Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH2:28])[CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[N:7]([C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:28][CH2:26][CH3:27])=[CH:10][N:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCN
Reactant: Cn1cc(Br)cc(N(C(=O)OC(C)(C)C)c2ccc(C=O)cn2)c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCNCc1ccc(N(C(=O)OC(C)(C)C)c2cc(Br)cn(C)c2=O)nc1
Yield: 63.5 %

Procedure:
(5-bromo-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (500 mg, 1.22 mmol), ethanamine (6.12 ml of a 2.0 M solution in THF), sodium triacetoxyborohydride (649 mg, 3.06 mmol), and acetic acid (147 mg, 2.45 mmol) were added to a 20 ml microwave vial. The vial was capped and heated in a sand bath at 40 degrees centigrade overnight. TLC and LCMS analysis showed the reaction to be incomplete. Another 6 ml of ethanamine was added to the vial and the reaction was heated again at 40 degrees centigrade overnight. The reaction was diluted with DCM and washed with saturated aqueous sodium bicarbonate, dried and concentrated. The crude product was purified by flash chromatography using 10% methanol in DCM to give 340 mg (63.5%) of (5-bromo-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-(5-ethylaminomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[C:18](=O)=[O:19].CN(C=O)C>C1COCC1.CCCCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([F:10])([F:11])[F:12])=[CH:6][C:7]=1[CH:18]=[O:19]
Reactant: O=C=O
Reactant: Fc1ccc(OC(F)(F)F)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CN(C)C=O
Product: O=Cc1cc(OC(F)(F)F)ccc1F
Reaction time: 0.25 h
Yield: 53 %

Procedure:
A solution of 1-fluoro-4-trifluoromethoxy-benzene (21.0 g, 117 mmol) in THF (233 ml) was cooled to <−70° C. Tert.-butyllithium (86 ml of a 1.5 molar solution in pentane, 129 mmol) was added at such a rate that temperature was kept <−70° C. Stirring in the dry ice bath was continued for 15 min, then DMF (11.6 ml, 150 mmol) was added dropwise keeping temperature <−70° C. After 30 min the reaction mixture was allowed to reach rt, quenched with saturated NH4Cl solution and extracted with ether. The organic phase was washed with brine, concentrated and chromatographed (SiO2, heptane:ethyl acetate=100:0 to 80:2). The title compound (11.0 g, 53%) was obtained as a light yellow oil. 1H-NMR (300 MHz, DMSO): δ=7.60 (t, J=9.2 Hz, 1H), 7.75-7.85 (m, 2H), 10.20 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([NH:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:31]=[CH:30][C:29]([NH:28][S:25]([CH3:24])(=[O:26])=[O:27])=[CH:34][CH:33]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(NS(C)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(methylsulfonylamino)phenylboronic acid acid following a procedure analogous to that described in Example 28. LC (method 10): tR=1.57 min; Mass spectrum (ESI+): m/z=474 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:16])([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH2:3][O:4][CH2:5][CH2:6][CH2:7]Cl.[CH2:17]([O:27][C:28]1[CH:29]=[N:30][C:31]([C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)=[N:32][CH:33]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:17]([O:27][C:28]1[CH:29]=[N:30][C:31]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH2:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([F:16])([F:1])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[CH:38][CH:39]=2)=[N:32][CH:33]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(F)C(F)(F)C(F)(F)COCCCCl
Product: CCCCCCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 3-(2,2,3,3,4,4,4-heptafluorobutoxy)propyl chloride (4.1 g of 68% purity, 10.7 mmol, prepared from 1,3-dichloropropane and 2,2,3,3,4,4,4-heptafluorobutanol) with 5-decyloxy-2-(4-hydroxyphenyl)pyrimidine (3.5 g, 10.7 mmol). The resulting crude product was isolated essentially as described in Example 3 and purified by chromatography on silica gel, eluting with 10 vol. % ethyl acetate in hexane, followed by Kugelrohr distillation (220° C. at 0.5 torr) to provide a yield of 4.8 g.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4](=[CH:13]N(C)C)[C:3]1=[O:17].[OH2:18]>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([CH:13]=[O:18])[C:3]1=[O:17]
Reactant: CN(C)C=C1C(=O)c2ccccc2N(C)C1=O
Reactant: O
Product: Cn1c(=O)c(C=O)c(O)c2ccccc21

Procedure:
The product from Step (1) was dissolved in distilled water (50 ml) by gentle warming and then the resulting solution was filtered. The clear filtrate was cooled in an ice bath and acidified to pH3 with mineral acid. The resulting crystalline precipitate was washed with water and dried to give 1 -methyl-3-formyl-4-hydroxy-2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data. MS: m/e 203 (M+); NMR (CDCl3): δ3.6 (s, 3H, NCH3), 10.28 (s, 1H, CHO) ppm.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:29])[C:16]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)([OH:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[OH-].[Na+]>Cl.O1CCOCC1>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:29])[C:16]([CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)([OH:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)C(O)(c2ccccc2)C2CCCC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(NC1CCNCC1)C(O)(c1ccccc1)C1CCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
752 Milligrams of N-(1-t-butoxycarbonylpiperidin-4-yl)- 2-cyclopentyl-2-hydroxy-2-phenylacetamide was dissolved in 7 ml of 4N hydrogen chloride-dioxane solution, and stirred for 12 hours at room temperature. The reaction mixture was made weakly basic with 1N sodium hydroxide solution and extracted with diethyl ether. The extract was washed with saturated saline solution, dried over anhydrous magnesium sulfate and removed of the solvent by reduced pressure distillation to give 420 mg of the title compound as a white solid.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][C:7]=1[C:22]1[NH:23][C:24](=[O:35])[C:25]2[N:30]([CH3:31])[N:29]=[C:28]([CH2:32][CH2:33][CH3:34])[C:26]=2[N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.CC(C)=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)(=[O:13])=[O:14])=[CH:8][C:7]=1[C:22]1[NH:23][C:24](=[O:35])[C:25]2[N:30]([CH3:31])[N:29]=[C:28]([CH2:32][CH2:33][CH3:34])[C:26]=2[N:27]=1)[CH:2]=[CH2:3]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3O)nc12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCC(C)=O
Product: C=CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 9.8 %

Procedure:
Allyl bromide (0.02 ml, 0.00023 mol) was added to a stirred suspension of 5-[2-hydroxy-5-(4-methylpiperazinylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (0.103 g, 0.00023 mol) and potassium carbonate (0.032 g, 0.00023 mol) in 2-butanone (10 ml) and the mixture heated under reflux for 8 hours. After cooling, the reaction mixture was evaporated under vacuum and the residue suspended in water (20 ml). The aqueous suspension was extracted with ethyl acetate (3×20 ml), the combined extracts dried (Na2SO4) and, after filtration, evaporated under vacuum to give an oil. Column chromatography on silica gel (2 g) using a methanol in dichloromethane elution gradient (0-3%), followed by evaporation under vacuum of appropriate fractions, gave a semi-solid which was dissolved in acetone; evaporation under vacuum of the solution gave the title compound (0.011 g, 10%), m.p. 151°-153° C., Rf 0.5 (silica; dichloromethane, methanol; 95:5), m/e 487 (M+ +1).
Reaction SMILES: [OH:1]/[N:2]=[CH:3]/[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:11][N:12]=2)[N:9]=1.[Cl:22]N1C(=O)CCC1=O>CN(C=O)C>[Cl:22]/[C:3](=[N:2]\[OH:1])/[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[N:11][N:12]=2)[N:9]=1
Reactant: CC(C)(C)OC(=O)NCc1nnc2ccc(/C=N/O)nn12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1nnc2ccc(/C(Cl)=N/O)nn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Dissolved (E)-tert-butyl (6-((hydroxyimino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (200 mg, 0.684 mmol) in 25 mL of DMF and added 1-chloropyrrolidine-2,5-dione (95.9 mg, 0.718 mmol). Let stir at rt for 2 h. Poured reaction mixture onto water (20 mL) and extracted with ether (3×20 mL). Washed organics with water (2×20 mL), brine (1×20 ml), dried over sodium sulfate, filtered and concentrated. Title compound used without further purification (220 mg, 97% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH:11]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[C:12]([CH3:17])([N+:14]([O-])=O)[CH3:13])=[CH:5][CH:4]=1.C(O)C>[Zn].C(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH:11]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[C:12]([CH3:17])([CH3:13])[N:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)CC(c2cccs2)C(C)(C)[N+](=O)[O-])cc1
Agent: [Zn]
Solvent: CCO
Solvent: O=CO
Product: COc1ccc(C2=NC(C)(C)C(c3cccs3)C2)cc1
Reaction time: 5 h

Procedure:
180 G. of zinc powder are added portionwise while stirring over a period of 5 hours to a solution of 194 g. of 4'-methoxy-4-methyl-4-nitro-3-(2-thienyl)-valerophenone in 400 ml. of ethanol and 400 ml. of formic acid. The temperature is held at 48°-50° C. during this addition. The zinc sludge is then filtered off and the filtrate strongly concentrated under reduced pressure. The residue is taken up in water and made alkaline with 3-N sodium hydroxide. The mixture is extracted with methylene chloride, the organic phase washed with water, dried over sodium sulfate and evaporated under reduced pressure. The oily residue is chromatographed on silica gel, elution being carried out firstly with pure benzene and then with benzene/acetone mixtures with increasing acetone content (up to 50% acetone). There is obtained 2-(p-methoxy-phenyl)-5,5-dimethyl-4-(2-thienyl)-1-pyrroline which melts at 84° C. after recrystallization from n-hexane.
Reaction SMILES: C(C(N[C@H](C(O)=O)C)C)(OCC1C=CC=CC=1)=O.Cl.C(OC(=O)[C@@H]1CCCN1)C1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:50]([CH:60]([NH:62][C@H:63]([C:65]([N:67]1[CH2:74][CH2:73][CH2:72][C@H:68]1[C:69]([OH:71])=[O:70])=[O:66])[CH3:64])[CH3:61])([O:52]CC1C=CC=CC=1)=[O:51]>N1C=CC=CC=1.C(N(CC)CC)C>[C:50]([CH:60]([NH:62][C@H:63]([C:65]([N:67]1[CH2:74][CH2:73][CH2:72][C@H:68]1[C:69]([OH:71])=[O:70])=[O:66])[CH3:64])[CH3:61])([OH:52])=[O:51]
Reactant: CC(N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(N[C@@H](C)C(=O)O)C(=O)OCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O)C(=O)O
Reaction time: 20 h

Procedure:
Dissolve 0.75 g of N-(1-carbobenzoxyethyl)-L-alanine in pyridine and add 7.5 ml of 1 M triethylamine in pyridine. Cool, and add 1.09 g L-proline benzyl ester hydrochloride and 0.678 g dicyclohexylcarbodiimide. Store at 0° C. for 20 hours. Filter, then concentrate the reaction mixture in vacuo. Dissolve the residue in ethyl acetate and wash this solution with saturated K2CO3, then brine. Dry the organic phase, concentrate in vacuo, then chromatograph the residue on silica gel with ethyl acetate-hexane to isolate the diastereoisomeric mixture of N-(1-carbobenzoxyethyl)-L-alanyl-L-proline.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[CH2:18][CH:17]([NH2:29])[CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH2:30]([N:37]=[C:38]=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([NH:37][C:38]([NH:29][CH:17]1[CH2:18][CH:19]([C:21]2[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=2)[CH2:20][N:15]([C:13]([CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)=[O:14])[CH2:16]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Reactant: O=C=NCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)NCc3ccccc3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
108 mg (0.22 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 7A) and 35 mg (0.26 mmol, 1.2 eq.) of benzyl isocyanate were reacted according to General Method 4. Yield: 74 mg (77% of theory)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[NH:14][C:15]1[N:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:25]3[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][C:26]=3[O:34][CH3:35])[CH:21]=2)[N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:36]1([NH2:39])[CH2:38][CH2:37]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[CH:36]1([NH:39][C:29]([C:28]2[CH:32]=[CH:33][C:25]([C:20]3[CH:21]=[C:22]4[C:17](=[CH:18][CH:19]=3)[N:16]=[C:15]([NH:14][C@@H:10]3[CH2:11][CH2:12][CH2:13][C@@H:9]3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[N:24]=[CH:23]4)=[C:26]([O:34][CH3:35])[CH:27]=2)=[O:30])[CH2:38][CH2:37]1
Reactant: COc1cc(C(=O)O)ccc1-c1ccc2nc(N[C@@H]3CCC[C@@H]3NC(=O)OC(C)(C)C)ncc2c1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CC2)ccc1-c1ccc2nc(N[C@@H]3CCC[C@@H]3NC(=O)OC(C)(C)C)ncc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
A mixture of 4-(2-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)amino)quinazolin-6-yl)-3-methoxybenzoic acid (57 mg, 0.12 mmol), cyclopropyl amine (0.012 mL, 0.18 mmol), HATU (68 mg, 0.18 mmol) and DIEA (0.052 mL, 0.30 mmol) in dichloromethane (1.5 mL) was stirred at room temperature for 30 minutes. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield tert-butyl ((1S,2R)-2-((6-(4-(cyclopropylcarbamoyl)-2-methoxyphenyl)quinazolin-2-yl)amino)cyclopentyl)carbamate (58 mg, 93%). MS (ES+) C29H35N5O4 requires: 517, found: 518 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20](Br)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:26][N:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[Sn](CCCC)(CCCC)CCCC>>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:28]5[N:27]([CH3:26])[CH:31]=[CH:30][CH:29]=5)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CCN2CCC(N3CCc4ccc(Br)cc43)CC2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Product: Cn1cccc1-c1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Yield: 16 %

Procedure:
1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-bromoindoline (0.1 g) and 1-methyl-2-tributylstannylpyrrole (0.37 g) synthesized in accordance with the method described in Tetrahedron Lett., 4407 (1986). were treated as in Production Example 13-2 to give the title compound (0.016 g) as a yellow oil (yield: 15.8%).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][CH:10]1[CH2:11][CH2:12][CH:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH2:23].[I-].ClC1C=CC=C[N+]=1C.C(=O)(O)[O-].[Na+]>O1CCCC1.C(N(CC)CC)C>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][CH:10]1[CH2:11][CH2:12][CH:13]2[C:18]([NH:23][N:22]([CH3:21])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCC2CN1C(=O)N2OCc1ccccc1
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(NC(=O)C1CCC2CN1C(=O)N2OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a solution of (2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (400 mg, 1.45 mmol) and tert-butyl 1-methylhydrazinecarboxylate (232 mg) in tetrahydrofuran (14 mL) were added triethylamine (972 μL) and 2-chloro-1-methylpyridin-1-ium iodide (554 mg), followed by stirring at room temperature overnight. To the reaction solution was added saturated sodium bicarbonate aqueous solution, followed by extracting with chloroform. The organic layer was dried over sodium sulfate, and then concentrated. The resulting crude product was purified by silica gel column chromatography to afford 458 mg of the title compound (yield 78%).
Reaction SMILES: [H-].[Na+].[I-].C[S+](C)(C)=O.O=[C:10]1[CH2:15][CH2:14][CH:13]([N:16]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[N:22]=3)=[C:19]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[N:18]=[CH:17]2)[CH2:12][CH2:11]1.O.[CH2:37]1[CH2:41][O:40]CC1>CS(C)=O>[O:40]1[CH2:41][CH:37]1[CH:10]1[CH2:11][CH2:12][CH:13]([N:16]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[N:22]=3)=[C:19]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[N:18]=[CH:17]2)[CH2:14][CH2:15]1
Reactant: COc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCC(=O)CC2)n1
Reactant: C1CCOC1
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Solvent: O
Product: COc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCC(C3CO3)CC2)n1
Reaction time: 4 h
Yield: 53 %

Procedure:
Added to a mixture of sodium hydride (0.05 g, 0.88 mmol) in DMSO (1 mL) was trimethyl sulfoxonium iodide (0.29 g, 1.3 mmol). After stirring the resultant mixture 1.5 h. (when gas evolution ceases), 1-(4-oxocyclohexyl)-4-(4-fluorophenyl)-5-[(2-methoxy)pyrimidin-4-yl]imidazole from example 1(j) (0.322 g, 0.88 mmol) suspended in dry THF (4 mL) was added and the mixture was stirred 4 h. The mixture was poured into H2O and extracted with EtOAc. The organic phase was dried (Na2SO4) and concentrated. The resulting residue was suspended in EtOAc/hexane (1:1) and filtered. The solid was purified by flash chromatography (silica gel 2% MeOH/CH2Cl2) to afford the title compound as white crystals (0.18 g, 53% yield) 1H NMR (CDCl3): δ 8.35 (d, 1H), 7.85 (s, 1H), 7.43 (q, 2H), 7.02 (t, 2H), 6.80 (d, 1H), 4.86 (m, 1H), 4.09 (s, 3H), 2.76 (s, 2H), 226 (m, 2H), 2.20-2.02 (m, 4H), 1.43 (d, 2H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)[N:17]=4)[S:12][C:11]=3[C:10]([O:34]C)=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.C(S)C.[H-].[Na+].Cl>CN(C=O)C.O>[CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][N:27]5[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]5)[N:17]=4)[S:12][C:11]=3[C:10]([OH:34])=[CH:9][CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: COc1ccc(C(=O)NC2CC2)c2cc(-c3nc(NCCCN4CCN(C)CC4)ncc3Cl)sc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)ccc(O)c4s3)n2)CC1
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 23.9 %

Procedure:
To a solution of 2-{5-chloro-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-7-methoxybenzo[b]thiophene-4-carboxylic acid cyclopropylamide (500 mg, 0.970 mmol) and ethanethiol (0.718 mL, 9.71 mmol) in dry DMF (10 mL) is added in one portion sodium hydride (388 mg, 9.71 mmol) at 0° C. The mixture is stirred for 5 minutes and heated to 110° C. in a preheated oil bath for 10 minutes. The mixture is cooled to room temperature and a solution of HCl (12%, 3.5 mL) is added. The mixture is diluted with water (100 mL) and concentrated. The residue is diluted with MeOH and filtered off. The filtrate is purified on silica gel, eluting with dichloromethane in MeOH 90:10 to 60:40, to give the title compound as a yellow solid (116 mg, 24% yield). ES+(m/z) 501 (35Cl) and 503 (37Cl) [M+H].
Reaction SMILES: BrC1C=CC=CC=1C(Cl)=O.[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])=[CH:28][C:27]=1[F:33].[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42]>C1(C)C=CC=CC=1.C(O)C>[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42].[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([NH:43][C:44]([NH:30][C:29]1[CH:31]=[CH:32][C:26]([O:25][C:16]2[C:15]3[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=3)[N:19]=[CH:18][CH:17]=2)=[C:27]([F:33])[CH:28]=1)=[S:45])=[O:42]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1ccccc1Br
Agent: O=C(N=C=S)c1ccccc1Br
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Br)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
2-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-bromo-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 (73 mg, yield 83%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]12[CH2:19][C:13]3(Br)[CH2:14][C:15](Br)([CH2:17][C:11]([CH3:21])([CH2:12]3)[CH2:10]1)[CH2:16]2.Br>>[CH3:8][C:9]12[CH2:19][C:13]3([C:4]4[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=4)[CH2:14][C:15]([C:4]4[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=4)([CH2:17][C:11]([CH3:21])([CH2:12]3)[CH2:10]1)[CH2:16]2
Reactant: CC12CC3(C)CC(Br)(C1)CC(Br)(C2)C3
Reactant: Oc1ccccc1
Agent: Br
Product: CC12CC3(C)CC(c4ccc(O)cc4)(C1)CC(c1ccc(O)cc1)(C2)C3

Procedure:
Adamantane bisphenols can be readily made available from the corresponding dibromoderivatives and phenol according to U.S. Pat. No. 3,594,427. Thus, 112 g of 1,3-dimethyl-5,7-dibromoadamantane (III) (0.35 m) (see Example 2a) and 900 g of phenol were heated together at 170° C. for six hours. After termination of the evolution of HBr, the mixture was heated to 220° C. for a further two hour period and the excess phenol was distilled off. The reaction mixture was poured into warm water and the white precipitate was filtered, washed with warm water and dried at 80° C. under vacuum. Yield 117.8 g (97%). The product was recrystallyzed from toluene. MP: 222°-224° C.