Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([OH:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCCCCC>CN(C)C=O.C(OCC)(=O)C>[CH2:16]([O:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[CH2:7][OH:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: OCc1ccccc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: OCc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
151 g of potassium t-butoxide were added, whilst ice-cooling and stirring, to a solution of 152 g of salicyl alcohol in 600 ml of dimethylformamide, and the resulting mixture was stirred at room temperature for 30 minutes; 160 ml of benzyl bromide were then added dropwise to the mixture. The reaction mixture was then stirred at a temperature of from 30° to 40° C. for 2 hours, after which it was partitioned between ethyl acetate and water. The organic layer was washed twice, each time with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The oily residue thus obtained was subjected to column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 228.5 g (yield 87%) of 2-benzyloxybenzyl alcohol as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.Br[CH2:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][N:10]([CH2:16][C:17]4[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=4)[C:20]#[N:21])[CH2:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(CN2CCc3[nH]c4ncc(Cl)cc4c3C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg; 0.24 mmol), 3-(bromomethyl)benzonitrile (56 mg; 0.29 mmol), and K2CO3 (0.04 ml; 0.72 mmol) where dissolved in DMF (2 ml) and stirred overnight at room temperature. Prep-LC-MS purification provided 16 as an off-white powder (21 mg, 27% yield). LC-MS (M+H=323, obsd.=323).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH3:15][NH:16][O:17][CH3:18].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CN(C1C=CN=CC=1)C.O.C(N(CC)CC)C>[CH3:18][O:17][N:16]([CH3:15])[C:11](=[O:13])[CH2:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CNOC
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To a solution of (4-nitrophenyl)acetic acid (30.0 g), N,O-dimethylhydroxylamine hydrochloride (21.0 g) and 1-hydroxybenzotriazole monohydrate (33.0 g) in DMF (450 ml) were added triethylamine (30 ml) and 4-(N,N-dimethylamino)pyridine (130 mg), and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (41.4 g) was added to the mixture, and then, the mixture was stirred overnight under nitrogen atmosphere. Water was added to the mixture, and the mixture extracted with ethyl acetate twice. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate once, with water twice, and with saturated brine once, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained solid was washed with hexane to give N-methoxy-N-methyl-2-(4-nitrophenyl)acetoamide (32.6 g) as colorless crystals.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1>>[F:24][C:21]1[CH:22]=[CH:23][C:18]2[N:19]([CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=2)[CH:20]=1
Reactant: Nc1ccc(F)cn1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(F)ccc2n1
Yield: 13 %

Procedure:
As described for Example 2, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (112 mg, 0.4 mmol) was converted, using 2-amino-5-fluoropyridine instead of 2-amino-3-methylpyridine, to the title compound (15 mg, 13%) which was obtained as a yellow solid. MS: m/e=294.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17](=O)[CH2:18][C:19](=[O:21])[CH3:20])[C@H:14]([C:23]([O:25][CH3:26])=[O:24])[CH2:13]1)(=[O:11])=[O:10].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17](=[S:36])[CH2:18][C:19](=[O:21])[CH3:20])[C@H:14]([C:23]([O:25][CH3:26])=[O:24])[CH2:13]1)(=[O:11])=[O:10]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1C(=O)CC(C)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1C(=S)CC(C)=O

Procedure:
In analogy to the procedure described in example 192 g, (2S,4R)-methyl 4-(2-chloro-4-fluorophenylsulfonyl)-1-(3-oxobutanoyl)pyrrolidine-2-carboxylate (example 375b) was reacted with Lawesson's reagent (CAS Reg. No. 19172-47-5) to give the title compound as orange foam. MS (ESI): m/z=421.9 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[NH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O.CCOC(C)=O>[C:20]1([CH2:19][N:16]2[CH2:17][CH2:18][CH:13]([CH2:12][NH:11][C:2]3[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][N:3]=3)[CH2:14][CH2:15]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NCC1CCN(Cc2ccccc2)CC1
Reactant: Clc1noc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(CN2CCC(CNc3noc4ccccc34)CC2)cc1
Temperature: 150 °C
Yield: 16.9 %

Procedure:
A mixture of 3-chloro-1,2-benzisoxazole (0.238 g, 1.55 mmol), 4-aminomethyl-1-phenylmethyl piperidine (0.316 g, 1.55 mmol), and K2CO3 (0.214 g, 1.55 mmol) in DMSO (10 mL) was heated at 150° C. for 20 hours. The cooled reaction mixture was diluted with EtOAc (75 mL) and poured over H2O (200 mL). The organic phase was separated and washed with brine, dried (MgSO4), filtered, and concentrated. The brown oil obtained was purified by silica gel flash chromatography (4% MeOH-CH2Cl2) to give the title compound (0.084 g, 17%) as pale yellow oil.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[BH4-].[Na+].O>C(O)C>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(OCCF)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1ccc(OCCF)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
The crude 4-(2-fluoroethoxy)benzaldehyde (35.6 g) was dissolved in 140 ml of ethanol, and 11.0 g of sodium borohydride was carefully added to the solution at 47° to 50° C. After adding sodium borohydride, the reaction was carried out at 50° C. for 2 hours. After the reaction, the reaction mixture was cooled to room temperature and water was added. The mixture was extracted with toluene. The toluene layer was washed with water and dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure to give 32.4 g of 4-(2-fluoroethoxy)benzyl alcohol as crystals (m.p. 37.3°-38.0° C.).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[O:2].[CH2:11](O)[CH2:12][OH:13].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:2]1[CH2:11][CH2:12][O:13][CH:1]1[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: OCCO
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C2OCCO2)cc1
Yield: 89.1 %

Procedure:
A solution of 4-formylbenzonitrile (10 g, 76.3 mmol), ethylene glycol (18.95 g, 305 mmol) and p-toluene sulfonic acid (7 mg, 0.003 mmol) in toluene (100 mL) was heated to reflux for 9 hours. During this time a Dean-Stark trap was used to remove water formed during the reaction. To the reaction was added aq. Na2CO3 (150 mL). The organic layer was washed twice with water (100 mL), then dried over Na2SO4. The solvent was removed under vacuum to provide 4-(1,3-dioxolan-2-yl)benzonitrile (12 g, 68 mmol). The compound had an HPLC retention time=4.24 min. −Column: HYPERSIL® BDS C18 (4.6×50 mm) Flow rate=0.8 mL/min. Solvent A=, 0.1% TFA in water; Solvent B=acetonitrile. 5%-100% B (0-6 min), 100% B (6-9 min), 100%-5% B (9-11 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH:16]=O.C[O-].[Na+]>CO>[Cl:12][C:13]1[CH:14]=[C:15](/[CH:16]=[C:8](/[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:11])\[C:9]#[N:10])[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: N#CCc1ccc(Cl)cc1F
Reactant: O=Cc1cc(F)cc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cc(F)cc(Cl)c1)c1ccc(Cl)cc1F
Yield: 88.7 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenylacetonitrile (3.4 g, 20 mmol) was reacted with 3-chloro-5-fluoro-benzaldehyde (Aldrich) (3.77 g, 24 mmol), methanolic solution (25 wt %) of sodium methoxide (4.99 mL, 22 mmol) in methanol (90 mL) at 50° C. for 3 h to give (Z)-3-(3-chloro-5-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a white powder (5.5 g, 90%).
Reaction SMILES: [ClH:1].O1CCOCC1.C(O)(C(F)(F)F)=O.[CH3:15][O:16][C:17]([NH:19][C@@H:20]([CH:68]([CH3:70])[CH3:69])[C:21]([N:23]1[C@H:28]([C:29]2[NH:30][C:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:41]=[C:42]5[C:47](=[CH:48][CH:49]=4)[CH:46]=[C:45]([C:50]4[NH:54][C:53]([C@@H:55]6[CH2:60][C@@H:59]7[C@@H:57]([CH2:58]7)[N:56]6C(OC(C)(C)C)=O)=[N:52][CH:51]=4)[CH:44]=[CH:43]5)=[CH:36][CH:35]=3)=[CH:32][N:33]=2)[CH2:27][C@@H:26]2[C@H:24]1[CH2:25]2)=[O:22])=[O:18]>C(Cl)Cl>[ClH:1].[ClH:1].[C@@H:57]12[CH2:58][C@@H:59]1[CH2:60][C@@H:55]([C:53]1[NH:54][C:50]([C:45]3[CH:46]=[C:47]4[C:42](=[CH:43][CH:44]=3)[CH:41]=[C:40]([C:37]3[CH:38]=[CH:39][C:34]([C:31]5[NH:30][C:29]([C@@H:28]6[CH2:27][C@@H:26]7[C@@H:24]([CH2:25]7)[N:23]6[C:21](=[O:22])[C@@H:20]([NH:19][C:17](=[O:18])[O:16][CH3:15])[CH:68]([CH3:70])[CH3:69])=[N:33][CH:32]=5)=[CH:35][CH:36]=3)[CH:49]=[CH:48]4)=[CH:51][N:52]=1)[NH:56]2
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H]6C[C@H]7C[C@H]7N6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H]6C[C@H]7C[C@H]7N6)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4N HCl in dioxane (2 mL, 8.00 mmol) was added to a stirred solution of a TFA salt of (1R,3S,5R)-tert-butyl 3-(5-(6-(4-(2-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (0.10 g, 0.12 mmol) in CH2Cl2 (20 mL) and the resulting yellow suspension was stirred at rt for 2 h. The reaction was concentrated under vacuum and the resulting residue was triturated with Et2O to yield an HCl salt of methyl(S)-1-((1R,3S,5R)-3-(5-(4-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate HCl (47 mg) as a yellow solid. LC/MS [M+H]+=656; Rt=1.73 min is product. Column Luna 3u C18 2×50 mm; start % B: 0, final % B: 100 Solvent A: 10% Acetonitrile/90% H2O+1% TFA; Solvent B: 90% Acetonitrile/10% H2O+1% TFA; flow rate 4 ml/min. Run time: 5 min. Purity=95%. 1H NMR (500 MHz, DMSO-d6) δ ppm 14.47-15.18 (2 H, m), 9.77-10.61 (2 H, m), 8.30-8.42 (2 H, m), 8.17 (1 H, s), 7.93-8.10 (10 H, m), 7.27 (1 H, d, J=8.55 Hz), 5.08 (1 H, t, J=7.93 Hz), 4.71 (1 H, t, J=8.39 Hz), 4.40-4.46 (1 H, m), 3.77 (1 H, br. s.), 3.52-3.58 (3 H, m), 3.38-3.44 (1 H, m), 2.52-2.61 (3 H, m), 2.39 (1 H, dt, J=13.58, 6.64 Hz), 2.14-2.21 (1 H, m), 1.94 (2 H, dd, J=8.24, 4.88 Hz), 1.15 (1 H, d, J=5.80 Hz), 0.93 (4 H, d, J=6.71 Hz), 0.75-0.89 (6 H, m).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[N:17][C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>O1CCOCC1>[ClH:27].[ClH:27].[N:21]1([C:18]2[N:17]=[CH:16][C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:20][N:19]=2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cnc(N3CCOCC3)nc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1nc(N2CCOCC2)ncc1NC1CCNCC1

Procedure:
A solution of 4-(2-morpholin-4-yl-pyrimidin-5-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.33 mmol) in dioxane (10 mL) and 4 M HCl in dioxane (10 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 264.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH:6]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:5][C:4]1([CH3:17])[CH3:16].[N:18]1[C:25]([Cl:26])=[N:24][C:22](Cl)=[N:21][C:19]=1[Cl:20].[OH-].[Na+]>C1(C)C(C)=CC=CC=1.O>[Cl:20][C:19]1[N:18]=[C:25]([Cl:26])[N:24]=[C:22]([NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:6]2[CH2:7][C:8]([CH3:10])([CH3:9])[N:3]([O:2][CH3:1])[C:4]([CH3:17])([CH3:16])[CH2:5]2)[N:21]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CON1C(C)(C)CC(CCCCN)CC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CON1C(C)(C)CC(CCCCNc2nc(Cl)nc(Cl)n2)CC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
39.7 g (163 mmoles) of N-(1-methoxy-2,2,6,6-tetramethyl-4-piperidyl)butylamine are slowly added to a solution of 30 g (163 mmoles) of cyanuric chloride in 180 ml of xylene, maintained at room temperature. After the addition, the mixture is stirred for ½ hour at room temperature and subsequently, a solution of 6.8 g (170 mmoles) of sodium hydroxide in 45 ml of water is slowly added, maintaining the temperature at room temperature.
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]3[C:7]([CH:8]=[CH:9][N:10]3[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C([O:23][B:24](OC(C)C)[O:25]C(C)C)(C)C.[Li+].CC([N-]C(C)C)C>C1COCC1>[C:16]([O:15][C:13]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[CH:12]=2)[CH:8]=[C:9]1[B:24]([OH:25])[OH:23])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(C3CC3)cc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(C3CC3)cc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To a solution of tert-butyl 6-cyclopropyl-1H-indole-1-carboxylate (1.93 g, 7.51 mmol) and triisopropylborate (2.58 mL, 11.26 mmol) in THF was added LDA (1.5 M in cyclohexane, 7.0 mL, 10.5 mmol) at −78° C. The mixture was stirred at −78° C. for 30 min, quenched with ice water (60 mL) and stirred for 15 min without cooling. The mixture was extracted with ethyl acetate 1:1 in hexane (20 mL). The aqueous layer was acidified with aq. 2 N HCl to pH 5 and then extracted with CH2Cl2 (60 mL). The organic layer was dried over Na2SO4 and concentrated to give 1-(tert-butoxycarbonyl)-6-cyclopropyl-1H-indol-2-ylboronic acid as a solid (2.0 g, 88% yield) that was used in the next step without further purification.
Reaction SMILES: [C:1]([O:9]C)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C[O-].[Na+].[CH3:14][C:15]([CH3:17])=[O:16].C(O)(=O)C>C(OCC)C>[O:9]=[C:1]([C:2]1[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=1)[CH2:14][C:15](=[O:16])[CH3:17]
Reactant: CC(C)=O
Reactant: COC(=O)c1ccncc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(=O)CC(=O)c1ccncc1
Reaction time: 2 h

Procedure:
To a suspension of methyl isonicotinate (96.0 g, 0.7 mol) and sodium methoxide (45.4 g, 0.84 mol) in ethyl ether (1 l), acetone (81.3 g, 1.4 mol) was added dropwise at 25°~30° C. and stirring was continued for 2 hrs. under reflux. After cooling, acetic acid (50.4 g, 0.84 mol) was added to the reaction mixture, the organic layer was separated, washed twice with H2O, dried over anhydrous MgSO4 and evaporated. The residue (87.5 g) was distilled under reduced pressure to give the title compound as a pale yellow oil which solidified in the refrigerator; yield: 40.2 g; bp 135°~138° C./10 mmHg; mp 62°~64.5° C. (Lit. bp 118°~120° C.; mp 66.5°~67° C.; R. Levine, J. K. Sneed, J. Am. Chem. Soc., 73, 5614 (1951).). ##STR30##
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[N:14]=[C:13]([NH:17][C:18]4[CH:23]=[C:22]([N:24]5[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]5)[CH:21]=[CH:20][C:19]=4[O:31][C:32]([F:35])([F:34])[F:33])[N:12]=[CH:11][C:10]=3[CH2:9][CH2:8][C:7]=2[C:6]([C:36]([NH2:38])=[O:37])=[N:5]1.C1CCN2C(=NCCC2)CC1>O>[CH3:30][N:27]1[CH2:28][CH2:29][N:24]([C:22]2[CH:21]=[CH:20][C:19]([O:31][C:32]([F:35])([F:34])[F:33])=[C:18]([NH:17][C:13]3[N:12]=[CH:11][C:10]4[CH2:9][CH2:8][C:7]5[C:6]([C:36]([NH2:38])=[O:37])=[N:5][N:4]([CH:3]=[CH2:2])[C:16]=5[C:15]=4[N:14]=3)[CH:23]=2)[CH2:25][CH2:26]1
Reactant: CN1CCN(c2ccc(OC(F)(F)F)c(Nc3ncc4c(n3)-c3c(c(C(N)=O)nn3CCCl)CC4)c2)CC1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: C=Cn1nc(C(N)=O)c2c1-c1nc(Nc3cc(N4CCN(C)CC4)ccc3OC(F)(F)F)ncc1CC2
Temperature: 80 °C
Yield: 72.2 %

Procedure:
A mixture of 1-(2-chloro-ethyl)-8-[5-(4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamino]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (350 mg, 0.63 mmol) and DBU (3.5 mL) was heated to 80° C. for 1 h. After cooling the reaction mixture was poured into water and filtered. The crude solid was purified by flash chromatography on silica gel (eluant: DCM/MeOH 95/5) to afford 234 mg (71% yield) of the title compound.
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1)=[O:8])([CH3:5])[CH3:4].C1COCC1.Cl[C:22]1[C:31]2[C:26](=[C:27]([Cl:32])[CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1>C(Cl)Cl>[CH:3]([O:6][C:7]([N:9]1[CH2:10][CH2:11][CH:12]([O:15][C:22]2[C:31]3[C:26](=[C:27]([Cl:32])[CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:13][CH2:14]1)=[O:8])([CH3:5])[CH3:4]
Reactant: Clc1ccnc2c(Cl)cccc12
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(Oc2ccnc3c(Cl)cccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 50 mL round-bottomed flask equipped with a N2 inlet septum was placed a stir bar, NaH (60% in mineral oil, 1.1 g, 30 mmol) and 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (0.93 g, 5 mmol). THF (anhydrous, 20 mL) was added to the mixture. The resulting suspension was stirred about 30 min at room temperature. 4,8-Dichloro-quinoline (1 g, 0.5 mmol) was then added in one portion. The mixture was stirred overnight under N2 at 80° C. and the resulting slurry turned slightly yellowish. The slurry was added CH2Cl2 and filtered. The filtrate was concentrated under vacuum to give the crude product. Purification by column chromatography gave 4-(8-chloro-quinolin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 1.26 (d, 6H), 1.97 (m, 2H), 2.05 (m, 2H), 3.58 (m, 2H), 3.73 (m, 2H), 4.82 (m, 1H), 4.94 (m, 1H), 6.81 (d, 1H), 7.42 (t, 1H), 7.84 (d, 1H), 8.16 (d, 1H), 8.87 (d, 1H). Exact mass calculated for C18H21ClN2O3 348.12, found 349.2 (MH+)
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:37]1[NH:42][CH2:41][CH2:40][N:39]2[CH2:43][CH2:44][CH2:45][C@H:38]12.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:42]3[CH2:41][CH2:40][N:39]4[CH2:43][CH2:44][CH2:45][C@@H:38]4[CH2:37]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C1C[C@@H]2CNCCN2C1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CCC[C@@H]3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 150 °C
Yield: 44.7 %

Procedure:
The title compound was prepared starting from 100 mg (0.187 mmole) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577), 70 mg (0.554 mmol) of (8aR)-octahydropyrrolo[1,2-a]pyrazine, 52.2 mg of potassium carbonate (0.377 mmol); the reagents were dissolved in 0.6 ml of DMSO and the reaction mixture was heated at 150° C. overnight. Obtained after flash chromatography 52 mg of the desired compound.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.[N-:25]=[N+:26]=[N-:27].[Na+].O>CS(C)=O.S(=O)(=O)(O)O>[N:25]([C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1])=[N+:26]=[N-:27]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N=[N+]=[N-])C[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 51.3 %

Procedure:
2α,3α-Epoxy-5α-pregnane-11,20-dione (500 mg) was dissolved in dimethylsulphoxide (25 ml) and sodium azide (1.5 g) added to the solution. Concentrated sulphuric acid (10 drops) was added and the mixture heated on a steam bath for 48 hours. The solution was poured into iced water (600 ml) and the precipitate extracted into ether (100 ml). The ether extract was washed with water (4 + 250 ml) and then saturated sodium bicarbonate solution (250 ml) and finally water (250 ml.). The organic solution was dried over anhydrous sodium sulphate and evaporated to a white foam which was purified by preparative T.L.C. using ethyl acetate/petrol (1/1) run twice. The main band gave title compound (290 mg;) as a foam, [α]D + 95° (c, 0.98).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16]O)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.P(Br)(Br)[Br:25]>C(OCC)C>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][Br:25])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCc1cccc(Oc2ccccc2)c1
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: c1ccncc1
Product: BrCCCc1cccc(Oc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 209.4 %

Procedure:
To a mixture of 21.0 grams (0.092 mole) of 3-(3-phenoxyphenyl)propanol and 1 mL of pyridine which had been cooled to 0° C. was added dropwise during a 20 minute period 8.27 grams (0.031 mole) of phosphorus tribromide. This mixture was stirred at 0° C. for 90 minutes and then at ambient temperature overnight. The reaction mixture was then diluted with 200 mL of diethyl ether, and the solution was washed successively twice with 50 mL of water, four times with 25 mL of a saturated, aqueous solution of sodium bicarbonate, once with 50 mL of water, and once with an aqueous solution of sodium chloride. After being dried over anhydrous sodium sulfate and filtered, the solvent was evaporated under reduced pressure, leaving 18.9 grams of 3-(3-phenoxyphenyl)propyl bromide as an oil. The nmr spectrum was consistent with the proposed structure.