhydrous potassium carbonate (55.2 g) were stirred together for 71/2 hours at 100° C. in dry dimethylformamide (500 ml) and then left at room temperature for 65 hours. The solvent was then removed under reduced pressure and the residue taken up in water and acidified with dilute hydrochloric acid. The solid which separated was washed with water, dissolved in ether and the solution dried and concentrated. The colourless solid which separated was recrystallised to give the benzoic acid derivative (24.0 g) with a melting point of 224°-226° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1>C1(C)C=CC=CC=1.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>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[N:3][CH:4]=1
Reactant: Cc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccn2)nc1
Yield: 193 %

Procedure:
A solution of 2-(tributyltin)pyridine (9.20 g, 25 mmol) and 2-bromo-5-methylpyridine (4.3 g, 25 mmol) in toluene was bubbled with argon gas for 10 min. The catalyst Pd(PPh3)4 (0.29 g, 0.25 mmol, 1 mol %) was added and the mixture was refluxed under argon atmosphere for 3 days. Removal of solvent gave an oil that was purified by chromatography over silica gel eluted with CH2Cl2 and then EtOAc. The brown liquid obtained was dried overnight under high vacuum providing 4.1073 g of 5-methyl-[2,2′]bipyridinyl as a brown liquid (24.13 mmol, yield 96.5%). 1H NMR (CDCl3, 300.16 MHz) δ (ppm) 8.66 (ddd, J=4.8, 1.8 & 0.9 Hz, 1H), 8.51 (dt, J=2.9 & 0.7 Hz, 1H), 8.35 (dt, J=8.0 & 1.1 Hz, 1H), 8.28 (d, J=8.1 Hz, 1H), 7.80 (td, J=7.7 & 1.8 Hz, 1H), 7.63 (ddd, J=8.1, 1.5 & 0.7 Hz, 1H), 7.28 (ddd, J=7.5, 4.8 & 1.2 Hz, 1H) and 2.39 (s, 3H). MS (ESI) m/z: 171 (M+1)+ and (2M+23)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[CH:15]1([C:18](Cl)=[O:19])[CH2:17][CH2:16]1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:18]([CH:15]1[CH2:17][CH2:16]1)=[O:19]
Reactant: O=C(Cl)C1CC1
Reactant: OCCCCCCCCCCCCBr
Product: O=C(OCCCCCCCCCCCCBr)C1CC1

Procedure:
In an analogous manner to that described in Example 2, from 12-bromododecan-1-ol and cyclopropane carboxylic acid chloride there is obtained cyclopropane carboxylic acid 12-bromododecyl ester of melting point 29°-31° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]3[C:20]4[CH2:29][N:28]([C:30]([CH:32]5[CH2:36][CH2:35][NH:34][CH2:33]5)=[O:31])[CH2:27][CH2:26][C:21]=4[N:22]([CH3:25])[C:23]=3[CH:24]=2)[C:12](=[O:37])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:38]CN(CC)CC.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]3[C:20]4[CH2:29][N:28]([C:30]([CH:32]5[CH2:36][CH2:35][N:34]([CH3:38])[CH2:33]5)=[O:31])[CH2:27][CH2:26][C:21]=4[N:22]([CH3:25])[C:23]=3[CH:24]=2)[C:12](=[O:37])[CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(C(=O)C1CCNC1)CC2
Reactant: CCN(CC)CC
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CO
Product: CN1CCC(C(=O)N2CCc3c(c4ccc(-n5ccc(OCc6ccccc6)cc5=O)cc4n3C)C2)C1
Temperature: 25 °C
Yield: 61.3 %

Procedure:
To a solution of 4-(benzyloxy)-1-(5-methyl-2-(pyrrolidine-3-carbonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one hydrochloride (105 mg, 0.197 mmol) in CH3OH (3 mL) was added Et3N (40 μL, 0.29 mmol), formaldehyde (23 μL, 0.29 mmol), and NaBH(OAc)3 (86 mg, 0.41 mmol). The reaction mixture was stirred at room temperature until the reaction was complete. Then the mixture was concentrated and the residue was dissolved in CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered and concentrated. Purification by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) gave 4-(benzyloxy)-1-(5-methyl-2-(1-methylpyrrolidine-3-carbonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (60 mg, 60%) as a yellow solid. The free base was converted to the HCl salt to give the title compound (43 mg, 80%) as a yellow solid and as a mixture of rotamers: mp 132-136° C.; 1H NMR (500 MHz, CD3OD) δ 7.61-7.33 (m, 8H), 7.02-6.98 (m, 1H), 6.29-6.27 (m, 1H), 6.12-6.11 (m, 1H), 5.17 (s, 2H), 4.79-4.76 (m, 2H), 4.09-3.97 (m, 2H), 3.81-3.79 (m, 1H), 3.69-3.67 (m, 4H), 3.49-3.42 (m, 1H), 3.22-3.16 (m, 2H), 3.00 (m, 1H), 2.92-2.91 (m, 1H), 2.81-2.78 (2×s, 3H), 2.52-2.36 (m, 1H), 2.18-2.00 (m, 1H); ESI MS m/z 497 [M+H]+; HPLC (Method B) 98.7% (AUC), tR=13.6 min.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][C:14]3[N:15]=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[O:17][C:18]=3[CH3:19])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[C:26]([O:28][CH3:29])=[O:27]>ClCCl>[CH3:19][C:18]1[O:17][C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:15][C:14]=1[CH2:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:2]=[C:3]([C:26]([O:28][CH3:29])=[O:27])[CH2:4][CH2:5]2
Reactant: COC(=O)C1CCc2cc(OCc3nc(-c4ccccc4)oc3C)ccc2C1O
Solvent: ClCCl
Product: COC(=O)C1=Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
Boron trifluoride diethyl ether complex (4.14 g) was added dropwise to a solution of methyl 1-hydroxy-6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1,2,3,4-tetrahydronaphthalene-2-carboxylate (5.46 g) in dichloromethane (200 ml) at 0° C. The mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was washed with water, dried over magnesium sulfate, and concentrated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform gave methyl 6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3,4-dihydronaphthalene-2-carboxylate (4.30 g, 83%). This product was recrystallized from dichloromethane-isopropyl ether. Colorless prisms, mp: 130-131° C.
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]2[C:5]([C:6]([F:21])([F:20])[CH2:7][CH2:8][C@@:9]32[C:14]([F:16])([F:15])[CH2:13][O:12][C:11]([NH2:17])=[N:10]3)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][CH:33]=[C:34]([CH:37]=2)[C:35]#[N:36])O1>>[NH2:17][C:11]1[O:12][CH2:13][C:14]([F:16])([F:15])[C@@:9]2([C:18]3[C:5](=[CH:4][CH:3]=[C:2]([C:30]4[CH:31]=[N:32][CH:33]=[C:34]([CH:37]=4)[C:35]#[N:36])[CH:19]=3)[C:6]([F:21])([F:20])[CH2:7][CH2:8]2)[N:10]=1
Reactant: NC1=N[C@@]2(CCC(F)(F)c3ccc(Br)cc32)C(F)(F)CO1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Product: N#Cc1cncc(-c2ccc3c(c2)[C@@]2(CCC3(F)F)N=C(N)OCC2(F)F)c1
Yield: 51 %

Procedure:
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-7-bromo-4,4,5′,5′-tetrafluoro-3,4,5′,6′-tetrahydro-2H-spiro[naphthalene-1,4′-[1,3]oxazin]-2′-amine (intermediate A6.4) with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile yielded the title compound (51% yield) as a yellow solid. MS (ISP): m/z=390.3 [M]+.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][C:6]=1[C:7](=[O:21])/[C:8](=[N:13]/[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[C:9]([O:11][CH3:12])=[O:10].[H-].[Na+]>C1COCC1>[N:23]1([CH2:22][C:4]2[S:3][C:2]3[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7](=[O:21])[C:6]=3[CH:5]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: COC(=O)/C(=N\Nc1ccccc1)C(=O)c1cc(CN2CCOCC2)sc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1nn(-c2ccccc2)c2sc(CN3CCOCC3)cc2c1=O
Reaction time: 8 h
Yield: 15.6 %

Procedure:
To a solution of methyl (2Z)-3-(2-chloro-5-(4-morpholinylmethyl)-3-thienyl)-3-oxo-2-(phenylhydrazono)propanoate (Preparation 65, 2.67 g) in dry THF (150 mL) is added NaH (0.43 g; 60% dispersion in mineral oil) portionwise at ambient temperature. The reaction is continued overnight and the solvent is removed in vacuo. Water (50 mL) is added to residue and the aqueous layer is extracted with EtOAc (3×50 mL). The organic layer is separated, dried over MgSO4, filtered, and concentrated in vacuo. The resulting precipitate is filtered to afford 0.38 g (16%) of the title compound as a brown solid. Physical characteristics: m.p. 167-169° C.; 1H NMR (400 MHz, CDCl3) δ7.67, 7.57, 7.43, 3.98, 3.68, 2.50; IR (diffuse reflectance) 2816, 1731, 1615, 1515, 1353, 1279, 1200, 1172, 1133, 1121, 1106, 1026, 867, 809, 749 cm−1; MS (ESI+) 386; HRMS (FAB) m/z 386.1180 (C19H19N3O4S+H). Anal. Found: C, 59.14; H, 5.02; N, 10.48.
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:20][CH2:21][CH3:22])=[N:9]1)C1C=CC=CC=1.C(O)C>[C].[Pd].C(O)=O>[CH2:21]([O:20][C:10]1[C:11]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][NH:8][N:9]=1)[CH3:22]
Reactant: CCOC(=O)CCc1cn(Cc2ccccc2)nc1OCC
Agent: [Pd]
Solvent: CCO
Solvent: O=CO
Product: CCOC(=O)CCc1c[nH]nc1OCC
Yield: 71.9 %

Procedure:
A mixture of ethyl 3-(1-benzyl-3-ethoxy-1H-pyrazol-4-yl)propionate (21.20 g), 5% palladium-carbon (40.00 g), ethanol (200 ml), and formic acid (100 ml) was refluxed for one hour. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was dissolved in ethyl acetate, which was washed with saturated aqueous sodium bicarbonate and then with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (10.70 g, yield: 72%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.ClC1C=C([N:16]2N=[N:19][C:18]([C:21]([OH:23])=[O:22])=[N:17]2)C=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[N:16]=[N:17][C:18]([C:21]([OH:23])=[O:22])=[N:19]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1nnn(-c2cccc(Cl)c2)n1
Reactant: Nc1cccc(F)c1
Product: O=C(O)c1nnn(-c2cccc(F)c2)n1

Procedure:
This intermediate was prepared from 3-fluoro-phenylamine in four steps according to the preparation of 2-(3-chloro-phenyl)-2H-tetrazole-5-carboxylic acid.
Reaction SMILES: C(O[C:5]1([CH3:16])[CH2:9][O:8][C:7](=[O:10])[CH:6]1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[CH3:16][C:5]1[CH2:9][O:8][C:7](=[O:10])[C:6]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCC1C(=O)OCC1(C)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: CCCCCC1=C(C)COC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.2 %

Procedure:
4-Acetoxy-4-methyl-3-pentyl-tetrahydrofuran-2-one (125.33 g, 549 mmol) is placed with 2.61 g (13.7 mmol) of p-toluenesulphonic acid and held at 150° C. for 4 hours while stirring. The acetic acid which is cleaved off is distilled off over a Vigreux column. The reaction solution, cooled to room temperature, is diluted with 500 ml of ether and washed in a separating funnel with 2×200 ml of sat. NaCl solution. Drying of the ether phase over MgSO4 and concentration on a rotary evaporator as well as distillation at 100°-103° C./0.12 mbar yields 71.34 g (77.3%) of 4-methyl-3-pentyl-2(5H)furanone.