Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]=[C:11]=[S:12])=[O:9].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1.C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH:10][C:11]([NH:32][C:31]1[CH:33]=[CH:34][C:28]([O:27][C:18]2[C:17]3[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=3)[N:21]=[CH:20][CH:19]=2)=[CH:29][C:30]=1[CH3:35])=[S:12])=[O:9]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: O=C(N=C=S)c1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Cl)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
Commercially available 2-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were 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 (47 mg, yield 57%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[O:11][C:12]1[CH:17]=[CH:16][C:15](B2OC(C)(C)C(C)(C)O2)=[CH:14][CH:13]=1.Br[C:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[N:30]([CH:37]([CH3:39])[CH3:38])[N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:39][CH:37]([N:30]1[C:31]2[C:32](=[N:33][CH:34]=[CH:35][CH:36]=2)[C:28]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:17][CH:16]=2)=[N:29]1)[CH3:38]
Reactant: Cn1c(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc2cccnc21
Reactant: CC(C)n1nc(Br)c2ncccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)n1nc(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncccc21
Yield: 95.6 %

Procedure:
A mixture of 3-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-3H-imidazo[4,5-b]pyridine (215 mg), 3-bromo-1-(1-methylethyl)-1H-pyrazolo[4,3-b]pyridine (147 mg), Pd(PPh3)4 (21 mg) and Na2CO3 (227 mg) in DME (5 mL) and water (1 mL) was refluxed overnight under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) and recrystallized from AcOEt/hexane to give the title compound (225 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1C(OC(C)(C)C)=O)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:21])[F:22])(=[O:11])=[O:12])[CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1

Procedure:
In analogy to the procedure described in example 253a, (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester was treated with trifluoroacetic acid in dichloromethane to give the title compound as yellow oil. MS (ESI): m/z=356.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N+:10]([O-])=[CH:9][CH:8]=[CH:7]2.P(Cl)(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:15][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc2ccc[n+]([O-])c12
Solvent: Cc1ccccc1
Product: Cc1cccc2ccc(Cl)nc12
Temperature: 80 °C
Yield: 81.5 %

Procedure:
To a solution of 8-methylquinoline 1-oxide (0.440 g, 2.764 mmol) in toluene (10 ml) was added phosphoryl trichloride (1.265 ml, 13.82 mmol), and the reaction was heated to 80° C. for 2 hours. The reaction was cooled to ambient temperature and concentrated. The crude material was taken up in EtOAc and washed with saturated sodium bicarbonate and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to yield the desired compound (0.4 g, 2.252 mmol, 81.47% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[C@H:13]12[CH2:19][C@H:16]([NH:17][CH2:18]1)[CH2:15][N:14]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:17]2[CH2:18][C@@H:13]3[CH2:19][C@H:16]2[CH2:15][N:14]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(Cl)nnc1Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Product: COC(=O)c1cc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)nnc1Cl
Yield: 41 %

Procedure:
Methyl 3,6-dichloropyridazine-4-carboxylate and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), were processed as described in Example 2A to provide the title compound (41% yield). 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 4.5H), 1.47 (s, 4.5H), 1.90-2.11 (m, 2H), 2.86 (d, J=9.93 Hz, 1H), 3.40-3.62 (m, 2H), 3.72 (d, J=9.90 Hz, 1H), 3.93 (s, 3H), 3.51 (s, 0.5H), 4.63 (s, 0.5H), 5.05-5.15 (m, 1H), 7.49 (s, 1H); MS (DCI/NH3) m/z 368 (M+H)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1(C)[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:1]1([C:10]2[CH:9]=[CH:8][C:13]([OH:14])=[CH:12][CH:11]=2)([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccccc1
Reactant: Cc1ccccc1O
Product: Oc1ccc(C2(c3ccc(O)cc3)CCCCC2)cc1

Procedure:
The procedure of Example 1 was repeated, except that 10500 g (111.6 moles) of phenol was substituted for o-cresol. The crude crystals that separated out were rinsed with methylene chloride; after airdrying they weighed 5170 g or 87% of theoretical. Recrystallization from methanol-water yielded pure CDP, mp 188-189° C., that was 99.8% pure by gas chromatography.
Reaction SMILES: [Cl:1][CH:2]([CH3:26])[CH:3]([NH:15][C:16]([CH:18]1[CH:21]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1.[CH2:27]1[O:29][CH2:28]1>>[Cl:1][CH:2]([CH3:26])[CH:3]([NH:15][C:16]([CH:18]1[CH:21]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][N:19]1[CH2:27][CH2:28][OH:29])=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1
Reactant: CCCCC1CNC1C(=O)NC(C(C)Cl)C1OC(SC)C(O)C(O)C1O
Reactant: C1CO1
Product: CCCCC1CN(CCO)C1C(=O)NC(C(C)Cl)C1OC(SC)C(O)C(O)C1O

Procedure:
A sample of 3-butyl-azetidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide prepared in example 91 was alkylated with ethyleneoxide as depicted in scheme 19 (R6=2-hydroxyethyl) to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:29]=[CH:28][C:13]([C:14]([NH:16][NH:17]C(OCC2C=CC=CC=2)=O)=[O:15])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H].C>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:16][NH2:17])=[O:15])=[CH:28][CH:29]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)NNC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)NN)cc1
Yield: 95.1 %

Procedure:
A solution of the product of step (a) (5.7 g) in methanol (120 ml) was hydrogenolysed over 10% palladium on carbon (0.5 g) until hydrogen uptake ceased (1 hour). Activated charcoal was added and the mixture was stirred, filtered through diatomaceous earth and concentrated to give 4-(t-butoxycarbonylaminomethyl)benzoylhydrazine (3.6 g) as a colourless solid; m.p. (from toluene) 114°-116° C.; NMR Spectrum 1.4 (9H, s); 3.2-4.0 (2H, br s); 4.2 (2H, s); 7.3 (2H, d); 7.4 (1H, t); 7.8 (2H, d); 9.7 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][NH2:12])=[O:10])=[CH:4][CH:3]=1.[C:13](=S)=[S:14].[OH-].[K+]>O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[O:10][C:13]([SH:14])=[N:12][N:11]=2)=[CH:6][CH:7]=1
Reactant: NNC(=O)Cc1ccc(Cl)cc1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Sc1nnc(Cc2ccc(Cl)cc2)o1
Yield: 45.3 %

Procedure:
A stirred solution of 7.0 grams (0.038 mole) of 4-chlorophenylacetic acid hydrazide, 3.0 grams (0.039 mole) of carbon disulfide and 2.8 grams (0.050 mole) of potassium hydroxide in 10 ml of water and 200 ml of ethanol was heated under reflux for four hours. The ethanol was removed under reduced pressure. The concentrate was taken up in water and the mixture washed with diethyl ether. The aqueous layer was acidified with aqueous 5% hydrochloric acid and then was extracted with diethyl ether. The extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 3.9 grams of 2-(4-chlorophenylmethyl)-5-mercapto-1,3,4-oxadiazole; m.p. 115° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[C:13]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][C:18]=1[NH:25][C:26](=[O:44])[CH2:27][CH:28]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]2[O:40][CH2:41][CH2:42][O:43][C:35]=12)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O.O>[C:13]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])=[CH:19][C:18]=1[NH:25][C:26](=[O:44])[CH2:27][CH:28]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]2[O:40][CH2:41][CH2:42][O:43][C:35]=12)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH3:14])([CH3:15])[CH3:16]
Reactant: CCCCCC(CC(=O)Nc1cc(CBr)ccc1C(C)(C)C)c1cccc2c1OCCO2
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCC(CC(=O)Nc1cc(CN2C(=O)c3ccccc3C2=O)ccc1C(C)(C)C)c1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
138 mg (0.745 mmol) of potassium phthalimide were added to a solution of 288 mg (0.573 mmol) of N-[2-t-butyl-5-bromomethyl-phenyl]-3-(2,3-ethylenedioxyphenyl)octanamide (prepared as described in Preparation 70E) in 5 ml of dimethylformamide, and the resulting mixture was stirred at room temperature for 4 hours. At the end of this time, the reaction mixture was diluted with water and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 295 mg (yield 91%) of the title compound as a colorless foam-like substance.
Reaction SMILES: CN(C)[C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:17][C:16]=1[F:28].[OH-:31].[Na+]>CCO>[CH:11]1([C:9]2[CH:8]=[CH:7][C:6]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:17][C:16]=3[F:28])=[C:5]([CH2:4][C:3]([OH:29])=[O:31])[CH:10]=2)[CH2:13][CH2:12]1
Reactant: CN(C)C(=O)Cc1cc(C2CC2)ccc1Nc1ccc(-c2ccc(F)cc2)cc1F
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)Cc1cc(C2CC2)ccc1Nc1ccc(-c2ccc(F)cc2)cc1F

Procedure:
A solution of N,N-dimethyl-5-cyclopropyl-2-[2′-fluoro-4′-(4-fluorophenyl)anilino]phenylacetamide (575 mg) in 10 mL of 4 N NaOH and 20 mL of EtOH is heated overnight at 80° C. After cooling, the EtOH is removed under reduced pressure and the residue is diluted with EtOAc and cold water. The mixture is cooled in an ice bath and cold 2.5 N HCl is added until the pH of the aqueous layer reaches 2. The organic phase is separated, washed with brine, dried (Na2SO4) and concentrated in vacuo to give a brown solid. The solid is purified by flash chromatography eluting with 10%, then 20%, then 30% EtOAc in hexane to give the title product, m.p. 182–183° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[S:9]([C:12]([F:15])([F:13])[F:14])(=[O:11])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(Nc1ccc(Br)cc1)C(F)(F)F
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(CN(c2ccc(Br)cc2)S(=O)(=O)C(F)(F)F)cc1
Yield: 97.1 %

Procedure:
A suspension of 1.52 g (5 mmol) of N-(4-bromophenyl)-C,C,C-trifluoro-methanesulphonamide (Example 13bv)), 1.56 g (10 mmol) of 4-methoxybenzyl chloride and 1.38 g (10 mmol) of powdered potassium carbonate in 15 ml of acetone was stirred at reflux for 18 hours. Thereafter, the mixture was concentrated and the residue was taken up in 100 ml of water and 100 ml of ethyl acetate, the organic phase was separated and the aqueous phase was extracted twice with 100 ml of ethyl acetate each time. The combined organic phases were washed neutral with sat. sodium chloride solution, dried over magnesium sulphate and evaporated. The resulting yellow oil was subjected to flash chromatography with hexane/ethyl acetate 95:5. 2.06 g (97%) of N-(4-bromophenyl)-C,C,C-trifluoro-N-(4-methoxy-benzyl)-methanesulphonamide were obtained as a colourless, viscous oil. MS (EI): 423 and 425 (M+, 3%), 121 ([CH2 --C6H4 --OCH3 ]+, 100%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[CH:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].[CH2:11]([O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[C:12]#[C:13][CH3:14]>>[CH3:2][O:3][C:4](=[O:10])[CH:5]([NH:6][S:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:11][C:12]#[C:13][CH3:14])=[CH:21][CH:20]=1)(=[O:24])=[O:23])[CH:7]([CH3:9])[CH3:8]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C(N)C(C)C
Agent: Cl
Product: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)C(C)C)cc1

Procedure:
According to the procedure of Example 20, 1.500 g (8.95 mmol) of D,L-valine methyl ester hydrochloride and 2.19 g (8.95 mmol) of 4-but-2-ynyloxybenzenesulfonyl chloride provided 2.15 g of the NH-sulfonamide ester, 2-(4-but-2-ynyloxy-benzenesulfonylamino)-3-methyl-butyric acid methyl ester, as a white solid.
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:20]1([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:18][O:17][CH2:16][CH2:15][N:4]1[C:3](=[O:19])[C:2]([NH:30][C:29]2[CH:28]=[CH:27][C:26]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:32][CH:31]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13]
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: COCCN1C(=O)C(Nc2ccc(N3CCOCC3)cc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 4-morpholin-4-ylaniline in a similar manner as described for Examples 9 and 13. 1H NMR (400 MHz, CD3CN): δ 2.92-2.97 (m, 4H), 3.38 (s, 3H), 3.70-3.75 (m, 6H), 3.90 (t, 2H), 6.51-6.56 (m, 2H), 6.68-6.72 (m, 2H), 7.08-7.16 (m, 4H), 7.22-7.27 (m, 1H), 7.67 (bs, 1H); Mass Spectrum: M+H+ 444.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[S:3][C:2]=1[N:10]=[C:11](SC)SC.Cl.Cl.[NH2:18][CH2:19][C@@:20]1([OH:27])[C@@H:25]2[CH2:26][N:22]([CH2:23][CH2:24]2)[CH2:21]1>>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[S:3][C:2]=1[NH:10][C:11]1[O:27][C@@:20]2([C@@H:25]3[CH2:26][N:22]([CH2:23][CH2:24]3)[CH2:21]2)[CH2:19][N:18]=1
Reactant: CSC(=Nc1nc2cccnc2s1)SC
Reactant: NC[C@]1(O)CN2CC[C@H]1C2
Agent: Cl
Product: c1cnc2sc(NC3=NC[C@@]4(CN5CC[C@H]4C5)O3)nc2c1
Yield: 67 %

Procedure:
Dimethyl thiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate and (3S*,4S*)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol dihydrochloride were reacted according to the method of EXAMPLE 4, STEP D to afford (3R*,4S*)—N-(thiazolo[5,4-b]pyridin-2-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine (87.6 mg, 0.290 mmol, 67% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.16 (br. s., 1H) 8.31 (dd, J=4.77, 1.51 Hz, 1H) 7.90 (dd, J=8.03, 1.51 Hz, 1H) 7.38 (dd, J=8.03, 4.77 Hz, 1H) 4.03 (d, J=10.54 Hz, 1H) 3.81 (d, J=10.54 Hz, 1H) 2.96 (dd, J=13.55, 1.76 Hz, 1H) 2.73-2.88 (m, 3H) 2.61-2.73 (m, 1H) 2.40-2.49 (m, 2H) 1.52-1.70 (m, 1H) 1.25-1.44 (m, 1H). MS(LC/MS) R.T.=0.32; (M+H=302.22).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][CH2:6][C@@H:7]([CH3:35])[O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[C:22]([Cl:34])[CH:21]=1)=[N:12][CH:13]=[N:14]2>>[Cl:34][C:22]1[CH:21]=[C:20]([NH:19][C:11]2[C:10]3[C:15](=[CH:16][CH:17]=[CH:18][C:9]=3[O:8][C@H:7]([CH3:35])[CH2:6][NH:5][C:3]([NH:2][CH3:1])=[O:4])[N:14]=[CH:13][N:12]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: CN=C=O
Reactant: C[C@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CNC(=O)NC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 43 %

Procedure:
The procedure described in Example 120 was repeated using methyl isocyanate and 5-[(1R)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 65, preparation of starting materials) to give the title compound as a solid in 43% yield; NMR spectrum (DMSO-d6 @ 373K) 1.40-1.45 (d, 3H), 2.50-2.55 (d, 3H), 3.38-3.48 (m, 1H), 3.50-3.60 (m, 1H), 4.83-4.92 (m, 1H), 5.28 (s, 2H), 5.55-5.65 (bs, 1H), 6.00-6.10 (bs, 1H), 7.19-7.24 (dd, 2H), 7.31-7.37 (m, 2H), 7.56-7.62 (m, 2H), 7.66-7.73 (t, 1H), 7.81-7.88 (dt, 1H), 8.06-8.08 (d, 1H), 8.48 (s, 1H), 8.55-8.60 (d, 1H), 9.95-10.05 (bs, 1H); Mass spectrum MH+ 493.4.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[OH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([NH:1][C:29](=[O:30])[C:28]4[CH:27]=[CH:26][C:25]([N:22]5[CH2:23][CH2:24][CH:19]([OH:18])[CH2:20][CH2:21]5)=[CH:33][CH:32]=4)=[CH:3][CH:4]=3)[NH:8][N:7]=2)=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Reactant: Nc1ccc(-c2n[nH]c3cc(N)ccc23)cc1
Product: Nc1ccc(-c2n[nH]c3cc(NC(=O)c4ccc(N5CCC(O)CC5)cc4)ccc23)cc1

Procedure:
Compound 976 was prepared according to the procedure described in Scheme IV from 6-amino-3-(4-aminophenyl)-1H-indazole, and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C25H25N5O2: 428.20; found 428.07.
Reaction SMILES: [CH2:1]([O:3][SiH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:11][C:12]1[CH:13]=[C:14]([N:19]([C:28]2[CH:35]=[CH:34][C:31]([CH:32]=[CH2:33])=[CH:30][CH:29]=2)[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]>C1(C)C=CC=CC=1>[CH3:27][C:22]1[CH:21]=[C:20]([N:19]([C:28]2[CH:29]=[CH:30][C:31]([CH2:32][CH2:33][Si:4]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])=[CH:34][CH:35]=2)[C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([CH3:11])[CH:13]=2)[CH:25]=[CH:24][C:23]=1[CH3:26]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=Cc1ccc(N(c2ccc(C)c(C)c2)c2ccc(C)c(C)c2)cc1
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1ccc(N(c2ccc(C)c(C)c2)c2ccc(C)c(C)c2)cc1)(OCC)OCC
Temperature: 25 °C
Yield: 94.2 %

Procedure:
Into a three-necked flask, 40 ml of toluene, 6.0 g (37 mmol) of triethoxysilane and 0.34 mmol of platinum (II) dichloro(h-cycloocta-1,5-diene) were placed, and 20 ml of a toluene solution containing 9.9 g of 4-[N,N-bis(3,4-dimethylphenyl)amino]styrene was added dropwise with stirring at room temperature. After the addition was completed, the mixture was stirred at 70° C. for 3 hours, and thereafter the solvent was removed under reduced pressure to obtain oily pale yellow 4-[N,N-bis(3,4-dimethylphenyl)amino]-[2-(triethoxysilyl)ethyl]benzene in an amount of 14.0 g (yield: 94.2%).
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[OH:19][CH2:20][C@H:21]([CH3:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24].N1C=CN=C1.O>C(Cl)Cl>[Si:5]([O:19][CH2:20][C@H:21]([CH3:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24])([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C[C@@H](C)CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: COC(=O)C[C@@H](C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.6 %

Procedure:
tert-Butyl(chloro)diphenylsilane (26.5 g) was added dropwise to a solution of methyl (R)-4-hydroxy-3-methyl-butyrate (11.0 g) and imidazole (8.5 g) in methylene chloride (200 mL) under ice cooling, and the mixture was then stirred at room temperature for 24 hours. Water was added thereto to separate an organic layer. The organic layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane→hexane/ethyl acetate=97/3) to obtain the title compound (29.8 g).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([OH:26])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[N:16][CH:15]=1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40]O)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][O:26][C:20]2[CH:19]=[C:18]3[C:23]([C:14]([Cl:13])=[CH:15][N:16]=[N:17]3)=[CH:22][C:21]=2[O:24][CH3:25])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1cc2c(Cl)cnnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)cnnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
DEAD (1.46 g, 8.38 mmol) was added to a suspension of 4-chloro-7-hydroxy-6-methoxycinnoline (1.47 g, 6.98 mmol), (prepared as described for the starting material in Example 1), 1-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine (1.65 g, 7.68 mmol), (prepared as described for the starting material in Example 6), and triphenylphosphine (2.74 g) in methylene chloride (40 ml). The mixture was stirred for 1 hour at ambient temperature, then poured onto silica and eluted with a gradient of ethyl acetate in methylene chloride (30/70 to 50/50). The fractions containing the expected product were combined and evaporated to give 7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-chloro-6-methoxycinnoline (561 mg, 58%).