Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH2:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1F)([O-:17])=[O:16].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N+:15]([O-:17])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccccc2[N+](=O)[O-])C1
Temperature: 110 °C
Yield: 60.4 %

Procedure:
A mixture of 3(R)-amino-piperidine-1-carboxylic acid tert-butyl ester (137 mg, 0.69 mmol) and 2-nitrofluorobenzene (102 mg, 0.72 mmol), K2CO3 (100 mg) was heated at 110° C. for 12 hr. The mixture was diluted with CH2Cl2, filtered and concentrated. The residue was purified by chromatography (5% EtOAc in hexane) to give a yellow oil (134 mg, 61%). 1H-NMR (300 MHz, CDCl3) δ 8.20 (d, J=8.55 Hz, 1H, NH), 8.10 (d, J=7.20 Hz, 1H), 7.48 (t, 1H), 7.01 (d, J=8.30 Hz, 1H), 6.70 (t, 1H), 4.00 (broad, 1H), 3.75 (m, 1H), 3.60 (m, 1H), 3.20 (m, 2H), 2.10 (m, 1H), 1.82-1.60 (m, 3H), 1.43 (s, 9H) ppm; IR (film) 3357, 2967, 2935, 2858, 1692, 1620, 1572, 15508, 1423, 1372, 1266, 1230, 1154 cm−1; LRMS (calculated for C16H23N2O4) 321. found 321.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2.C([OH:20])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:20])[NH:13]2
Reactant: CCO
Reactant: Fc1cccc(-c2cccc3[nH]ccc23)c1F
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To the suspension of 4-(2,3-difluoro-phenyl)-1H-indole (2.85 g, 12.4 mmol) in t-BuOH: ethanol: acetic acid (78.5 mL: 46.5 mL: 24.13 mL) was added pyridinium tribromide (11.93 g, 37.3 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added with acetic acid (60 mL). Zinc dust (4.1 g, 62.2 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (5×), sat NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 2.32 g (76%) of 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one as an earth colored solid.
Reaction SMILES: [NH2:1][C:2](=[O:93])[CH2:3][NH:4][C:5](=[O:92])[C@@H:6]([NH:13][C:14](=[O:91])[C@@H:15]([N:17]([CH3:90])[C:18]([C@H:20]([CH2:86][C:87](O)=[O:88])[NH:21][C:22](=[O:85])[C@H:23]([CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[NH:24][C:25](=[O:77])[C@H:26]([CH:74]([CH3:76])[CH3:75])[NH:27][C:28](=[O:73])[C@H:29]([CH3:72])[NH:30][C:31](=[O:71])[C@H:32]([CH2:67][CH:68]([CH3:70])[CH3:69])[N:33]([CH3:66])[C:34](=[O:65])[CH2:35][NH:36][C:37](=[O:64])[C@H:38]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[N:39]([CH3:56])[C:40](=[O:55])[C@H:41]([CH3:54])[NH:42][C:43](=[O:53])[CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:19])[CH3:16])[CH2:7][O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[C:94]1([CH2:100][SH:101])[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=1.CC(C)N=C=NC(C)C>ClCCl.CN(C=O)C.CN(C)C1C=CN=CC=1>[NH2:1][C:2](=[O:93])[CH2:3][NH:4][C:5](=[O:92])[C@@H:6]([NH:13][C:14](=[O:91])[C@@H:15]([N:17]([CH3:90])[C:18]([C@H:20]([CH2:86][C:87](=[O:88])[S:101][CH2:100][C:94]1[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=1)[NH:21][C:22](=[O:85])[C@H:23]([CH2:78][C:79]1[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=1)[NH:24][C:25](=[O:77])[C@H:26]([CH:74]([CH3:75])[CH3:76])[NH:27][C:28](=[O:73])[C@H:29]([CH3:72])[NH:30][C:31](=[O:71])[C@H:32]([CH2:67][CH:68]([CH3:69])[CH3:70])[N:33]([CH3:66])[C:34](=[O:65])[CH2:35][NH:36][C:37](=[O:64])[C@H:38]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[N:39]([CH3:56])[C:40](=[O:55])[C@H:41]([CH3:54])[NH:42][C:43](=[O:53])[CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:50])([CH3:51])[CH3:49])=[O:19])[CH3:16])[CH2:7][O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: SCc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(=O)O)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](COC(C)(C)C)C(=O)NCC(N)=O)C(C)C)N(C)C(=O)CNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](C)NC(=O)CNC(=O)OC(C)(C)C
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(=O)SCc1ccccc1)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](COC(C)(C)C)C(=O)NCC(N)=O)C(C)C)N(C)C(=O)CNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](C)NC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
(9S,12S,18S,21S,24S,27S,30S)-30-(((S)-1-(((S)-1-((2-Amino-2-oxoethyl)amino)-3-(tert-butoxy)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamoyl)-12,27-dibenzyl-18-isobutyl-24-isopropyl-2,2,9,11,17,21-hexamethyl-4,7,10,13,16,19,22,25,28-nonaoxo-3-oxa-5,8,11,14,17,20,23,26,29-nonaazadotriacontan-32-oic acid (Compound P-145, (Boc-Gly-Ala-MePhe-Gly-MeLeu-Ala-Val-Phe-Asp-MeAla-Ser(tBu)-Gly-NH2)) (50.0 mg, 0.038 mmol) was dissolved in dichloromethane (320 μL) and DMF (80 μL), phenylmethanethiol (9.49 mg, 0.076 mmol), DIC (9.64 mg, 0.076 mmol) and N,N-dimethylpyridin-4-amine (3.54 mg, 0.029 mmol) were added and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (10 mM aqueous ammonium acetate solution:methanol) to afford the title compound (11.8 mg, 21.8%).
Reaction SMILES: CC1C=CC(S(O[N:12]=[C:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]2)(=O)=O)=CC=1.C(O)(=[O:26])C>>[O:26]=[C:13]1[NH:12][CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: CC(=O)O
Reactant: CCOC(=O)C1CCC(=NOS(=O)(=O)c2ccc(C)cc2)CC1
Product: CCOC(=O)C1CCNC(=O)CC1

Procedure:
A solution of ethyl 4-({[(4-methylphenyl)sulfonyl]oxy}imino)cyclohexanecarboxylate (22.0 g) in acetic acid (150 mL) was stirred at room temperature for 1 hr, and the reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (8.62 g).
Reaction SMILES: [S:1]([OH:5])(O)(=O)=O.S1[CH2:11][CH2:10][N:9]([C:12]2[C:21]3[C:16](=[C:17]([O:22][CH3:23])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[C:14]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:13]=2)[CH2:8][CH2:7]1.S1CCN(C2C3C(=C(OC)C=CC=3)C=C(N3CCNCC3)N=2)CC1.OO.O.O.O.Cl.C(O)(C)C>S(=O)(=O)(O)O>[O:5]=[S:1]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]3[C:16](=[C:17]([O:22][CH3:23])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[C:14]([N:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)[N:13]=2)[CH2:8][CH2:7]1
Reactant: O=S(=O)(O)O
Reactant: COc1cccc2c(N3CCSCC3)nc(N3CCNCC3)cc12
Agent: Cl
Agent: OO
Solvent: O
Solvent: CC(C)O
Product: COc1cccc2c(N3CCS(=O)CC3)nc(N3CCNCC3)cc12
Yield: 36 %

Procedure:
1-(1-Oxido--thiomorpholino)-3-piperazino-5-methoxy-isoquinoline was prepared analogous to Example 12 from 1-thiomorpholino-3-piperazino-5-methoxy-isoquinoline hemisulfate by oxidation with hydrogen peroxide in dilute sulfuric acid. M.p. of its hydrochloride trihydrate: 151°-153°C (decomposition; from isopropanol). Yield: 36% of theory.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)(C)C>[CH2:24]([NH:31][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: NCc1ccccc1
Solvent: CC(C)O
Product: CCCC(C(=O)OC)c1c(C)nc(NCc2ccccc2)nc1-c1ccc(C)cc1
Yield: 45.4 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.300 mmol), and benzylamine (0.164 mL; 1.502 mmol) were placed in a 2 mL reaction tube and dissolved in isopropanol (1.5 mL). The tube was sealed and irradiated in a microwave oven at 180° C. for 1 h. The reaction mixture was partitioned between brine and dichloromethane, filtered over a phase separator filter (1PS) and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (5-40%) in heptane to give 55 mg (33%) of the title compound as a colorless oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:17]2[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1>[Pd].C1COCC1.CO>[OH:8][C:9]1[CH:10]=[C:11]([C:17]2[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COC(=O)c1cccc(-c2ccc(OC)c(OCc3ccccc3)c2)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cccc(-c2ccc(OC)c(O)c2)n1

Procedure:
In a mixed solvent of THF-methanol, methyl 6-(3-benzyloxy-4-methoxyphenyl)pyridine-2-carboxylate was stirred in the presence of palladium/carbon under a hydrogen atmosphere to obtain methyl 6-(3-hydroxy-4-methoxyphenyl)pyridine-2-carboxylate. The obtained compound is reacted with cyclopropylmethyl bromide and potassium carbonate in DMF under heating to obtain methyl 6-(3-cyclopropylmethoxy-4-methoxyphenyl) pyridine-2-carboxylate, which was further reacted in a mixed solvent of THF-methanol under heating with adding a 1M aqueous sodium hydroxide solution to obtain an objective compound.
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[C:7]([C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[NH2:14])([CH3:10])([CH3:9])[CH3:8].N1C=CC=CC=1>C(Cl)Cl>[C:7]([C:11]1[CH:12]=[C:13]([NH:14][C:1](=[O:5])[CH:2]=[CH:3][CH3:4])[CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: C/C=C/C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC=CC(=O)Nc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 41.5 %

Procedure:
Crotonyl chloride (4.7 g, 45 mmol) in 10 ml of methylene chloride was added slowly to a stirred solution of 10 g (45 mmol) of 3,5-di-tert-butyl-4-hydroxyaniline in 50 ml of methylene chloride at 0° C. Ten minutes later 3.6 g (45 mmol) of pyridine was added and, after three hours, the mixture was filtered. The filtered soid was washed with water and triturated in ether to yield 5.4 g of N-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-butenamide having a melting point of 215°-218° C.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]2[C:19](=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[CH2:18][C@:8]1([C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]1=[O:17])[CH2:7]2.[CH3:25][Si:26]([CH3:33])([CH3:32])[CH2:27][CH2:28][O:29][CH2:30]Cl>CN(C=O)C>[I:3][C:4]1[CH:5]=[C:6]2[C:19](=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[CH2:18][C@:8]1([C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:30][O:29][CH2:28][CH2:27][Si:26]([CH3:33])([CH3:32])[CH3:25])[C:9]1=[O:17])[CH2:7]2
Reactant: O=C1Nc2ncccc2[C@@]12Cc1cc(I)c([N+](=O)[O-])cc1C2
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)[C@]2(Cc3cc(I)c([N+](=O)[O-])cc3C2)c2cccnc21
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 525 mg, 13.1 mmol) was added to a solution of (2R)-5-iodo-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step A (5.14 g, 12.6 mmol) in DMF (40 mL) at 0° C. and the mixture was stirred for 5 min. 2-(Trimethylsilyl)ethoxymethyl chloride (2.23 mL, 12.6 mmol) was then added dropwise, and the reaction mixture was stirred at 0° C. for 2 h. The reaction was quenched with dilute aqueous NaHCO3 (200 mL) and the mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound, which was of sufficient purity for use in the next step. MS: m/z=538 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.CCOC(/N=N/C(OCC)=O)=O.[CH2:41]([C:43]1[CH:65]=[CH:64][CH:63]=[CH:62][C:44]=1[NH:45][C:46]1[C:55]2[C:50](=[CH:51][C:52](O)=[C:53]([O:56][CH3:57])[CH:54]=2)[N:49]=[CH:48][C:47]=1[C:59]([NH2:61])=[O:60])[CH3:42]>C(Cl)Cl.C1COCC1>[CH2:41]([C:43]1[CH:65]=[CH:64][CH:63]=[CH:62][C:44]=1[NH:45][C:46]1[C:55]2[C:50](=[CH:51][C:52]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[C:53]([O:56][CH3:57])[CH:54]=2)[N:49]=[CH:48][C:47]=1[C:59]([NH2:61])=[O:60])[CH3:42]
Reactant: OCCN1CCNCC1
Reactant: CCc1ccccc1Nc1c(C(N)=O)cnc2cc(O)c(OC)cc12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1ccccc1Nc1c(C(N)=O)cnc2cc(OCCN3CCNCC3)c(OC)cc12
Yield: 50.4 %

Procedure:
Triphenylphosphine (0.12 g, 0.44 mmol) and 1-(2-hydroxyethyl)piperazine (25 μl, 0.22 mmol) was dissloved in CH2Cl2 and THF at −15° C. and stirred for 30 min. DEAD (70 μl, 0.44 mmol) was added dropwise at −15° C. 4-(2-ethylanilino)-7-hydroxy-6-methoxy-3-quinolinecarboxamide (0.50 g, 0.15 mmol) was suspended in THF and then added to the reaction. The reaction was stirred over night, allowing the temperature rise to ˜10° C. The solvent was removed under reduced pressure and the product was purified using preparative HPLC affording 34 mg (24%) of a clear oil.
Reaction SMILES: C(Br)CBr.Br[C:6]([CH3:8])=[CH2:7].[CH:9](=[O:15])[CH2:10][CH2:11][C:12]#[C:13][CH3:14].[Cl-].[NH4+]>O1CCCC1>[CH3:8][C:6]([CH:9]([OH:15])[CH2:10][CH2:11][C:12]#[C:13][CH3:14])=[CH2:7]
Reactant: C=C(C)Br
Reactant: CC#CCCC=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: C=C(C)C(O)CCC#CC
Temperature: 25 °C
Yield: 85 %

Procedure:
Magnesium (14.4 g, 0.6 g atom) was dried in a 250 ml flask fitted with reflux condenser, mechanical stirrer and addition funnel. After initiation of reaction under dry N2 with about one ml ethylene dibromide in 70 ml tetrahydrofuran, 36.0 g (0.30 mole) 2-bromopropene was added dropwise at such a rate as to maintain reflux without external heating. The Grignard solution was then stirred until it cooled to room temperature (30 minutes-1hour). It was then cooled further to -15° in ice-salt, and the total crude 4-hexynal from part (c) above was added dropwise over 15 minutes. The reaction mixture was stirred for 2 hours at room temperature, saturated ammonium chloride solution was added and the product was extracted with ether. There was obtained 23.50 g of 2-methyloct-1-en-6-yn-3-ol (85%, based on 4-methyl hexynoate) as a pale yellow oil.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([NH2:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](Cl)(=[O:21])[CH3:20]>>[CH:1]([N:14]1[CH2:17][CH:16]([NH:18][C:19](=[O:21])[CH3:20])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(=O)Cl
Product: CC(=O)NC1CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared from 1-benzhydryl-azetidin-3-ylamine and acetyl chloride by a procedure analogous to Example 70A. MS: 281 (MH+); HPLC Rf: 5.57 min; HPLC purity: 93%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1Br.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22].O>C(NCC)C.[Cu](I)I>[F:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20]
Reactant: CCCc1ccc(C#Cc2ccc(Br)c(F)c2)cc1
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: O
Solvent: CCNCC
Product: CCCc1ccc(C#Cc2ccc(C#C[Si](C)(C)C)c(F)c2)cc1
Yield: 63.4 %

Procedure:
33 mmol of 2-fluoro-4-[2-(4-propylphenyl)ethynyl]bromobenzene, 1.2 mmol of copper iodide and 1.2 mmol of dichlorobistriphenylphosphine palladium were dissolved in 100 ml of diethylamine and the solution was stirred under an argon stream. To the reaction solution were added dropwise 20 ml of a diethylamine solution of 50 mmol of trimethylsilylacetylene and the solution was stirred at room -temperature for 5 hours. After completion of the agitation, water was added to the reaction solution which was extracted with heptane. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a brown oily product. This product was isolated and purified by a silica gel column chromatography to afford 7 g of 1-[2-fluoro-4-[2-(4-propylphenyl)ethynyl]phenyl]-2-trimethylsilylacetylene as a colourless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1.CCCCC.[H-].[Na+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[N:13]([CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=1)[C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C1CCCc2[nH]c3c(F)cccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: O=C1CCCc2c1c1cccc(F)c1n2Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
8-Fluoro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.1416 g, 0.70 mmol) is added to a slurry of pentane-washed NaH (0.0400 g, 0.0010 mol) in DMF (2 mL) and after stirring for 30 min, p-fluorobenzyl bromide (0.11 mL, 0.88 mmol) is added. After the mixture had stirred for 2.3 h, it is partitioned between aq. sodium bicarbonate and ethyl acetate. The organic layer is dried over sodium sulfate and concentrated to dryness. The resulting solids are chromatographed on silica gel (100 mL) using first dichloromethane (100%) and then methanol/dichloromethane (2/98). The product fractions are combined and rechromatographed on silica gel (50 mL) using acetone/heptane/NH4OH (15/85/0.25) and then recrystallized using ethyl acetate/hexane to give 0.0932 g (43%) of the title compound; mp 177-178° C.; MS (ESI−) for C19H15F2NO m/z 310.1 (M−H)−; IR (drift) 1638, 1630, 1509, 1496, 1459, 1436, 1413, 1361, 1249, 1222, 1194, 1158, 1125, 830, 790 cm−1; 1H NMR (CDCl3) δ2.24, 2.58, 2.86, 5.47, 6.89-7.02, 7.16, 8.06. Anal. Calcd for C19H15F2NO: C, 73.30; H, 4.86; N, 4.50. Found: C, 73.40; H, 4.83; N, 4.50.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:25])[CH2:20][CH:19]4[O:34][CH2:35][C:36]4[CH:37]=[CH:38][C:39]5[O:44][CH2:43][CH2:42][N:41]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[C:40]=5[CH:50]=4)=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CI.[H-].[Na+].[C:55](=O)([O-])O.[Na+]>CN(C)C=O>[CH3:49][O:48][CH2:47][CH2:46][CH2:45][N:41]1[C:40]2[CH:50]=[C:36]([CH2:35][O:34][CH:19]3[CH:18]([C:15]4[CH:14]=[CH:13][C:12]([CH:11]([O:10][C:5]5[CH:6]=[CH:7][CH:8]=[C:9]6[C:4]=5[CH:3]=[CH:2][NH:1]6)[CH3:55])=[CH:17][CH:16]=4)[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH2:20]3)[CH:37]=[CH:38][C:39]=2[O:44][CH2:43][CH2:42]1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(COc4cccc5[nH]ccc45)cc3)cc21
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(C(C)Oc4cccc5[nH]ccc45)cc3)cc21
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
The solution of 0.100 g of benzyl 4-[4-(1H-indol-4-yloxymethyl)phenyl]-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 346a), 0.0424 g of methyl iodide and 1.5 ml of N,N-dimethylformamide is admixed with stirring at −10° C. with 0.012 g of sodium hydride dispersion (60%). The reaction mixture is stirred at −10° C. for 1.5 hours, then poured onto saturated aqueous sodium hydrogencarbonate solution (45 ml) and extracted with tert-butyl methyl ether (2×75 ml). The combined organic phases are washed with 75 ml of brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a violet oil from the residue. Rt=5.90.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[C:4]([CH3:13])([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:5][CH2:6][CH:7]=1.[CH3:15][Mg]Cl>C1COCC1.C1(C)C=CC=CC=1>[CH3:15][C:3]1([OH:14])[C:4]([CH3:13])([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:5][CH2:6][CH:7]=[C:2]1[CH3:1]
Reactant: C[Mg]Cl
Reactant: CC(C)=CCC1(C)CCC=C(C)C1=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)=CCC1(C)CCC=C(C)C1(C)O
Temperature: 15 °C
Reaction time: 0.75 h
Yield: 78 %

Procedure:
2,6-Dimethyl-6-(3-methyl-but-2-enyl)-cyclohexenone (245 g, 1.28 mol) was added dropwise to a solution of methyl magnesium chloride (105 g, 1.41 mol) in THF (400 ml) and toluene (1.5 L) at room temperature. The temperature rose to 50° C. The mixture was stirred for additional 45 min, was then cooled to 15° C. and poured on ice. The organic phase was separated and washed with water (0.5 L) and brine (0.5 L), dried (MgSO4) and concentrated in vacuo. The residue was distilled over a 70 cm silverplated column (bp. 83-85° C./0.1 Torr) to yield 208 g (78%) product as a mixture of two diastereomers. 1H-NMR (400 MHz, CDCl3): 5.39 (bs, 1H, 3-H), 5.29-5.24 (m, 1H, 2′-H), 2.26-2.05 (m, 2H, 2′-H), 1.98-1.88 (m, 2H, 4-H), 1.75-1.71 (m, 6H, 2-CH3, 3′-CH3), 1.63 (s, 3H, 4′-H), 1.60 (bs, 1H, O—H), 1.50-1.46 (m, 2H, 5-H), 1.24/1.23 (2s, 3H, 1a,b-CH3), 0.96/0.90 (2s, 3H, 6a,b-CH3) ppm. GC/MS (EI), Isomer a: 208 (M+, 1), 190 (20), 175 (17), 147 (56), 121 (100), 105 (46), 98 (52), 83 (45), 43 (82). Isomer b: 208 (M+, 2), 190 (8), 175 (6), 147 (58), 121 (75), 105 (46), 98 (100), 83 (52), 43 (78). IR (ATR): 3476s, 2967vs, 2922vs, 1450s, 1376s, 1073vs, 921m, 902 m cm−1.
Reaction SMILES: [I-].[I-].[CH3:3][N+:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([O:12][C:13]2[CH:30]=[CH:29][C:28]3[C@@H:27]4[C@H:18]([C@H:19]5[C@@:23]([CH2:25][CH2:26]4)([CH3:24])[C@@H:22]([O:31][C:32]([C:34]4[CH:35]=[N+:36]([CH3:40])[CH:37]=[CH:38][CH:39]=4)=[O:33])[CH2:21][CH2:20]5)[CH2:17][CH2:16][C:15]=3[CH:14]=2)=[O:11])[CH:5]=1.C1(CN2C=CC(C(N)=O)=CC2)C=CC=CC=1>C(#N)C.C(Cl)Cl>[CH3:3][N:4]1[CH:9]=[CH:8][CH2:7][C:6]([C:10]([O:12][C:13]2[CH:30]=[CH:29][C:28]3[C@@H:27]4[C@H:18]([C@H:19]5[C@@:23]([CH2:25][CH2:26]4)([CH3:24])[C@@H:22]([O:31][C:32]([C:34]4[CH2:39][CH:38]=[CH:37][N:36]([CH3:40])[CH:35]=4)=[O:33])[CH2:21][CH2:20]5)[CH2:17][CH2:16][C:15]=3[CH:14]=2)=[O:11])=[CH:5]1
Reactant: C[n+]1cccc(C(=O)Oc2ccc3c(c2)CC[C@@H]2[C@@H]3CC[C@]3(C)[C@@H](OC(=O)c4ccc[n+](C)c4)CC[C@@H]23)c1
Agent: NC(=O)C1=CCN(Cc2ccccc2)C=C1
Agent: [I-]
Solvent: CC#N
Solvent: ClCCl
Product: CN1C=CCC(C(=O)Oc2ccc3c(c2)CC[C@@H]2[C@@H]3CC[C@]3(C)[C@@H](OC(=O)C4=CN(C)C=CC4)CC[C@@H]23)=C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
One gram (1.31 mmol) of the product of Example 71 was dissolved in 100 mL of dry acetonitrile. To that solution, which was flushed with nitrogen, 0.28 g (1.31 mmol) of 1-(phenylmethyl)-4-(aminocarbonyl)-1,2-dihydropyridine was added, and the reaction mixture was stirred at 0° C. for 1 hour. Removal of the solvent under reduced pressure afforded a solid, which was suspended in methylene chloride and removed by filtration. The filtrate was chromatographed several times on a neutral alumina column prepared with methylene chloride. Purification and evaporation of the solvent in vacuo gave a solid foam. The product had the formula ##STR105## as confirmed by UV, NMR and elemental analyses.