Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]#[N:12].[CH2:13]([Mg]Br)[CH3:14]>C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[CH2:10][C:11]1([NH2:12])[CH2:14][CH2:13]1
Reactant: N#CCC1Cc2ccccc2C1
Reactant: CC[Mg]Br
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Product: NC1(CC2Cc3ccccc3C2)CC1
Yield: 66.2 %

Procedure:
By using 2,3-dihydro-1H-inden-2-yl acetonitrile (157 mg, 1.00 mmol) described in WO 1998/005651, ethyl magnesium bromide (3 M diethyl ether solution, 0.67 mL, 2.00 mmol), tetraisopropoxy titanium (0.33 mL, 1.10 mmol), and trifluoroborane-diethyl ether complex (0.25 mL, 2.00 mmol), the reaction was carried out in the same manner as the method described in J. Org. Chem. 2002, 67, 3965 to give the title compound as a white solid (124 mg, yield 66%).
Reaction SMILES: C([O:8][C:9](=[O:40])[CH2:10][NH:11][C:12]([C:14]1[N:15]=[C:16]([CH3:39])[C:17]2[C:22]([C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:21][CH:20]=[C:19]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:18]=2)=[O:13])C1C=CC=CC=1.[OH-].[K+]>CCO>[CH2:25]([O:24][C:23]1[C:22]2[C:17](=[CH:18][C:19]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:20][CH:21]=2)[C:16]([CH3:39])=[N:15][C:14]=1[C:12]([NH:11][CH2:10][C:9]([OH:40])=[O:8])=[O:13])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1nc(C(=O)NCC(=O)OCc2ccccc2)c(OCc2ccccc2)c2ccc(Oc3ccccc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(C(=O)NCC(=O)O)c(OCc2ccccc2)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.1 %

Procedure:
A mixture of [(4-benzyloxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid benzyl ester (160 mg, 0.3 mmol; Example D-81 d), KOH (325 mg, 5 mmol) and EtOH (10 ml) was stirred at ambient temperature for 18 h before the solvent was evaporated in vacuo. To the residue was added water (5 ml) and the mixture was washed with Et2O (2×20 ml). Then the solution was acidified by addition of aqueous 6N HCl and extracted with EtOAc (2×20 ml). The combined organic phases were dried over MgSO4 and concentrated in vacuo to give the title compound as a tan gum (93 mg); MS-(+)-ion: M+1=443.0.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])[CH:8]=2)[N:3]=1.[BH4-].[Na+].C(=O)(O)[O-]>C(Cl)Cl.CO>[NH2:1][C:2]1[C:11]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[CH:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[OH:26])[CH:8]=2)[N:3]=1
Reactant: Cc1cccc(C(=O)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc(C(O)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 25 °C

Procedure:
(2-(2-Amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(phenyl)methanone (0.152 g, 0.359 mmol) was dissolved in a mixture of DCM (4.0 mL) and MeOH (5.0 mL). Sodium borohydride (0.041 g, 1.077 mmol) was added to the mixture in three portions (each portion added at 3 h intervals) and the mixture was stirred at ambient temperature. The mixture was treated with DCM (10 mL) and saturated aqueous bicarbonate (10 mL) and stirred for 20 min. The phases were separated and the organic layer was concentrated to afford a yellow solid (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(phenyl)methanol which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C(=O)(O)[O-].[Na+].O>[C:19]1([C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9]3([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:12][CH2:11][CH2:10]3)=[N:6][CH:7]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc(NC2(c3ccccc3)CCC2)nc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(-c2ccc(NC3(c4ccccc4)CCC3)nc2)cc1
Temperature: 140 °C
Yield: 26.4 %

Procedure:
To a 3 mL microwave reaction vessel was added 5-bromo-N-(1-phenylcyclobutyl)pyridin-2-amine (102 mg, 340 μmol, 1.0 equiv), phenylboronic acid (59 mg, 505 μmol, 1.5 equiv), Cl2Pd(dppf) (25 mg, 34 μmol, 0.1 equiv), potassium carbonate (116 mg, 842 μmol, 2.5 equiv), dioxane (1 mL) and water (500 μL). The reaction was heated in a microwave reactor at 140° C. for 20 min and then diluted with saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (10% EtOAc/hexanes), affording 27 mg of 5-phenyl-N-(1-phenylcyclobutyl)pyridin-2-amine as a white solid (m/z [M+H]=301.2).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=12.[K+].[Br-:13]>>[Br:13][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]2=[N:1][CH:2]=1
Reactant: [Br-]
Reactant: O=Cc1cccn2ccnc12
Agent: [K+]
Product: O=Cc1cccn2c(Br)cnc12

Procedure:
From 4a (yield: 35%); mp 104-106° C.; IR (KBr) 1694, 1186 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.09 (t, 1H J=7 Hz), 7.74 (s, 1H), 7.86 (d, 1H, J=7 Hz), 8.32 (d, 1H, J=7 Hz), 10.66 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 96.4, 112.9, 124.2, 127.1, 128.5, 134.6, 144.2, 188.2; MS m/z 226 (M++2, 45), 224 (M+, 46), 198 (99), 196 (100), 117 (76), 90 (54), 63 (30).
Reaction SMILES: C(C1(CCCCCCCC)C2C=CC=CC=2C2C1=CC=CC=2)CCCCCCC.[C:30]1([O:36][CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[CH3:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1OC.[CH2:48]1[N:53]([N+:54]([O-:56])=[O:55])[CH2:52][N:51]([N+:57]([O-:59])=[O:58])[CH2:50][N:49]1[N+:60]([O-:62])=[O:61].[CH2:63]([O:80][N+:81]([O-:83])=[O:82])[C:64]([CH2:75][O:76][N+:77]([O-:79])=[O:78])([CH2:70][O:71][N+:72]([O-:74])=[O:73])[CH2:65][O:66][N+:67]([O-:69])=[O:68]>C1COCC1.C(#N)C>[C:30]1([O:36][CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[CH2:50]1[N:49]([N+:60]([O-:62])=[O:61])[CH2:48][N:53]([N+:54]([O-:56])=[O:55])[CH2:52][N:51]1[N+:57]([O-:59])=[O:58].[CH2:75]([O:76][N+:77]([O-:79])=[O:78])[C:64]([CH2:65][O:66][N+:67]([O-:69])=[O:68])([CH2:63][O:80][N+:81]([O-:83])=[O:82])[CH2:70][O:71][N+:72]([O-:74])=[O:73].[N+:54]([C:43]1[CH:44]=[CH:45][C:40]([O:39][CH3:38])=[CH:41][CH:42]=1)([O-:56])=[O:55]
Reactant: COc1ccccc1OC
Agent: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccccc21
Agent: O=[N+]([O-])N1CN([N+](=O)[O-])CN([N+](=O)[O-])C1
Agent: O=[N+]([O-])OCC(CO[N+](=O)[O-])(CO[N+](=O)[O-])CO[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: COc1ccccc1
Solvent: CC#N
Product: COc1ccc([N+](=O)[O-])cc1
Yield: 1 %

Procedure:
To probe the scope of the photonitration reaction, the nitration of 9,9-dioctylfluorene, anisole and 1,2-dimethoxybenzene by RDX and PETN was investigated. Extended photolysis (5 h) of a mixture of 9,9-dioctylfluorene and either RDX or PETN in 1:1 acetonitrile:THF at either 254, 313, 334, or 356 nm did not generate any observable products and 9,9-dioctylfluorene was recovered in ca. 90% yield. Photolysis of anisole with RDX or PETN yielded only trace amounts of 4-nitroanisole (<1% GC yield) after 4 hours. Photolysis of 1,2-dimethoxybenzene with either RDX or PETN yielded 1,2-dimethoxy-4-nitrobenzene in only ca. 8% yield after 2 hours; moreover this reaction did not proceed cleanly and numerous polar photoproducts were observed. Based on this set of experiments, anilines were selected as candidates for potential indicators. To create fluorogenic indicators based on the facile nitration reaction between aromatic amines and the photofragmentation products of RDX and PETN, 9,9-disubstituted 9,10-dihydroacridines (DHAs) were targeted as chemosensory.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[C:18]([OH:20])=[O:19].[CH2:21]1C[O:24][CH2:23][CH2:22]1.C(Cl)(=O)CC>N1C=CC=CC=1>[C:12]1([C:7]2[CH:6]=[C:5]([C:18]([OH:20])=[O:19])[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:23](=[O:24])[CH2:22][CH3:21])[CH:3]=3)[N:8]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1CCOC1
Reactant: Nc1ccc2nc(-c3ccccc3)cc(C(=O)O)c2c1
Agent: CCC(=O)Cl
Solvent: c1ccncc1
Product: CCC(=O)Nc1ccc2nc(-c3ccccc3)cc(C(=O)O)c2c1

Procedure:
6-amino-2-phenylquinoline-4-carboxylic acid (378 mg, 1.4 mmol) was suspended in pyridine (0.2 mL) and anhydrous THF (25 mL), and propionyl chloride (370 mg, 4 mmol) was added dropwise to the suspension with vigorous stirring. After reflux for 1.5 hours, the reaction solution was concentrated to approximately 10 mL. To the residue, ethyl acetate was added, and the deposited precipitate was collected by filtration and washed with water and ethyl ether. The crystal was recrystallized from glacial acetic acid to obtain the title compound (362 mg, 1.13 mmol) as a yellow powder.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@:7]1([NH:12][C:13]([C@@H:15]2[CH2:19][C@@H:18]([OH:20])[CH2:17][NH:16]2)=[O:14])[CH2:9][C@H:8]1[CH:10]=[CH2:11])=[O:6])[CH3:3].[CH2:21]([O:24][CH2:25][CH2:26][CH2:27][C@H:28]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:29](O)=[O:30])[CH:22]=[CH2:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.C(#N)C.O.C(OCC)(=O)C>[CH2:21]([O:24][CH2:25][CH2:26][CH2:27][C@H:28]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:29]([N:16]1[CH2:17][C@H:18]([OH:20])[CH2:19][C@H:15]1[C:13]([NH:12][C@:7]1([C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:9][C@H:8]1[CH:10]=[CH2:11])=[O:14])=[O:30])[CH:22]=[CH2:23]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1)C(=O)OCC
Reactant: C=CCOCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C=CCOCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1R,2S)-ethyl-1-((2S,4R)-4-hydroxypyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate hydrochloride salt (WO2005095403) (2.44 g, 7.76 mmol), (S)-5-(allyloxy)-2-(tert-butoxycarbonylamino)-pentanoic acid (WO2004094452) (2.02 g, 7.39 mmol) and HATU (3.09 g, 8.13 mmol) in toluene (36 mL) and ACN (4 mL) was added DIEA (2.58 mL, 14.78 mmol) at 0° C. The reaction warmed to rt and stirred at rt for 1 hr. Ethyl acetate (30 mL) and water (20 mL) was added. The organic layer was separated and washed with brine, dried over sodium sulfate. After removal of solvent, the residue was purified by chromatography (Ethyl acetate) to give (1R,2S)-ethyl 1-((2S,4R)-1-((S)-5-(allyloxy)-2-(tert-butoxycarbonylamino)pentanoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate as white wax solid (3.55 g, 92%). MS: Calcd.: 523; Found: [M+H]+ 524.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[CH:10]=[N:11][N:12]([CH:19]3[CH2:21][CH2:20]3)[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([Cl:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1>CCOC(C)=O>[Cl:32][C:26]1[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=[C:24]([NH:23][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[CH:10]=[N:11][N:12]([CH:19]3[CH2:21][CH2:20]3)[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:25]=1
Reactant: Cn1cc(N)cc(Cl)c1=O
Reactant: CCOC(=O)c1c(C(O)c2ccc(Cl)cc2)cnn1C1CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C(Nc2cc(Cl)c(=O)n(C)c2)c2ccc(Cl)cc2)cnn1C1CC1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-cyclopropyl-1H-pyrazole-5-carboxylate (Step 34.3) and 5-amino-3-chloro-1-methylpyridin-2(1H)-one (Step 5.2). tR: 5.04 min (HPLC 1); tR: 1.13 min (LC-MS 2); ESI-MS: 461 [M+H]+ (LC-MS 2); Rf=0.47 (EtOAc).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11]([O:14][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][CH:16]1Br)(=[O:13])[CH3:12]>C(Cl)Cl.C(#N)C.[N-]1C=CN=C1.[Ag+].[Cl-].[Zn+2].[Cl-]>[C:11]([O:14][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@H:16]1[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:10])[CH3:9])[CH:3]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Br)[C@@H]1OC(C)=O
Agent: [Ag+]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(C(C)=O)c1
Yield: 13.8 %

Procedure:
If the procedure described in Preparation LXXXIII is followed starting from 3.45 g (25.3.10-3 mol) of 1-(3-hydroxyphenyl)ethanone, 6 g (16.9.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide, 3 g (17.10-3 mol) of silver imidazolate and 4.6 g (33.7.10-3 mol) of zinc chloride in 90 ml of methylene chloride and 30 ml of acetonitrile, 0.96 g (yield: 14%) of the expected product is obtained after purification by chromatography on silica gel using a toluene/ethyl acetate mixture (6/1 v/v) as the eluent, and crystallization from ether.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CCO>[C:1]([C:5]1[N:6]=[CH:7][C:8]([CH2:9][OH:10])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
6-tert-Butylnicotinaldehyde (363.0 mg, 2.22 mmol) was dissolved in EtOH (20 ml). NaBH4 (193.5 mg, 5.12 mmol) was added. The mixture was stirred at r.t. for 1.0 h. The solvent was removed under reduced pressure. The residue was suspended in aqueous Na2CO3 and the product extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered and concentrated yielding 311.5 mg the title compound as a colourless oil (85%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][C:12]([C:14]([O:16]CC)=[O:15])=[CH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].S([O-])(O)(=O)=O.[K+]>C(O)C>[C:4]([O:3][C:1]([N:8]1[CH2:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:5])[CH3:6]
Reactant: CCOC(=O)C1=CCCN(C(=O)OC(C)(C)C)C1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC=C(C(=O)O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In 5 ml of ethanol, 2.5 g of N-Boc-5-ethoxycarbonyl-1,2,3,6-tetrahydropyridine was dissolved, and 10 ml of a 1M aqueous solution of sodium hydroxide was added thereto. The reaction mixture was stirred for 4 hours at room temperature, and subsequently, a 5% aqueous solution of potassium hydrogensulfate was added thereto for acidification. The reaction mixture, was extracted with ethyl acetate. The extract was washed with saturated brine, and was subsequently dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure to yield crystals of crude 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-5-carboxylic acid. The obtained crude 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-5-carboxylic acid was dissolved in a mixed solution of 15 ml of chloroform and 2 ml of dimethylformamide, and subsequently, 1.6 g of 1-hydroxybenzotriazole hydrate and 2.0 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added thereto. The reaction mixture was stirred for 30 minutes at room temperature, and was subsequently ice-cooled. 28% aqueous ammonia in an amount of 0.64 ml was added thereto, and the reaction mixture was stirred for 1 hour. The reaction mixture was warmed up to room temperature, and subsequently concentrated under reduced pressure. A 5% aqueous solution of potassium hydrogencarbonate was poured thereinto. The reaction mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and saturated brine, and was then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=1:2) to yield 1.4 g of 1-tert-butoxycarbonyl-5-carbamoyl-1,2,3,6-tetrahydropyridine as a crystal.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:11])[CH2:8][CH2:9][CH3:10].Cl[C:13]1[N:18]=[C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:16]([N+:29]([O-:31])=[O:30])=[CH:15][CH:14]=1>C(#N)C>[CH2:7]([NH:11][C:13]1[N:18]=[C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[C:16]([N+:29]([O-:31])=[O:30])=[CH:15][CH:14]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCNc1ccc([N+](=O)[O-])c(NCCCN2CCCCC2)n1
Temperature: 25 °C
Yield: 98 %

Procedure:
Potassium carbonate (930 mg, 2 eq) and a solution of 1-butylamine (300 mg, 1.2 eq) in acetonitrile (2 ml) are added successively to a solution of 6-chloro-3-nitro-N-(3-piperidin-1-ylpropyl)pyridin-2-amine (1 g, 1 eq; prepared according to Example A2) in acetonitrile (80 ml). The mixture is heated to reflux for 15 hours then cooled down to ambient temperature and concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (200 ml) and water (90 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue obtained, by flash chromatography on silica gel (eluent: heptane/ethyl acetate 9:1 to 100% ethyl acetate), produces the expected compound (1.1 g; 98% yield).
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@H:14]([CH3:26])[C@:15]3([OH:25])C(=O)CO)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1.[O-][Bi](=O)=O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@H:14]([CH3:26])[C:15]3=[O:25])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Agent: O=[Bi](=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)C1=O
Yield: 65.2 %

Procedure:
A solution of 4.7 g (12.0 mmole) of 9-fluoro-16β-methyl-11β,17,21-trihydroxypregna-1,4-diene-3,20-dione in 50% acetic acid (600 ml) was stirred with 18 g of sodium bismuthate at room temperature for 2 hours. The brown suspension was filtered through a bed of deactivated silica powder and washed with 100 ml of 50% acetic acid. The filtrate was concentrated in vacuo to 100 ml, diluted with 100 ml of 20% hydrochloric acid and extracted with chloroform. The chloroform solution was washed with 20% hydrochloric acid and water, dried over anhydrous Na2SO4 and evaporated in vacuo to give a solid. This was dissolved in chloroform and chromatographed on a 30 g silica gel column, eluting successively with chloroform and 1:4 ethyl acetate-chloroform to give 2.6 g of the title compound, melting point 281°-283° C., dec.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:9][OH:10].C(N(CC)CC)C.O>ClCCl>[CH3:11][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:7])[CH:9]=[O:10]
Reactant: CC(C)(CO)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C=O)c1ccccc1
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
To a solution of oxalylchloride (4.1 ml) in dichloromethane (100 ml) was added dropwise a solution of dimethylsufoxide (7.14 g) in dichloromethane (10 ml) at -60° C., and the mixture was stirred for 10 minutes. To the resultant mixture was added a solution of 2-methyl-2-phenylpropanol (6.16 g) in dichloromethane (15 ml) at the same temperature. After stirring for one hour, to the mixture was added triethylamine (20.7 g). The mixture was further stirred for 30 minutes and allowed to room temperature. After adding water, the mixture was extracted with dichloromethane. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resultant residue was subjected to silica gel (40 g) column chromatography and elution with 2% ethyl acetate hexane solution gave 4.93 g of 2-methyl-2-phenylpropanal.
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)=O.[CH3:19][O:20]CCO.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:19][O:20][CH2:2][CH2:3][NH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(F)(F)F)cc1
Reactant: COCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NCCOC)cc1
Reaction time: 4 h
Yield: 31.1 %

Procedure:
To a solution of ethyl 4-(2,2,2-trifluoro-acetylamino)-benzoate (1.58 g, 6.05 mmol, CASRN 24568-14-7) in dry THF was added 2-methoxyethanol (1.192 mL, 15.12 mmol), diisopropyl azodicarboxylate (2.94 mL, 15.12 mmol) and P (3.97 g, 15.12 mmol) and the resulting solution stirred for 4 h. The reaction mixture was concentrated, dissolved in EtOAc, washed sequentially with water and brine, dried (MgSO4), filtered and concentrated. The crude product was purified by SiO2 chromatography eluting with 50% EtOAc/hexane to afford 0.42 g of ethyl 4-(2-methoxy-ethylamino)-benzoate (338).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]3[CH2:17][NH:16][C:15](=[O:18])[CH2:14]3)=[CH:10][CH:11]=2)[N:6]([CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:5]=1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CN1C(=O)N(C)CCC1>O1CCCC1>[CH2:28]([N:16]1[CH2:17][CH:13]([C:9]2[CH:8]=[C:7]3[C:12]([C:4]([CH3:3])=[CH:5][N:6]3[CH2:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:11][CH:10]=2)[CH2:14][C:15]1=[O:18])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cn(CCCc2ccccc2)c2cc(C3CNC(=O)C3)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: Cc1cn(CCCc2ccccc2)c2cc(C3CC(=O)N(Cc4ccccc4)C3)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
A solution of sodium hydride (0.013 g) in tetrahydrofuran at 0° C., under argon, was treated with a solution of 4-[3-methyl-1-(3-phenyl-propyl)-1H-indole-6-yl]-pyrrolidine-2-one (0.184 g, Example 20) and benzyl bromide (0.094 g) in dry tetrahydrofuran. The mixture was allowed to warm to room temperature then treated with N,N′-dimethylpropyleneurea (0.05 g). After stirring at room temperature overnight the solution was partitioned between ethyl acetate (15 ml)and 1N hydrochloric acid (15 ml). The organic phase was dried over magnesium sulphate then evaporated. The residue was subjected to preparative layer chromatography on silica using a mixture of ethyl acetate and hexane (3:7, v/v) as eluent to yield the title compound (0.18 g) as an oil. [Elemental analysis:— C, 79.16; H, 6.98; N, 6.14%. Calculated for C29H30N2O.H2O:— C, 79.04; H, 7.33; N, 6.36%].
Reaction SMILES: [O:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=[CH:2]1.[Br:11][C:12]1[C:17]([Br:18])=[C:16]([Br:19])[CH:15]=[CH:14][C:13]=1F>>[Br:11][C:12]1[C:17]([Br:18])=[C:16]([Br:19])[CH:15]=[CH:14][C:13]=1[O:10][CH:9]1[CH2:8][NH:7][CH2:6][C:5]2[O:1][CH:2]=[CH:3][C:4]1=2
Reactant: OC1CNCc2occc21
Reactant: Fc1ccc(Br)c(Br)c1Br
Product: Brc1ccc(OC2CNCc3occc32)c(Br)c1Br

Procedure:
The same method as in Example 1 was conducted using 4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 4) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,3,4-tribromo-1-fluorobenzene instead of 1-fluoronaphthalene 1 to give the objective compound.