Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[C:26](Br)=[CH:25][CH:24]=[C:23]([Cl:28])[N:22]=3)[C@@H:15]([CH3:29])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([CH3:44])([CH3:43])[CH2:41][OH:42])=[CH:36][C:35]=1B1OC(C)(C)C(C)(C)O1>C(=O)([O-])[O-].[K+].[K+].C1COCC1>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[C:26]([C:35]4[CH:36]=[C:37]([C:40]([CH3:44])([CH3:43])[CH2:41][OH:42])[CH:38]=[CH:39][C:34]=4[O:33][CH3:32])=[CH:25][CH:24]=[C:23]([Cl:28])[N:22]=3)[C@@H:15]([CH3:29])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1ccc(C(C)(C)CO)cc1B1OC(C)(C)C(C)(C)O1
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)CO)cc1-c1ccc(Cl)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: 25 °C

Procedure:
A mixture of (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazinan-2-one (intermediate 2, 32 mg, 0.06 mmol), 2-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylpropan-1-ol (Intermediate x, 18 mg, 0.06 mmol) and 1,1-bis(ditbutylphosphino)ferrocene palladium dichloride (4 mg, 0.006 mmol) in aqueous potassium carbonate/THF (3 mL, 3 mL) was heated at reflux for 2 h under N2. After cooling to room temperature, the aqueous phase was separated and extracted with EtOAc (3×20 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography on silica gel (0-15% EtOAc in hexanes gradient) to (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-({6-chloro-3-[5-(2-hydroxy-1,1-dimethylethyl)-2-methoxyphenyl]pyridine-2-yl}methyl)-4-methyl-1,3-oxazinan-2-one as a colorless oil. LCMS=631.1 (M+1)+. 1H NMR (CDCl3, 500 MHz, 1:1 mixture of atroisomers): δ 7.87 (br s, 2H), 7.82 (s, 1H), 7.58 (brs, 1H), 7.44 (br d, J=6.8 Hz, 1H), 7.32 (brs, 1H), 7.24 (brs, 1H), 7.02 (d, J=8.7 Hz, 1H), 5.62-5.41 (br m, 0.5H), 5.26-5.20 (brm, 0.5H), 5.16-5.11 (brm, 1H), 4.34 (brm, 3H), 3.80 (s, 3H), 3.62-3.44 (brm, 3H), 1.34 (brs, 3H), 1.22 (brm, 6H).
Reaction SMILES: [I:1][C@H:2]1[C@H:8]2[CH2:9][C@H:5]([C:6](=[O:10])[O:7]2)[CH2:4][CH2:3]1.[O:11]1CCCC1>O.Cl>[OH:7][C@H:8]1[C@H:2]([I:1])[CH2:3][CH2:4][C@@H:5]([C:6]([OH:10])=[O:11])[CH2:9]1
Reactant: C1CCOC1
Reactant: O=C1O[C@@H]2C[C@H]1CC[C@H]2I
Agent: Cl
Solvent: O
Product: O=C(O)[C@@H]1CC[C@@H](I)[C@H](O)C1

Procedure:
(1R*,4R*,5R*)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-one (2.8 g) was dissolved in a mixed solvent of tetrahydrofuran (27 ml) and water (3 ml), concentrated hydrochloric acid (0.1 ml) was added, and the mixture was heated under reflux for 1 hour. The solvent was distilled off under reduced pressure to obtain (1R*,3R*,4R*)-3-hydroxy-4-iodocyclohexanecarboxylic acid (3.23 g) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([NH:9][C:10]2([C:16]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[NH2:31])[CH2:21][CH:20]3[OH:32])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[CH:3]=1.C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([NH:9][C:10]2([C:16]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[NH2:31])[CH2:21][C:20]3=[O:32])=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[O:8])[CH:3]=1
Reactant: Cc1cc(C(=O)NC2(C(=O)NC3CCN(c4ccccc4N)CC3O)CCCCC2)no1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)NC2(C(=O)NC3CCN(c4ccccc4N)CC3=O)CCCCC2)no1
Temperature: 0 °C
Reaction time: 4 h
Yield: 74.9 %

Procedure:
To the solution of 4-[N-[1-[N-(5-methyl-isoxazol-3-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-aminophenyl)piperidin-3-ol (1.1 g) obtained in Step 1 in 5 ml of dimethyl sulfoxide, was added 1.2 ml of triethylamine. The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (0.9 g) was added to the reaction mixture, which was then stirred for about 4 hours at room temperature. The reaction mixture was diluted with 20 ml of ethyl acetate and washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was filtered and dried to give 820 mg of the titled compound as white color.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C@@:11]([CH2:16][S:17][CH3:18])([OH:15])[CH2:10]2)[C:5]([F:19])=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]2[C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][N:27]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[C:24]2=[N:25][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.O.CCOC(C)=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:20][C:21]1[CH:22]=[C:23]2[C:29]([C:2]3[N:7]=[C:6]([NH:8][C@H:9]4[CH2:14][CH2:13][CH2:12][C@@:11]([CH2:16][S:17][CH3:18])([OH:15])[CH2:10]4)[C:5]([F:19])=[CH:4][N:3]=3)=[CH:28][N:27]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:40])=[O:41])[C:24]2=[N:25][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Reactant: CSC[C@@]1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
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: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CSC[C@@]1(O)CCC[C@H](Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1
Temperature: 140 °C

Procedure:
To a solution of (1R,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-(methylthiomethyl)cyclohexanol, 49d, (0.09 g, 0.28 mmol) in CH3CN (4 mL) was added 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.14 g, 0.33 mmol) followed by aqueous Na2CO3 (0.42 mL of 2 M solution, 0.83 mmol). The reaction was degassed with nitrogen for 15 min and tetrakis triphenylphosphinepalladium(0) (0.02 g, 0.01 mmol) was added. The reaction was heated to 140° C. via microwave irradiation for 20 minutes. The mixture was cooled to room temperature and was diluted with water/EtOAc. The layers were separated and the organic phase was washed with brine, dried over MgSO4, filtered and evaporated to dryness. The crude residue was purified via silica gel chromatography (0-100% EtOAc/hexanes gradient).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([N:21]1[CH2:31][CH2:30][C:24]2[N:25]=[CH:26][N:27]=[C:28](Cl)[C:23]=2[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:28]2[C:23]3[CH2:22][N:21]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:31][CH2:30][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ncnc3c2CN(Cc2ccccc2)CC3)C1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 85.4 %

Procedure:
To a solution of (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (0.94 g, 5.01 mmol) in THF (20 mL) was added under argon NaH (0.23 g, 5.78 mmol). The mixture was stirred at rt for 25 min., then 6-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (1 g, 3.85 mmol) was added and stirring continued at rt for 4 h. The mixture was quenched with H2O, extracted with CH2Cl2. The organic layer was filtered and evaporated to dryness. Purification by flash chromatography on silica gel (heptanes/ethyl acetate, 1/1) gave the (S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.35 g, 85% yield) as a yellow gum. 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.39 (s, 9 H) 2.00-2.20 (m, 2 H) 2.35-2.81 (m, 4 H) 3.36-3.63 (m, 6 H) 3.70 (br.s, 2 H) 5.50-5.59 (m, 1 H) 7.25-7.37 (m, 5 H) 8.56 (s, 1 H). LCMS: [M+H]+=411.6, Rt(7)=1.00 min
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:44])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:40]([CH3:43])[CH2:41][CH3:42])[C@H:33]([O:38][CH3:39])[CH2:34][C:35](O)=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:46][O:47][C@@H:48]([C@@H:66]1[CH2:70][CH2:69][CH2:68][NH:67]1)[C@@H:49]([CH3:65])[C:50]([NH:52][C@H:53]([C:61]([O:63][CH3:64])=[O:62])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:51].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:44])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:40]([CH3:43])[CH2:41][CH3:42])[C@H:33]([O:38][CH3:39])[CH2:34][C:35]([N:67]3[CH2:68][CH2:69][CH2:70][C@H:66]3[C@H:48]([O:47][CH3:46])[C@@H:49]([CH3:65])[C:50]([NH:52][C@@H:53]([CH2:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:61]([O:63][CH3:64])=[O:62])=[O:51])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)[C@@H](OC)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C

Procedure:
According to general procedure D, from #32 (353 mg, 0.488 mmol, 1 eq.) in dichloromethane (10 mL, 0.04 M), amine #67 (271 mg, ≦0.588 mmol, 1.3 eq.), HATU (223 mg, 0.586 mmol, 1.2 eq.) and diisopropylethylamine (238 μL, 1.71 mmol, 3.5 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 40% acetone in heptane), affording #68 (404 mg, 88% over two steps) as a solid. LC-MS: m/z 940.7 [M+H+], 962.7 [M+Na+], retention time=1.04 minutes; HPLC (Protocol C): retention time=9.022 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [8.25 (br d, J=8 Hz) and 8.48 (br d, J=8 Hz), total 1H], 7.89 (d, J=7.4 Hz, 2H), 7.67-7.75 (m, 2H), 7.38-7.44 (m, 2H), 7.31-7.36 (m, 2H), 7.14-7.24 (m, 5H), 4.43-4.69 (m, 3H), 4.17-4.26 (m, 3H), 3.91-3.99 (br m, 1H), 3.63 and 3.65 (2 s, total 3H), 3.19 and 3.24 (2 s, total 3H), 3.14 and 3.15 (2 s, total 3H), 2.90 and 2.99 (2 br s, total 3H), 1.36 and 1.37 (2 br s, total 3H), 1.30 and 1.32 (2 s, total 3H), [1.02 (d, J=6.8 Hz) and 1.06 (d, J=6.6 Hz), total 3H].
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.[BH4-].[Na+].C(O)(=O)C>CO>[OH:19][CH:1]1[C:2]2[C:3](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:4](=[O:14])[N:5]1[CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: O=C1c2ccccc2C(=O)N1CSc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1c2ccccc2C(O)N1CSc1ccncc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.3 %

Procedure:
To a solution of 4.01 g (14.8 mmol) of 4-(phthalimidomethylthio)pyridine in 25 ml of methanol, a solution of 1.08 g (29.7 mmol) of sodium borohydride in 20 ml of methanol was added. The mixture was stirred at room temperature for 4 hours. Glacial acetic acid (0.5 ml) was added to quench the reaction, and then the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, and the solvent was distilled off. The residue was purified by recrystallization (recrystallization solvent: ethanol) to obtain 2.35 g of the desired compound (yield: 58.3%, yellow crystals).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[C:9]#[C:10][C:11]1[N:12]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:15]=1.FC1C=CC(N2C(C(OCC)=O)=CN=C2I)=CC=1.C(C1C=CC=CC=1[C:54]([F:57])([F:56])[F:55])#C.C(NC(C)C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[F:27][C:24]1[CH:23]=[CH:22][C:21]([N:12]2[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:15]=[C:11]2[C:10]#[C:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:54]([F:57])([F:56])[F:55])=[CH:26][CH:25]=1
Reactant: C#Cc1ccccc1C(F)(F)F
Reactant: CCOC(=O)c1cnc(C#Cc2c(F)cccc2Cl)n1-c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCOC(=O)c1cnc(I)n1-c1ccc(F)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(C#Cc2ccccc2C(F)(F)F)n1-c1ccc(F)cc1

Procedure:
Ethyl 1-(4-fluorophenyl)-2-((2-(trifluoromethyl)phenyl)ethynyl)-1H-imidazole-5-carboxylate (46) was prepared in a similar manner as that described for the synthesis of compound 42 using ethyl 1-(4-fluorophenyl)-2-iodo-1H-imidazole-5-carboxylate (38) (900 mg, 2.5 mmol), 1-ethynyl-2-(trifluoromethyl)benzene (0.42 mL, 3.0 mmol), PdCl2(PPh3)2 (88 mg, 0.13 mmol), copper (I) iodide (23 mg, 0.13 mmol), diisopropyl amine (7 mL), and THF (50 mL).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2([CH3:23])[CH3:22])[C:9]2[C:4](=[C:5]([O:24][CH3:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>CN(C)C=O>[ClH:1].[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:2]2[N:11]=[C:10]([N:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3([CH3:23])[CH3:22])[C:9]3[C:4](=[C:5]([O:24][CH3:25])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:29][CH:28]=1
Reactant: Nc1ccc(F)cc1
Reactant: COc1cccc2c(N3CCc4ccccc4C3(C)C)nc(Cl)nc12
Solvent: CN(C)C=O
Product: COc1cccc2c(N3CCc4ccccc4C3(C)C)nc(Nc3ccc(F)cc3)nc12
Product: Cl
Yield: 49 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 1.80 g of the compound (5.0 mM) prepared in Example 13 and 10 ml of dimethyl-formamide, 1.10 ml of 4-fluoroaniline(11 mM) was added, 1.14 g of the title compound was prepared.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH2:14])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:26](=[O:27])[C:25]3[CH:24]=[CH:23][C:22]([N:19]4[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]4)=[CH:30][CH:29]=3)[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-c2cccnc2Cl)n1
Reactant: CN1CCN(c2ccc(C(=O)Cl)cc2)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(C(=O)Nc3nccc(-c4cccnc4Cl)n3)cc2)CC1
Temperature: 50 °C
Reaction time: 17 h

Procedure:
In a 48 mL sealed pressure vessel, added 4-(2-chloropyridin-3-yl)pyrimidin-2-amine (Step 1, 0.72 g, 3.5 mmol), 4-(4-methylpiperazin-1-yl)benzoyl chloride (1.0 g, 4.2 mmol), chloroform (5.0 mL), and N,N-diisopropylethylamine (0.73 mL, 4.2 mmol). The mixture was stirred at 50° C. for 17 hours, and concentrated to yield N-(4-(2-chloropyridin-3-yl)pyrimidin-2-yl)-4-(4-methylpiperazin-1-yl)benzamide as a light brown solid. MS (M+H)+=409; Calc'd 408.88 for C21H21ClN6O.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[N:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:31][C:32]1[CH:33]=[C:34]([S:38]([NH2:41])(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1>CC(O)C>[N:11]1([C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH:31][C:32]3[CH:33]=[C:34]([S:38]([NH2:41])(=[O:39])=[O:40])[CH:35]=[CH:36][CH:37]=3)[N:10]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[N:12]1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: CS(=O)(=O)c1nccc(-n2ncc3ccccc32)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: NS(=O)(=O)c1cccc(Nc2nccc(-n3ncc4ccccc43)n2)c1

Procedure:
A solution of 1-(2-methylsulfonyl-pyrimidin-4-yl)-1H-indazole (100 mg, 0.36 mmol) and p-toluenesulfonic acid (139 mg, 0.73 mmol) in i-PrOH (4 ml) was treated with 3-aminobenzene-sulfonamide (251 mg, 1.46 mmol) in a microwave synthesizer at 150° C. for 20 min. The mixture was partitioned between water and ethyl acetate, the organic layer separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was absorbed on silica gel and purified by flash chromatography (EtOAc/hexane, gradient from 30:70 to 50:50) to afford the title compound. This residue was triturated with aqueous NaOH (1 M), the solid collected by filtration, washed with water and dried under vacuum to afford 3-(4-indazol-1-ylpyrimidin-2-ylamino)-benzenesulfonamide (50 mg, 37% yield). MS=367 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Br:23]>>[Cl-:14].[NH2:1][C:2]1[N:6]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Br:23])[C:5]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[CH:10][C:4]=2[N+:3]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Br:23]
Reactant: ClCOc1ccccc1Br
Reactant: CCOc1ccc2nc(N)[nH]c2c1
Product: CCOc1ccc2c(c1)[n+](COc1ccccc1Br)c(N)n2COc1ccccc1Br
Product: [Cl-]

Procedure:
Following the procedure of Example 2 and replacing 2-aminobenzimidazole with 2-amino-5-ethoxybenzimidazole and replacing 2-bromo-4-chlorophenyl chloromethyl ether with 2-bromophenyl chloromethyl ether, the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([C:20]#[N:21])=[CH:19][C:13]=2[N:12]=1.C(N(CC)CC)C.Cl.[NH2:30][OH:31]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([C:20]([NH:30][OH:31])=[NH:21])=[CH:19][C:13]=2[N:12]=1
Reactant: NO
Reactant: N#Cc1ccc2[nH]c(-c3cc([N+](=O)[O-])ccc3Cl)nc2c1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: N=C(NO)c1ccc2[nH]c(-c3cc([N+](=O)[O-])ccc3Cl)nc2c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
To a stirred solution of 2-(2-chloro-5-nitro-phenyl)-1H-benzoimidazole-5-carbonitrile (2.00 g; 6.70 mmol) in ethanol (20 ml) in a sealable tube was added triethylamine (1.90 ml; 13.4 mmol). A solution of hydroxylamine hydrochloride (933 mg; 13.4 mmol) in water (4 ml) was added, the tube sealed and the mixture stirred at 75° C. for 2 hours. After cooling to room temperature, water (100 ml) was added, the precipitate filtered and washed with more water to leave 2-(2-chloro-5-nitro-phenyl)-N-hydroxy-1H-benzoimidazole-5-carboxamidine (1.76 g, 82%).
Reaction SMILES: O=[O+][O-].[CH3:4]SC.[Cl:7][C:8]([Cl:45])([Cl:44])[CH2:9][O:10][C:11](=[O:43])/[C:12](/[N:16]1[CH:19]([S:20][S:21][C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)[CH:18]([NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:17]1=[O:42])=[C:13](\O)/[CH3:14]>>[Cl:44][C:8]([Cl:7])([Cl:45])[CH2:9][O:10][C:11](=[O:43])[CH:12]([N:16]1[CH:19]([S:20][S:21][C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)[CH:18]([NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:17]1=[O:42])[C:13](=[CH2:4])[CH3:14]
Reactant: C/C(O)=C(/C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2s1
Reactant: CSC
Agent: O=[O+][O-]
Product: C=C(C)C(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2s1

Procedure:
Analogously to Example 6a), 647 mg (1 mM) of 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyric acid 2,2,2-trichloroethyl ester and 1.2 equivalents of ozone, with subsequent splitting of the ozonide with dimethyl sulphide, give 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1 -yl]-3-hydroxy-crotonic acid 2,2,2-trichloroethyl ester; melting point 129-130° C. (ether/petroleum ether).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH2:23])[N:17]=3)[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.CCO.[Cl:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=[CH:32][CH:31]=1.Cl>O>[ClH:29].[NH2:23][C:18]1[N:17]=[C:16]([NH:15][C:11]2[CH:10]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:24]=[CH:25][C:2]([NH:1][C:30]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=[CH:32][CH:31]=4)=[CH:3][CH:4]=3)[CH:14]=[CH:13][CH:12]=2)[CH:21]=[C:20]([CH3:22])[N:19]=1
Reactant: Clc1ccnc2ccccc12
Reactant: Cc1cc(Nc2cccc(NC(=O)c3ccc(N)cc3)c2)nc(N)n1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(Nc2cccc(NC(=O)c3ccc(Nc4ccnc5ccccc45)cc3)c2)nc(N)n1

Procedure:
To a solution of amine E4 (0.26 g, 0.63 mmol) in 1:2 EtOH:H2O (30 mL) were sequentially added 4-chloroquinoline (0.62 g, 3.78 mmol) and c.HCl (0.17 mL, 5.67 mmol), and the resulting mixture refluxed for 3 h (reaction progress followed by TLC, eluting with the top phase of a 5:4:1 mixture of n-BuOH:H2O:acetic acid; product Rf=0.43, yellow spot after staining with KMnO4). After this time, solvent was removed under reduced pressure, and the residue dried via three MeOH-azeotrope cycles. The residue was re-precipitated from MeOH:EtOAc to give Cpd. II as an amorphous lemon-yellow solid (0.27 g, 79%); mp 251-255° C. (powder-glue); 1H NMR (400 MHz, DMSO): δ 14.78 (v br s, 1H, quinolinyl-N+—H), 12.79 (v br s, 1H, pyrimidinyl-N+—H), 11.14 (s, 1H, ArNHAr), 10.64 (br s, 1H, ArC(O)NHAr), 10.52 (s, 1H, ArNHAr), 8.87 (d, J=8.44 Hz, 1H, ArH), 8.61 (d, J=6.94 Hz, 1H, ArH), 8.30-7.45 (m, 12H, ArH & ArNH2), 7.38 (t, J=8.07 Hz, 1H, ArH), 7.00 (d, J=6.94 Hz, 1H, ArH), 6.22 (s, 1H ArH), 2.29 (s, 3H, ArCH3); LCMS (APCI+): 463 (100%); HPLC: 95.4%.
Reaction SMILES: [C:1](=[S:3])=[S:2].C[O-].[Na+].Cl[C:8]1[CH:14]=[C:13]([Cl:15])[C:12]([Cl:16])=[CH:11][C:9]=1[NH2:10].Cl>CN(C=O)C.O>[Cl:16][C:12]1[C:13]([Cl:15])=[CH:14][C:8]2[S:2][C:1]([SH:3])=[N:10][C:9]=2[CH:11]=1
Reactant: Nc1cc(Cl)c(Cl)cc1Cl
Reactant: S=C=S
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Sc1nc2cc(Cl)c(Cl)cc2s1
Temperature: 115 °C
Yield: 88.2 %

Procedure:
To a suspension of CS2 (0.64 mL, 10.6 mmol) and sodium methylate (0.55 g, 10.2 mmol) in DMF (10 mL) was added 2,4,5-trichloroaniline (7, 1.00 g, 5.09 mmol) in DMF (5 mL) under N2. The reaction mixture was heated at 110-120° C. for 16 h. After cooling, the reaction mixture was diluted with water (30 mL) and acidified with 1N HCl. The precipitate was collected by filtration, washed with water, and dried over P2O5 under vacuum to give yield compound 8 (1.06 g). This crude material was used in subsequent reactions without further purification.
Reaction SMILES: O.O.[Sn](Cl)Cl.[N:6]1([C:12]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:13]=2[C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C(O)C>CCOC(C)=O>[NH2:24][C:21]1[CH:22]=[CH:23][C:12]([N:6]2[CH2:7][CH2:8][O:9][CH2:10][CH2:11]2)=[C:13]([CH:20]=1)[C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15]
Reactant: C=CCOC(=O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: C=CCOC(=O)c1cc(N)ccc1N1CCOCC1
Yield: 53.7 %

Procedure:
Tin(II) chloride dihydrate (17.37 g, 77 mmol) was added to a solution of allyl 2-morpholin-4-yl-5-nitrobenzoate (11.24 g, 38.5 mmol) in EtOAc (250 mL) and the mixture was stirred and heated under reflux for 4 h. Ethanol (150 mL) was added, followed by another portion of Tin(II) chloride dihydrate (17.4 g) and the mixture was heated for another 2 h. The mixture was cooled and filtered then the filtrate was washed repeatedly with aqueous ammonium hydroxide and re-filtered. The organic layer was dried and concentrated by evaporation to give the title compound (Intermediate 76, 5.42 g, 54%) as a solid; 1H NMR δ 6.90 (1H, d), 6.80 (1H, s), 6.70 (1H, d), 6.10-5.95 (1H, m), 5.40 (1H, d), 5.30 (1H, d), 5.00 (2H, s), 4.80 (2H, s), 3.70-3.60 (4H, m), 3.20-3.10 (4H, m); MS m/e MH+ 263.