Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29].C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:26]1[CH:27]=[C:28]([NH:29][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:30]=[CH:31][CH:32]=1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Reactant: Nc1cccc(Oc2ccccn2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(Oc2ccccn2)c1)c1ccn2c1CSC2c1cccnc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 51.6 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (12 g) is added, at a temperature between 60° and 68° C., to a solution of 3-(2-pyridyloxy)aniline (7.4 g) and triethylamine (8.1 g) in dioxane (200 cc) which is heated to a temperature in the vicinity of 60° C., in the course of 5 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 7 hours and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (300 cc). The solution obtained is washed twice with distilled water (500 cc in total), twice with an aqueous 1N sodium hydroxide solution (300 cc in total) and twice with distilled water (500 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. A crude product (15.8 g) is thereby obtained, which is dissolved in boiling acetonitrile (100 cc). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 20° C. for 3 hours. The crystals formed are separated by filtration, washed 3 times with acetonitrile (45 cc in total) and 3 times with diethyl ether (90 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-[3-(2-pyridyloxy)phenyl]-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (8.5 g) in the form of cream-coloured crystals, m.p. 132° C., is thereby obtained.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH2:16][CH2:15][C:14]=3[CH:18]=2)[C:5]([NH2:19])=[N:4][CH:3]=1.[N:20]([O-])=O.[Na+]>CC(O)=O.O>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][C:10]3[CH:11]=[CH:12][C:13]4[O:17][CH2:16][CH2:15][C:14]=4[CH:18]=3)[N:20]=[N:19][C:5]2=[N:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ncc(Br)nc1NCc1ccc2c(c1)CCO2
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Brc1cnc2nnn(Cc3ccc4c(c3)CCO4)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a solution of 6-bromo-N2-(2,3-dihydro-benzofuran-5-ylmethyl)-pyrazine-2,3-diamine (1.0 g, 3.12 mmol) in AcOH:H2O (8 mL: 8 mL) was added the solution of NaNO2 (2.12 g, 31.2 mmol) in water (5 mL). The mixture was stirred at room temperature for 1 hour, and then heated at 65° C. for 16 hours. The solvents were removed, and then EtOAc (20 mL) and water (20 mL) were added. The aqueous layer was extracted with EtOAc (3×20 mL). The combined extracts were dried over Na2SO4, concentrated and purified by silica gel chromatography with EtOAc: Hexanes to provide 6-bromo-1-(2,3-dihydro-benzofuran-5-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (543 mg, 52% yield).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:3]([CH2:2][NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16])([O:5][CH3:6])=[O:4]
Reactant: NCCCN1CCCC1=O
Reactant: COC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CNCCCN1CCCC1=O
Reaction time: 12 h

Procedure:
Methyl bromoacetate (1.35 mL, 14.3 mmol) was added dropwise to a solution of 3-aminopropyl-2-pyrrolidinone (2.0 mL, 14.3 mmol) and diisopropylethylamine (2.7 mL) in CH2Cl2. The reaction was stirred for 12 hours and was then concentrated in vacuo, and carried forward without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[CH:11]1(C(C2C(CCC3C=CC=CC=3)=NN(C3C=CC=CC=3)C=2)O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1(B(O)O)C=CC=CC=1.N1C=CC=CC=1>CC(N(C)C)=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: OC(c1cn(-c2ccccc2)nc1CCc1ccccc1)C1CCCCC1
Reactant: COC(=O)c1c[nH]nc1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OB(O)c1ccccc1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cn(-c2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
Methyl 3-methyl-1H-pyrazole-4-carboxylate (14.4 g) synthesized in Example 1, (3) was dissolved in dimethylacetamide (200 mL), phenylboronic acid (25.0 g), copper acetate (36.4 g) and pyridine (32 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (100 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:1, volume ratio) to give the title object compound (11.4 g, 53%) as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[Cl:10].BrC1C=C2C(=CC=1)C=[N:17][CH:16]=[CH:15]2>>[F:1][C:2]1[CH:9]=[C:8]2[C:5](=[CH:4][C:3]=1[Cl:10])[CH:6]=[N:17][CH:16]=[CH:15]2
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: Brc1ccc2cnccc2c1
Product: Fc1cc2ccncc2cc1Cl

Procedure:
Starting from 4-Fluoro-3-chlorobenzaldehyde, the title compound was synthesized by the protocol described for 6-Bromo-isoquinoline (3). Rt=0.77 min (Method A). Detected mass: 182.1/184.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH3:15])([C:12]([OH:14])=O)[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Li].[C:17]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:22]=[CH:21][C:20]([CH:23]([NH:30][CH3:31])[CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:17]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:22]=[CH:21][C:20]([CH:23]([N:30]([CH3:31])[C:12](=[O:14])[C:10]([CH3:11])([CH3:15])[NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:19][CH:18]=1
Reactant: CC(C)(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: CNC(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C(=O)C(C)(C)Nc1ccc(Cl)c(Cl)c1)C(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
N-(3,4-dichlorophenyl)-2-methylalanine, lithium salt (100 mg, 0.4 mmol), [1-(4-biphenylyl)-2-(1-pyrrolidinyl)ethyl]methylamine (124 mg, 0.44 mmol), triethylamine (246 uL, 1.77 mmol), and (1 H-1,2,3-benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate (BOP Reagent, 215 mg, 0.486 mmol) were added in that order to a 4 mL screw capped vial that contained 2 mL of anhydrous DMF. The reaction mixture was stirred for 20 hours at room temperature, then filtered through a 0.45 um PTFE Acrodisk, and purified by reverse-phase HPLC (Xterra Prep RP C-18, 30×150 mm, 50 mL/min, A: acetonitrile B: water, pH 10 w/NH4OH, A: 20 to 99% over 9 min, UV detection at 214 nm) to give the title compound as a white solid. MS (ES) m/e 510 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12].[NH3:13].Cl>>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[S:4][CH2:3][CH2:2][NH2:13]
Reactant: N
Reactant: COc1ccccc1SCCCl
Agent: Cl
Product: COc1ccccc1SCCN

Procedure:
by the reaction of o-(2-chloroethylthio)-anisole in liquid ammonia for 8 hours at 120° C.; oil; b.p. 118°-122° C./0.05 mm.Hg.; hydrochloride m.p. 163°-167° C.;
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]2[CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:3]=1[F:21].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.Cl>O1CCOCC1>[C:12]([C:11]1[C:2]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:3]([F:21])[CH:4]=[C:5]2[C:10]=1[N:9]([CH:14]1[CH2:16][CH2:15]1)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:6]2=[O:20])#[N:13]
Reactant: N#Cc1c(Cl)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: C1CNCCN1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1c(N2CCNCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
0.5 g of the product from Example 1 and 0.42 g of piperazine are boiled in 8 ml of dioxane for 3 hours. The mixture is then concentrated in vacuo and 8 ml of water are added to the residue. The solution formed is rendered neutral with HCl and the solid which has precipitated out isolated, washed and dried.
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([OH:18])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C([N:21](CC)CC)C.ClC(OCC(C)C)=O>C(Cl)(Cl)Cl>[C:1]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([NH2:21])=[O:18])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Solvent: ClC(Cl)Cl
Product: NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To a solution of the resulting (S)-1-carbobenzoxypyrrolidine-2-carboxylic acid (52.2 g:0.21 mole) and triethylamine (21.2 g:0.21 mole) in 525 ml of chloroform was added isobutyl chloroformate (28.7 g:0.21 mole) with stirring under cooling on ice, followed by continuing the stirring for 15 minutes. Dried ammonia gas was bubbled into the mixture for 1 hour and then the mixture was allowed to warm to room temperature and stand overnight. The resulting white precipitate was removed by the filtration, and the filtrate was evaporated under reduced pressure. The residue was dissolved in 200 ml of chloroform and was washed with diluted aqueous hydrochloric acid and water, and dried over magnesium sulfate. Chloroform was distilled off to give 45.8 g of (S)-1-carbobenzoxypyrrolidine-2-carboxamide. Yield: 88%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].Br[CH2:37][CH2:38][OH:39].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[OH:39][CH2:38][CH2:37][N:33]1[CH2:32][CH2:31][CH:30]([NH:29][C:27]([C:4]2[N:5]([CH3:26])[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]([CH2:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:8](=[O:25])[C:7]=3[C:3]=2[O:2][CH3:1])=[O:28])[CH2:35][CH2:34]1
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C(=O)NC2CCN(CCO)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 100 °C
Reaction time: 15 h
Yield: 33 %

Procedure:
A mixture of the compound of Example 77 (200 mg, 0.399 mmol), 2-bromoethanol (42.5 μL, 0.599 mmol), potassium carbonate (248 mg, 1.80 mmol) and DMF (5 mL) was stirred at 100° C. for 15 hr. The reaction mixture was diluted with water, and extracted twice with ethyl acetate. The extract was combined, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate), and the obtained solid was recrystallized from ethyl acetate-ethanol to give the title compound (68.0 mg, 33%) as white crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[F:13]C1C=CC([N+]([O-])=O)=C(O)C=1.CI>>[F:13][C:7]1[CH:2]=[CH:3][C:4]([O:11][CH3:12])=[C:5]([CH:6]=1)[NH2:8]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Solvent: CI
Product: COc1ccc(F)cc1N
Yield: 98 %

Procedure:
Reduction of 1-fluoro-3-methoxy-4-nitrobenzene (0.11 mol) (prepared by methylation of 5-fluoro-2-nitrophenol with methyl iodide was carried out according to Step (b) of Example XII to provide 14.8 g (98% yield) of 5-fluoro-2-methoxyaniline used without further purification.
Reaction SMILES: C([C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:5][CH:4]=1)=O.C1C[O:22][CH2:21]C1.CO.[BH4-].[Na+]>O>[OH:22][CH2:21][C:5]1[CH:4]=[CH:3][CH:18]=[CH:17][C:6]=1[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: C1CCOC1
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(OCc1ccccc1)c1ccccc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.3 g (43 mmol) of benzyl 4-formylbenzoate, 50 ml of THF and 50 ml of methyl alcohol are introduced into a round-bottomed flask. While cooling in an icebath, 820 mg (21.5 mmol) of sodium borohydride are added in small portions and the mixture is stirred at room temperature for two hours. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated. 10.4 g (100%) of the expected product, melting point 55°-56° C., are collected.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][N:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:22][C:23]1[CH:27]=[CH:26]OC=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][N:17]=[CH:18][CH:19]=3)[N:14]([CH2:22][CH2:23][CH2:27][CH3:26])[CH:13]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3cnccc23)CC1
Reactant: BrCc1ccoc1
Product: CCCCn1cc(C2CCN(C(=O)OCC)CC2)c2ccncc21
Yield: 43 %

Procedure:
This compound was prepared following the procedure described in example 24, part C, starting with 4.9 g (18 mmol) of 4-(1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester and 35.4 ml (21.6 mmol) of a 0.61 M solution of 3-bromomethylfurane. After standard work-up and purification, 6.14 g (43% of yield) of 4-(1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:25])=[C:7]([C:14]([NH:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[O:15])[C:8](=[O:13])[N:9]2[CH3:12])=[N:4][CH:3]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[OH:25][C:6]1[C:5]2[C:10](=[CH:11][C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:3][N:4]=2)[N:9]([CH3:12])[C:8](=[O:13])[C:7]=1[C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15]
Reactant: OB(O)c1ccccc1
Reactant: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)c(O)c2ncc(Br)cc21
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2ncc(-c3ccccc3)cc21

Procedure:
The title compound was prepared similarly to the procedures described for Example 2 from tert-butyl 2-(7-bromo-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamido)acetate (Example 1 (f)) and phenylboronic acid. MS (ESI, pos. ion) m/z: 354 (M+1). 1H NMR (400 MHz, CD3OD) δ ppm: 8.86 (s, 1 H), 8.20 (s, 1 H), 7.84 (d, J=7.4 Hz, 2 H), 7.44-7.63 (m, 3 H), 4.16 (s, 2 H), 3.78 (s, 3 H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11](O)[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C[SiH](C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(O)C(C)(C)C)cc1
Agent: C[SiH](C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCOc1ccc(CC(C)(C)C)cc1
Reaction time: 0.5 h

Procedure:
1-(4-Allyloxyphenyl)-2,2-dimethylpropan-1-ol (1.2 g, 6.1 mmol) and trimethylsilane (mL, 61.0 mmol) were dissolved in dichloromethane (5.0 mL) and trifluoroacetic acid (2.1 g, 18.3 mmol) was added at 0° C. After 30 min, the reaction mixture was concentrated to give esentially pure 1-allyloxy-4-neopentylbenzene. The crude product was dissolved in 1,2,4-trichlorobenzene (5.0 mL) and the solution was heated to reflux for 4 hrs. Removal of solvent and chromatography of the residue on silica gel eluting with 9:1 hexane:ethyl acetate gave 0.70 g 2-allyl-4-(2,2-dimethyl-propyl)phenol.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].[CH3:32][N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:39][CH:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)=[O:27])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NC3CCN(C)CC3)cn2)c1O

Procedure:
The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-methylpiperidin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.71-1.85 (m, 2H) 1.92-2.14 (m, 2H) 2.38-2.47 (m, 3H) 2.70-2.89 (m, 3H) 3.06-3.18 (m, 2H) 3.24-3.40 (m, 1H) 3.49 (d, J=11.87 Hz, 1H) 3.98-4.24 (m, 1H) 7.67 (d, J=7.58 Hz, 1H) 7.71-7.87 (m, 2H) 8.21 (d, J=12.13 Hz, 1H) 8.35-8.59 (m, 2H) 8.72 (d, J=6.32 Hz, 1H) 8.88-8.98 (m, 1H) 9.46 (br. s., 1H) 12.72-13.42 (m, 1H). MS m/z [M+H]+ 417.2.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:11][CH:10]([CH2:12][CH2:13][OH:14])[CH2:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.C(OCC)(=O)C>[Br:34][C:35]1[CH:40]=[CH:39][C:38]([O:14][CH2:13][CH2:12][CH:10]2[CH2:9][CH:8]([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH2:11]2)=[CH:37][CH:36]=1
Reactant: OCCC1CC(OC2CCCCO2)C1
Reactant: Oc1ccc(Br)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1ccc(OCCC2CC(OC3CCCCO3)C2)cc1
Temperature: 25 °C
Yield: 32.5 %

Procedure:
2-[3-(Tetrahydro-2H-pyran-2-yloxy)cyclobutyl]ethanol (1.08 g, 5.39 mmol) was dissolved in tetrahydrofuran (20 mL) and was cooled in an ice bath. Triphenylphosphine (2.12 g, 8.09 mmol) and 4-bromo-phenol (1.12 g, 6.47 mmol) were added and the reaction was stirred until dissolved. Diethylazodicarboxylate (1.45 g, 8.09 mmol) was added dropwise to the reaction and the reaction was then warmed to room temperature and stirred for 48 hours. The reaction was diluted with ethyl acetate and washed with 1 N aqueous sodium hydroxide. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give a clear oil. Purification on silica gel with heptane-ethyl acetate (15% ethyl acetate) gave 2-({3-[2-(4-bromophenoxy)ethyl]cyclobutyl}oxy)tetrahydro-2H-pyran (622 mg, 32.4%) as a clear oil. Partial 1H NMR indicated a ˜4:1 mix of unknown cis-trans isomers. (CDCl3, δ ppm, key peaks are 4.08 (m, 0.80H), 4.38 (m, 0.20H), 6.74 (d, J=8.98, 2H), 7.34 (d, J=9.18, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:36]>CN(C)C=O.O.Cl>[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:36])[CH:15]=[C:14]2[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(C(=O)OCc4ccccc4)cc23)c(OC)c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)OCc4ccccc4)cc23)c(OC)c1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
A solution of methyl 4-(5-benzyloxycarbonylindol-3-ylmethyl)-3-methoxybenzoate (46.1 g) in N,N-dimethylformamide (200 mL) was added to a slurry of sodium hydride (2.83 g) in N,N-dimethylformamide (300 mL) at 5° C. under a nitrogen atmosphere. The mixture was stirred for 30 minutes at 5° C., then was treated with iodomethane (16.6 g), allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was then poured into ice/water (400 mL), diluted with water (250 mL) and 1N hydrochloric acid (250 mL). The resulting aqueous solution was extracted with ethyl acetate. The combined organic extract was washed (1N hydrochloric acid, water, brine), dried (MgSO4), filtered and evaporated. The residue was triturated with warm diethyl ether and filtered to give methyl 4-(5-benzyloxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxybenzoate as an ivory solid (42.4 g, 89%); partial NMR (300 MHz, CDCl3): 3.75 (s, 3H, NCH3), 3.87 (s, 3H, CO2CH3), 3.90 (s, 3H, OCH3), 4.12 (s, 2H, CH2), 5.36 (s, 2H, OCH2), 6.82 (s, 1H, indole-H(2)), 8.38 (d, 1H, indole-H(4)).
Reaction SMILES: Br.Br.Br.[NH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[O:12])[N:9]=1.[F:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30](O)=[O:31]>>[F:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][C:11]([N:13]2[CH2:14][CH2:15][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH2:17][CH2:18]2)=[O:12])[N:9]=1)=[O:31]
Reactant: COc1ccc(C(=O)O)cc1F
Reactant: CN1CCC(N2CCN(C(=O)Cc3csc(N)n3)CC2)CC1
Agent: Br
Product: COc1ccc(C(=O)Nc2nc(CC(=O)N3CCN(C4CCN(C)CC4)CC3)cs2)cc1F

Procedure:
In analogy to example 47.3, 2-(2-amino-thiazol-4-yl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-ethanone trihydrobromide (example 47.2) was coupled with 3-fluoro-4-methoxybenzoic acid, using general method D, to give 3-fluoro-4-methoxy-N-(4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-benzamide. Off-white amorphous solid. MS 476.3 ([M+H]+)
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[NH:15][NH2:16]>>[CH2:19]([O:18][C:14](=[O:17])[NH:15][N:16]=[CH:12][C:10]1[N:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:8][CH:9]=1)[CH3:20]
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Reactant: CCOC(=O)NN
Product: CCOC(=O)NN=Cc1c[nH]c(-c2ccccc2)n1

Procedure:
A mixture of 8.16 gm. of 2-phenyl-4-imidazolecarboxaldehyde and 5.52 gm. of ethyl carbazate are reacted as described in Example 32 giving the desired product, m.p. 196°-200° C.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[OH:16])[CH:2]=[CH2:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:3][CH:2]1[CH2:1][CH:4]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[O:16]1
Reactant: C=CCC1CCCCCCCCCCC1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1CC2CCCCCCCCCCC2O1
Yield: 98 %

Procedure:
1 mole of 2-(2-propenyl)-cyclododecanol is dissolved, together with 20 g of p-toluenesulphonic acid, in 1000 ml of toluene, and the mixture is refluxed for 15 hours. The mixture is then neutralized with 10% sodium carbonate solution, the phases are separated and the organic phase is worked up by distillation. After the toluene has been drawn off, 14-methyl-13-oxabicyclo[10.3.0]pentadecane is obtained, in a yield of 98% of the theoretical yield, at a boiling range of from 85° to 88° C. at 0.05 torr. Colorless oil; scent: warm, vetiver-like sandalwood fragrance.