Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([O:31][CH3:32])[CH2:22][S:23]([CH2:26][CH2:27][CH2:28][CH2:29][OH:30])(=[O:25])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>ClCCl>[CH2:1]([O:19][CH2:20][CH:21]([O:31][CH3:32])[CH2:22][S:23]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][S:34]([CH3:33])(=[O:36])=[O:35])(=[O:25])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOCC(CS(=O)(=O)CCCCO)OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOCC(CS(=O)(=O)CCCCOS(C)(=O)=O)OC
Yield: 94.9 %

Procedure:
In 50 ml of dichloromethane is dissolved 2.5 g of 4-[(3-octadecyloxy-2-methoxypropyl)sulfonyl]butanol, to which 0.78 g of methanesulfonyl chloride and 0.95 ml of triethylamine are added dropwise with stirring under ice cooling. After being stirred at room temperature for 40 minutes, the mixture is washed with water, an aqueous sodium bicarbonate solution and water, and dried. The solvent is distilled off under reduced pressure to leave 2.76 g of 4-mesyloxybutyl 3-octadecyloxy-2-methoxypropyl sulfone. This is dissolved in 40 ml of toluene containing 8 g of trimethylamine, and the solution is stirred at room temperature for 40 hours. The reaction mixture is concentrated and reprecipitated from chloroform-acetone to give 2.1 g of the captioned compound.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:7](=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>CN(C)C=O.O>[CH3:35][O:34][C:32](=[O:33])[CH2:31][N:19]1[C:20]([CH3:21])=[C:6]2[C:7]([CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]3[CH:3]=[C:2]([Cl:1])[CH:23]=[CH:22][C:5]=32)=[CH:18]1
Reactant: Cc1[nH]cc2c1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: COC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc2c(c1C)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In one portion, 2.0 g (5.8 mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine were added to an ice-cooled solution of 0.8 g (7.1 mmol) of potassium t-butoxide in 30 ml of dry dimethylformamide. After stirring at 0° C. for 15 minutes, 0.65 ml (7.7 mmol) of methyl bromoacetate was added, and the resulting solution was stirred for 5 minutes. The mixture was diluted with water and extracted with ether. The ether solution was washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to an oily residue. Purification of the residue by column chromatography (silica gel, 40 g; eluent, 5% ether in methylene chloride) gave after crystallization from a mixture of ether and petroleum ether 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-acetic acid methyl ester as off-white prisms, mp 174°-176° C.
Reaction SMILES: [C:1]1([CH:7]([CH3:10])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl.Cl[CH2:15][C:16]1[N:17]=[CH:18][NH:19][CH:20]=1>CN(C)C=O>[NH:19]1[CH:20]=[C:16]([CH2:15][C:7]([CH3:10])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]#[N:9])[N:17]=[CH:18]1
Reactant: ClCc1c[nH]cn1
Reactant: CC(C#N)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C#N)(Cc1c[nH]cn1)c1ccccc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
As described in Example 1, 5.82 g. of 2-phenylpropanenitrile, 2.04 g. of 50% sodium hydride, and 3.06 g. of 4-chloromethylimidazole hydrochloride were reacted in 40 ml. of dimethylformamide. The mixture was stirred for 5 hours at 100° C., and for 16 hours at ambient temperature. The solvent was then evaporated away under vacuum, and the residue was worked up as described in Example 1 to obtain 0.4 g. of crude free base. The product was purified by preparative thin layer chromatography on silica gel with ethyl acetate as the eluant. The purified product was converted to 0.11 g. of the hydrochloride salt of the desired product, m.p. 187°-189° C.
Reaction SMILES: [C:1]([C:5]1[CH:32]=[CH:31][C:8]([NH:9][C:10]2[CH:29]=[CH:28][C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([OH:27])=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][C:11]=2[F:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1.CN(C)C=O>O>[C:1]([C:5]1[CH:32]=[CH:31][C:8]([NH:9][C:10]2[CH:29]=[CH:28][C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH2:41][CH2:42][N:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][C:11]=2[F:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCN1CCOCC1
Reactant: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)c(F)c3)ccnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)c(F)c3)ccnc2cc1OCCN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
4-{4-[4-(Tert-butyl)anilino]-3-fluorophenoxy}-6-methoxy-7-quinolinol (starting compound 6) (1.75 g), potassium carbonate (2.80 g), and 4-(2-chloroethyl)morpholine hydrochloride (1.13 g) were added to N,N-dimethylformamide (20 ml), and the mixture was stirred at 80° C. overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and was dried over sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude thus obtained was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (1.44 g, yield 64%).
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9]C)=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH2:13][C:12]=3[C:25](=[O:27])[O:26][C:5]=2[CH:4]=1>Br>[OH:2][C:3]1[C:8]([OH:9])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[CH2:13][C:12]=3[C:25](=[O:27])[O:26][C:5]=2[CH:4]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCN(CCN1CCOCC1)C3
Agent: Br
Product: O=c1oc2cc(O)c(O)cc2c2c1CN(CCN1CCOCC1)CC2
Yield: 68.3 %

Procedure:
A solution of 8.7 g of 1,2,3,4-tetrahydro-8,9-dimethoxy-3-(2-morpholinoethyl)-5H[1]benzopyrano[3,4-c]pyridin-5-one in 60 cc of 48% HBr was refluxed for 17 hr then cooled. Crystallization of precipitate from water afforded 5.5 g of product; mp 299°-302°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:10][C:11]([C:15]([O:17]CC)=O)=[C:12]([CH3:14])[N:13]=1.O.[NH2:21][NH2:22]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:10][C:11]([C:15]([NH:21][NH2:22])=[O:17])=[C:12]([CH3:14])[N:13]=1
Reactant: NN
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2Cl)nc1C
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccc(Cl)cc2Cl)sc1C(=O)NN
Yield: 88.3 %

Procedure:
Ethyl 2-(2,4-dichlorophenyl)-4-methylthiazole-5-carboxylate (250 mg) prepared in the Step 23-1-1 was dissolved in ethanol (10 ml), and hydrazine monohydrate (794 mg) was added thereto. The mixture was heated under reflux for 23 hours. After the mixture was allowed to cool, the precipitated crystal was separated by filtration, washed with water, and dried to give 2-(2,4-dichlorophenyl)-4-methylthiazole-5-carboxylic acid hydrazide (211 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:42][N:43]1[C:48]([CH3:50])([CH3:49])[CH2:47][CH:46]([NH2:51])[CH2:45][C:44]1([CH3:53])[CH3:52]>C1COCC1.CC#N>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([C:13]([NH:51][CH:46]4[CH2:45][C:44]([CH3:52])([CH3:53])[N:43]([CH3:42])[C:48]([CH3:50])([CH3:49])[CH2:47]4)=[O:15])=[CH:16][CH:17]=3)[NH:8][C:4]=2[CH:3]=1
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Reactant: O=C(O)c1ccc(-c2nc3ccc(Cl)cc3[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCOC1
Product: CN1C(C)(C)CC(NC(=O)c2ccc(-c3nc4ccc(Cl)cc4[nH]3)cc2)CC1(C)C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
A mixture of 4-(5-chlorobenzimidazol-2-yl)benzoic acid (0.5 g, 1.63 mmol), 1-hydroxybenzotriazole (0.242 g, 1.79 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.34 g, 1.89 mmol) in THF (15 ml) was heated for 1 h at 35–40° C. 1,2,2,6,6-Pentamethyl-4-aminopiperidine (0.333 g, 1.96 mmol) in THF (3 ml) was added dropwise and the reaction was left 1 h at 60° C. After cooling, the solvent was removed under reduced pressure and the residue was treated with 2N NaOH (15 ml) and extracted with ethyl acetate (20 ml). the organic layer was washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure to give a residue that was treated with CH3CN. The suspension was stirred for 1 h, filtered and dried at 50° C. to give 0.35 g of the title compound (yield 50.5%) as a yellow solid, mp>250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:31][N:32]1[CH2:36][CH2:35][CH2:34][C:33]1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:10]4[CH2:11][CH2:12][CH:31]([N:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)[CH2:14][CH2:9]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CN1CCCC1=O
Reactant: COc1cc2c(Nc3ccc(Sc4ccccn4)c(Cl)c3)c(C#N)cnc2cc1F
Product: COc1cc2c(Nc3ccc(Sc4ccccn4)c(Cl)c3)c(C#N)cnc2cc1N1CCC(N2CCCC2)CC1

Procedure:
Following the procedure of Example 11, a mixture of 150 mg (0.34 mmol) of 4-[3-Chloro-4-(pyridin-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile and 264 mg (1.71 mmol) of 4-(1-pyrrolidinylpiperidine) are refluxed in 1-methyl 2-pyrrolidinone (1 mL) at 105° C. for 12 hours to yield the crude product. Purification by silica gel chromatography (95:5 methylene chloride/methanol) gives 126 mg of 4-[3-chloro-4-(pyridin-2-ylsulfanyl)-phenylamino]-6-methoxy-7-(4-pyrrolidin-1-yl-piperidin-1-yl)quinoline-3-carbonitrile as a yellow solid, mp 203-205° C.
Reaction SMILES: [O:1]([C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][C@:23]([OH:31])([CH2:29][OH:30])[CH2:24]2)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[C:40](Cl)=[O:41])=[CH:35][CH:34]=1>N1C=CC=CC=1>[O:1]([C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][C@@:23]([CH2:29][O:30][C:40](=[O:41])[N:39]([C:36]1[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=1)[C:43]1[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=1)([OH:31])[CH2:24]2)[Si:2]([C:15]([CH3:17])([CH3:18])[CH3:16])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CC[C@](O)(CO)C2)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)N(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](Oc1cccc2c1CC[C@](O)(COC(=O)N(c1ccc(F)cc1)c1ccc(F)cc1)C2)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 47.3 %

Procedure:
A mixture of (2R)-5-t-butyldiphenylsiloxy-2-hydroxy-2-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalene (0.49 g) and N,N-di(4-fluorophenyl)carbamoyl chloride (1.08 g) in pyridine (2.3 ml) was stirred at 100° C. for 1.5 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, 1N-HCl, and evaporated in vacuo. The residue was purified by chromatography on silica gel (50 ml) using a mixture of AcOEt and n-hexane to give (2R)-5-t-butyldiphenylsiloxy-2-{[N,N-di(4-fluorophenyl)-carbamoyloxy]methyl}-2-hydroxy-1,2,3,4-tetrahydronaphthalene (0.356 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=O.N1CCCCC1.C(O)(=O)C>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[CH:19][C:15]1[S:14][CH:18]=[CH:17][CH:16]=1)[C:8]2=[O:13]
Reactant: COc1cccc2c1CCCC2=O
Reactant: O=Cc1cccs1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COc1cccc2c1CCC(=Cc1cccs1)C2=O
Temperature: 130 °C
Yield: 78.3 %

Procedure:
A mixture of 5-methoxy-1-tetralone (1 g; 5.67 mmol), thiophene-2-carboxaldehyde (800 μl 8.51 mmol), piperidine (168 μl; 1.7 mmol) and acetic acid (97 μl; 1.7 mmol) was heated at 130° C. for 2 hours. The mixture was taken up in CH2C2 and washed in water and in a saturated aqueous solution of NaCl. The organic phase was dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel, eluting with petroleum ether/ethyl acetate (95/5) to give 5-methoxy-2-(2-thienylmethylene)-1-tetralone (1.2 g; 80%)
Reaction SMILES: NC(N)=[S:3].Cl[C:6]1[N:7]2[C:11]([N:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:14]=1)=[N:10][CH:9]=[N:8]2>C(O)C>[SH:3][C:6]1[N:7]2[C:11]([N:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:14]=1)=[N:10][CH:9]=[N:8]2
Reactant: NC(N)=S
Reactant: CC(C)(C)c1cc(Cl)n2ncnc2n1
Solvent: CCO
Product: CC(C)(C)c1cc(S)n2ncnc2n1

Procedure:
8.7 g of thiourea was dissolved in 150 ml of ethanol and thereto was added 4-chloro-6-t-butyl-1,3,3a,7-tetraazaindene. The resulting mixture was refluxed for 1.5 hours over a water bath. At the conclusion of the refluxing the product precipitated as crystals. Upon distilling off the ethanol, needle crystals were obtained. Repeated recrystallization from 1.8 l of ethanol gave 7.4 g of intended compound having a melting point of 285° to 286° C.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[NH2:13][C:14]1[C:22]2[NH:21][C:20](=[O:23])[NH:19][C:18]=2[CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:9]([O:8][C:7]1[C:6](=[O:11])[C:5](=[O:12])[C:4]=1[NH:13][C:14]1[C:22]2[NH:21][C:20](=[O:23])[NH:19][C:18]=2[CH:17]=[CH:16][CH:15]=1)[CH3:10]
Reactant: Nc1cccc2[nH]c(=O)[nH]c12
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2cccc3[nH]c(=O)[nH]c23)c(=O)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.4 %

Procedure:
0.86 ml of 3,4-diethoxycyclobut-3-ene-1,2-dione (5.9 mmol, 1.5 eq) was added to a solution of 0.59 g of 4-amino-1,3-dihydrobenzoimidazol-2-one (4.0 mmol, 1 eq) in 21 ml of ethanol. The reaction medium was stirred at ambient temperature for 2 days (formation of a precipitate). Ethanol was added in order to promote the fall of the precipitate, which was filtered off, washed with diethyl ether and dried under vacuum at 45° C. The residue was chromatographed on silica gel, eluted with 90/10 dichloromethane/methanol. 0.42 g of product was obtained in the form of a white solid. Yield=38.6%.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH2:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]2[CH:11]=[C:12]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH:13]=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCCN1CCC(c2cccc(O)c2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN1CCC(c2cccc(OS(C)(=O)=O)c2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 3-(1-propyl-piperidin-4-yl)-phenol (340 mg) and triethylamine (187 mg) in 20 ml of CH2Cl2 was cooled to 0° C. Then methanesulfonyl chloride (194 mg) dissolved in 10 ml of CH2Cl2 was added dropwise. The reaction mixture was allowed to reach room temperature and then stirred for 2.5 h at 25° C. The reaction was finally quenched with water. The organic layer was separated and washed with 10% HCl and then 10% Na2CO3.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=1)=[O:26]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To a 40 ml vial is added 4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-amine (1.5 g, 5.50 mmol), 3-bromobenzoic acid (1.66 g, 8.2 mmol), HBTU (3.13 g, 8.2 mmol) and Hunig's base (2.0 ml, 11.0 mmol). The mixture is dissolved in DMF (10 ml), flushed with argon, sealed and agitated at room temperature for 8 hrs. The crude mixture is diluted with water (100 ml) and partitioned with EtOAc (100 ml). The organic layer is washed with water (100 ml). The combined aqueous layers are extracted with EtOAc (2×50 ml). The combined organic layers are dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (5% MeOH in ethyl acetate) to afford 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide (1.27 g, 48%). MS: 455 (M+1).
Reaction SMILES: [CH:1]1([N:7]([CH3:26])[C:8]([N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([N+:23]([O-])=O)[CH:16]=3)[N:12]=[CH:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C(OCC)(=O)C.CO>[NH2:23][C:17]1[CH:16]=[C:15]([C:13]2[N:12]=[CH:11][N:10]([C:8]([N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH3:26])=[O:9])[CH:14]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1ccc(-c2cn(C(=O)N(C)C3CCCCC3)cn2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(-c2cn(C(=O)N(C)C3CCCCC3)cn2)cc1N

Procedure:
10% Palladium on carbon (0.16 g, 0.15 mmol) was added to a stirred solution of N-cyclohexyl-4-(4-methoxy-3-nitrophenyl)-N-methyl-1H-imidazole-1-carboxamide (1.075 g, 3 mmol) in a mixture of ethyl acetate (50 mL) and methanol (50 mL) at room temperature under an argon atmosphere. Hydrogen was bubbled through the solution for 1 h. The solution was then filtered through celite and the pad was washed with ethyl acetate. The combined filtrate was evaporated to give a brown oily solid that was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[ClH:10].[CH3:11]O>>[ClH:10].[NH2:1][C:2]1([C:7]([O:9][CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CO
Reactant: NC1(C(=O)O)CCCC1
Agent: Cl
Product: COC(=O)C1(N)CCCC1
Reaction time: 0.5 h

Procedure:
A solution of 1-aminocyclopentanecarboxylic acid (20.0 g, 155 mmol) in MeOH (300 mL) was saturated with HCl (g), aged for 30 min, and saturated again with HCl (g). The mixture was aged at ambient temperature for 2 h and concentrated to dryness in vacuo. To the white solid was added saturated aqueous NaHCO3 (350 mL), carefully, with ice cooling, and the resulting mixture was extracted with EtOAc (4×250 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=144 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=O>C(#N)C.CCOC(C)=O>[CH2:7]([N:23]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:15]=[CH:27][S:24]1(=[O:26])=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: CS(=O)(=O)Nc1ccccc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=S1(=O)C=Cc2ccccc2N1Cc1ccccc1
Temperature: 60 °C
Yield: 86.8 %

Procedure:
Cesium carbonate (18.0 g, 55 mmol) and benzyl bromide (6.6 mL, 55 mmol) were added to a solution of N-(2-formylphenyl)methanesulfonamide (5.50 g, 27.6 mmol) in acetonitrile (120 mL). The reaction mixture was heated at 60° C. for 16 h and then cooled to ambient temperature. The mixture was diluted with EtOAc (200 mL) and filtered. The filtration cake was washed with EtOAc (200 mL) and the combined organics were concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane=1:5) to afford 1-benzyl-1H-benzo[c][1,2]thiazine 2,2-dioxide (6.5 g, 87% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][CH2:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33]OS(C)(=O)=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][CH2:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCc1ccccn1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)CNc1ccccc12
Product: O=C(c1cn(Cc2ccccn2)c2cc(Cl)ccc12)N1CCC2(CC1)CNc1ccccc12

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-1,2-dihydrospiro[indole-3,4′-piperidine] (prepared according to example 8) with methanesulfonic acid pyridin-2-ylmethyl ester (described in WO 9955318) gave the title compound. ES-MS m/e (%): 457.2(M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[F:15].[Li]CCCC.CC([O:24][B:25](OC(C)C)[O:26]C(C)C)C>O1CCCC1>[F:15][C:3]1[CH:4]=[C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][C:2]=1[B:25]([OH:26])[OH:24]
Reactant: Fc1cc(Oc2ccccc2)ccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(Oc2ccccc2)cc1F
Temperature: -75 °C
Yield: 92.1 %

Procedure:
Into a 100 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of 1-bromo-2-fluoro-4-phenoxybenzene (2 g, 7.49 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). BuLi (1M) (8 mL) was added dropwise with stirring at −70 to −80° C. The resulting solution was stirred for 30 min at −70-80° C. in a liquid nitrogen bath. Tris(propan-2-yl)borate (1.7 g, 9.04 mmol, 1.21 equiv) was added dropwise with stirring at −70 to −80° C. The resulting solution was allowed to react, with stirring, for an additional 2 h while the temperature was maintained at −70 to −80° C. The reaction was then quenched by the addition of 100 mL of water, extracted with ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20) to give 1.6 g (92%) of (2-fluoro-4-phenoxyphenyl)-boronic acid as a white solid.