Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([Cl:22])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[OH:23][C:24]1[CH:35]=[CH:34][CH:33]=[CH:32][C:25]=1[O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[Cl:22][C:14]1[CH:13]=[C:12]([O:11][C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH:3]=2)[O:23][C:24]2[CH:35]=[CH:34][CH:33]=[CH:32][C:25]=2[O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:17]=[CH:16][C:15]=1[C:18]([F:21])([F:20])[F:19]
Reactant: COC(=O)COc1ccccc1O
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)c(Cl)c2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)COc1ccccc1Oc1cc(Oc2ccc(C(F)(F)F)c(Cl)c2)ccc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 20.1 %

Procedure:
A mixture of 2-chloro-α,α,α-trifluoro-p-tolyl 3-fluoro-4-nitrophenyl ether (1.0 g, 3.0 mmol), methyl (o-hydroxyphenoxy)acetate (0.81 g, 4.5 mmol) and potassium carbonate (0.62 g, 4.5 mmol) in N,N-dimethylformamide is heated at 50° C. for 18 hours, cooled to room temperature, poured into water and extracted with ether. The organic extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a white oil. Column chromatography of the oil using silica gel and a 15% ethyl acetate in hexanes solution gives the title product as a clear liquid (0.3 g) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:39][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: NC1CCCCC1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)NC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.6 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Cyclohexylamine (2.77 g, 0.028 mole) was added and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated to dryness and the residue was treated with water. The solid was collected by filtration, washed with water, and dried under high vacuum over the weekend. The solid was recrystallized from isopropyl alcohol-95% ethanol, collected by filtration, washed with water, and dried under high vacuum at 50° C. overnight to give 3.75 g (73%) of crystals, mp 240°-241° C.
Reaction SMILES: [CH2:1]([OH:14])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].ClCCl>CN(C)C=O>[Si:20]([O:14][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCC#CC#CCCCCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCC#CC#CCCCCO
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5,7-Dodecadiyn-1,12-diol (1) (4 g, 20.6 mmol) and imidazole (2.8 g, 41 mmol) were dissolved in dimethylformamide (15 ml). To the solution, tert-butyldimethylsilylchloride (2.38 g, 18.8 mmol) was added at once. The solution was stirred for 20 hours at room temperature under a nitrogen atmosphere. At this point, the reaction mixture was transferred into a separatory funnel along with dichloromethane (100 ml) and washed with saturated sodium bicarbonate solution and water successively. The organic layer was died (MgSO4) and concentrated followed by purification of the residue by flash column chromatography (silica gel, 7% acetone in dichloromethane) affording 3.17 g of a pale yellow oil (55% yield) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:13]=3[CH:28]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].N[C:30]([CH3:34])([CH3:33])[CH2:31][OH:32]>C1(Cl)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH3:33][C:30]1([CH3:34])[CH2:31][O:32][C:1]([C:3]2[CH:4]=[C:5]([C:9]3[CH:10]=[CH:11][C:12]4[O:16][C:15]([C:17]5[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=5)=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:13]=4[CH:28]=3)[CH:6]=[CH:7][CH:8]=2)=[N:2]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C#N)c3)cc12
Reactant: CC(C)(N)CO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C4=NC(C)(C)CO4)c3)cc12
Temperature: 200 °C
Reaction time: 168 h
Yield: 14.6 %

Procedure:
Zinc chloride (1 mg) was added to a stirring solution of 5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (40 mg, 0.108 mmol) and 2-amino-2-methylpropan-1-ol (10 mg, 0.108 mmol) in PhCl (3 mL) at 130° C. It was allowed to stir for 7 days. ˜20% conversion was observed. Additional amounts of ZnCl (8 mg) and 2-amino-2-methylpropan-1-ol (50 mg) were added and the reaction was heated in the microwave for 1 hr at 200° C. The reaction had progressed ˜50%. The mixture was concentrated and purified on silica gel (Biotage, EtOAc/hexanes gradient, Rf ˜0.2 in 50% EtOAc/hexanes; fraction collection at λ=254 nm) followed by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (7 mg, 14%). 1H NMR (500 MHz, CD3OD) δ ppm 8.24 (1 H, s), 7.97 (2 H, dd, J=8.09, 5.65 Hz), 7.93 (1 H, s), 7.88 (2 H, dd, J=11.44, 8.39 Hz), 7.68 (2 H, s), 7.57 (1 H, t, J=7.78 Hz), 7.27 (2 H, t, J=8.55 Hz), 4.25 (2 H, s), 2.99 (3 H, s), 1.42 (6 H, s). LC-MS retention time 1.60 min; m/z (MH+): 443. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=12.24 min, purity=95%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 μm, Rt=10.02 min, purity=95%.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:40][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Reactant: NCc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NCc4ccccc4)ncnc32)[C@]1(C)F
Yield: 95.9 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.2 g, 0.43 mmol) in ethanol (about 8 ml) was added benzylamine (about 0.56 ml, 5.19 mmol) and refluxed for about 30 minutes. Completion of the reaction monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 3% methanol in dichloromethane as eluent furnished title compound (0.22 g) as a colorless solid. Yield: 97%; 1H NMR (300 MHz, CDCl3): δ 8.44 (s, 1H), 8.13-7.96 (m, 3H), 7.59-7.57 (m, 1H), 7.49-7.28 (m, 7H), 6.57 (d, 1H, J=23.1 Hz), 6.24 (bs, 1H), 4.89-4.79 (m, 3H), 4.50-4.43 (m, 1H), 2.18 (s, 3H), 1.90 (d, 3H, J=2.1 Hz), 1.47 (d, 3H, J=23.1 Hz); Mass: [M+1]+ 534 (85%), [M+Na]+ 556 (100%). IR cm−: 3385, 1751, 1720, 1619, 1528, 1476, 1369, 1274, 1062, 712; HPLC: 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([N:65]([CH2:74][CH3:75])[CH2:66][CH2:67][CH:68]1[CH2:73][CH2:72][CH2:71][CH2:70][NH:69]1)[CH3:64]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:69]1[CH2:70][CH2:71][CH2:72][CH2:73][CH:68]1[CH2:67][CH2:66][N:65]([CH2:63][CH3:64])[CH2:74][CH3:75])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCN(CC)CCC1CCCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN(CC)CCC1CCCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-(2-diethylamino-ethyl)-piperidine in DMSO at ambient temperature.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@H:11]3[CH2:15][C@H:14]([OH:16])[C@H:13]([CH2:17][OH:18])[CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C=O)C>[NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@H:11]3[CH2:15][C@H:14]([OH:16])[C@H:13]([CH2:17][O:18][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1ccn2[C@@H]1C[C@@H](CO)[C@@H](O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](n2ccc3c(N)ncnc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of (1S,2S,4R)-4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)cyclopentanol (43.0 mg, 0.173 mmol) and imidazole (25.0 mg, 0.367 mmol) in dry DMF (2.00 mL) at 0° C. was added tert-butyldimethylsilyl chloride (29.0 mg, 0.192 mmol). The solution was stirred at rt for 2 h and concentrated in vacuo, the residue was dissolved in water and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (50.8 mg, 81%), which was taken on without further purification. LC/MS: Rt=1.38 min, ES+ 364 (FA standard).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:25]=[O:26])[C:8]2[C:9](=[O:24])[N:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=3[CH2:22][OH:23])[N:11]=[CH:12][C:13]=2[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].ClC(Cl)C.[BH4-].[Na+].Cl>CO>[C:1]([C:5]1[CH:14]=[C:13]2[C:8](=[C:7]([CH2:25][OH:26])[CH:6]=1)[C:9](=[O:24])[N:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[CH2:22][OH:23])[N:11]=[CH:12]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C=O)c2c(=O)n(-c3cccc(Cl)c3CO)ncc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CO
Product: CC(C)(C)c1cc(CO)c2c(=O)n(-c3cccc(Cl)c3CO)ncc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 26.4 %

Procedure:
The above 7-tert-butyl-3-[3-chloro-2-(hydroxymethyl)phenyl]-4-oxo-3,4-dihydrophthalazine-5-carbaldehyde (147 mg, 0.396 mmol) was combined with dichloroethane (5 mL) and methanol (5 mL) to give a yellow solution. Sodium borohydride (27 mg, 0.714 mmol) was added and the mixture was stirred at room temperature for 4 hrs. The mixture was treated with 1N hydrochloric acid and extracted with dichloromethane. The organic layer was washed with brined and dried over sodium sulfate. After the evaporation of solvents, the residue was purified by flash column chromatography (silica gel 40 g, 0% to 40% ethyl acetate in heptane) to give 6-tert-butyl-2-[3-chloro-2-(hydroxymethyl)phenyl]-8-(hydroxymethyl)phthalazin-1(2H)-one as a light yellow solid (39 mg, 26.4%). LC/MS calcd for C20H21ClN2O3 (m/e) 372.12, obsd 371.1 (M−H, ES−).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=3)[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20].CO>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:1]1([N:7]2[CH:11]=[C:10]([C:12]3[CH2:13][CH2:14][N:15]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH2:16][CH:17]=3)[N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)OC(=O)Cl
Reactant: C1=C(c2cn(-c3ccccc3)nn2)CCNC1
Solvent: c1ccncc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)OC(=O)N1CC=C(c2cn(-c3ccccc3)nn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[1-phenyl-1H-[1,2,3]triazol-4-yl]-1,2,3,6-tetra-hydropyridine (35 mg) prepared in the above 1) was dissolved in 1 ml of pyridine and 1 ml of chloroform, 32 μl of isopropyl chloroformate was added and the mixture was stirred at room temperature for 1 hour. After an excessive reagent was decomposed by addition of methanol, the reaction solution was concentrated in vacuo and the resulting residue was separated and purified by a preparative thin-layer chromatography (chloroform/methanol 60/1) to give 47 mg of the title compound as a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[C:13]([C:20]([OH:22])=O)=[CH:12]2)=[CH:7][CH:6]=1>>[ClH:3].[Cl:3][C:20]([C:13]1[C:14]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:11]([C:8]2[CH:9]=[CH:10][N:5]=[CH:6][CH:7]=2)[CH:12]=1)=[O:22]
Reactant: O=C(O)c1cn(-c2ccncc2)c2ncccc12
Reactant: O=S(Cl)Cl
Product: Cl
Product: O=C(Cl)c1cn(-c2ccncc2)c2ncccc12

Procedure:
15 cm3 of thionyl chloride were added, at a temperature in the region of 25° C. under an argon atmosphere, to 1.67 g (7 mmol) of 1-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid. After stirring at reflux for 2 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The residue was 3 times in succession triturated with 20 cm3 of dichloromethane and then concentrated to dryness under reduced pressure (2.7 kPa) to give 1.8 g of 3-chlorocarbonyl-1-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride in the form of a yellow powder which was used directly in the following stage.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](O)=[O:9])[CH:5]=[N:6][CH:7]=1.CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)c1cncc(Br)c1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CO
Product: OCc1cncc(Br)c1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 75.2 %

Procedure:
To a solution of 12 g (59.4 mmol) of 5-bromopyridine-3-carboxylic acid in 300 mL of anhydrous THF, under argon, are added, at −10° C., 6.6 mL of NMM and then 5.7 mL (59.4 mmol) of ethyl chloroformate. After stirring for 20 minutes at −10° C., 6.8 g (179.8 mmol) of sodium borohydride are added portionwise. The medium is then cooled to −70° C. and 400 mL of MeOH are added over 1 hour 30 minutes. The temperature is then allowed to rise to room temperature and stirring is continued for 12 hours. The medium is then concentrated under reduced pressure and then purified by chromatography on a column of silica gel, eluting with a 98/2 DCM/MeOH mixture. 8.4 g of (5-bromopyridin-3-yl)methanol are obtained in the form of a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][CH3:14].[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][CH3:14])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(=O)[nH]cnc2cc1O
Solvent: c1ccncc1
Product: COc1cc2c(=O)[nH]cnc2cc1OC(C)=O
Temperature: 120 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
Pyridine (20 ml) was added to a suspension of 7-hydroxy-6-methoxy-3,4-dihydroquinazolin-4-one (20.5 g, 107 mmol) in acetic anhydride (150 ml, 1.6 mol). The reaction mixture was heated to 120° C. for three hours, during which time the solid dissolved. The reaction mixture was allowed to cool then poured into ice-water (900 ml). The reaction mixture was stirred for one hour then the solid was removed by filtration and dried over phosphorus pentoxide yielding 7-acetoxy-6-methoxy-3,4-dihydroquinazolin-4-one as a white solid (20.98 g, 84%).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)(=O)=O.O.[C-:21]#[N:22].[Na+]>C(O)C>[C:21]([CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)#[N:22]
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CC#N)CC1
Reaction time: 24 h
Yield: 58.7 %

Procedure:
tert-Butyl 4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (15.3 g) was dissolved in ethanol (80 mL), water (20 mL) and sodium cyanide (4.0 g, 80 mmol) were added, and stirring was conducted at 80° C. for 24 hours. Ethanol was distilled off, water and ethyl acetate were added, and then the resultant mixture was subject to Celite filtration, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure, and the obtained residue was purified by using silica gel column chromatography (hexane:ethyl acetate=3:1→2:1) to give tert-butyl 4-(cyanomethyl)piperidine-1-carboxylate (6.87 g, 77%, 3 steps) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:22][C:23]1[CH:31]=[C:30]2[C:26]([CH:27]=[CH:28][NH:29]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[NH:29]1[C:30]2[C:26](=[CH:25][CH:24]=[C:23]([O:22][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH:31]=2)[CH:27]=[CH:28]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCS(C)(=O)=O
Reactant: Oc1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cc[nH]c4c3)ncnc2cc1OCCCS(C)(=O)=O
Temperature: 90 °C
Yield: 50.7 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (200 mg, 0.6 mmol), (prepared as described for the starting material in Example 50), and 6-hydroxyindole (97 mg, 0.73 mmol) in DMF (3 ml) containing potassium carbonate (125 mg, 0.91 mmol) was heated at 90° C. for 2.5 hours. After cooling, water was added. The precipitate was filtered, washed with water and dried under vacuum. The residue was triturated with ether, filtered, washed with ether and dried under vacuum to give 4-(indol-6-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (130 mg, 50%).
Reaction SMILES: O.O[C:3]1(O)[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([Cl:20])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]1[C:21](=[O:24])[CH:22]=[O:23].O[C:27]1(O)C=C(OC2C3C(=CC=CC=3)C(Cl)=CC=2)C=C[CH:28]1C(=O)C=O.[NH2:50][C:51]1[CH:59]=[CH:58][C:54]([C:55]([OH:57])=[O:56])=[CH:53][CH:52]=1.C(=O)C>>[Cl:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:9][C:7]2[CH:8]=[CH:3][C:4]([C:21](=[O:24])[CH:22]([NH:50][C:51]3[CH:59]=[CH:58][C:54]([C:55]([OH:57])=[O:56])=[CH:53][CH:52]=3)[O:23][CH2:27][CH3:28])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=CC(=O)C1C=CC(Oc2ccc(Cl)c3ccccc23)=CC1(O)O
Agent: CC=O
Solvent: O
Product: CCOC(Nc1ccc(C(=O)O)cc1)C(=O)c1ccc(Oc2ccc(Cl)c3ccccc23)cc1

Procedure:
A mixture of 4.2 g. of 2,2-dihydroxy-4-(4-chloro-1-naphthyloxy)-α-oxo-benzeneacetaldehyde hemihydrate, 1.76 g. of p-aminobenzoic acid and 30 ml. of absolute ethanal was refluxed overnight under argon. The solid was collected, boiled in ethanol, cooled and filtered, giving the desired product as a pale yellow solid, m.p. 155°-165° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]2([CH2:19][C:18]3[C:20]([CH3:27])=[C:21]([OH:26])[C:22]([CH3:25])=[C:23]([CH3:24])[C:17]=3[O:16]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1.O>CN(C)C=O>[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]2([CH2:19][C:18]3[C:20]([CH3:27])=[C:21]([O:26][CH2:34][C:33]4[CH:36]=[CH:37][C:30]([O:29][CH3:28])=[CH:31][CH:32]=4)[C:22]([CH3:25])=[C:23]([CH3:24])[C:17]=3[O:16]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1c(C)c2c(c(C)c1O)CC1(CCN(Cc3ccccc3)CC1)O2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2c(C)c(C)c3c(c2C)CC2(CCN(Cc4ccccc4)CC2)O3)cc1
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
Sodium hydride (60% liquid paraffin dispersion, 134.6 mg, 3.37 mmol) was added to a solution of 1′-benzyl-4,6,7-trimethylspiro[benzofuran-2(3H),4′-piperidine]-5-ol (1.01 g. 2.98 mmol) in N,N-dimethylformamide (15 mL) at 0° C., and the mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was added 4-methoxybenzyl chloride (584.9 mg, 3.43 mmol) and the mixture was stirred for further 30 minutes at room temperature. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain the title compound (1.15 g, yield 85%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6](Cl)(=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl[Sn](Cl)(Cl)Cl.Cl>C1C=CC=CC=1>[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC(=O)Cl
Reactant: c1ccsc1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCC(=O)c1cccs1
Yield: 77.1 %

Procedure:
In a 5 liter-five-necked flask, 187.3 g (2.23 mol) of thiophene, 300 g (2.23 mol) of n-hexanoyl chloride and 2.7 liter of dry benzene were placed and cooled below 0° C. To the mixture under stirring, 237.9 g (9.13×10-1 mol) of SnCl4 was added dropwise in 1 hour below 0° C. The mixture was stirred for 30 min. below 0° C., followed by stirring for 3.5 hours while being gradually restored to room temperature. After the reaction, 2 liter of 10% HCl was added to the reaction mixture, followed by stirring for 10 min. The separated organic layer was successively washed three times with 500 ml each of 10% HCl, water, 5% Na2CO3 and water, followed by drying with CaCl2 and distilling-off of the solvent to obtain 408 g of a crude product. The crude product was subjected to reduced-pressure distillation in an atmosphere of nitrogen to obtain 313.4 g of a pure product (yield: 77.2%).