Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3[C:14]([NH2:17])=[N:15][O:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N-:18]=[C:19]=[O:20].[Na+]>CC(O)=O.O>[NH2:17][C:14]1[C:13]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:19]([NH2:18])=[O:20])=[CH:7][CH:6]=3)=[CH:9][CH:10]=[CH:11][C:12]=2[O:16][N:15]=1
Reactant: [N-]=C=O
Reactant: Nc1ccc(-c2cccc3onc(N)c23)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccc(-c2cccc3onc(N)c23)cc1
Yield: 65.2 %

Procedure:
A solution of Example 261A (45 mg, 0.2 mmol) and sodium isocyanate (26 mg, 0.4 mmol) in HOAc (0.5 mL) and H2O (0.5 mL) was stirred overnight at rt, then diluted with water. The precipitated solid was collected by filtration and recrystallized from THF/hexanes to give an offwhite solid (35 mg, 65%). 1H NMR (300 MHz, DMSO-D6) δ ppm 5.20 (s, 2H) 5.92 (s, 2H) 7.11 (dd, J=7.3, 0.9 Hz, 1H) 7.37 (d, J=8.5 Hz, 2H) 7.46 (dd, J=8.5, 1.0 Hz, 1H) 7.57 (d, J=8.5 Hz, 2H) 7.57 (dd, J=8.1, 7.1 Hz, 1H) 8.72 (s, 1H) MS (ESI(+)) m/e 269.0 (M+H)+.
Reaction SMILES: [CH2:1]([S:8]([NH:11][NH:12][C:13]1[C:14](=[O:24])[N:15]([CH2:20][CH2:21][CH2:22]Br)[C:16]([CH3:19])=[CH:17][N:18]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.N1C(C)=CC=CC=1C>O1CCOCC1>[CH2:1]([S:8]([NH:11][NH:12][C:13]1[C:14](=[O:24])[N:15]([CH2:20][CH2:21][CH2:22][C:28]2[CH:27]=[C:26]([NH2:25])[CH:31]=[CH:30][N:29]=2)[C:16]([CH3:19])=[CH:17][N:18]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cnc(NNS(=O)(=O)Cc2ccccc2)c(=O)n1CCCBr
Reactant: Nc1ccncc1
Solvent: Cc1cccc(C)n1
Solvent: C1COCCO1
Product: Cc1cnc(NNS(=O)(=O)Cc2ccccc2)c(=O)n1CCCc1cc(N)ccn1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
To a solution of 3-(2-benzylsulfonylhydrazino)-1-(3-bromopropyl)-6-methylpyrazinone, the product of Example 32, (0.174 g, 0.42 mmol) in dioxane (15 mL), are added 4-aminopyridine (0.048 g, 0.51 mmol) and 2,6-lutidine (0.099 mL, 0.85 mmol). The resulting mixture is stirred at 90° C. for about 15 hours and then is concentrated under reduced pressure. The crude residue is purified by RP-HPLC using acetonitrile/water/trifluoroacetic acid as eluent to afford the title compound.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][NH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=O)=[CH:13][CH:12]=1.[OH-].[Na+]>O>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=[C:15]1[C:14]1[CH:18]=[CH:19][C:11]([NH:10][CH3:9])=[CH:12][CH:13]=1
Reactant: Nc1ccccc1N
Reactant: CNc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNc1ccc(-c2nc3ccccc3[nH]2)cc1
Temperature: 80 °C

Procedure:
5.00 g (46.2 mmol) o-Phenylene diamine and 6.99 g (46.2 mmol) 4-(methylamino)benzoic acid are stirred in 40.0 g polyphosphoric acid at 210° C. for 4 hours. The mixture is cooled to 80° C., poured into water and stirred over night at RT. The mixture is alkalinized with sodium hydroxide solution. The precipitate is filtered off and washed with water. The product is dried in vacuo at 70° C.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[F:27])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:28][CH3:29])C1C=CC=CC=1>C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:28][CH3:29])[CH:11]=3)[N:16]=[CH:15][N:14]=2)=[C:21]([F:27])[CH:22]=1
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1O
Yield: 90.7 %

Procedure:
A solution of 7-benzyloxy-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (451 mg, 1.1 mmol) in TFA (4.5 ml) was heated at reflux for 3 hours. The mixture was diluted with toluene and the volatiles removed by evaporation. The residue was triturated with methylene chloride, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (320 mg, 90%).
Reaction SMILES: [CH:1]([N:4]1[C:9]2[N:10]=[C:11](S(C)=O)[N:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]1=[O:17])([CH3:3])[CH3:2].[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.[O-2].[Al+3].[O-2].[O-2].[Al+3]>C(Cl)(Cl)Cl>[CH:1]([N:4]1[C:9]2[N:10]=[C:11]([NH:29][C:28]3[CH:27]=[CH:26][C:25]([N:22]4[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]4)=[CH:31][CH:30]=3)[N:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]1=[O:17])([CH3:3])[CH3:2]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CC(C)n1c(=O)ccc2cnc(S(C)=O)nc21
Agent: [Al+3]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(C)n1c(=O)ccc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Temperature: 175 °C
Yield: 49.7 %

Procedure:
To 8-isopropyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (212 mg, 0.85 mmol) was added 4-(4-methylpiperazin-1-yl)-aniline (323 mg, 1.69 mmol). The reaction mixture was heated at 175° C. for 10 minutes then cooled to room temperature and partitioned between saturated sodium bicarbonate and chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with 10% methanol in ethyl acetate. The fractions containing product were concentrated, and hexane and ethyl acetate were added to give a solid that was dissolved in chloroform and passed through an aluminum oxide column. The fractions containing product were concentrated, and upon addition of hexane and ethyl acetate, a solid formed providing 160 mg (50%) of 8-isopropyl-2-[4-(4-methylpiperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one, mp 221-222° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([OH:8])=[CH:6][CH:7]=1.CO[C:12](OC)([CH3:14])[CH3:13]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:12]([CH3:14])([CH3:13])[O:9][C:4]=2[CH:3]=1
Reactant: Oc1ccc(Br)cc1O
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)Oc2ccc(Br)cc2O1
Yield: 63.3 %

Procedure:
To benzene (50 mL) in a 250 mL round bottom flask was added 4-bromobenzene-1,2-diol (1 g, 5.29 mmol), 2,2-dimethoxypropane (2.204 g, 21.16 mmol), and p-toluene sulfonic acid monohydrate (0.050 g, 0.265 mmol). The flask was fitted with a Dean-Stark trap and heated to reflux for 18 h. Upon cooling, the reaction mixture was transferred to a separatory funnel and washed with 2 N NaOH solution (100 mL) and saturated NaCl solution (100 mL). The organic layer was dried with MgSO4, filtered, and concentrated to yield 5-bromo-2,2-dimethylbenzo[d][1,3]dioxole as a dark brown oil (767 mg, 63%): 1H NMR (400 MHz, CDCl3) δ 6.91-6.85 (m, 2H), 6.62-6.57 (m, 1H), 1.66 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 146.81 (s), 144.25 (s), 123.64 (s), 121.02 (s), 112.05 (s), 109.40 (s), 108.46 (s), 25.83 (s); ESIMS m/z 230 ([M+H]+), 228 ([M−H]−).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[S:6][CH:7]=1)=[CH2:2].Cl.C(OCC)C.[OH-].[Na+]>ClCCl>[CH:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[S:6][CH:7]=1)=[CH2:2]
Reactant: C=Cc1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: C=Cc1csc(C2CCNCC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1,1-dimethylethyl 4-(4-ethenyl-2-thiazolyl)-1-piperidinecarboxylate (i.e. the product of Example 4, Step A) (471 mg, 1.6 mmol) in dichloromethane (5 mL) was added a solution of hydrogen chloride in diethyl ether (2.0 M, 7 mL, 14 mmol). The reaction mixture was stirred under nitrogen at room temperature for 4 h, and then 1 N aqueous sodium hydroxide solution was added until pH of the reaction mixture increased to about 10. The resulting mixture was extracted with dichloromethane (2×). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give 302 mg of the title compound as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)=[O:5])C.O1CCCC1.[OH-].[Li+]>O>[Cl:36][C:32]1[CH:31]=[C:30]([C:7]2[N:8]=[C:9]([N:11]3[C:15]4[CH:16]=[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]5[CH2:25][CH2:26][O:27][CH2:28][CH2:29]5)[CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[S:10][C:6]=2[C:4]([OH:5])=[O:3])[CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1sc(-n2cnc3ccc(CCCCN4CCOCC4)cc32)nc1-c1cccc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1sc(-n2cnc3ccc(CCCCN4CCOCC4)cc32)nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To a mixture of 0.078 g (0.15 mmole) of 4-(3-chloro-phenyl)-2-[6-(4-morpholin-4-yl-butyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid ethyl ester (I.41f), 2 mL of tetrahydrofuran and 2 mL of water was added 0.034 g (1.49 mmole) of lithium hydroxide. The mixture was stirred at ambient temperature for 2 hours, then concentrated under reduced pressure and diluted with 5 mL of water. The pH was adjusted to ca. 6-7 by addition of 3M hydrochloric acid. The precipitate was collected by filtration to give 0.054 g of 4-(3-chloro-phenyl)-2-[6-(4-morpholin-4-yl-butyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid (I.41 g) as a white solid.
Reaction SMILES: O=[C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1.[F:14][C:15]1[CH:16]=[C:17]([Mg]Br)[CH:18]=[CH:19][CH:20]=1>[Pd]>[F:14][C:15]1[CH:20]=[C:19]([CH:2]2[C:6]3[NH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:5]=3[CH2:4][CH2:3]2)[CH:18]=[CH:17][CH:16]=1
Reactant: Fc1cccc([Mg]Br)c1
Reactant: COC(=O)c1cc2c([nH]1)C(=O)CC2
Agent: [Pd]
Product: COC(=O)c1cc2c([nH]1)C(c1cccc(F)c1)CC2

Procedure:
The title compound was synthesized in two steps. First, methyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (447 mg, 2.5 mmol) was reacted with (3-fluorophenyl)magnesium bromide (0.5 M in hexanes, 13 mL, 6.3 mmol) according to General Procedure 3. The resulting crude product was converted to the title compound by hydrogenation according to General Procedure 6 (with 5% Pd/C). The crude product was purified by chromatography, eluting with heptane-EtOAc, gradient 0 to 40% EtOAc. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.24-2.35 (m, 1H), 2.61-2.71 (m, 1H), 2.71-2.81 (m, 1H), 2.87-2.98 (m, 1H), 3.81 (s, 3H), 4.24 (t, J=7.54 Hz, 1H), 6.71 (d, J=1.51 Hz, 1H), 6.81 (dt, J=9.81, 1.85 Hz, 1H), 6.88-6.93 (m, 2H), 7.25 (s, 1H), 8.60 (br. s, 1H).
Reaction SMILES: C([O:8][C:9]1[N:14]=[CH:13][C:12]([NH:15][C:16]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:28][CH2:27]3)=[CH:22][C:17]=2[C:18]([O:20]C)=[O:19])=[CH:11][C:10]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[CH:26]1([C:23]2[CH:24]=[CH:25][C:16]([NH:15][C:12]3[CH:13]=[N:14][C:9]([OH:8])=[C:10]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:11]=3)=[C:17]([CH:22]=2)[C:18]([OH:20])=[O:19])[CH2:27][CH2:28]1
Reactant: COC(=O)c1cc(C2CC2)ccc1Nc1cnc(OCc2ccccc2)c(-c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(C2CC2)ccc1Nc1cnc(O)c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of methyl 2-(6-(benzyloxy)-5-phenylpyridin-3-ylamino)-5-cyclopropylbenzoate (0.34 mmol, 0.155 g) in TFA (1.3 ml) was stirred at 45° C. for 30 minutes. The solvent was removed under reduced pressure. The crude mixture was solved in ethanol (2 ml), 2N aqueous NaOH were added and stirred at room temperature for 16 hours. The solvent was removed and the crude was neutralised with 2N aqueous HCl and extracted with CHCl3. The crude mixture was purified by ionic exchange through a SCX cartridge affording 0.060 g (50% of yield).
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[C@H:14]([NH2:18])([CH2:16][CH3:17])[CH3:15]>O>[C@H:14]([NH:18][C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1)([CH2:16][CH3:17])[CH3:15]
Reactant: CC[C@@H](C)N
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Solvent: O
Product: CC[C@@H](C)NC1=NS(=O)(=O)c2sc(Cl)cc2N1

Procedure:
The title compound was prepared from 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide and (R)-(-)-sec-butylamine by a procedure analogous to the procedure described in example 1Bb; mp 215°-220° C. (water), 1H-NMR (DMSO-d6): δ 0.88 (t. 3H), 1.11 (d, 3H), 1.48 (m, 2H), 3.69 (m, 1H), 7.07 (s, 1H), 7.14 (br. s, 1H), 10.75 (br. s, 1H).
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7](O)([CH3:11])[CH2:8][CH2:9][OH:10].[C:13](#[N:15])[CH3:14]>>[CH3:14][C:13]1[O:10][CH2:9][CH2:8][C:7]([CH3:11])([CH3:6])[N:15]=1
Reactant: CC#N
Reactant: CC(C)(O)CCO
Agent: O=S(=O)(O)O
Product: CC1=NC(C)(C)CCO1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 50 %

Procedure:
Acetonitrile (22.6 g, 0.25 mol) was dripped into concentrated H2SO4 (150 mL) at 0° C. Upon complete addition of acetonitrile, 3-methyl-butane-1,3-diol (Fluka, 22.6 g, 0.55 mol) was added over 0.5 h maintaining the reaction temperature at or below 5° C. The resulting mixture was stirred for 1.5 h at 5° C. then poured onto crushed ice. When the ice had melted, the aqueous was extracted with ether (2×250 mL). The organic was discarded and the aqueous was treated with 40% NaOH to pH 12. The basic aqueous was extracted with ether. The organic was washed with brine and dried (MgSO4). The ether was removed under vacuum at 25° C. affording the desired product as a colorless oil (25.4 g, 50%): 1H NMR (DMSO-d6) δ 4.04 (t, 2H, J=6 Hz), 1.72 (s, 3H), 1.61 (t, 2H, J=6 Hz), 1.07 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:44]=[N:43][CH:42]=[CH:41][N:40]=2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:44]=[N:43][CH:42]=[CH:41][N:40]=2)[CH:34]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnccn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(methyl-propyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J17) (347 mg, 1.0 mmol) and 3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K14) (298 mg, 1.0 mmol) according to the general procedure M. Obtained as a light red foam (350 mg, 61%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:14]=O.C(O)(C(F)(F)F)=O>C(O)(C)C>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:14]=[N:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8]
Reactant: N#Cc1ccsc1N
Reactant: O=Cc1cccs1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccsc1N=Cc1cccs1
Yield: 69.4 %

Procedure:
2-Amino-thiophene-3-carbonitrile (50 mg) and thiophene-2-carboxaldehyde (54 mg) were mixed in isopropanol with TFA and refluxed for 20 hours. The reaction was then purified by flash chromatography, resulting in 61 mg (70%) of the title compound as an orange solid. M.p. 58°-60° C. 1H-NMR (300 MHz, [D] acetone): δ=8.49 (s, 1H), 7.90 (d, 1H, 3J=5.0 Hz), 7.82 (dd, 1H, 3J=3.7 Hz and 1.0 Hz), 7.42 (d, 1H, 3J=5.7 Hz), 7.27 (m, 2H, 3J=5.6 Hz). 13C-NMR (300 MHz, [D] acetone): δ=163.4, 155.4, 141.8, 136.2, 133.9, 129.0, 128.1, 122.5, 114.6, 105.8.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.[S:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)(=[O:14])(=[O:13])[NH2:12]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[N:19][C:18]1[CH:20]=[CH:21][C:15]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:16][CH:17]=1
Reactant: Cc1ccc(C=O)cc1C
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: Cc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1C

Procedure:
Following a procedure similar to that described in Example 1(i), but using 3,4-dimethylbenzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a pale yellow powder (yield 45%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[O:18][C:19]([C:22](OCC)=[O:23])=[CH:20][CH:21]=3)=[N:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[O:18][C:19]([CH2:22][OH:23])=[CH:20][CH:21]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(-c2nn(Cc3ccc(Cl)s3)c3ccccc23)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1ccc(-c2nn(Cc3ccc(Cl)s3)c3ccccc23)o1

Procedure:
The compound was prepared similarly to Example 14 from 1-((5-chloro-2-thienyl)methyl)-3-(5-ethoxycarbonyl-2-furyl)indazole by reduction with lithium aluminum hydride.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].ClCCl.C(OC(=O)[NH:17][CH2:18][C@@H:19]1[O:23][C:22](=[O:24])[N:21]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[S:32][CH2:33][C:34](=[S:37])[NH:35][N:36]=3)=[C:27]([F:38])[CH:26]=2)[CH2:20]1)(C)(C)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:17][CH2:18][C@@H:19]1[O:23][C:22](=[O:24])[N:21]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[S:32][CH2:33][C:34](=[S:37])[NH:35][N:36]=3)=[C:27]([F:38])[CH:26]=2)[CH2:20]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc(C3=NNC(=S)CS3)c(F)c2)C(=O)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC[C@H]1CN(c2ccc(C3=NNC(=S)CS3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20% Trifluoroacetic acid/dichloromethane (2 ml) is added to {3-[3-fluoro-4-(5-thioxo-5,6-dihydro-4H-[1,3,4]thiadiazin-2-yl)-phenyl]-2-oxo-oxazolidin-5(S)-ylmethyl}-carbamic acid tert-butyl ester and the mixture is stirred at room temperature for 30 minutes. The reaction is evaporated to dryness and the trifluoroacetate salt is used directly in the next step.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[F:10][C:11]([C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][CH:34]=1)[O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([NH2:31])=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=2)=[CH:20][CH:19]=1)([F:13])[CH3:12]>C1COCC1>[F:10][C:11]([C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][CH:34]=1)[O:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:25]3=[N:31][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=2)=[CH:22][CH:23]=1)([F:13])[CH3:12]
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1cnc(N)c(-c2ccc(Oc3cccc(C(C)(F)F)c3)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=CN2CCS(=O)(=O)N=C2C(c2ccc(Oc3cccc(C(C)(F)F)c3)cc2)=C1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 96 mg) in THF (dry) (10 ml) was added 2-chloroethanesulfonyl chloride (0.101 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-(3-(1,1-difluoroethyl)phenoxy)phenyl)-5-methylpyridin-2-amine (164 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen overnight. The mixture was quenched with water at 0° C. Water, EtOAc and THF were added and the mixture was extracted. Silica-gel was added to the organic phase and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo to give 9-{4-[3-(1,1-difluoroethyl)phenoxy]phenyl}-7-methyl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide as a white solid. Platinum(IV) oxide (30 mg) was added to a solution of the prepared 9-{4-[3-(1,1-difluoroethyl)phenoxy]phenyl}-7-methyl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide in THF (dry) (15 mL) and MeOH (15 ml). The mixture was stirred at room temperature under hydrogen for 3 hr. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc, to remove catalytic poison). Platinum(IV) oxide (30 mg) was added and the mixture was stirred at room temperature under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (47.6 mg) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:28]=[CH:27][C:11]([NH:12][C:13]2[C:18]([C:19](OCC)=[O:20])=[C:17]([CH3:24])[N:16]=[C:15]([S:25][CH3:26])[N:14]=2)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>C(O)C>[OH:20][CH2:19][C:18]1[C:13]([NH:12][C:11]2[CH:27]=[CH:28][C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[CH:9][CH:10]=2)=[N:14][C:15]([S:25][CH3:26])=[N:16][C:17]=1[CH3:24]
Reactant: CCOC(=O)c1c(C)nc(SC)nc1Nc1ccc(C(=O)OC(C)(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CSc1nc(C)c(CO)c(Nc2ccc(C(=O)OC(C)(C)C)cc2)n1
Reaction time: 4 h

Procedure:
To a suspension of compound E (30 g; 0.0743 mol) in 500 mL of anhydrous ethanol at 45° C. NaBH4 (15 g; 0.397 mol) was added portion-wise under vigorous stirring. After 4 h the reaction mixture was brought to room temperature and was poured into 2 L of iced water, vigorously stirred for 10′ and extracted with ethyl acetate (2×600 mL). The organic phase was washed with water until neutral pH, with brine and dried over anhydrous sodium sulphate. After evaporation the crude compound F (22 g; 82%) was used without further purification in the next step.
Reaction SMILES: CO[C:3](=[O:17])[C@@H:4]1[CH2:8][C@H:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)[CH2:6][NH:5]1.C([O-])([O-])=O.[K+].[K+].[Cl:24][C:25]1[CH:26]=[C:27]([N:32]=[C:33]=[O:34])[CH:28]=[C:29]([Cl:31])[CH:30]=1.O>CN(C=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([N:32]2[C:3](=[O:17])[C@@H:4]3[CH2:8][C@H:7]([O:9][C:10]4[CH:11]=[CH:12][C:13]([Br:16])=[CH:14][CH:15]=4)[CH2:6][N:5]3[C:33]2=[O:34])[CH:28]=[C:29]([Cl:31])[CH:30]=1
Reactant: COC(=O)[C@@H]1C[C@H](Oc2ccc(Br)cc2)CN1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1[C@@H]2C[C@H](Oc3ccc(Br)cc3)CN2C(=O)N1c1cc(Cl)cc(Cl)c1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
The compound of formula (II), wherein R11 is 4-bromo, m is 0, W=O, and the bonds depicted as wavy bonds define the 7aS,6S stereoisomer, was prepared as follows. To a solution of cis-4-(4-bromo-phenoxy)-L-proline methyl ester (0.2 g) (0.66 mmol) (Preparation 4) and K2CO3 (0.09 g) (1 eq.) in 10 mL of DMF at 0° C. was added 3,5-dichlorophenyl isocyanate (0.12 g) (1 eq.). The reaction mixture was allowed to warm to 20° C. and was stirred overnight. After adding water, the mixture was extracted with EtOAc. The combined organic extracts were washed with water, dried over MgSO4, and evaporated under reduced pressure to afford after SiO2 chromatography (eluent: DCM), the above-titled compound (60 mg). Mp=116° C. NMR (DMSO, 200 MHz): 7.75 (1H, m), 7.5-7.4 (4H, d+d), 6.85 (2H, d), 5.1 (1H, m), 4.6 (1H, dd), 3.95 (1H, dd), 3.35 (1H, dd), 2.7-2.5 (1H, m), 2.25 (1H, bd).