Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2]([SH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O[CH:14]1[NH:17][C:16](=[O:18])[CH2:15]1)(=O)C>C(O)C>[CH2:2]([S:9][CH:14]1[NH:17][C:16](=[O:18])[CH2:15]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: SCc1ccccc1
Reactant: CC(=O)OC1CC(=O)N1
Agent: [Na]
Solvent: CCO
Product: O=C1CC(SCc2ccccc2)N1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
Sodium (8.1 g, 0.35 mol) was dissolved in ethanol (250 ml) and benzyl mercaptan (45.2 g, 0.37 mol) added dropwise over 20 minutes keeping the temperature between 20° C.-25° C. whilst bubbling nitrogen through the mixture. After 15 minutes, the reaction was cooled to 5° C. and a solution of 4-acetoxyazetidin-2-one (45.0 g, 0.35 mol) in ethanol (50 ml) was added dropwise over 15 minutes whist maintaining the temperature at 5° C. The mixture was stirred at room temperature for 60 minutes and evaporated to dryness under reduced pressure. Water (500 ml) was added, the mixture extracted with dichloromethane (2×300 ml), the extracts dried (MgSO4) and evaporated under reduced pressure to an oil. The oil was cooled to -20° C. and titurated with ether (400 ml) to give a white solid which was isolated by filtration (50.2 g, 79%), mp 50-51.0° C.
Reaction SMILES: CS(C)=O.[CH3:5][C:6]([O:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])([CH3:8])[CH3:7].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26](F)[CH:27]=1)[C:23]#[N:24].C(=O)([O-])[O-].[K+].[K+]>O>[C:23]([C:22]1[CH:25]=[C:26]([N:16]2[CH2:15][CH2:14][CH:13]([NH:12][C:10](=[O:11])[O:9][C:6]([CH3:5])([CH3:7])[CH3:8])[CH2:18][CH2:17]2)[CH:27]=[C:20]([F:19])[CH:21]=1)#[N:24]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: N#Cc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(F)cc(C#N)c2)CC1
Temperature: 100 °C
Yield: 85 %

Procedure:
A DMSO (25 mL, 0.1M) solution containing 4-N—BOC-aminopiperidine (500 mg, 2.5 mmol, 1.0 eq), 3,5-difluorobenzonitrile (348 mg, 2.5 mmol, 1.0 eq), and potassium carbonate (691 mg, 5.0 mmol, 2.0 eq) was heated to 100° C. for 18 h. The resulting mixture was cooled to RT, poured in H2O (ca 50 mL), and extracted (3×) with EtOAc. The combined extracts were washed (2×) with H2O, dried over MgSO4, and concentrated in vacuo. The resulting solid was purified via flash chromatography using 1:1 hexanes/EtoAc as the mobile phase. Isolated 677 mg (2.12 mmol, 85% yield).
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:25][CH2:24][C:19]3(OCC[O:20]3)[CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:26][CH3:27])[N:7]=1>Cl.C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:25][CH2:24][C:19](=[O:20])[CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:26][CH3:27])[N:7]=1
Reactant: COc1cc(NS(=O)(=O)N2CCC3(CC2)OCCO3)nc(SCc2cccc(F)c2F)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(NS(=O)(=O)N2CCC(=O)CC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-{2-[(2,3-Difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}-1,4-dioxa-8-azaspiro[4.5]decane-8-sulfonamide (the product of step (0.85 g) was heated to 50° C. in a mixture of 2M aqueous hydrochloric acid (17 mL) and THF (17 mL). After 24 h, the reaction was allowed to cool to room temperature then diluted with ethyl acetate, the layers separated and the organic material washed with saturated aqueous sodium bicarbonate, water, saturated aqueous sodium chloride, dried with sodium sulfate, filtered and evaporated to afford the subtitle compound as a yellow oil. Yield: 0.83 g
Reaction SMILES: Cl.[OH:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[OH-].[Na+].Br[C@@H:12]([CH3:16])[C:13]([OH:15])=[O:14].Cl>>[O:2]=[C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]1[CH:12]([CH3:16])[C:13]([OH:15])=[O:14]
Reactant: Oc1ncccn1
Reactant: C[C@H](Br)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)n1cccnc1=O
Temperature: 80 °C

Procedure:
To 2-hydroxypyrimidine hydrochloride (1.27 g, 9.54 mmol) was added 5 N sodium hydroxide solution (5.7 mL) followed by (2S)-2-bromopropanoic acid (0.95 mL, 11 mmol). The reaction mixture was heated at 80° C. for 4 h. After cooled down to ambient temperature, it was neutralized with 2N hydrochloric acid (4.8 mL) and then directly purified by reverse phase HPLC (TMC Pro-Pac C18; 0-50% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). Removal of the volatiles in vacuo afforded the title compound as a white solid. LC/MS 169.1 (M+1).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:6]=1[C:7](OC)=[O:8].N.C(O)CO>>[N+:15]([C:13]1[CH:14]=[C:5]2[C:6](=[CH:11][CH:12]=1)[C:7](=[O:8])[NH:2][CH:3]=[CH:4]2)([O-:17])=[O:16]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1/C=C/N(C)C
Agent: N
Solvent: OCCO
Product: O=c1[nH]ccc2cc([N+](=O)[O-])ccc12
Temperature: 140 °C
Yield: 85 %

Procedure:
To Intermediate 3B (1.54 g, 6.15 mmol) in a microwave tube was added 8.0 N ammonia in ethylene glycol (7.69 mL, 61.5 mmol). The tube was placed in microwave and heated at 140° C. for 30 min. The reaction mixture was triturated with EtOAc, stored at 0° C. over night. The precipitate was collected to give Intermediate 3C (0.995 g, 5.23 mmol, 85% yield) as a brown solid. The filtrate was washed with water. The organic layer was dried over sodium sulfate. After evaporation of solvent, the crude was triturated with EtOAc to give additional product. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.35 (br. s., 1H) 8.63 (d, J=2.20 Hz, 1H) 8.39 (d, J=8.79 Hz, 1H) 8.19 (dd, J=8.79, 2.20 Hz, 1H) 7.36 (d, J=7.03 Hz, 1H) 6.82 (d, 1H); MS (ESI) m/z: 191.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][CH:7]=[N:6][C:5]2=[O:14].CO.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:24][CH3:25]>O.CC#N>[CH2:24]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][CH:7]=[N:6][C:5]2=[O:14])[CH3:25]
Reactant: COc1cc2[nH]cnc(=O)c2cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CC#N
Solvent: O
Product: CCOc1cc2c(=O)nc[nH]c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
A mixture of 6-hydroxy-7-(methyloxy)-4(1H)-quinazolinone (1 g, 5.2 mmol) in water (12 mL), MeCN (6 mL), and MeOH (1 mL) at 25° C. was treated with Cs2CO3 (1.7 g, 5.2 mmol). After the mixture was stirred for 30 minutes, iodoethane (0.42 mL, 5.2 mmol) was added and the mixture was stirred at 60° C. for 40 hours before being cooled to room temperature. The solid was collected by filtration and washed with MeOH to give 6-(ethyloxy)-7-(methyloxy)-4(1H)-quinazolinone (560 mg, 49%). MS (m/z) 221.1 (M+H+).
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[CH2:27][CH2:28]Br.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C.C(OCC)(=O)C.O>[C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:28][CH2:27][C:26]3[CH:30]=[CH:31][CH:32]=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:12][CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(OCC2CCNCC2)c2ccccc2)cc1
Reactant: COc1cccc(CCBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cccc(CCN2CCC(COC(c3ccccc3)c3ccccc3)CC2)c1
Yield: 53.9 %

Procedure:
A mixture of 4-(diphenylmethoxymethyl)piperidine (1.40 g, 5.0 mmol--see Preparation 2), 3-methoxyphenethyl bromide (1.08 g, 5.0 mmol), sodium carbonate (1.06 g) and sodium iodide (0.50 g) in acetonitrile (30 ml) was heated under reflux for 16 hours, diluted with ethyl acetate and water and the layers separated. The organic layer was washed with water, dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica using dichloromethane plus 0-5% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (1.12 g) as a colourless oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH2:21][C:22]([O:24]C)=[O:23])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)=[CH2:2].[OH-].[Na+]>>[CH:1]([C:3]1[CH:4]=[C:5]([CH2:21][C:22]([OH:24])=[O:23])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)=[CH2:2]
Reactant: C=Cc1cc(CC(=O)OC)ccc1OCc1ccc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Product: C=Cc1cc(CC(=O)O)ccc1OCc1ccc2ccccc2n1

Procedure:
In analogy to the procedure of Example XV, the title compound is prepared from 1.1 g (3.3 mmol) of the compound from Example XXXII and 5 ml (5 mmol) of 1N sodium hydroxide solution.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=[O:20])[NH:18][CH3:19])=[C:15]3[N:10]([N:11]=[CH:12][C:13]([C:21]4[C:22]([CH3:33])=[CH:23][C:24]([O:31][CH3:32])=[C:25]([CH:30]=4)[C:26]([O:28]C)=[O:27])=[CH:14]3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=[O:20])[NH:18][CH3:19])=[C:15]3[N:10]([N:11]=[CH:12][C:13]([C:21]4[C:22]([CH3:33])=[CH:23][C:24]([O:31][CH3:32])=[C:25]([CH:30]=4)[C:26]([OH:28])=[O:27])=[CH:14]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nn2ncc(-c3cc(C(=O)OC)c(OC)cc3C)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)nn2ncc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution containing methyl 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-b]pyridazin-5-yl)-2-methoxy-4-methylbenzoate (0.061 g, 0.14 mmol) and dioxane (0.7 mL) was added aqueous sodium hydroxide (0.7 mL, 2.0 M). The mixture was stirred at room temperature for 2 h. The solution was adjusted to below pH 4 with aqueous HCl (1.5 mL, 1.0 N). 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-b]pyridazin-5-yl)-2-methoxy-4-methylbenzoic acid precipitated as a tan solid. It was filtered off, washed with water (3×4 mL) and air dried. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.66 (d, J=2.5 Hz, 1H), 8.38 (d, J=2.5 Hz, 1H), 8.16 (s, 1H), 7.83-7.73 (m, 2H), 7.29-7.22 (m, 2H), 7.05 (s, 1H), 5.68 (br. s., 1H), 4.17 (s, 3H), 2.89 (d, J=5.0 Hz, 3H), 2.48 (s, 3H). LCMS retention time: 3.508 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 3 micron, C18, 2.0×50 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 0.8 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% methanol/90% H2O/10 mM TFA and solvent B was 10% H2O/90% methanol/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 435 (MH+).
Reaction SMILES: FC(F)(F)C1C=C(C=CC=1)CC1OC2C=CC=CC=2C=1.COC1C=CC(S(Cl)(=O)=O)=CC=1.C[O:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([C:44]2[C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=3[O:46][C:45]=2[CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([C:60]([F:63])([F:62])[F:61])[CH:55]=2)(=[O:43])=[O:42])=[CH:37][CH:36]=1>>[OH:34][C:35]1[CH:36]=[CH:37][C:38]([S:41]([C:44]2[C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=3[O:46][C:45]=2[CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([C:60]([F:63])([F:62])[F:61])[CH:55]=2)(=[O:43])=[O:42])=[CH:39][CH:40]=1
Reactant: COc1ccc(S(=O)(=O)c2c(Cc3cccc(C(F)(F)F)c3)oc3ccccc23)cc1
Agent: COc1ccc(S(=O)(=O)Cl)cc1
Agent: FC(F)(F)c1cccc(Cc2cc3ccccc3o2)c1
Product: O=S(=O)(c1ccc(O)cc1)c1c(Cc2cccc(C(F)(F)F)c2)oc2ccccc12

Procedure:
Acylation of 2-(3-trifluoromethylbenzyl)benzofuran with 4-methoxybenzenesulfonyl chloride as described in the procedure described above followed by demethylation of the 3-(4-methoxyphenylsulfonyl)-2-(3-trifluoromethylbenzyl)benzofuran thus formed also as described above gives 3-(4-hydroxyphenylsulfonyl)-2-(3-trifluoromethylbenzyl)benzofuran.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:31][CH:32]([CH3:34])[CH3:33])=[C:13]([C:15]2[NH:30][C:18]3=[N:19][CH:20]=[C:21]([CH2:23][NH:24][CH2:25][C:26]([O:28]C)=[O:27])[CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:31][CH:32]([CH3:34])[CH3:33])=[C:13]([C:15]2[NH:30][C:18]3=[N:19][CH:20]=[C:21]([CH2:23][NH:24][CH2:25][C:26]([OH:28])=[O:27])[CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CNCc1cnc2[nH]c(-c3cc(OCc4ccccc4)ccc3OC(C)C)nc2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2cc(CNCC(=O)O)cnc2[nH]1
Yield: 66.7 %

Procedure:
A solution of methyl N-({2-[5-(benzyloxy)-2-isopropoxyphenyl]-3H-imidazo[4,5-b]pyridin-6-yl}methyl)glycinate (15 mg) and 1N aqueous sodium hydroxide solution (0.1 ml) in methanol (2 ml) was stirred at room temperature for 18 hr. The reaction mixture was adjusted with 1N aqueous citric acid solution to pH 4. The precipitated crystals were collected by filtration and washed with diethyl ether to give the title compound (9.7 mg, yield 66%) as colorless crystals. melting point 182-184° C. purity 86%. M+H: 447. 1H NMR (DMSO-d6) δ: 1.48 (6H, d, J=6.0 Hz), 3.46 (2H, s), 3.98 (2H, s), 4.72-4.80 (1H, m), 5.17 (2H, s), 6.99-7.12 (2H, m), 7.29-7.51 (5H, m), 8.05 (1H, s), 8.19 (1H, s), 8.34 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[C:19](Cl)=[O:20].[Cl:22][C:23]1[CH:24]=[C:25]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][C@@H:37]([NH2:44])[C:38]3[O:42][N:41]=[C:40]([CH3:43])[N:39]=3)=[CH:32][CH:31]=2)[CH:26]=[CH:27][C:28]=1[F:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][C@@H:37]([NH:44][C:19]([C:4]3[CH:5]=[C:6]([C:9]4[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=4)[CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[O:20])[C:38]3[O:42][N:41]=[C:40]([CH3:43])[N:39]=3)=[CH:32][CH:31]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)Cl
Reactant: Cc1noc([C@H](N)Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)n1
Product: COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)c1nc(C)no1
Yield: 90.2 %

Procedure:
4-Methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (55 mg) was prepared from 4-Methoxy-4′-trifluoromethyl-biphenyl-3-carbonyl chloride (31 mg, 0.1 mmol) and 2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine (40 mg, 0.12 mmol) following the general procedure M.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH:8]=[C:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]>ClCCl.FC(F)(F)C(O)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:22][CH:23]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccc([N+](=O)[O-])cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(C=C2CCNCC2)cc1
Yield: 75.9 %

Procedure:
tert-Butyl 4-(4-nitrobenzylidene)piperidine-1-carboxylate (31.4 mmol, 10 g) was stirred in a mixture of dichloromethane/trifluoroacetic acid for 3 hours. The reaction was concentrated under reduced pressure and water was added. Solid sodium hydrogen carbonate was added portionwise until no further gas was evolved. The aqueous mixture was extracted with ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated under reduced pressure to give the title compound (5.2 g). MS (ESI) m/z 219.1 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](I)[CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([NH:7][CH3:8])=[O:6])[CH:9]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: CNC(=O)c1cc(Br)cc(I)c1
Product: CNC(=O)c1cc(Br)cc(-c2ccccc2)c1

Procedure:
In a manner similar to that of Example 1(e), by reacting 4.9 g (14 mmol) of 3-bromo-5-iodo-N-methyl-benzamide and 1.93 g (15.8 mmol) of phenylboronic acid, and after purification by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture(8/2), 2.1 g (50%) of the expected product are obtained in the form of a white solid with a melting point of 132° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>CS(C)=O.O>[N:12]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: COC(=O)c1ccc(Cl)nc1
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2CCNCC2)nc1
Yield: 76.3 %

Procedure:
A solution of methyl 6-chloronicotinate (25.4 g) and piperazine (38.3 g) in dimethylsulfoxide (125 ml) was heated at 100° C. for 2 hours then cooled and diluted with water, followed by extraction with ethyl acetate (4×). The combined organic layers were washed with water then dried over magnesium sulfate, filtered and evaporated to give a crude product that was triturated with isopropyl ether-hexane to yield methyl 6-(1-piperazinyl)nicotinate (25 g) as a light yellow powder.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5]1.[CH2:18](I)[CH2:19][CH2:20][CH3:21].[Cl-].[NH4+]>CN(C)C=O>[CH2:18]([O:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:6][CH2:5]1)[CH2:19][CH2:20][CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: CCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCCO[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 60% sodium hydride (168 mg) and anhydrous N,N-dimethylformamide (25 ml) under ice-cooling was added t-butyl trans-4-hydroxycyclohexyl-carbamate (600 mg). The mixture was stirred for 5 minutes, then butyl iodide (821 mg) was added thereto and the mixture was stirred for 3 hours under heating at 80° C. Saturated aqueous ammonium chloride was added to the reaction mixture. The mixture was extracted with toluene, and the organic layer was washed with brine, dried over sodium sulfate, and then the solvent was removed in vacuo. The residue was purified by a silica gel chromatography (eluent: gradient from 100% hexane/0% ethyl acetate to 0% hexane/100% ethyl acetate) to give 630 mg of t-butyl (trans-4-butoxycyclohexyl)carbamate.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]3[C:14]4[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:22]([N:12]1[C:8]2=[N:9][C:10]3[C:5]([C:6](=[O:21])[N:7]2[C:14]2[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]1=2)=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=3)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc2c(=O)n3c(nc2c1)[nH]c1cc(Cl)c(Cl)cc13
Reactant: O=C(Cl)c1ccccc1
Product: Cc1ccc2c(=O)n3c4cc(Cl)c(Cl)cc4n(C(=O)c4ccccc4)c3nc2c1

Procedure:
6-Benzoyl-3-methyl-8,9-dichlorobenzimidazo[2,1-b]-quinazolin-12(6H)one is prepared with 3-methyl-8,9-dichlorobenzimidazo[2,1-b]quinazolin-12(6H)one and benzoyl chloride.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.Cl[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:22]([CH3:24])=[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(OC)c(F)cc3OCC3CC3)ncnc12
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(OC)c(F)cc3OCC3CC3)ncnc12

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester (example D.a10) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: ClS(O)(=O)=[O:3].[CH2:6]([P:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9].Cl>>[CH2:15]([P:10](=[O:3])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCP(CCCC)CCCC
Agent: Cl
Product: CCCCP(=O)(CCCC)CCCC
Yield: 120.5 %

Procedure:
116.5 g (1 mol) chlorosulfonic acid was placed in an apparatus as described in Example 4 and reacted therein within 60 minutes with 208 g (1 mol) tributylphosphane at 18°-20° C. while cooling with ice. Towards the end of the reaction when cooling was stopped, the reaction temperature rose to 34° C. The whole was stripped at 70° C. under a pressure of 0.5 millibar. This was accompanied by a violent exothermal reaction. The temperature rose up to 140° C. The material was stripped once again at 80° C. under a pressure of 1 millibar. 263 g tributylphosphane oxide was obtained in the form of a HCl-adduct (determined by elementary analysis and 31P -NMR-spectroscopy). 90% P was in the form of a tributylphosphane oxide HCl-adduct.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][C:14]([F:17])([F:16])[F:15])[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:43]1([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][C:14]([F:15])([F:16])[F:17])[C:3]=1[C:18]([N:46]1[CH2:45][CH2:44][N:43]([C:49]2[CH:50]=[CH:51][C:52]([OH:55])=[CH:53][CH:54]=2)[CH2:48][CH2:47]1)=[O:20]
Reactant: Nc1onc(-c2ccccc2OC(F)(F)F)c1C(=O)O
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Nc1onc(-c2ccccc2OC(F)(F)F)c1C(=O)N1CCN(c2ccc(O)cc2)CC1
Yield: 73.9 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-amino-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 4-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (608 mg, 1.36 mmol, 73%) was obtained.