Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[CH2:11][CH2:12][OH:13].[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][CH2:12][OH:13])=[CH:5][CH:4]=1
Reactant: OCCCl
Reactant: COc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(OCCO)cc1
Yield: 35.4 %

Procedure:
A mixture of 148.8 g (1.20 mole) of p-methoxyphenol, 170 g (2.11 mole) of 2-chloroethanol and 47.2 g (1.18 mole) of sodium hydroxide in 1.5 liter of absolute ethanol was heated at reflux for 22 hr. The solution was filtered, and the solvent was removed from the filtrate in vacuo. The residue was crystallized from methylene chloride-hexane to give 71.4 g (35%) of title compound as a white crystalline solid, mp 69°-71° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]3[CH:12]=[N:13][CH:14]=[C:15]([C:18]=3[NH:19][C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[C:16]#[N:17])=[CH:8][C:7]=2[CH:29]=1)=O.[CH3:30][NH:31][CH3:32].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[CH3:30][N:31]([CH2:1][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]3[CH:12]=[N:13][CH:14]=[C:15]([C:18]=3[NH:19][C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[C:16]#[N:17])=[CH:8][C:7]=2[CH:29]=1)[CH3:32]
Reactant: N#Cc1cncc(-c2cc3cc(C=O)ccc3s2)c1Nc1cccc2[nH]ccc12
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C)Cc1ccc2sc(-c3cncc(C#N)c3Nc3cccc4[nH]ccc34)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To 5-(5-formyl-1-benzothien-2-yl)-4-(1H-indol-4-ylamino)nicotinonitrile 223 (166 mg, 0.38 mmol) in THF (7 mL) was added dimethylamine in THF (2.0 M, 0.58 mL, 1.15 mmol) followed by acetic acid (126 mg, 2.09 mmol). The resulting mixture was stirred at r.t. for 1 h and additional dimethylamine (1.2 mL, 2.30 mmol) was added. After stirring at r.t. for an additional hour, Na(OAc)3BH (242 mg, 1.15 mmol) was added. The reaction mixture was stirred at r.t. for 2 h and was partitioned between diluted HCl and EtOAc. The combined aqueous extracts were basified with aqueous NaHCO3 and extracted with EtOAc. The combined organics were dried over Na2SO4, concentrated and purified by flash column chromatography to give 115 mg (65%) of 5-{5-[(dimethylamino)methyl]-1-benzothien-2-yl}-4-(1H-indol-4-ylamino)nicotinonitrile 224 as a pale yellow solid. MS: 424.2 (M+H); HPLC retention time: 2.1 min.(a).
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[H-].[Na+].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:17]Br>O1CCCC1.CN(C)C=O.CN(C)C=O>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:17][O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:10]
Reactant: Fc1ccc(CBr)cc1F
Reactant: OCCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: OCCCCCCCCOCc1ccc(F)c(F)c1
Yield: 46.2 %

Procedure:
A solution of 1,8-octanediol (300 mg, 2.05 mmol) in tetrahydrofuran/N,N-dimethylformamide 2:1 (3 mL) was added dropwise at 0° C. to a suspension of sodium hydride (60% dispersion in mineral oil, 90 mg, 2.3 mmol) in N,N-dimethylformamide (1.5 mL), then after 2 h 3,4-difluorobenzyl bromide (445 mg, 2.15 mmol) was added. After 4 h the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded 8-(3,4-difluoro-benzyloxy)-octan-1-ol (258 mg, 46%). Colorless oil, m/e=273.3 ([M+H]+).
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].Cl[CH2:21][CH2:22][CH2:23][CH2:24][P:25]([O:30][CH2:31][CH3:32])(=[O:29])[O:26][CH2:27][CH3:28]>>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[N:12]([CH2:21][CH2:22][CH2:23][CH2:24][P:25](=[O:29])([O:30][CH2:31][CH3:32])[O:26][CH2:27][CH3:28])[CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Reactant: CCOP(=O)(CCCCCl)OCC
Product: CCCCn1c(=O)c2c(ncn2CCCCP(=O)(OCC)OCC)n(CCCC)c1=O

Procedure:
The title substance was prepared from 1,3-dibutylxanthine and diethyl 4-chlorobutanephosphonate analogously to Example 9.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][CH2:8][C@@H:7]([S:10]C(=O)C)[CH2:6]1)=[N+:2]=[N-:3]>O1CCCC1.C[O-].[Na+].CO>[N:1]([CH2:4][C@H:5]1[O:9][CH2:8][C@@H:7]([SH:10])[CH2:6]1)=[N+:2]=[N-:3]
Reactant: CC(=O)S[C@@H]1CO[C@H](CN=[N+]=[N-])C1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: [N-]=[N+]=NC[C@@H]1C[C@H](S)CO1
Yield: 64.8 %

Procedure:
The title compound is prepared by the procedure of Example 16 using 0.310 g of product from Example 61 in 4.5 ml of tetrahydrofuran and 0.30 ml of 25% sodium methoxide/methyl alcohol to give 0.159 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[N+:11]([O-])([OH:13])=[O:12].O>S(=O)(=O)(O)O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:4]([CH:3]=1)[C:5]([OH:7])=[O:6]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc(F)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a solution of 3-fluorobenzoic acid (7.9 g, 56 mmol) in conc. sulphuric acid (50 mL) cooled to 0° C. was added fuming nitric acid (4.7 g, 67 mmol) dropwise. After the addition the solution was warmed to room temperature and stirring continued for 1 h. The solution was poured into water (750 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to yield 5-fluoro-2-nitrobenzoic acid as a pale yellow solid (9.6 g, 52 mmol, 93%).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[CH2:9]([O:12][C:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][C:18](F)=[CH:19][CH:20]=2)[N:15]([CH3:25])[CH:14]=1)[CH:10]=[CH2:11]>O1CCOCC1>[CH2:9]([O:12][C:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][C:18]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:19][CH:20]=2)[N:15]([CH3:25])[CH:14]=1)[CH:10]=[CH2:11]
Reactant: OCC(F)(F)F
Reactant: C=CCOc1cn(C)c2cc(F)ccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=CCOc1cn(C)c2cc(OCC(F)(F)F)ccc2c1=O

Procedure:
2,2,2-Trifluoroethanol (7.0 ml) was added to a stirred suspension of sodium hydride (4.0 g of a 50% dispersion in mineral oil) in dioxan (60 ml). After 30 minutes 3-allyloxy-7-fluoro-1-methyl-4-quinolone (2.8 g) was added and the mixture heated under reflux for 24 hours. The solvent was removed by evaporation under reduced pressure at 40°. The residue was dissolved in water (150 ml) and the solution extracted with dichloromethane (3×150 ml). The combined extracts were dried over magnesium sulphate and evaporated to give the novel compound 3-allyloxy-1-methyl-7-(2,2,2-trifluoroethoxy)-4-quinolone, m.p. 120°.
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH:14]2[CH2:18][O:17][C:16]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[S:15]2)=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:43])C=1>C(Cl)Cl>[C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH2:13][CH:14]2[CH2:18][O:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[S:15]2)=[O:43])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSCC2COC(CCC(=O)O)(CCC(=O)O)S2)ccc(C(C)=O)c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCc1c(OCCCS(=O)CC2COC(CCC(=O)O)(CCC(=O)O)S2)ccc(C(C)=O)c1O
Yield: 44 %

Procedure:
The title compound was prepared according to the procedure of Example 46 using the sulfide obtained in Example 3 (0.15 g, 0.0003 mol) and m-chloroperbenzoic acid (0.062 g, 0.0003 mol) in methylene chloride (3 ml). The crude product was chromatographed on silica gel using ethyl acetate containing 0.5% acetic acid to give 0.070 g (45%) of the desired product as an oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:26]1([CH2:32][CH2:33][C:34](Cl)=[O:35])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:34](=[O:35])[CH2:33][CH2:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)CCc2ccccc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (99 mg, 0.40 mmol) and triethylamine (83 μL, 0.42 mmol) in methylene chloride (20 mL) was added dropwise 3-phenylpropionyl chloride (72 mg, 0.42 mmol) in methylene chloride (5 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 120 mg (61%) of the title compound as white crystals: mp 184-186° C.; [α]21D +6.5° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 374 (54, M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[C@H:4]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:5][C:6](=[O:30])[C@H:7]([CH2:26][C:27](=[O:29])[OH:28])[NH:8][C:9](=[O:25])[C@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1C(OCC1C=CC=CC=1)=O.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:38])[C@H:4]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[NH:5][C:6](=[O:30])[C@H:7]([CH2:26][C:27](=[O:28])[OH:29])[NH:8][C:9](=[O:25])[C@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1
Reactant: [H][H]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H]1CCCN1
Yield: 87.8 %

Procedure:
N-Benzyloxycarbonyl-D-prolyl-α-L-aspartyl-L-phenylalanine methyl ester (2.6 g) was dissolved in 100 ml of 80% aqueous acetic acid, and the solution was subjected to catalytic reduction in a hydrogen gas stream at room temerature for four hours using palladium/carbon as catalyst. After filtering off the catalyst, the filtrate was concentrated to dryness under reduced pressure, affording 1.7 g of white powder. M.p.: 238°-241.5° C.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH:12]=[O:13])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].Br[C:16](=[CH:18][CH3:19])[CH3:17].[Cl-].[NH4+]>O1CCCC1.O>[C:1]1([C:7]2[CH:11]=[C:10]([CH:12]([OH:13])[C:16]([CH3:17])=[CH:18][CH3:19])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC=C(C)Br
Reactant: O=Cc1cc(-c2ccccc2)no1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC=C(C)C(O)c1cc(-c2ccccc2)no1

Procedure:
To a solution of 5.0 g (28.9 mmol) of 3-phenyl-isoxazole-5-aldehyde in 40 ml of tetrahydrofuran, was added dropwise at -30° C. a solution of 1.5 g of metallic magnesium and 10.1 g (74.8 mmol) of 2-bromo-2-butene in 80 ml of tetrahydrofuran. After they were reacted at the same temperature for 30 minutes, the temperature of the reaction mixture was allowed to rise to room temperature and a saturated aqueous solution of ammonium chloride was added to terminate the reaction. Water was added, followed by extraction with ethyl ether. The organic layer was successively washed with water and saturated saline and then dried over anhydrous sodium sulfate. After ethyl ether was distilled off, the residue was purified by chromatography on a silica gel column (eluent: 9:1 hexane/ethyl acetate) so that 3-phenyl-5-(1-hydroxy-2-methyl-2-butenyl)isoxazole was obtained as oil.
Reaction SMILES: [BH4-].[Na+].[F:3][CH:4]1[C:9](=[O:10])[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1>CO>[C:14]([O:13][C:11]([N:6]1[CH2:7][CH2:8][C@@H:9]([OH:10])[C@H:4]([F:3])[CH2:5]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](F)C1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 49.6 %

Procedure:
Sodium borohydride (1.53 g, 40.5 mmol) was added to a stirred solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (OmegaChem, 8 g, 36.8 mmol) in dry methanol (100 mL) maintained at 0° C. The reaction mixture was stirred at same temperature for 45 min, it was then quenched with dry acetone (20 mL) and evaporated under reduced pressure. The residue was diluted with EtOAc and washed with water and brine. It was dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica (Pet. Ether: EtOAc, 80:20) afforded the titled compound as white solid (4.0 g, 50%). 1H NMR (400 MHz, DMSO-d6) δ 4.61 (ddd, J=39, 8.6, 3.2 Hz, 1H), 3.93 (m, 2H), 3.71 (bs, 1H), 3.42 (brs, 1H), 3.06-3.00 (m, 1H), 1.88-1.83 (m, 2H), 1.45 (s, 9H). HPLC (Condition A): Rt 2.7 min (purity 97%).
Reaction SMILES: [NH2:1][C:2]1([C:18]2[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][N:19]=2)[C:15]2[CH:14]=[C:13]([Cl:16])[N:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:17])=[CH:6][CH:7]=2.C([O-])(=O)C.[K+].[N:30]#[C:31]Br.C(Cl)Cl>CO>[Br:17][C:5]1[CH:4]=[C:3]2[C:2]3([C:18]4[N:19]=[CH:20][CH:21]=[CH:22][C:23]=4[O:24][C:31]([NH2:30])=[N:1]3)[C:15]3[CH:14]=[C:13]([Cl:16])[N:12]=[CH:11][C:10]=3[O:9][C:8]2=[CH:7][CH:6]=1
Reactant: N#CBr
Reactant: NC1(c2ncccc2O)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: NC1=NC2(c3cc(Br)ccc3Oc3cnc(Cl)cc32)c2ncccc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)pyridin-3-ol (0.40 g, 1.00 mmol) in MeOH 5 mL was added potassium acetate (0.13 mL, 1.99 mmol) followed by the dropwise addition of cyanogen bromide, 3.0M solution in DCM (0.40 mL, 1.20 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was concentrated, washed with saturated NaHCO3, extracted with DCM, dried over sodium sulfate and concentrated. The resulting product was dissolved in 1,2-dichloroethane followed by the addition of 4.0 M HCl in dioxane (15 mL) and stirred at RT for 1.5 h. The reaction mixture was concentrated, diluted with DCM and washed with sat NaHCO3, brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography on silica gel using 0-100% EtOAc/hexanes to give 0.18 g of desired product.
Reaction SMILES: Cl[C:2]1[N:11]2[CH:12]=[N:13][N:14]=[C:10]2[C:9]2[CH:8]=[C:7]([O:15][CH3:16])[C:6]([O:17][CH3:18])=[CH:5][C:4]=2[N:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(O)C>[O:22]1[CH2:23][CH2:24][N:19]([C:2]2[N:11]3[CH:12]=[N:13][N:14]=[C:10]3[C:9]3[CH:8]=[C:7]([O:15][CH3:16])[C:6]([O:17][CH3:18])=[CH:5][C:4]=3[N:3]=2)[CH2:20][CH2:21]1
Reactant: C1COCCN1
Reactant: COc1cc2nc(Cl)n3cnnc3c2cc1OC
Solvent: CCO
Product: COc1cc2nc(N3CCOCC3)n3cnnc3c2cc1OC

Procedure:
A mixture of 10.0 g. of 5-chloro-8,9-dimethoxy-1,2,4-triazolo[4,3-c]quinazoline, 38.8 g. of morpholine and 100 ml. of ethanol is refluxed for 1.5 hours and the resulting mixture evaporated in vacuo to dryness. The residue is taken up with ethanol and diethyl ether and filtered. The resulting solid is then recrystallized from benzene, filtered, washed with diethyl ether, recrystallized from ethanol and dried in a high vacuum to obtain 5-morpholino-8,9-dimethoxy-1,2,4-triazolo[4,3-c]quinazoline, m.p. 216°-218° C.
Reaction SMILES: C(OP(=O)(OCC)O[C:6]([CH3:26])([CH3:25])[C:7]#[C:8][C:9]1[CH:24]=[CH:23][C:12]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)=[N:14][S:15][C:11]=2[CH:10]=1)C.[CH2:31]([NH:33][CH2:34][CH2:35][OH:36])[CH3:32].C1COCC1.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Br:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[C:12]3[CH:23]=[CH:24][C:9]([C:8]#[C:7][C:6]([N:33]([CH2:31][CH3:32])[CH2:34][CH2:35][OH:36])([CH3:25])[CH3:26])=[CH:10][C:11]=3[S:15][N:14]=2)=[CH:21][CH:20]=1
Reactant: CCOP(=O)(OCC)OC(C)(C)C#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CCNCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(CCO)C(C)(C)C#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Temperature: 50 °C

Procedure:
To 45 mg (0.09 mmol) Phosphoric acid 3-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-1,1-dimethyl-prop-2-ynyl ester diethyl ester and 16 μl (0.18 mmol) 2-Ethylaminoethanol in 0.5 ml THF 10.2 mg (0.01 mmol) tetrakis(triphenylphosphine)palladium was added and the suspension stirred at 50° C. over night. The mixture was added to a saturated aqueous solution of NaHCO3 and EtOAc, the phases were separated and the inorganic one was extracted with EtOAc. The combined organic phases were washed with brine and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2:MeOH 95:5 gave 2-((3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6 yl]-1,1-dimethyl-prop-2-ynyl)-ethyl-amino)-ethanol as yellow semisolid, MS: 443 (MH+, 1Br).
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N+:9]([C:12]1[C:13]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[N+:9]([C:12]1[C:13]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:25][CH:24]=2)=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)([O-:11])=[O:10]
Reactant: CCOC(=O)C(C)Br
Reactant: O=[N+]([O-])c1cc2ccccc2nc1Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(Nc2nc3ccccc3cc2[N+](=O)[O-])cc1

Procedure:
A mixture of ethyl 2-bromopropionate (0.5 g), 4-[N-(3-nitro-2-quinolinyl)amino]phenol (0.5 g), anhydrous potassium carbonate (0.3 g) and ethyl methyl ketone (20 ml) was refluxed for 4 hours. The solvent was removed under reduced pressure and the residue was partitioned between methylene chloride and water. The organic layer was dried and evaporated to give ethyl 2-{4-[N-(3-nitro-2-quinolinyl)amino]phenoxy}propionate as an orange oil which was purified by chromatography over silica gel. Proton magnetic resonance spectrum: (CDCl3, δ in ppm): 9.6 (1H, s, NH); 8.9 (1H, s, C4 quinoline proton); 7.8-7.6 (4H, m, quinoline protons); 6.8 (4H, s, phenyl protons); 4.6 (1H, q, CHCH3); 4.2 (2H, q, OCH2CH3); 1.6 (3H, d, CHCH3); 1.2 (3H, t, OCH2CH3).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1.N1N=CN(C2C=[C:21]3C(=CC=2)NC=[C:22]3[CH2:28][CH2:29][OH:30])C=1>CO>[N:1]1([CH2:6][C:7]2[CH:13]=[C:12]3[C:10](=[CH:9][CH:8]=2)[NH:11][CH:21]=[C:22]3[CH2:28][CH2:29][OH:30])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Nc1ccc(Cn2cncn2)cc1
Reactant: OCCc1c[nH]c2ccc(-n3cnnc3)cc12
Solvent: CO
Product: OCCc1c[nH]c2ccc(Cn3cncn3)cc12

Procedure:
Prepared from 4-(1,2,4-triazol-1-ylmethyl)aniline (EP497512) as described for Intermediate 3, δ (250 MHz, D4 -MeOH) 2.96 (2H, t, J=7.2 Hz, CH2), 3.80 (2H, t, J=7.2 Hz, CH2), 5.46 (2H, s, CH2), 7.08 (1H, dd, J=1.7 and 8.6 Hz, Ar--H), 7.11 (1H, s, Ar--H), 7.33 (1H, d, J=8.6 Hz, Ar--H), 7.58-7.59 (1H, d, J=1.7 Hz, Ar--H), 7.97 (1H, s, Ar--H), 8.44 (1H, s, Ar--H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1.COC1C(C=O)=CC=C2C=1[CH:24]=[N:25][N:26]2[CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38]>>[CH3:19][O:18][C:5]1[C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:2]=[C:3]2[C:4]=1[CH:24]=[N:25][N:26]2[CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38]
Reactant: COc1c(C=O)ccc2c1cnn2COCC[Si](C)(C)C
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Product: COc1c(C(O)C#Cc2ccccc2)ccc2c1cnn2COCC[Si](C)(C)C
Yield: 98 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 4-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-5-carbaldehyde was reacted to give the title compound as a colourless oil (100 mg, 98%). LCMS (Method B): RT=4.84 min, [M+Na]+=431.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH2:18][CH2:17]2.C(N(CC)CC)C>ClCCl>[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH2:18][CH2:17]2
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1ccc2c(c1)CCN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)N2CCc3cc(Br)ccc32)cc1
Temperature: 25 °C

Procedure:
5.09 g of commercially available 4-cyano-benzenesulfonyl chloride were dissolved in 125 ml dichloromethane. Then 5.0 g 5-Bromo-2,3-dihydro-1H-indole were added followed by 12.2 ml triethylamine. The mixture was stirred at room temperature for thirty minutes. Then the solvent was removed in vacuo. The residue was diluted with 100 ml of ethyl acetate and the mixture washed with 100 ml water and 100 ml saturated NaHCO3 solution. The organic layer was then dried over MgSO4. The solvent was removed in vacuo. The resulting crude material was purified by chromatography on silica gel to obtain 5.46 g of 4-(5-Bromo-2,3-dihydro-indole-1-sulfonyl)-benzonitrile.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17][OH:18])[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[CH3:27][C:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[CH:30][N:29]=1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C@:13]2([CH2:16][CH2:17][OH:18])[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:32]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:27])[CH:33]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:20][CH:21]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCO)(c4ccc(F)cc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=0.945 min, m/z=435.5; 1H NMR (CD3OD) 1.56 (d, 3H), 1.92 (m, 1H), 2.01 (m, 1H), 2.17 (m, 2H), 2.36 (m, 2H), 2.48 (m, 1H), 2.56 (m, 3H), 3.12 (m, 1H), 3.62 (m, 1H), 5.62 (m, 1H), 7.05 (m, 4H), 7.30 (m, 2H), 7.44 (m, 1H), 7.54 (m, 3H), 8.39 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:4]=1[NH2:5].Br[C:20]1[N:24]([CH2:25][CH2:26][O:27][CH3:28])[C:23]([CH3:29])=[N:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([C:20]2[N:24]([CH2:25][CH2:26][O:27][CH3:28])[C:23]([CH3:29])=[N:22][CH:21]=2)[CH:7]=[CH:6][C:4]=1[NH2:5]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: COCCn1c(Br)cnc1C
Product: COCCn1c(-c2ccc(N)c(OC)c2)cnc1C

Procedure:
The title compound was prepared according to the method described for Preparation 158 using 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and 5-bromo-1-(2-methoxyethyl)-2-methyl-1H-imidazole (Preparation 209).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH:24]([CH2:28][OH:29])[CH2:23]1.C([Li])CCC>CCCCCC.O1CCCC1>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:22]3[CH2:27][CH2:26][CH2:25][CH:24]([CH2:28][OH:29])[CH2:23]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Reactant: OCC1CCCNC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1nc(-c2ccccc2)nc2ccccc12)N1CCCC(CO)C1

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (3 g), piperidine-3-methanol (2.9 g), a 1.6M solution of butyllithium in hexane (31 ml) and tetrahydrofuran (20 ml) as the starting materials. After recrystallisation from ethyl acetate, 1-[(2-phenylquinazolin-4-yl)-carbonyl]-piperidine-3-methanol (1 g), melting at 142° C., is obtained.