Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH:19][C:20]4[S:21][CH:22]=[CH:23][N:24]=4)=[O:18])[C:10]=3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CS(C)=O.O>[Cl:1][C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH:19][C:20]4[S:21][CH:22]=[CH:23][N:24]=4)=[O:18])[C:10]=3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[O:28]1[CH2:29][CH2:30][N:25]([C:2]2[C:7]([C:8]3[NH:12][C:11]4[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH:19][C:20]5[S:21][CH:22]=[CH:23][N:24]=5)=[O:18])[C:10]=4[N:9]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:26][CH2:27]1
Reactant: C1COCCN1
Agent: O=C(Nc1nccs1)c1cccc2[nH]c(-c3cccnc3Cl)nc12
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1nccs1)c1cccc2[nH]c(-c3cccnc3N3CCOCC3)nc12
Temperature: 140 °C
Reaction time: 0.42 h
Yield: 120.7 %

Procedure:
2-(2-Chloropyridin-3-yl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide 9 was prepared according to the general procedure outlined above using the appropriate aldehyde component. A mixture containing this material, namely 2-(2-chloropyridin-3-yl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide (9; 19 mg, 0.053 mmol) and morpholine (48; 46 mg, 0.53 mmol) in DMSO (1.2 mL) were stirred at 140° C. in a microwave reactor for 25 min. The reaction mixture was cooled to room temperature and diluted with water. The precipitated solids were collected by filtration and dried. The solids were redissolved in EtOAc and enough petroleum ether was added to precipitate the product out again. The solids were collected by filtration, washed with MeOH and dried to afford 2-(2-morpholinopyridin-3-yl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide (Compound 250) as a white solid (13 mg, 60%). MS (ESI) calcd for C20H18N6O2S (m/z): 406.12; found: 407 [M+H].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.C1(C)C=CC=C(O[C:16](=[NH:20])[NH:17][C:18]#[N:19])C=1>C(O)(C)C>[C:16]([NH:17][C:18]([NH:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1)=[NH:19])#[N:20]
Reactant: Cc1cccc(OC(=N)NC#N)c1
Reactant: NCCc1c[nH]cn1
Solvent: CC(C)O
Product: N#CNC(=N)NCCc1c[nH]cn1

Procedure:
3.62 g. histamine (0.0300 mole) and 5.26 g. (0.0300 mole) O-m-tolyl-N-cyanoisourea are combined in 75 ml. of isopropanol. The mixture is heated 25 minutes to reflux and refluxed 70 minutes. The reaction solution is cooled and stripped to a light orange oil, triturated in benzene, decanted, and the residue is recrystallized from MeOH/CH3CN to obtain N-cyano-N'-[2-(4-imidazolyl)ethyl] guanidine having a m.p. of 152°-154° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[N:10]=[CH:11][C:12]3[N:13]([CH:24]=[N:25][CH:26]=3)[C:14]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19](I)=[CH:18][C:17]=2[F:23])=[O:8])[CH2:3][CH2:2]1.COC(C1N=CC2N(C=NC=2)C=1NC1C=CC([Br:44])=CC=1F)=O>>[Br:44][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]2[N:13]3[CH:24]=[N:25][CH:26]=[C:12]3[CH:11]=[N:10][C:9]=2[C:7]([NH:6][O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[O:8])=[C:17]([F:23])[CH:18]=1
Reactant: O=C(NOCC1CC1)c1ncc2cncn2c1Nc1ccc(I)cc1F
Reactant: COC(=O)c1ncc2cncn2c1Nc1ccc(Br)cc1F
Product: O=C(NOCC1CC1)c1ncc2cncn2c1Nc1ccc(Br)cc1F

Procedure:
The title compound was prepared in an analogous fashion to N-(cyclopropylmethoxy)-5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyrazine-6-carboxamide, using 5-(4-bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid methyl ester as the starting material. 1H NMR (MeOD, 400 MHz) 8 ppm 8.74 (s, 1H), 7.87 (s, 1H), 7.84 (s, 1H), 7.48 (dd, J=10.4 Hz, 3.2 Hz, 1H), 7.30 (d, 8.4 Hz, 1H), 6.75 (t, J=8.4 Hz, 1H), 3.79 (d, J=7.2 Hz, 2H), 1.26-1.13 (m, 1H), 0.62-0.55 (m, 2H), 0.36 to 0.30 (m, 2H); LCMS (method D1): RT=0.985 min, [M+H]+=420/422.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:14]=[O:15])C1C=CC=CC=1.[CH3:16][C:17]1[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][C:18]=1[OH:19]>CCOCC>[OH:19][C:18]1[C:17]([CH3:16])=[C:23]([OH:24])[CH:22]=[CH:21][C:20]=1[CH:14]=[O:15]
Reactant: Cc1c(O)cccc1O
Reactant: CN(C=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: Cc1c(O)ccc(C=O)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
Phosphorus oxychloride (80 mL, 0.86 mol) was added to a stirred mixture of N-methylformanilide (102 mL, 0.82 mol) in ether (250 mL). The mixture was stirred for 1 hour at room temperature and then cooled in ice. 2-Methyl resorcinol (Aldrich, 100 g, 0.81 mol) was added and the mixture was allowed to warm to room temperature while stirring overnight. The precipitated intermediate product was collected by filtration and rinsed with ether (3×). The intermediate was hydrolyzed by dissolving in a mixture of acetone (250 mL) and water (250 mL) and stirring for 30 minutes. Water (2 L) was added, the mixture was brought to a boil, and then allowed to cool and deposit crystalline product. This was recrystallized a second time from water (4 L) to afford pure product (70 g, 57%). M.p. 150° C. (Lit. 152°-3° C. [W. Baker et al., J. Chem. Soc., 2834-5 (1949)⟧ NMR (DMSO-d6): δ1.973 (s, 3H), 6.551 (d, J=8.5 hz, 1H), 7.428 (d, J-8.5 hz, 1H), 9.703 (s, 1H), 10.745 (s, 1H), and 11.592 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([C:36]([NH:35][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:37])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: O=C=Nc1ccccc1
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(=O)Nc4ccccc4)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)-ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), phenyl isocyanate (0.00519 g, 0.0436 mmol), DIPEA (0.033 mL, 0.19 mmol) in DMF (1 mL) was stirred at rt for 15 min. Purification by HPLC afforded the title compound as a colorless solid. 1H NMR (CD3OD, 400 MHz): δ=1.90 (d, J=6.8 Hz, 3H), 2.58 (br. s., 2H), 3.77 (t, J=5.7 Hz, 2H), 4.25 (d, J=2.5 Hz, 2H), 6.32 (br. s., 1H), 6.52 (d, J=6.8 Hz, 1H), 7.04 (t, J=7.3 Hz, 1H), 7.17-7.32 (m, 3H), 7.34-7.46 (m, 3H) 7.69 (s, 1H), 8.23 (s, 1H). MS (ES+): m/z 541.03/543.05 (100/68) [MH+]. HPLC: tR=3.39 min (ZQ3, polar—5 min).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]([OH:16])=O.C(Cl)(=O)C([Cl:20])=O.CN(C=O)C>C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]([Cl:20])=[O:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCN1C(=O)c2ccccc2C1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.5 %

Procedure:
To a solution of 137g (20.0 g, 91 mmol) in DCM (250 mL) were added oxalyl chloride (13.8 g, 109 mmol) and DMF (0.1 mL). See FIG. 2. The mixture was stirred at RT for 4 h. Upon reaction completion, the mixture was concentrated to give 3-(1,3-dioxoisoindolin-2-yl)propanoyl chloride 137h (20.0 g, 92%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.[CH3:38][C:39]1[C:43]([C:44]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[O:45])=[C:42]([CH3:52])[O:41][N:40]=1>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C@H:11]2[C@@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:9]([C:27]([N:49]3[CH2:50][CH2:51][N:46]([C:44]([C:43]4[C:39]([CH3:38])=[N:40][O:41][C:42]=4[CH3:52])=[O:45])[CH2:47][CH2:48]3)=[O:28])[C:8]([C:6]3[C:5]([O:30][CH2:31][CH3:32])=[CH:4][C:3]([C:33]([CH3:34])([CH3:35])[C:36]#[N:37])=[C:2]([Cl:1])[CH:7]=3)=[N:12]2)=[CH:18][CH:17]=1
Reactant: Cc1noc(C)c1C(=O)N1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)c2c(C)noc2C)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(3,5-dimethyl-isoxazole-4-carbonyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-2-chloro-5-ethoxy-phenyl)-2-methyl-propionitrile was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone (example 13) in an analogous manner as described in example 25. LR-MS: 747.3 [(M+H)+]
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:19][C:20]1[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[C:22]([O:29][C@@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:40])[F:39])[CH3:31])[CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+].C>O1CCOCC1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCCCCCC>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH:19][C:20]3[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[C:22]([O:29][C@@H:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]([F:41])([F:39])[F:40])[CH3:31])[CH:21]=3)[CH:3]=2)[CH2:13][CH2:14]1
Reactant: COC(=O)c1sc(N)cc1O[C@H](C)c1ccccc1C(F)(F)F
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])c(Br)c2)CC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCCCCCC
Product: COC(=O)c1sc(Nc2cc(CN3CCN(C)CC3)ccc2[N+](=O)[O-])cc1O[C@H](C)c1ccccc1C(F)(F)F
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
A mixture of 1-[(3-bromo-4-nitrophenyl)methyl]-4-methylpiperazine (0.675 g, 2.15 mmol), methyl 5-amino-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate (0.794 g, 2.30 mmol), Cs2CO3 (3.50 g, 10.7 mmol), XANTPHOS (0.053 g, 0.088 mmol) and tris(benzylideneacetone)dipalladium(0) (0.039 g, 0.043 mmol) in dioxane (5.4 mL) was heated to 55° C. for 1.5 h, analysed by HPLC, then cooled to room temperature. Heptane (2.4 mL), charcoal (0.27 g) and celite (0.27 g) were added. The suspension was stirred for 30 min at room temperature, and then filtered over celite, rinsing with toluene (13.5 mL×3). The filtrate was concentrated under reduced pressure and purified by flash column chromatography (DCM:MeOH:NEt3 9:1:0.1) to give the title compound (0.867 g, 70%) as a red amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[N:27]=2)[CH:8]=1)=[O:6]
Reactant: FC(F)(F)c1cccc(CBr)n1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(C(F)(F)F)n3)c3ccccc3c2=O)cc1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Compound 4xx was prepared following the procedure described in Step 3 of Example 1 using 55 mg (0.20 mmol) of 3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one, 10 mg (0.26 mmol) of 60% sodium hydride and 62 mg (0.26 mmol) of 2-bromomethyl-6-trifluoromethyl-pyridine, and 1.7 mL N,N-dimethylformamide and stirring the reaction mixture for 6 h at rt. The crude product was purified by flash chromatography using 20-75% ethyl acetate in hexane yielded to provide 45 mg of the product as white solid: LC-MSD, m/z for C25H19F3N2O2 [M+H]+: 437.3; Reverse phase HPLC gradient, 20-95% acetonitrile with 0.1% TFA in 4 minutes, retention time=2.8 min; 1H NMR (400 MHz, CDCl3): δ 2.25 (s, 3H), 2.3 (s, 3H), 5.6 (s, 2H), 7.1-7.2 (m, 1H), 7.2-7.3 (m, 1H), 7.3-7.4 (m, 2H), 7.5-7.65 (m, 15 4H), 7.8-7.9 (m, 1H), 8.35 (s, 1H), 8.4-8.5 (m, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14](=[O:16])[CH3:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1.C(N(CC)CC)C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:17]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[S:9][C:10]([C:14](=[O:16])[CH3:15])=[C:11]([CH3:13])[N:12]=3)=[CH:4][CH:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: CC(=O)c1sc(-c2ccc(I)cc2)nc1C
Reactant: C1=CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1sc(-c2ccc(C3=CCCCC3)cc2)nc1C
Temperature: 80 °C
Yield: 39 %

Procedure:
A solution of 4-iodophenylthiazole 4i (100 mg, 0.3 mmol) in dry DMF (5 mL) was charged with Pd(OAc)2 (5 mg), cyclohexene (1 mL) and triethylamine (0.5 mL). The reaction mixture was heated at 80° C. for 5 h. The reaction mixture was quenched with distilled water (10 mL) and extracted with ethyl acetate (30 mL). The organic layer was separated and dried over anhydrous Na2SO4. After evaporation of solvent under reduced pressure, the oily residue was collected and purified by silica gel flash chromatography, using hexane-ethyl acetate (9:1), to yield faint yellowish oil (35 mg, 39%). 1H NMR (CDCl3) δ 7.90 (d, J=8.1 Hz, 2 H), 7.29 (d, J=8.1 Hz, 2 H), 5.76 (m, 2 H), 2.80 (m, 1 H), 2.77 (s, 3 H), 2.55 (s, 3 H), 2.27-1.24 (m, 6 H); 13C NMR (CDCl3) δ 190.45, 169.54, 159.46, 150.94, 130.84, 130.63, 128.42, 127.60, 126.97, 126.33, 40.06, 32.98, 30.73, 29.40, 25.59, 18.45; CIMS m/z (rel intensity) 298 (MH+, 100); HRMS (EI), m/z 297.1189 M+, calcd for C18H19NOS 297.1187.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Br:13])[CH:12]=1.[CH3:14][O:15]C=O>C1COCC1>[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Br:13])[C:12]=1[CH:14]=[O:15]
Reactant: COC=O
Reactant: Brc1cncc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c(Br)cncc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of diusopropylamine (6.6 mL, 46.43 mmol) in THF (40 mL) at 0° C. was treated with n-butyllithium in hexanes (2.50 M solution, 18.6 mL, 46.43 mmol) over 15 minutes, stirred at 0° C. for 30 minutes, diluted with THF (200 mL), cooled to −78° C., treated with 3,5-dibromopyridine (10 g, 42.21 mmol) in THF (110 mL) over 95 minutes, stirred at −78° C. for 30 minutes, treated dropwise with methylformate (5.2 mL, 84.42 nunol), stirred at −78° C. for 2 hours, transferred to ice-cold saturated NaHCO3 solution, stirred for 15 minutes, and extracted with diethyl ether. The extract was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 10% acetone/hexane to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.Cl[C:12]1[S:13][C:14]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:15]=2[N:16]=1.C([O-])([O-])=O.[K+].[K+].Cl>CS(C)=O.O>[Cl:8][C:6]1[CH:7]=[C:2]([NH2:1])[CH:3]=[C:4]([Cl:10])[C:5]=1[O:9][C:12]1[S:13][C:14]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1
Yield: 49.3 %

Procedure:
To the solution of 4-amino-2,6-dichloro phenol (6 g, 26.5 mmol) and 2,6-dichlorobenzothiazole (363) (6 g, 29.4 mmol, 1.1 eq) in DMSO (25 ml), was added K2CO3 (11 g, 80 mmol, 3.0 eq). The mixture was stirred and heated to 160 degree. After 5.5-hr water (20 ml) was added to the reaction mixture, which was neutralized with 2N HCl., and was extracted with AcOEt three times. And the organic layer was washed with Brine and was dried over anhydrous MgSO4, and then concentrated. Crude residue was purified by column chromatography (CHCl3/Acetone=9/1, 180 g of silica gel) to afford 3,5-Dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine (364) as a black solid (4.52 g, 49%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[N:10]=1)[C:5]([OH:7])=[O:6].[CH2:13]([NH2:17])[CH2:14][CH:15]=[CH2:16]>O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:13]([NH:17][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[N:10]=1)[C:5]([OH:7])=[O:6])[CH2:14][CH:15]=[CH2:16]
Reactant: COc1cc(C(=O)O)cc(Cl)n1
Reactant: C=CCCN
Agent: [Cu+2]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: C=CCCNc1cc(C(=O)O)cc(OC)n1
Temperature: 140 °C
Reaction time: 36 h

Procedure:
A mixture of 1.0 g (5.3 mmol) 2-chloro-6-methoxy-isonicotinic acid, 4.4 g (53 mmol, 86% pure by NMR) but-3-enylamine and 85 mg (0.53 mmol) CuSO4 in 10 ml H2O is stirred in a pressurized reaction vessel for 36 h at 140° C. The reaction mixture is diluted with an 0.5 M aqueous citric acid and extracted two times with EtOAc. The combined extracts are washed with citric acid solution, water and brine, dried over Na2SO4, filtered and the solvent is evaporated. Chromatography on silica gel yields the title compound as an off-white powder.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCCCC.[Li:15]CCCC>C1COCC1>[Li:15][C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Li]C#Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of fresh LiC≡CPh was prepared by reacting 0.118 mL of phenylacetylene (1.08 mmol) and 0.48 mL of 1.5M hexane nBuLi solution (0.72 mmol) in 50 mL of dry THF at −78° C. for 0.5 hour. The solution was added drop wise via cannula to a solution of 150 mg of Ir(ppy)2(MeOH)2OTf (0.18 mmol) in 10 mL of dry THF at −78° C. The mixture was reacted for 1 h at −78° C. and the temperature was raised to RT over 2 hours. The solvent was removed under reduced pressure obtaining the Ir(ppy)2(CCPh)2Li.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][CH:13]1[C:18](=[O:19])[N:17]([CH2:20][C:21](O)=[O:22])[C:16]2[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=2[S:14]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([NH2:31])[CH2:29][CH3:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([O:8][N:9]([CH2:12][CH:13]1[C:18](=[O:19])[N:17]([CH2:20][C:21]([NH:31][CH2:28][CH2:29][CH3:30])=[O:22])[C:16]2[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=2[S:14]1)[CH:10]=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCN
Reactant: O=CN(CC1Sc2ccccc2N(CC(=O)O)C1=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)CN1C(=O)C(CN(C=O)OCc2ccccc2)Sc2ccccc21
Reaction time: 8 h

Procedure:
To a solution of {2-[(benzyloxy-formyl-amino)-methyl]-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl}-acetic acid (0.13 mmol) in anhydrous DMF, propylamine (0.13 mmol) is added followed by DIEA (0.13 mmol) and HATU (0.13 mmol). The reaction mixture is stirred overnight and the desired product 2-{2-[(benzyloxy-formyl-amino)-methyl]-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl}-N-propyl-acetamide is obtained and used in the next step without further purification. MS: (ES+): 428.2 [M+1].
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8](=[NH:20])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])N=1.[CH3:21]S(O)(=O)=O.C1(N)CCCCC1>>[NH2:20][C:8]([NH:4][CH:5]1[CH2:7][CH2:21][CH2:1][CH2:2][CH2:6]1)=[N:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)O
Reactant: Cc1ccc(S(=O)(=O)NC(=N)n2nc(C)cc2C)cc1
Solvent: NC1CCCCC1
Product: Cc1ccc(S(=O)(=O)N=C(N)NC2CCCCC2)cc1

Procedure:
The compound of Example 4 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of cyclohexylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 295.40; found mol. wt. (M+H) 296.1; 591.5 (Dimer)
Reaction SMILES: [CH:1]1([C:4]2[C:5]3[C:12](I)=[CH:11][N:10]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[C:6]=3[N:7]=[CH:8][N:9]=2)[CH2:3][CH2:2]1.C([Mg]Cl)(C)C.[C:29]([O:33][C:34](=[O:52])[N:35]([C:45]1[CH:46]=[N:47][C:48]([Cl:51])=[CH:49][CH:50]=1)[C:36]1[CH:41]=[CH:40][C:39]([CH:42]=[O:43])=[C:38]([F:44])[N:37]=1)([CH3:32])([CH3:31])[CH3:30].O>O1CCCC1>[C:29]([O:33][C:34](=[O:52])[N:35]([C:45]1[CH:46]=[N:47][C:48]([Cl:51])=[CH:49][CH:50]=1)[C:36]1[CH:41]=[CH:40][C:39]([CH:42]([C:12]2[C:5]3[C:4]([CH:1]4[CH2:2][CH2:3]4)=[N:9][CH:8]=[N:7][C:6]=3[N:10]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:16])[CH3:17])[CH:11]=2)[OH:43])=[C:38]([F:44])[N:37]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2c(C3CC3)ncnc21
Reactant: CC(C)(C)OC(=O)N(c1ccc(Cl)nc1)c1ccc(C=O)c(F)n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2ccc(N(C(=O)OC(C)(C)C)c3ccc(Cl)nc3)nc2F)c2c(C3CC3)ncnc21
Temperature: -5 °C
Yield: 55.4 %

Procedure:
To 4-cyclopropyl-5-iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine (19, 0.72 g, 1.64 mmol) in 6.0 mL of tetrahydrofuran at −40° C. under nitrogen, isopropylmagnesium chloride (0.82 mL, 2.01 M in tetrahydrofuran, 1.65 mmol) is added slowly. The reaction is allowed to warm to −5° C. in 75 minutes, then cooled to −45° C. and (6-chloro-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (80, 0.48 g, 1.38 mmol) in 5.0 mL is added. The reaction is allowed to warm to room temperature in 2 hours, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (81, 0.51 g). MS (ESI) [M+H+]+=667.2).
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:28])[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CN(C)C=O.[Pd]>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][C:16]([O:15][CH2:14][CH2:13][O:12][C:10](=[O:11])[CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:30][CH:29]=2)=[O:28])=[CH:20][CH:21]=1
Reactant: [H][H]
Reactant: O=C(COc1ccc([N+](=O)[O-])cc1)OCCOC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc(OCC(=O)OCCOC(=O)COc2ccc(N)cc2)cc1
Yield: 75.8 %

Procedure:
(4-Nitrophenoxy)-acetic acid-2-[2-(4-nitrophenoxy)-acetoxy]-ethyl ester 24 (100 g, 238 mmol) was dissolved in dry dimethyl formamide (500 ml) in a pressure vessel, palladium on carbon (5%, 22 g) was added, and the mixture stirred under an atom-sphere of hydrogen (4 kg) for 6 hours. The catalyst was removed by filtration and ice water (2.5 L) was added to the filtrate. Crude 25 was filtered off, dried and recrystal-lised in a mixture of methanol:chloroform (1:1) to give pure 25 (65 g, 78%) as a light brown shining powder with an m.p. between 124-125.8° C.