Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:31]=[CH:32][C:33](=[O:36])[NH:34][N:35]=2)[CH:27]=[CH:28][CH:29]=1>>[CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][O:23][C:24]3[CH:25]=[C:26]([C:30]4[CH:31]=[CH:32][C:33](=[O:36])[NH:34][N:35]=4)[CH:27]=[CH:28][CH:29]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NCCOc1cccc(-c2ccc(=O)[nH]n2)c1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CCC1
Product: O=c1ccc(-c2cccc(OCCNCC(O)COc3ccc(CCOCC4CCC4)cc3)c2)n[nH]1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[3-(2-aminoethoxy)phenyl]-3(2H)-pyridazinone.
Reaction SMILES: [Cl:1][CH2:2][CH2:3]Br.[CH3:5][C:6]1[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=1[CH2:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C>O>[ClH:1].[ClH:1].[Cl:1][CH2:2][CH2:3][N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[CH3:5])[CH2:10][CH2:11]1
Reactant: ClCCBr
Reactant: Cc1ccccc1CN1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccccc1CN1CCN(CCCl)CC1
Product: Cl
Yield: 44.8 %

Procedure:
First, 2-chlorobromoethane (48 g) is added to a solution of 2-methylbenzylpiperazine (12 g) and triethylamine (32 g). The resulting mixture is refluxed for 30 minutes; water is then added and the product is extracted with ether, dried (magnesium sulfate) and concentrated in vacuo to give an oil, which is purified on a silica gel column (methylene chloride: methanol, 9:1). The resulting oil is dissolved in ether and the salt precipitated with ethereal hydrochloric acid to give 9.2 g of 1-(2-chloroethyl)-4-(2-methylbenzyl)piperazine dihydrochloride as colorless crystals.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[OH:8][NH:9][C:10](=[O:18])[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O1CCOCC1.[C:25]1(C)[C:26]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:28]=C[CH:30]=1>C1(C)C=CC=CC=1.O>[C:6]1([CH3:7])[CH:28]=[CH:27][C:26]([S:31]([O:8][NH:9][C:10](=[O:18])[O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:33])=[O:32])=[CH:25][CH:30]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: O=C(NO)Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)ONC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
20.4 Parts of triethylamine are added to a stirred mixture of 30.4 parts of phenyl N-hydroxycarbamate, 100 parts of dioxan and 38.1 parts of toluenesulphonylchloride at 0° C, keeping the pH in the range 2 to 5. The mixture is then stirred for 18 hours at 25° C and added to 500 parts of water. The oily precipitate is taken up in 500 parts of toluene and the solution is washed with water, dried, filtered and evaporated to constant weight at 40° C under reduced pressure to give 59 parts of phenyl N-p-toluenesulphonyloxycarbamate as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:22]2[CH:21]=[N:20][CH:19]=[C:18]([O:17][CH3:16])[CH:23]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1cncc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.35 g, 1.4 mmol), 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.50 g, 2.12 mmol), palladium tetrakistriphenylphosphine (0.16 g, 0.14 mmol), potassium carbonate (0.49 g, 4.23 mmol) in toluene (2.8 mL) at 100° C. for 17.6 h to give 4-chloro-5,7-difluoro-2-(5-methoxypyridin-3-yl)-3-methylquinoline as a white solid. Mass Spectrum (ESI) m/e=321.0 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[O-:6])[CH2:3][CH2:2]1.[Na+].C(C(CCCC)CO)C.[OH:22][C:23]1[CH:28]=[C:27]([Cl:29])[N:26]=[N:25][C:24]=1Cl.C1(C2C=CC=C(C)C=2O)CC1>C1(C)C=CC=CC=1.O>[Cl:29][C:27]1[N:26]=[N:25][C:24]([O:6][C:5]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:23]([OH:22])[CH:28]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1[O-]
Agent: Cc1cccc(C2CC2)c1O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCC(CC)CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
To a mixture of 25.5 g (150 mmol) of sodium 2-cyclopropyl-6-methylphenoxide and 12.5 g of 2-ethyl-1-hexanol was added 2.5 g (purity: 99%; 15.0 mmol) of 4-hydroxy-3,6-dichloropyridazine at room temperature. Then, the resultant mixture was heated from room temperature to 140° C. to effect a reaction for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 100 g of pure water and 120 g of toluene were added to the cooled mixture, and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. Then, the resultant aqueous phase containing a sodium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was quantitatively determined by an HPLC internal standard analysis method, which showed that 2.85 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 69.0%) and 9.0 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.2%) were obtained.
Reaction SMILES: Cl.[N:2]1([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.C[N:26](C=O)C>ClCCl>[N:2]1([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:26])=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1ccc(OCCN2CCCC2)cc1
Reaction time: 1 h
Yield: 93 %

Procedure:
To a suspension of 4-[2-(1-pyrrolidinyl)ethoxy]benzoic acid hydrochloride (750 mg, 2.76 mmol) in dry dichloromethane (10 mL) was added oxalyl chloride (0.481 mL, 5.62 mmol, 2.0 eq.) then a catalytic amount of DMF. After 1 h, the reaction mixture was filtered through a pad of diatomaceous earth, then the solvent was removed under reduced pressure. The residue was treated with excess concentrated ammonium hydroxide in THF (5 mL each). The layers were separated by the addition of brine (10 mL); then the aqueous layer was extracted with THF (2×20 mL). The combined extracts were concentrated to dryness under reduced pressure to give the desired amide as a white solid (602 mg, 93%) after drying under vacuum at ambient temperature.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][NH:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][N:15]1[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: c1ccc2c(c1)CCNC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1N1CCc2ccccc2C1

Procedure:
4.0 g (19.4 mmol) of ethyl 2-chloronicotinate, together with 3.2 g (19.4 mmol) of 1,2,3,4-tetrahydroisoquinoline hydrochloride and 5.36 g of potassium carbonate were heated at 110° C. for 3 h in 50 ml of DMF while stirring. Water was then added and the whole was extracted with ether; the ether phase was then washed with ammonium chloride, dried and evaporated. The crude product was purified chromatographically (silica gel/heptane-ethyl acetate 20-1), giving a yield of 4.8 g (87%).
Reaction SMILES: C(OP([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:11]1=2)(=O)OCC)C.C([Sn](CCCC)(CCCC)[C:28]1[O:29][CH:30]=[CH:31][CH:32]=1)CCC.[H-].[Na+].[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([S:50][C:51]2[CH:58]=[CH:57][CH:56]=[CH:55][C:52]=2[CH:53]=O)=[CH:46][CH:45]=1>O1CCOCC1>[ClH:43].[ClH:43].[Cl:43][C:44]1[CH:45]=[CH:46][C:47]([S:50][C:51]2[CH:58]=[CH:57][CH:56]=[CH:55][C:52]=2[CH:53]=[CH:9][C:10]2=[N:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]3[CH:18]=[C:19]([C:30]4[O:29][CH:28]=[CH:32][CH:31]=4)[CH:20]=[CH:21][C:11]2=3)=[CH:48][CH:49]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: CCOP(=O)(C=C1NCCN(C)c2cc(Br)ccc21)OCC
Reactant: O=Cc1ccccc1Sc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN1CCN=C(C=Cc2ccccc2Sc2ccc(Cl)cc2)c2ccc(-c3ccco3)cc21
Product: Cl
Temperature: 80 °C
Reaction time: 18 h
Yield: 105.3 %

Procedure:
To 123 mg (0.32 mmol) of (8-bromo-1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester (prepared as described in Example 41) in 2 ml of dioxane was added 135 mg (0.38 mmol) of 2-(tributylstannyl)furan, followed by 11.1 mg (0.016 mmol) of palladium (II) bis-triphenylphosphine-dichloride. The mixture was heated at 80° C. for 18 hours. To the mixture at ambient temperature was added 55 mg (1.37 mmol) of sodium hydride (60% dispersion in mineral oil). After 5 minutes 82 mg (0.33 mmol) of 2-(4-chlorophenylthio)benzaldehyde was added and the mixture was stirred for 18 hours. The solvent was removed and the product was purified by column chromatography eluting with 24-40% acetone/petroleum ether (40-60° C.) and treated with 0.10 ml of 4M hydrogen chloride in dioxan. The solvent was evaporated and the residue was dissolved from acetone/petroleum ether (40 60° C.). The solvent was removed and the residue was recrystallised from acetone/petroleum ether (40 60° C.) to give 63 mg of (E)-5-[2-(4-chlorophenylthio)styryl]-8-(2-furyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepine dihydrochloride as dark red crystals; MS: m/e 471 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15](C1CCCCO1)[N:14]=[C:13]2[C:25]1[CH:30]=[C:29]([O:31]CC2C=CC(OC)=CC=2)[N:28]=[C:27]([N:41]([CH3:43])[CH3:42])[N:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[C:13]2[C:25]1[N:26]=[C:27]([N:41]([CH3:42])[CH3:43])[NH:28][C:29](=[O:31])[CH:30]=1
Reactant: COc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc(Nc5c(F)cccc5F)cc34)nc(N(C)C)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1nc(-c2n[nH]c3ccc(Nc4c(F)cccc4F)cc23)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 26 h
Yield: 50.1 %

Procedure:
N-(2,6-Difluorophenyl)-3-(2-(dimethylamino)-6-((4-methoxybenzyl)oxy)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (260 mg, 0.443 mmol) in DCM (2.0 mL) was treated with TFA, 99% (2.0 mL, 26.9 mmol) at RT and stirred at 50° for 26 h. The mixture was cooled to RT and evaporated to dryness. The residue was diluted with DCM and extracted with sat'd NaHCO3 solution. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude material was purified with silica gel chromatography (eluting with 0-8% MeOH in DCM with 2 M NH3) to give 6-(5-((2,6-difluorophenyl)amino)-1H-indazol-3-yl)-2-(dimethylamino) pyrimidin-4(3H)-one (85 mg, 0.222 mmol, 50.2% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 383 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.90 (s, 6 H), 6.28 (br. s., 1 H), 7.05-7.25 (m, 4 H), 7.45 (d, J=8.80 Hz, 1H), 7.51 (br. s., 1 H), 7.74 (s, 1 H), 10.86 (br. s., 1 H), 13.21 (br. s., 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][N:10]=[N:9]2)=[C:4]([O:14][CH:15]([CH3:17])[CH3:16])[CH:3]=1.[C:18]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH3:18])[N:10]=[N:9]2)=[C:4]([O:14][CH:15]([CH3:17])[CH3:16])[CH:3]=1
Reactant: CC(C)Oc1cc(F)ccc1-n1nn[nH]c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(F)ccc1-n1nnn(C)c1=O
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A mixture of 1-(4-fluoro-2-isopropoxyphenyl)-1H-tetrazol-5(4H)-one (4.10 g, 17.2 mmol, 1 equiv), K2CO3 (7.15 g, 52.0 mmol, 3 equiv), and iodomethane (3.25 mL, 52.0 mmol, 3 equiv) in DMF (40 mL) was stirred at RT ON. The reaction mixture was partitioned between water and EtOAc, then the layers were separated. The aqueous layer was extracted with EtOAc 2×, and the combined organic layer was washed with brine 1×. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness to provide 1-(4-fluoro-2-isopropoxyphenyl)-4-methyl-1H-tetrazol-5(4H)-one (3.50 g, 81%) as a brown oil that was used without further purification. 1H NMR (300 MHz; d6-DMSO) δ 7.46-7.51 (dd, 1H, J=6.3 Hz, 8.4 Hz), 7.20-7.25 (dd, 1H, J=2.7 Hz, 11 Hz), 6.87-6.94 (td, 1H, J=2.7 Hz, 8.1 Hz), 4.63-4.75 (hept, 1H, J=6.0 Hz), 3.59 (s, 3H), 1.16-1.18 (d, 6H, J=6.0 Hz); 19F NMR (282 MHz; d6-DMSO) δ −107.0 (sextet); m/z=253 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[ClH:5].[F:6][C:7]([F:11])([F:10])[CH2:8][NH2:9].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[ClH:5].[F:6][C:7]([F:11])([F:10])[CH2:8][NH:9][CH:2]([CH3:4])[CH3:1]
Reactant: NCC(F)(F)F
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)NCC(F)(F)F
Yield: 65.1 %

Procedure:
After briskly stirring a mixture of acetone (1.10 ml; 15 mmol), 2,2,2-trifluoroethylamine hydrochloride (1 g; 7.4 mmol), AcOH (2 ml) and 3 Å molecular sieves (5 g) in 30 ml of CH2Cl2 for 2 hour at room temperature, sodium triacetoxyborohydride (3.20 g; 15 mmol) was added. After stirring 18 hours at room temperature, the reaction mixture was filtered through celite and 5 ml of ethereal HCl were added. After removing the volatiles in vacuo the residue was partitioned between ether (100 ml) and 1N NaOH (100 ml). The organic layer was washed with brine (50 ml), dried (MgSO4) and filtered. Ethereal HCl (5 ml) was added and the volatiles were removed in vacuo to afford 855 mg (65%) of the title compound of this step as a white powder. mp (melting point)=80°-90° C.
Reaction SMILES: [NH2:1][C:2]([CH2:14][CH3:15])([C:10]([O:12]C)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].O.CO>O1CCCC1>[NH2:1][C:2]([CH2:14][CH3:15])([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCC(N)(Cc1ccccc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCC(N)(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
To a stirring solution of D,L-Phe(αEt)-OMe (24 g, 116 mmol) in tetrahydrofuran (200 mL) was added 5N NaOH (24 mL, 120 mmol), followed by water (50 mL) and methanol (50 mL) and the solution was heated to reflux. After 16 h, the solution was cooled to room temperature and the solvents were removed in vacuo. The residue was dissolved in water and washed three times with diethyl ether. The pH was adjusted to 6 with 5N HCl and the solution was concentrated to a volume of about 50 mL in vacuo. The precipitate was filtered, washed with water and dried to give 17.5 g (78% yield) of white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([N:7]([CH3:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[NH2:15][C:16]1[C:32]([Cl:33])=[CH:31][C:19]([C:20]([NH:22][C@H:23]2[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]2[O:29][CH3:30])=[O:21])=[C:18]([O:34][CH3:35])[CH:17]=1.C(N(CC)CC)C.[I-].[K+]>CN(C)C=O>[OH2:6].[NH2:15][C:16]1[C:32]([Cl:33])=[CH:31][C:19]([C:20]([NH:22][C@H:23]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][C:5]([N:7]([CH3:14])[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:6])[CH2:25][C@H:24]2[O:29][CH3:30])=[O:21])=[C:18]([O:34][CH3:35])[CH:17]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Reactant: CN(C(=O)CCCCl)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCC(=O)N(C)c2ccccc2)C[C@H]1OC
Product: O
Yield: 40.4 %

Procedure:
A mixture of 2.54. parts of 4-chloro-N-methyl-N-phenylbutanamide, 3.14 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide, 2.45 parts of N,N-diethylethanamine, 0.1 parts of potassium iodide and 90 parts of N,N-dimethylformamide was stirred for 20 hours at 80° C. The reaction mixture was evaporated. The residue was taken up in water and sodium carbonate. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile and a small amount of water. The product was filtered off and dried, yielding 2.05 parts (40.4%) of cis-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-N-methyl-N-phenyl-1-piperidinebutanamide monohydrate; mp. 97.4° C. (compound 23).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:23](Br)[C:24]#[CH:25]>CC(C)=O>[C:23]([O:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1)#[C:24][CH3:25]
Reactant: C#CCBr
Reactant: O=c1c2ccccc2oc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#COc1ccc2oc3ccccc3c(=O)c2c1

Procedure:
A mixture of 2-hydroxyxanthen-9-one (2.12 g, 0.01 mol), K2CO3 (2.8 g, 0.02 mol), Kl (0.166 g, 0.001 mol), propargyl bromide (1.78 g, 0.015 mol) and acetone (100 mL) was refluxed 10 h and hot filtered. The solvent was evaporated and the residue was crystallized by toluene. This yields 2.25 g of a product with the following characteristics: m.p.153-154° C.; 1H NMR (CDCl3) δ: 2.58 (m, 1H), 4.8 (s, 2H), 7.35-8.38 (m, 7H).
Reaction SMILES: C1(OC)C=CC=CC=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[NH:26][C:25](=O)[C:24]3=[CH:28][CH:29]=[CH:30][N:23]3[CH2:22][C:21]=2[CH:31]=1.[OH-].[NH4+]>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C(O)(C)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[N:26]=[C:25]([N:13]3[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]3)[C:24]3=[CH:28][CH:29]=[CH:30][N:23]3[CH2:22][C:21]=2[CH:31]=1
Reactant: CN1CCNCC1
Reactant: O=C1Nc2ccc(Cl)cc2Cn2cccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Product: CN1CCN(C2=Nc3ccc(Cl)cc3Cn3cccc32)CC1
Temperature: 60 °C

Procedure:
A mixture of 15 ml. of dry toluene, 1.5 ml. of anisole and 0.8 ml. of titanium tetrachloride is cooled under argon. A solution of 2.8 ml. of N-methylpiperazine in 10 ml. of toluene is added. A 1.55 g. portion of 7-chloro-5,10-dihydro-11H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one and 1.4 ml. of N-methylpiperazine are added in succession. The reaction mixture is heated at reflux for 5 hours, cooled to 60° C. and 2.2 ml. of isopropanol, 2 ml. of concentrated ammonium hydroxide and 1 g. of celite are added. After cooling to 30° C., 20 ml. of toluene are added and the mixture is filtered and washed with toluene. The toluene layer is washed twice with water, concentrated to remove the solvent and cooled. The solid is washed onto a filter with hexane, treated with 10 ml. of 1 N acetic acid and the insoluble material is collected and washed with water. The aqueous layer is treated with 10 ml. of 1 N ammonium hydroxide. The precipitate is collected, washed with water, dried in vacuo and recrystallized from ethanol, giving the desired product, m.p. 186°-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(C2CCCN2)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2ccc(F)c(Cl)c2)cc1

Procedure:
The title compound, off-white solid, m.p. 96° C. and MS: m/e=354.2 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(3-chloro-4-fluoro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]3O)=[CH:12][CH:13]=2)[N:8]([CH3:29])[S:7]1(=[O:31])=[O:30].C(Cl)Cl.CCN(S(F)(F)[F:42])CC>CO.O>[F:32][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:17][CH:16]3[F:42])=[CH:12][CH:13]=2)[N:8]([CH3:29])[S:7]1(=[O:31])=[O:30]
Reactant: CN1c2nc(C3CCN(C(=O)OC(C)(C)C)CC3O)ccc2N(CC2CC2(F)F)S1(=O)=O
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CN1c2nc(C3CCN(C(=O)OC(C)(C)C)CC3F)ccc2N(CC2CC2(F)F)S1(=O)=O
Temperature: 25 °C

Procedure:
To a round bottom flask was added tert-butyl 4-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-3-hydroxypiperidine-1-carboxylate (27-1) (74 mg, 0.156 mmol), anhydrous DCM (1 mL), the reaction mixture was cooled to 0 C while stirring under an atmosphere of nitrogen, then added DAST (0.035 ml, 0.265 mmol) dropwise. Reaction mixture was continued to stir at 0 C for 10 minutes, then permitted to warm to room temperature. After 1 hour reaction mixture was diluted with MeOH & drops of water, then purified by reverse-phase chromatography (10-100% CH3CN:0.1% TFA in H2O) to yield tert-Butyl 4-{1-[(2,2-difluorocyclopropypmethyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-3-fluoropiperidine-1-carboxylate (29-1). HRMS (M+H)+: observed=477.1785, calculated=477.1778.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8](F)=[C:9](I)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[S:16][C:15]=1[NH2:23].[SH:24][C:25]1[N:29]([CH3:30])[CH:28]=[N:27][N:26]=1>>[CH3:30][N:29]1[CH:28]=[N:27][N:26]=[C:25]1[S:24][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:23][C:15]1[S:16][C:17]2[C:22]([N:14]=1)=[CH:21][CH:20]=[CH:19][N:18]=2
Reactant: Cn1cnnc1S
Reactant: Fc1cc2ncnc(Cl)c2cc1I
Reactant: Nc1nc2cccnc2s1
Product: Cn1cnnc1Sc1ccc2ncnc(Nc3nc4cccnc4s3)c2c1

Procedure:
The compound of Example 13 was manufactured by the same method as in Example 1, by a similar method thereto or by a combination of such a method with a conventional method using 4-chloro-7-fluoro-6-iodo-quinazoline, thiazolo[5,4-b]-pyridin-2-yl-amine and 3-mercapto-4-methyl-1,2,4-triazole.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)(O)O.[NH2:27][C:28]([NH2:30])=[NH:29]>CN1CCCC1=O.CCOCC>[N:11]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:29][C:28]([NH2:30])=[NH:27])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=S(=O)(c1ccc(F)cc1)N1CCOCC1
Reactant: N=C(N)N
Agent: O=C(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: N=C(N)Nc1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 87.5 °C
Reaction time: 24 h

Procedure:
A mixture of 4-[(4-fluorophenyl)sulfonyl]morpholine (0.25 g, 1 mmol), cesium carbonate (1.30 g, 4 mmol), and guanidine carbonate (1.08 g, 6 mmol) in 2 ml of 1-methyl-2-pyrrolidinone (NMP) is stirred at 85 to 90° C. for 24 hrs. It is then cooled to room temperature and diluted with ether. The resulting suspension is filtered, and the precipitate extracted with tetrahydrofuran (THF) to yield, after evaporation of solvent, 0.12 g of a yellow solid; mp 102-105° C.; MS (ESI) m/z 285.1 (M+H); HRMS: calcd for C11H16N4O3S, 284.0943; found (ESI_FT), 285.1011 (M+H).