Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]([C:23]1[C:31]2[C:26](=[C:27]([CH2:32][S:33][CH3:34])[CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[CH:13]1C(=O)O[C:16](C)([CH3:20])[O:15][C:14]1=[O:22]>N1C=CC=CC=1.C(O)C.[Cu]>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=1[CH:12]([C:23]1[C:31]2[C:26](=[C:27]([CH2:32][S:33][CH3:34])[CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[CH2:13][C:14]([O:15][CH2:16][CH3:20])=[O:22]
Reactant: CSCc1cccc2c(C(c3ccc(C(F)(F)F)cc3Cl)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CC(c1ccc(C(F)(F)F)cc1Cl)c1c[nH]c2c(CSC)cccc12

Procedure:
2.8 mg (45 μmol) of copper powder were added to a solution of 3.64 g (approx. 5.12 mmol, 72% purity) of the compound from Example 93A in 41 ml of pyridine and 10 ml of ethanol. The reaction mixture was heated under reflux overnight. It was concentrated, and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to result in 1.34 g (57% of theory) of the title compound.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH2:4]=[O:5].[C:6](Cl)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O>[C:6]([CH:4]([OH:5])[C:1]#[N:2])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=O
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Product: N#CC(O)C(=O)c1ccccc1
Temperature: 0 °C

Procedure:
To an ice cooled solution of potassium cyanide (65 g, 1 mol) in 125 ml water, is added a mixture of formaldehyde 37% (85 ml, 1 mol) and 65 ml water, at a rate to insure that the temperature is kept below 10° C. (takes approximately 30 min). To the cooled solution is added benzoylchloride (116 ml, 1 mol) under vigourous stirring, which is continued for an additional hour. Water is added to dissolve the formed salts and the to phases are separated. The water phase is extracted repeatedly with diethylether and the combined organic phases is washed with water and brine, dried over sodiumsulphate and concentrated in vacuo. Vacuum distillation 86°-90° C./1 mbar yields benzoylglycolonitrile.
Reaction SMILES: [C:1]([C:3]1[C:23]([N+:24]([O-])=O)=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)#[N:2]>CCOC(C)=O.[Pd]>[NH2:24][C:23]1[C:3]([C:1]#[N:2])=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](COc2cccc([N+](=O)[O-])c2C#N)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](COc2cccc(N)c2C#N)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.2 %

Procedure:
To a solution of (S)-tert-butyl 3-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate (Example 1e, 13 g, 36 mmol) in EtOAc (200 mL) was added Pd/C (3.82 g, 3.6 mmol 10% solution) and the mixture was stirred at room temperature under H2 for 6 hours until the reaction was complete. The mixture was filtered and concentrated. The residue was purified by chromatography on silica gel (EtOAc/hexanes) to yield the title compound (11 g, 92.3%). (M+H)−Boc=232.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH3:11])[C:6]=2[C:5]([F:12])=[C:4]([F:13])[CH:3]=1.C1C(=O)[N:18](Br)[C:16](=O)C1.[C-]#N.[Na+].[OH-].[Na+]>O.C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][C:16]#[N:18])[C:6]=2[C:5]([F:12])=[C:4]([F:13])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1coc2c(Br)cc(F)c(F)c12
Agent: [C-]#N
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: N#CCc1coc2c(Br)cc(F)c(F)c12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To the compound (98.8 mg, 0.400 mmol) of Step 1 of Example 21, NBS (78.3 mg, 0.440 mmol), and a catalytic amount of BPO, carbon tetrachloride (4 mL) was added, and heated under reflux overnight. The resultant was returned to room temperature, and the solvent was distilled away under reduced pressure. The resulting residue was diluted with dichloromethane, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was dissolved in acetonitrile (2 mL), and sodium cyanide (39.2 mg, 0.800 mmol) and water (0.2 mL) were added thereto, and stirred at 50° C. for 30 minutes. To the reaction solution, a 1 N sodium hydroxide aqueous solution was added. After concentrated under reduced pressure, the resultant was diluted with ethyl acetate, washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel chromatography to thus obtain the title compound.
Reaction SMILES: NC(N)=[S:3].[ClH:5].Cl.[C:7]1([CH:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][Cl:24])[CH2:17][CH2:16]2)[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[OH-].[Na+]>O.C(O)C>[ClH:24].[ClH:5].[C:7]1([CH:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][SH:3])[CH2:17][CH2:16]2)[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(N)=S
Reactant: CC(c1ccccc1)N1CCN(CCCCl)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(c1ccccc1)N1CCN(CCCS)CC1
Yield: 50.4 %

Procedure:
The procedure described in Example 1(b) was followed, using 9.8 g of thiourea, 29.0 g of 1-(1-phenylethyl)-4-(3-chloropropyl)piperazine dihydrochloride, 8.3 g of triethylamine and 250 ml of reagent ethanol. The hydrolysis was effected with 6.0 g of sodium hydroxide in 40 ml of water. Work-up, as above, gave 14.5 g (51% of theory) of 3-[4-(1-phenylethyl)piperazin-1-yl]propanethiol dihydrochloride as a white crystalline solid, M.p. 252°-255° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].CCN(C(C)C)C(C)C.Br[CH2:21][CH2:22][O:23][CH2:24][CH2:25]Br>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: BrCCOCCBr
Reactant: COc1ncc(N)cc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ncc(N2CCOCC2)cc1Br
Temperature: 120 °C
Yield: 53 %

Procedure:
To a solution of 5-bromo-6-methoxypyridin-3-amine (1.0 equiv.) in DMF was added DIEA (3.0 equiv.) and 1-bromo-2-(2-bromoethoxy)ethane (1.0 equiv.). The solution was heated to 120° C. for 24 hours. Upon cooling to room temperature, the reaction was partitioned between water and ethyl acetate, the aqueous phase was extracted three times with ethyl acetate, the organics were combined, dried with sodium sulfate, filtered and concentrated. The crude material was purified via silica gel column chromatography eluting with 0-50% ethyl acetate in heptanes. The pure fractions were concentrated to yield 4-(5-bromo-6-methoxypyridin-3-yl)morpholine in 53% yield as an orange oil. LCMS m/z (M+H)=273/275, Rt=0.61 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 2.93-3.18 (m, 4H) 3.80-4.05 (m, 7H) 7.50 (d, J=2.74 Hz, 1H) 7.74 (d, J=2.74 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1)[CH3:12]>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([O:13][CH2:11][CH3:12])=[CH:15][C:16]=2[N+:21]([O-:23])=[O:22])=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Product: CCOc1ccc(NC(=O)c2ccc(C)nc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 6-methylnicotinic acid and 4-ethoxy-2-nitroaniline and was obtained as a yellow solid as described in Example 15. 1H NMR (CDCl3): 11.09 (s, 1H), 9.12 (d, J=2.1, 1H), 8.85 (d, J=9.3, 1H), 8.16-8.13 (m, 1H), 7.73 (d, J=3.0, 1H), 7.34-7.29 (m, 2H), 4.11 (q, J=6.9, 2H), 2.67 (s, 3H), 1.46 (t, J=6.9, 3H).
Reaction SMILES: [CH3:1]OC(OC)N(C)C.FC(F)(F)C(O)=O.[CH3:16][N:17]([CH2:19][C:20]1[C:28]([OH:29])=[C:27]([F:30])[CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][N:24]2[S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH3:18]>CN(C=O)C>[F:30][C:27]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][N:24]2[S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[C:20]([CH2:19][N:17]([CH3:16])[CH3:18])[C:28]=1[O:29][CH3:1]
Reactant: COC(OC)N(C)C
Reactant: CN(C)Cc1c(O)c(F)cc2c1ccn2S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1c(F)cc2c(ccn2S(=O)(=O)c2ccccc2)c1CN(C)C

Procedure:
N,N-dimethylformamide dimethyl acetal (0.964 ml, 7.233 mmol) was added to a solution of 4-[(dimethylamino)methyl]-6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol (252 mg, 0.723 mmol; Example 146) in DMF (8 ml) and the mixture was divided into two tubes and heated in microwave oven at 180 0 C for 180 s. Solvent was evaporated and residue purified on Gilson HPLC using 30-70% MeCN in 50 nM ammonium bicarbonate buffer as eluent (Xterra). Yield: 101.7 mg (39%); white solid. MS (ESI+) for C18H19FN2O3S m/z 363 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:36])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[O:35])[C:18](=[N:33][OH:34])[C:19](=O)[CH2:20][O:21][C:22]23[CH2:31][CH:26]4[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]4)[CH2:23]2)[CH2:29]3)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:41].[CH:42]1([CH:48]=O)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>C(O)(=O)C>[CH2:1]([O:8][C:9](=[O:36])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]([C:18]2[N:33]([OH:34])[C:48]([CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[N:41][C:19]=2[CH2:20][O:21][C:22]23[CH2:29][CH:28]4[CH2:27][CH:26]([CH2:25][CH:24]([CH2:30]4)[CH2:23]2)[CH2:31]3)=[O:35])[CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CC1CCCCC1
Reactant: O=C(COC12CC3CC(CC(C3)C1)C2)C(=NO)C(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)c1cccc(NC(=O)c2c(COC34CC5CC(CC(C5)C3)C4)nc(C3CCCCC3)n2O)c1
Temperature: 80 °C
Yield: 71.9 %

Procedure:
A mixture of 3-[4-(adamantan-1-yloxy)-2-hydroxyimino-3-oxo-butyrylamino]-benzoic acid benzyl ester (1.16 g, 2.36 mmol), ammonium acetate (3.64 g, 47.2 mmol) and cyclohexane carboxaldehyde (0.38 ml, 3.14 mmol) in acetic acid (30 ml) was heated at 80° C. under argon for 2 h. The mixture was cooled to room temperature and concentrated to remove most of the acetic acid. The residue was dissolved in ethyl acetate (50 ml) and neutralised with sat. sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (30 ml), the combined organic phases were washed with brine (50 ml), dried (MgSO4) and the solvent was evaporated. The crude product was purified by flash column chromatography (silica, DCM/MeOH 95:5) to afford yellow foam (990 mg, 72%). 1H NMR (300MHz, CDCl3) (mixture of rotamers) 13.30 and 9.12 (1H, 2×br s), 13.08 and 10.89 (1H, 2×s), 8.28 and 8.17 (1H, 2×s), 8.10-7.80 (2H, 4×d), 7.40 (6H, m), 5.38 and 5.37 (2H, 2×s), 4.97 and 4.79 (2H, 2×s), 3.27 and 2.92 (1H, 2×m), 2.20 and 2.14 (3H, 2×br s), 1.94-1.34 (22H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH3:32])=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Reactant: Cc1ccccc1B(O)O
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: O
Solvent: COCCOC
Product: Cc1ccccc1-c1ccccc1C(=O)NCCc1c[nH]c2ccc(Cl)cc12
Yield: 62.8 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), o-tolylboronic acid (0.025 g; 0.176 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) furnished 0.043 g (63%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-2-carboxamide as a white solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.C[C:26]1([CH3:52])C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:40]3[O:41][C:42]4[C:48]([CH:49]([CH3:51])[CH3:50])=[CH:47][CH:46]=[CH:45][C:43]=4[N:44]=3)=[CH:35][CH:34]=2)[O:27]1.NC1N=CN=C2N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=C(C3C=CC(NC4[O:71][C:72]5[CH:78]=CC=CC=5N=4)=C(F)C=3)C=12>>[C:26]([OH:71])(=[O:27])[CH3:52].[C:72]([OH:71])(=[O:27])[CH3:78].[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:33]3[CH:38]=[CH:37][C:36]([NH:39][C:40]4[O:41][C:42]5[C:48]([CH:49]([CH3:51])[CH3:50])=[CH:47][CH:46]=[CH:45][C:43]=5[N:44]=4)=[CH:35][CH:34]=3)[C:10]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1
Reactant: CC(C)c1cccc2nc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)oc12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Product: CC(=O)O
Product: CC(C)c1cccc2nc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)oc12

Procedure:
Cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-7-isopropyl-1,3-benzoxazol-2-amine diacetate was prepared from cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.250 g, 0.566 mmol) and N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-7-isopropyl-1,3-benzoxazol-2-amine (0.339 g, 0.708 mmol) in a manner similar to that used for the preparation of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine. The compound was formed as an off-white solid (0.205 g, 64%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:12])[C:10]=2[CH:11]=1.[F:13][C:14]([F:27])([F:26])[O:15][C:16]1[CH:25]=[CH:24][C:19]([CH2:20][N:21]=[C:22]=[O:23])=[CH:18][CH:17]=1>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([NH:12][C:22]([NH:21][CH2:20][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:14]([F:13])([F:27])[F:26])=[CH:25][CH:24]=1)=[O:23])[CH:8]=[CH:7][CH:6]=2
Reactant: Cc1cc2c(N)cccc2cn1
Reactant: O=C=NCc1ccc(OC(F)(F)F)cc1
Product: Cc1cc2c(NC(=O)NCc3ccc(OC(F)(F)F)cc3)cccc2cn1

Procedure:
Prepared from 3-methylisoquinolin-5-amine (Description 45) and [4-(trifluoromethoxy)benzyl]isocyanate (Description 59) according to the procedure of Description 61. m/z (ES+) 376 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[C:28]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:27][C:8]([CH:9]=[C:10]2[C:15](=[O:16])[N:14]([CH2:17][C:18]3[NH:22][N:21]=[N:20][N:19]=3)[C:13]3[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=3[S:11]2)=[CH:7][C:6]=1[C:33]([CH3:36])([CH3:35])[CH3:34])(=O)C.[OH-].[K+].Cl>C(O)C.O>[C:29]([C:28]1[CH:27]=[C:8]([CH:7]=[C:6]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:5]=1[OH:4])[CH:9]=[C:10]1[C:15](=[O:16])[N:14]([CH2:17][C:18]2[NH:22][N:21]=[N:20][N:19]=2)[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[S:11]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(C=C2Sc3ccccc3N(Cc3nnn[nH]3)C2=O)cc1C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(C=C2Sc3ccccc3N(Cc3nnn[nH]3)C2=O)cc(C(C)(C)C)c1O

Procedure:
To a solution of 2-(4-acetoxy-3,5-di-tert.- butylbenzylidene)-3,4-dihydro-3-oxo-4-(1H-tetrazol-5-ylmethyl)2H-1,4-benzothiazine (compound No. 8-1, 0.19 g) in ethanol (10 ml), potassium hydroxide (0.58 g) dissolved in water (10 ml) was added. The mixture was refluxed over night. 6N hydrochloric acid was added to the mixture to acidify it. The mixture was concentrated in vacuo and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by silica gel column chromatography to give the titled compound. The physical property of the compound obtained above was the same as the compound (No. 2-1) prepared in Example 2.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[F:14][C:13]([F:16])([F:15])[C:11]1[CH:10]=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([NH2:27])=[N:29][CH:30]=3)[N:3]=[CH:4]2)[N:12]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)cc1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.1) (0.44 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.22 g, 1.0 mmol) according to the general procedure VI. Obtained as a yellow solid (0.031 g, 7%). MS (ISP) 451.0 [(M+H)+]; mp 286° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[N:13]1([C:18]2[S:19][CH:20]=[CH:21][C:22]=2[NH2:23])[CH:17]=[N:16][CH:15]=[N:14]1>>[N:13]1([C:18]2[S:19][CH:20]=[CH:21][C:22]=2[NH:23][C:10](=[O:12])[CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: Nc1ccsc1-n1cncn1
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(CC(=O)Nc2ccsc2-n2cncn2)cc1

Procedure:
The title compound was prepared from 2-(4-methoxyphenyl)acetic acid (233 mg, 1.41 mmol) and 2-(1H-1,2,4-triazol-1-yl)thiophen-3-amine (234 mg, 1.41 mmol) according to protocol B. Retention time (min)=2.847, method [7], MS (ESI) 315.2 (M+H); 1H NMR (300 MHz, CDCl3) δ 9.27 (s, 1H), 8.31 (s, 1H), 7.99 (d, J=5.3 Hz, 1H), 7.83 (s, 1H), 7.22 (d, J=8.1 Hz, 2H), 7.09 (d, J=5.3 Hz, 1H), 6.94 (d, J=8.1 Hz, 2H), 3.87 (s, 3H), 3.72 (s, 2H).
Reaction SMILES: O=[C:2]1[CH:8]([CH2:9][C:10](O)=[O:11])[CH2:7][CH2:6][S:5][C:4]2[S:13][CH:14]=[CH:15][C:3]1=2.O.[NH2:17][NH2:18]>C(O)C>[N:17]1[NH:18][C:10](=[O:11])[CH2:9][CH:8]2[CH2:7][CH2:6][S:5][C:4]3[S:13][CH:14]=[CH:15][C:3]=3[C:2]=12
Reactant: NN
Reactant: O=C(O)CC1CCSc2sccc2C1=O
Solvent: O
Solvent: CCO
Product: O=C1CC2CCSc3sccc3C2=NN1
Yield: 71.2 %

Procedure:
A suspension of 2.0 g of 4-oxo-4,5,6,7-tetrahydrothieno[2,3-b]thiepin-5-acetic acid and 0.6 g of hydrazine hydrate in 20 ml of ethanol is refluxed under heating for 5 hours. After cooling, the precipitated crystals are collected by filtration and recrystallized from a mixed solvent of chloroform and ethanol to give 1.4 g of 4,4a,5,6-tetrahydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as white crystals, melting at 215°-217° C.
Reaction SMILES: [C:1](=[N:6][CH:7]([CH3:9])[CH3:8])=[N:2][CH:3]([CH3:5])[CH3:4].[CH3:10][C:11]([OH:14])([CH3:13])[CH3:12]>[Cu]Cl>[CH:3]([NH:2]/[C:1](=[N:6]\[CH:7]([CH3:9])[CH3:8])/[O:14][C:11]([CH3:13])([CH3:12])[CH3:10])([CH3:5])[CH3:4]
Reactant: CC(C)(C)O
Reactant: CC(C)N=C=NC(C)C
Agent: Cl[Cu]
Product: CC(C)/N=C(\NC(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.3 %

Procedure:
To a solution of N,N′-methanediylidenebis(propan-2-amine) (307 ml, 1981 mmol) in t-BuOH (227 ml, 2377 mmol) at r.t. was added copper(I) chloride (1.961 g, 19.81 mmol). The reaction was stirred at room temperature for 24 h and the resulting mixture was distilled under reduced pressure to afford (E)-tert-butyl N,N′-diisopropylcarbamimidate (279 g, 1393 mmol, 70.3% yield) as a colorless liquid. 1H NMR (400 MHz, CHLOROFORM-d4) δ ppm 1.04 (d, J=−6.06 Hz, 6 H) 1.08 (d, J=6.57 Hz, 6 H) 1.46 (s, 9 H) 2.98-3.19 (m, 1 H) 3.25 (m, 1 H) 3.64 (s, 1 H)
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([S:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])(=[O:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].C(O)C.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([S:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])(=[O:16])=[O:15])=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1cc(S(=O)(=O)Nc2ccccc2F)c(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(S(=O)(=O)Nc2ccccc2F)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To the product of Step A was added ethanol (8 mL) followed by a solution of NaOH (0.378 g, 9.45 mmol) in water (8 mL). The reaction was stirred at ambient temperature for 45 minutes. To the mixture was added 1 N HCl (23 mL), and the mixture was stirred overnight. The solids were collected by filtration, washed with water (1×5 mL), and dried by vacuum filtration to give 2,4-dichloro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid: 1H NMR (400 MHz, DMSO-d6) δ ppm 13.50 (bs, 1H), 10.30 (bs, 1H), 8.22 (s, 1H), 8.04 (s, 1H), 7.28-7.11 (m, 4H); MS (ESI) m/z 362.3 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18](I)[C:9]=2[C:8]1=[O:20].[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18]([C:34]3[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=3)[C:9]=2[C:8]1=[O:20]
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C1c2c(I)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C1c2c(-c3ccc(F)cc3)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 100.7 %

Procedure:
In a similar manner to Reference Example 5, 5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (compound of Reference Example 3; 300 mg) was reacted with 4-fluorophenylboronic acid (143 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (284 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:22]([F:21])[CH:23]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: Nc1cccc(F)c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(Nc1cccc(F)c1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 3-fluoro-aniline (43 mg, 0.39 mmol). The title compound was obtained as a solid (75 mg, 52% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.68 (1H, s), 9.01 (2H, s), 8.71 (1H, s), 7.61 (1H, m), 7.42 (1H, m), 6.97 (1H, m). MS m/z: 442.07, 444.05 [M+H]+.