Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:22]Cl)[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:5]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])[C:6]=1[Br:7].[OH-].[Na+].O.O.[CH3:28][N:29]([CH3:33])[C:30](=[S:32])[S-:31].[Na+].CN(C)C=O>O>[CH3:28][N:29]([CH3:33])[C:30](=[S:31])[S:32][CH2:22][N:3]1[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:5]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])[C:6]([Br:7])=[C:2]1[Br:1]
Reactant: CN(C)C(=S)[S-]
Reactant: O=S(=O)(c1c(Br)c(Br)n(CCl)c1-c1ccc(Cl)cc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=S)SCn1c(Br)c(Br)c(S(=O)(=O)C(F)(F)F)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 31.7 %

Procedure:
2,3-Dibromo-1-(chloromethyl)-5-(p-chlorophenyl)-4-[(trifluoromethyl)sulfonyl]pyrrole (1.0 g, 0.00194 mol) is added to a mixture of sodium hydroxide (0.084 g, 0.0021 mol), sodium dimethyldithiocarbamate dihydrate (0.376 g, 0.0021 mol) and dimethylformamide. The reaction mixture is stirred for six hours at room temperature, poured into water and extracted with ethyl acetate. The combined organic extracts are washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a yellow gum. The gum is stirred with hexanes overnight and filtered to give the title product as a white solid (0.37 g, mp 185°-187° C.) which is identified by 1HNMR and 19FNMR spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:16][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:10]=2[N:9]=1.[OH-].[Na+].Cl[CH2:20][C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH:22]=1>CN(C=O)C>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:22]=[C:21]([CH2:20][N:13]3[CH:14]=[CH:15][C:10]4=[N:9][C:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])=[N:16][C:11]4=[CH:12]3)[O:25][N:24]=2)=[CH:31][CH:30]=1
Reactant: Fc1ccccc1-c1nc2ccncc2[nH]1
Reactant: ClCc1cc(-c2ccc(Cl)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1ccccc1-c1nc2ccn(Cc3cc(-c4ccc(Cl)cc4)no3)cc-2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a suspension of 2-(2-fluorophenyl)-3H-imidazo[4,5-c]pyridine (11.0 g, 50.0 mmoles) in DMF was added a 10% (w/v) solution of aqueous NaOH. To this solution, 5-(chloromethyl)-3-(4-chlorophenyl)isoxazole (13.68 g, 60.0 mmoles) dissolved in DMF was added. The reaction mixture was stirred at room temperature and monitored every half hour by LCMS. The reaction was stopped at 4 hours, after LCMS showed no progress between at 2 hour and 4 hour monitor points. The reaction product was triturated with first with water and then with EtoAc (3×). The material was crystallized by dissolving the material in MeOH with heat, followed by precipitation with water. This crystallization process was then repeated yielding 5-((3-(4-chlorophenyl)isoxazol-5-yl)methyl)-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine (15.385 g, 38 mmole) as white crystal at a yield of 74%. 1H 300 Mhz (d6-DMSO) sigma 6.02 (s, 2p); 7.13 (s, 1p); 7.26-7.35 (m, 2p); 7.43-7.52 (m, 1p); 7.56 (d, 2p); 7.84 (d, 1); 7.89 (d, 2p); 8.24 (d, 1); 8.28-8.36 (m, 1p); and 9.19 (s, 1p). LCMS data M/Z=405.31
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:18]1[O:22][C:21](=[O:23])[CH2:20][CH2:19]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:30][O:31][CH2:32][CH2:33]I>CN(C=O)C.O1CCOCC1>[C:1]([NH:8][C@H:9]([C@H:18]1[O:22][C:21](=[O:23])[CH2:20][CH2:19]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:33][CH2:32][O:31][CH3:30])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COCCI
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)[C@@H]1CCC(=O)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CCC(=O)O2)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
3.17 g (9.86 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-hydroxyphenyl)ethyl]dihydrofuran-2-(3H)-one in 190 ml of DMF/dioxane, 1:1, are treated, under an N2 atmosphere, with 6.4 g (19.7 mmol) of Cs2CO3 and 2.0 g (9.86 mmol) of 2-methoxyethyl iodide. Since HPLC indicates that unreacted 5(S)-[1(S)-(Boc-amino)-2-(p-hydroxyphenyl)ethyl]dihydrofuran-2-(3H)-one is still present after 18 h at RT, a further 1.2 g of 2-methoxyethyl iodide are added in portions. As soon as HPLC indicates that the reaction is complete, the reaction mixture is poured onto 190 ml of ice-water, and the whole is extracted 3× with methylene chloride. The organic phases are washed with water and saline, dried with Na2SO4 and evaporated. Stirring up the residue with hexane in an ultrasonication bath affords the title compound: TLC Rf (D)=0.08; FAB-MS (M+H)+ =380.
Reaction SMILES: FC1C=C(C(Cl)=O)C=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([F:33])[CH:27]=1.[F:34][C:35]1[CH:36]=[C:37]([C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:38]=[CH:39][CH:40]=1>C1(C)C=CC=CC=1.C(O)C>[F:34][C:35]1[CH:36]=[C:37]([C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:38]=[CH:39][CH:40]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:44]([NH:43][C:41](=[O:42])[C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([F:34])[CH:36]=2)=[S:45])=[C:28]([F:33])[CH:27]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1cccc(F)c1
Agent: O=C(N=C=S)c1cccc(F)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(F)c4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
3-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (71 mg, yield 90%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]=[C:6]=[O:7])=[O:4].C1(C)C=CC=CC=1.[C:15]([CH:17]1[CH2:19][NH:18]1)#[N:16].C>C(OCC)(=O)C>[Cl:1][CH2:2][C:3]([NH:5][C:6]([N:18]1[CH2:19][CH:17]1[C:15]#[N:16])=[O:7])=[O:4]
Reactant: N#CC1CN1
Reactant: O=C=NC(=O)CCl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#CC1CN1C(=O)NC(=O)CCl

Procedure:
A solution of 36 g. chloroacetyl isocyanate in 100 ml. toluene is added dropwise, while stirring and cooling, at a temperature of 20° to 30° C. to 20.4 g. 2-cyanoaziridine dissolved in 200 ml. toluene. The resulting suspension is further stirred for 1 hour at ambient temperature, then filtered with suction. The solid material obtained is washed with toluene and triturated with diethyl ether to give 62 g. of crude product. This is introduced into about 2.5 to 3 liters ethyl acetate at a temperature of 60° C., boiled for a short time and the clear solution treated with active charcoal. After filtration, the clear and still hot filtrate is evaporated in a vacuum and the evaporation residue is triturated with anhydrous diethyl ether and dried for 1 hour at 70° C. There are obtained 39.3 g. of product with a melting point of 152°-155° C. After further purification by stirring for 5 minutes with 200 ml. ethyl acetate at 60° C. and trituration of the crystals obtained with diethyl ether, there are obtained, after drying in a vacuum at 70° C. 28.9 g. 1-(N-chloroacetyl-carbamoyl)-2-cyanoaziridine; m.p. 152°-155° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][N:4]=1.C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]([Cl:15])=[O:11])[CH:6]=[CH:5][N:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CSc1nccc(C(=O)O)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSc1nccc(C(=O)Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a solution of 2-methylsulfanyl-pyrimidine-4-carboxylic acid (20 g, 117.7 mmol) in CH2Cl2 (100 mL) is added oxalyl chloride (17.2 g, 197 mmol) and DMF (20 drops). The reaction solution is stirred at room temperature for 18 hours after which the solvent is removed in vacuo to afford 21.2 g, (95% yield) of the desired product as a dark green solid.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([CH3:10])=[CH:9][C:2]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)#[N:5]
Reactant: Cc1ccc(C#N)c(Br)c1
Reactant: C1CNCCN1
Product: Cc1ccc(C#N)c(N2CCNCC2)c1

Procedure:
2-Bromo-4-methyl-benzonitrile was coupled to piperazine using Preparation 1A Buchwald chemistry to afford 4-(2-cyano-5-methyl-phenyl)-piperazine. 4-(2-cyano-5-methyl-phenyl)-piperazine is converted to 4(2-hydroxymethyl-5-methyl-phenyl)-piperazine in a manner similar to preparation 54A Steps 1 and 2.4-(2-Hydroxymethyl-5-methyl-phenyl)-piperazine was converted to the title compound in a manner similar to Preparation 60A except that pyrrolidine was used to displace the mesylate. LRMS (ESI+): 360.3 (M+1)
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])N.[F:12][C:13]([F:35])([F:34])[C:14]1[CH:33]=[CH:32][C:17]2[C:18](=NNC3C=CC=CC=3C(O)=O)[CH2:19][O:20][C:16]=2[CH:15]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.O>[F:35][C:13]([F:12])([F:34])[C:14]1[CH:33]=[CH:32][C:17]2[C:18]3[NH:1][C:3]4[C:11]([C:19]=3[O:20][C:16]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][C:4]=4[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccccc1NN=C1COc2cc(C(F)(F)F)ccc21
Reactant: NNc1ccccc1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc2c1[nH]c1c3ccc(C(F)(F)F)cc3oc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.4 %

Procedure:
150 mg 6a was dissolved in ethanol (5.2 ml) and 2-hydrazino benzoic acid was dissolved in water (10.3 ml). These two homogenous mixtures were mixed together and stirred at room temperature for 4 hrs. Precipitation is filtered and first washed with water and then ethanol. The filtrate was put in vacuum oven for 4 hrs for complete evaporation. The mixture of 2-[N′-(6-trifluoromethyl-benzofuran-3-yl-idene)-hydrazino]-benzoic acid (120 mg), p-TsOH (1˜2 Eqv) and ethanol (5 ml) were refluxed for 30 hrs. Cooled to room temperature and evaporated in vacuo. Resulting mixture was purified by chromatography to afford compound 8 (CHCl3:MeOH=30:1).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[C:8](=[O:23])[CH2:7]1)=[O:5])[CH3:2].[CH:24](OCC)(OCC)OCC>>[CH2:1]([O:3][C:4]([CH:6]1[C:14]2[C:9](=[CH:10][C:11]([N:15]3[C:16]4=[N:17][CH:18]=[CH:19][CH:20]=[C:21]4[N:22]=[CH:24]3)=[CH:12][CH:13]=2)[C:8](=[O:23])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC(=O)c2cc(Nc3ncccc3N)ccc21
Reactant: CCOC(OCC)OCC
Product: CCOC(=O)C1CC(=O)c2cc(-n3cnc4cccnc43)ccc21

Procedure:
A solution of (R/S)-5-(3-Amino-pyridin-2-ylamino)-3-oxo-indan-1-carboxylic acid ethyl ester (754 mg, 2.42 mmol) in triethyl orthoformate (25 mL) is heated at 145° C. for 30 min. The solvent is evaporated and the residue purified by flash chromatography eluting with Hexane/EtOAc. (R/S)-5-Imidazo[4,5-b]pyridine-3-yl-3-oxo-indan-1-carboxylic acid ethyl ester is obtained as a colourless solid. Title compound: 1H NMR: (DMSO-d6): 9.0 (s, 1H), 8.5 (d, 1H), 8.4 (d, 1H), 8.3 (s, 1H), 8.2 (d, 1H) 7.9 (d, 1H), 7.4 (dd, 1H) 4.5 (m, 1H), 4.2 (m, 2H), 3.0 (m, 2H), 1.2 (t, 3H); tR=1.2 min (System 2).
Reaction SMILES: [N:1]1([C:6]([O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16]3[N:24]=[C:23]4[C:19]([NH:20][C:21](=[O:33])[N:22]4[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][CH3:32])=[C:18]([C:34]([O:36]CC)=O)[N:17]=3)[CH2:11][CH2:10]2)=[O:7])C=CN=C1.[NH2:39]C1C(C(OCC)=O)=NC(N[C@H]2CC[C@H](O)CC2)=NC=1NC1C=CC=CC=1OC>ClCCl>[C:6](=[O:7])([O:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([NH:15][C:16]2[N:24]=[C:23]3[C:19]([NH:20][C:21](=[O:33])[N:22]3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[C:18]([C:34](=[O:36])[NH2:39])[N:17]=2)[CH2:13][CH2:14]1)[NH2:1]
Reactant: CCOC(=O)c1nc(N[C@H]2CC[C@H](O)CC2)nc(Nc2ccccc2OC)c1N
Reactant: CCOC(=O)c1nc(N[C@H]2CC[C@H](OC(=O)n3ccnc3)CC2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@H]3CC[C@H](OC(N)=O)CC3)nc21

Procedure:
Ethyl 2-(trans-4-(1H-imidazole-1-carbonyloxy)cyclohexylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. Ethyl 5-amino-2-(trans-4-hydroxycyclohexyl amino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate (0.240 g, 0.598 mmol) and 1,1′-1,1′-carbonyldiimidazole (0.968 g, 5.98 mmol) in dichloromethane (20 mL) were reacted according to general procedure F and purified using biotage chromatography (40-100% ethyl acetate in hexanes) to afford a mixture of the title product and the cleaved free hydroxyl product. MS (ESI) m/z 522.5 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:7]([CH:9]=1)[NH2:8])#[N:2].[C:16](Cl)(Cl)=[S:17]>O1CCOCC1.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:7]([N:8]=[C:16]=[S:17])[CH:9]=1)#[N:2]
Reactant: N#Cc1ccc(N2CCOCC2)c(N)c1
Reactant: S=C(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(N2CCOCC2)c(N=C=S)c1

Procedure:
Reaction of 5-cyano-2-morpholinoaniline (2 g) with thiophosgene (1.15 ml) in dioxan (2 ml) and water (25 ml) at 0° C. for 30 minutes and then at room temperature for 2 hours yielded a residue which was extracted with dichloromethane to give 5-cyano-2-morpholinophenyl isothiocyanate as an oil.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.Cl[CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>>[OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:30])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:16])([CH3:17])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1
Reactant: O=C(CCl)Nc1ccccc1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)Nc2ccccc2)CC1

Procedure:
The above-titled compound was prepared by reacting 10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine with 2-chloro-N-phenylacetamide according to the method of Example 1; m.p. 125°-127°.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:16]([S:26][CH3:27])[C:17]([NH:19][C:20]([CH3:25])([C:22]#[C:23][CH3:24])[CH3:21])=[O:18]>>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][CH:16]([S:26][CH3:27])[C:17]([NH:19][C:20]([CH3:21])([C:22]#[C:23][CH3:24])[CH3:25])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Oc2ccccc2)c1
Reactant: CC#CC(C)(C)NC(=O)C(Cl)SC
Product: CC#CC(C)(C)NC(=O)C(Oc1cccc(Oc2ccccc2)c1)SC

Procedure:
In a similar procedure, 3-phenoxyphenol was reacted with 2-chloro-2-methylthio-N-(2-methylpent-3-yn-2-yl)acetamide to give 2-(3-phenoxyphenoxy)-2-methylthio-N-(2-methylpent-3-yn-2-yl)acetamide (Compound No. 4 of Table 1).
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:17][C:16]1[O:15][N:14]=[C:13]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:23])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(OCc2c(N3CCCC3)noc2C)nc1
Reactant: NC1CCOCC1
Product: Cc1onc(N2CCCC2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 49 %

Procedure:
As described for example 40f, 6-(5-methyl-3-pyrrolidin-1-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (100 mg, 0.28 mmol), was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (30 mg, 49%) which was obtained as a white solid after purification by chromatography (silica, 40 to 90% ethyl acetate in heptane). MS: m/e=387.2 [M+H]+.
Reaction SMILES: Cl.[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([CH:12]([NH2:15])[CH2:13][CH3:14])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([CH:12]([NH:15][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:13][CH3:14])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(N)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: ClCCl
Product: CCC(NS(C)(=O)=O)C1CCC2(CC1)OCCO2
Temperature: 0 °C

Procedure:
Into a 50 mL round-bottom flask was placed a solution of 1-1,4-dioxaspiro[4.5]decan-8-ylpropan-1-amine hydrochloride (as prepared in Example 104 Step B) (50 mg, 0.21 mmol, 1.00 equiv) in dichloromethane (10 mL) and TEA (42.8 mg, 0.42 mmol, 2.00 equiv). This was followed by the addition of methanesulfonyl chloride (29.1 mg, 0.25 mmol, 1.20 equiv) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 2×20 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[N:14]([C:15]4[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=4)[NH2:18])[CH:13]=[CH:12][N:10]3[N:11]=2)[CH:2]=1.[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:38])([F:37])([F:36])([F:35])[F:34])[CH:32]=1)[C:27](O)=[O:28])#[N:23]>>[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:37])([F:38])([F:34])([F:35])[F:36])[CH:32]=1)[C:27]([NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([N:14]2[C:9]3[N:10]([N:11]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)[CH:12]=[CH:13]2)[CH:16]=1)=[O:28])#[N:23]
Reactant: N#Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: Nc1cccc(-n2ccn3nc(-c4cccnc4)cc23)c1
Product: N#Cc1cc(C(=O)Nc2cccc(-n3ccn4nc(-c5cccnc5)cc34)c2)cc(S(F)(F)(F)(F)F)c1

Procedure:
Analogously to the process described in Example 26, 100 mg (0.363 mmol) of the compound of Example 62A and 117 mg (0.363 mmol) of the compound of Example 23A gave 62 mg (32% of theory) of the title compound. In this case, the reaction time was about 15 h.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([NH2:8])[CH:7]=1.[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[S:16](Cl)(=[O:18])=[O:17]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([NH:8][S:16]([C:12]2[O:11][CH:15]=[CH:14][CH:13]=2)(=[O:18])=[O:17])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccco1
Reactant: CSc1ccc(Cl)cc1N
Product: CSc1ccc(Cl)cc1NS(=O)(=O)c1ccco1
Yield: 47.2 %

Procedure:
Following General Procedure B, the title compound (215 mg, 47%) was prepared from 5-chloro-2-methylsulfanyl-phenylamine (260 mg, 1.50 mmol) and furan-2-sulfonyl chloride (250 mg, 1.50 mmol).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[S:8][C:9]([C:11]([O-:13])=O)=[N:10][C:4]=2[CH2:3]1.[Li+].[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH:31]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:30]1)(=[O:28])=[O:27])[CH:20]=[CH:19]2>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([S:26]([N:29]1[CH2:34][CH2:33][N:32]([C:11]([C:9]3[S:8][C:5]4[CH2:6][NH:7][CH:2]([CH3:1])[CH2:3][C:4]=4[N:10]=3)=[O:13])[CH:31]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:30]1)(=[O:27])=[O:28])[CH:20]=[CH:19]2
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Reactant: COC(=O)CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1
Agent: [Li+]
Product: COC(=O)CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1nc2c(s1)CNC(C)C2

Procedure:
Starting materials: lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate, 1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[methoxycarbonylmethyl]piperazine
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)[CH2:7][CH2:6][CH2:5]2.C(N(CC)CC)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[C:32](Cl)=[O:33]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:32](=[O:33])[C:31]3[CH:30]=[C:29]([Cl:28])[CH:37]=[C:36]([Cl:38])[CH:35]=3)=[CH:15][CH:14]=1)[CH2:7][CH2:6][CH2:5]2
Reactant: Nc1ccc(C(=O)N2CCCc3cc(F)ccc32)cc1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2CCCc3cc(F)ccc32)cc1)c1cc(Cl)cc(Cl)c1
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
6-Fluoro-1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline (0.15 g) is dissolved in dichloromethane (10 ml) and thereto is added triethylamine (0.31 ml). To the mixture is added dropwise a solution of 3,5-dichlorobenzoyl chloride (0.14 g) in dichloromethane (2.0 ml) under ice-cooling, and the mixture is stirred for 30 minutes under ice-cooling, and further, at room temperature for 1 hour. To the mixture are added triethylamine (0.31 ml) and 3,5-dichlorobenzoyl chloride (0.14 ml). The mixture is stirred at room temperature for 4 hours. The reaction mixture is washed with water, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:5→1:4), and recrystallized from ethyl acetate/n-hexane to give 6-fluoro-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.12 g) and 6-fluoro-1-{4-[bis-(3,5-dichlorobenzoyl)amino]benzoyl}-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](O)=[N:5][C:6]([C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1)=[N:7]2.C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([NH:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1)=[N:5][C:6]([C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1)=[N:7]2
Reactant: NCc1ccccn1
Reactant: Oc1nc(-c2cncnc2)nc2cccc(Br)c12
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Brc1cccc2nc(-c3cncnc3)nc(NCc3ccccn3)c12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 19.6 %

Procedure:
To a stirred suspension of 5-bromo-2-(pyrimidin-5-yl)quinazolin-4-ol (2.0 g, 6.5 mmol) in DMF (20 mL) was added diisopropylethyl amine (3.4 ml, 19 mmol) followed by PyBroP (3.7 g, 7.9 mmol). After 5 min stirring at room temperature, 2-aminomethylpyridine (1.0 mL, 9.8 mmol) was added to the reaction. Upon completion of addition, the reaction mixture was warmed to 80° C. where it stirred for 2 h (during which time reaction became a clear solution). At the conclusion of this period, the reaction mixture was quenched by the addition of cold water and then extracted into 50% ethyl acetate and hexane mixture (200 mL). The organic extracts were dried, concentrated, purified by column chromatography using ethyl acetate and hexanes as eluent to yield the crude produce. The crude product was further purified by trituration with ethyl acetate and hexane to yield 5-bromo-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine (0.5 g, 20% yield). 1H NMR (400 MHz, CDCl3, δ): 5.07 (d, J=4.4 Hz, 2H); 7.26 (m, 1H); 7.41 (d, J=7.6 Hz, 1H); 7.53 (t, J=8 Hz, 1H); 7.71-7.73 (m, 2H); 7.86 (dd, J=0.8 Hz, 8.4 Hz, 1H); 8.65 (d, J=4 Hz, 1H); 9.30 (s, 1H); 9.38 (br s, 1H); 9.75 (s, 2H). ES-MS: [M++1]=393 and [M++3]=395.