Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[CH3:10][CH:11]1[CH2:16][NH:15][CH:14]([CH3:17])[CH2:13][NH:12]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:12]2[CH2:13][CH:14]([CH3:17])[NH:15][CH2:16][CH:11]2[CH3:10])=[CH:4][CH:3]=1
Reactant: CC1CNC(C)CN1
Reactant: ClCc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: CC1CN(Cc2ccc(Cl)cc2)C(C)CN1

Procedure:
Was synthesized in the same way as A) from 1-chloro-4-chloromethyl-benzene (1.27 g, 7.89 mmol) and 2,5-dimethyl-piperazine (11.0 g, 8.77 mmol) in DMF. Yield 701 mg, 37%
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH3:11][O:12][C:13]1[CH:46]=[CH:45][C:16]([CH2:17][S:18][C@@H:19]2[CH2:23][N:22]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)=[O:25])[C@H:21]([C:37]([NH:39][C@H:40]3[CH2:44][CH2:43][NH:42][CH2:41]3)=[O:38])[CH2:20]2)=[CH:15][CH:14]=1.Cl[C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=1)=[O:49]>CN(C)C1C=CN=CC=1.C(#N)C>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][S:18][C@@H:19]2[CH2:23][N:22]([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=3)=[O:25])[C@H:21]([C:37]([NH:39][C@H:40]3[CH2:44][CH2:43][N:42]([C:48]([O:50][CH2:51][C:52]4[CH:53]=[CH:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][CH:57]=4)=[O:49])[CH2:41]3)=[O:38])[CH2:20]2)=[CH:45][CH:46]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N[C@H]3CCNC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N[C@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
230 mg of diisopropylethylamine were added to a suspension of 1.0 g of (2S,4S)-4-(4-methoxybenzylthio)-2-[(3S)-pyrrolidin-3-ylaminocarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine hydrochloride [prepared as described in step (ii) above] and 240 mg of 4-dimethylaminopyridine in 10 ml of dry acetonitrile, and the resulting mixture was cooled to 0° C. A solution of 430 mg of 4-nitrobenzyl chloroformate in 4 ml of dry acetonitrile was then added to the mixture. The mixture was then stirred at room temperature for 3 hours, after which a solution of 117 mg of 4-nitrobenzyl chloroformate in 2 ml of dry acetonitrile was added and the mixture was stirred at the same temperature for 1 hour. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the residue was diluted with 50 ml of methylene chloride. The diluted solution was washed with a saturated aqueous solution of sodium chloride. The aqueous washings were extracted with methylene chloride. The organic extract and the methylene chloride solution were combined and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 4:1 by volume mixture of methylene chloride and acetonitrile as the eluent, to give 862 mg of the title compound as a powder.
Reaction SMILES: COC1C=CC(CN(CC2C=CC(OC)=CC=2)C2N=CC(C3C4CCNC=4N=C(N4CCOCC4)N=3)=CN=2)=CC=1.NC1C(C)=C(C(N2CCN(C)CC2)=O)C=CC=1.CN1CCNCC1.CC1C=CC(N2CCOCC2)=CC=1N.[CH3:79][C:80]1[C:85]([C:86]([N:88]2[CH2:93][CH2:92][N:91]([CH3:94])[CH2:90][CH2:89]2)=[O:87])=[CH:84][CH:83]=[CH:82][C:81]=1[NH:95][C:96]([N:98]1[C:102]2[N:103]=[C:104]([N:132]3[CH2:137][CH2:136][O:135][CH2:134][CH2:133]3)[N:105]=[C:106]([C:107]3[CH:108]=[N:109][C:110]([N:113](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)=[N:111][CH:112]=3)[C:101]=2[CH2:100][CH2:99]1)=[O:97]>>[CH3:79][C:80]1[C:85]([C:86]([N:88]2[CH2:93][CH2:92][N:91]([CH3:94])[CH2:90][CH2:89]2)=[O:87])=[CH:84][CH:83]=[CH:82][C:81]=1[NH:95][C:96]([N:98]1[C:102]2[N:103]=[C:104]([N:132]3[CH2:137][CH2:136][O:135][CH2:134][CH2:133]3)[N:105]=[C:106]([C:107]3[CH:108]=[N:109][C:110]([NH2:113])=[N:111][CH:112]=3)[C:101]=2[CH2:100][CH2:99]1)=[O:97]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)Nc3cccc(C(=O)N4CCN(C)CC4)c3C)cn2)cc1
Agent: CN1CCNCC1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: Cc1c(N)cccc1C(=O)N1CCN(C)CC1
Product: Cc1c(NC(=O)N2CCc3c(-c4cnc(N)nc4)nc(N4CCOCC4)nc32)cccc1C(=O)N1CCN(C)CC1
Yield: 29 %

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (150 mg), and (3-amino-2-methyl-phenyl)-(4-methyl-piperazin-1-yl)-methanone (71 mg) obtained using 1-methyl-piperazine instead of morpholine in the same manner as Step A and Step B in Example 1-D-243, instead of 2-methyl-5-morpholin-4-yl-phenylamine, in the same manner as Step C in Example 1-D-237, 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [2-methyl-3-(4-methyl-piperazine-1-carbonyl)-phenyl]-amide was obtained as a crude product. The PMB groups were removed according to Deprotection method 2, to obtain the desired compound (D-244) (45 mg, 29%).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]#[N:4].[C:18]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:19][C:20]([CH3:22])=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:3]([CH:2]([NH:1]/[C:20](/[CH3:22])=[CH:19]/[C:18]([O:24][CH2:25][CH3:26])=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:4]
Reactant: N#CC(N)c1ccccc1Oc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C(\C)NC(C#N)c1ccccc1Oc1ccccc1
Temperature: 0 °C
Yield: 98.5 %

Procedure:
A mixture of Example 85a (1.063 g, 4.74 mmol), ethyl acetoacetate (0.602 mL, 4.74 mmol), and p-toluenesulfonic acid (0.05 g, 0.263 mmol) in toluene (10 mL) was heated at 80° C. for 4 hours. The reaction mixture was cooled to 0° C. and added to cold saturated NaHCO3. The mixture was extracted with ethyl acetate (2×). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (1.57 g, 98% yield) which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:4][CH:3]=1.[N:34]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1.C(N(CC)CC)C>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][N:24]([S:39]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)(=[O:41])=[O:40])[CH2:25][CH2:26]2)=[CH:32][CH:31]=1
Reactant: O=S(=O)(Cl)N1CCCC1
Reactant: Oc1cc(NC2CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(N1CCCC1)N1CCC(Nc2cc(O)nc3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 8-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4-[(piperidin-4-yl)amino]quinolin-2-ol (70 mg, 0.15 mmol, 1.00 equip), dichloromethane (3 mL), pyrrolidine-1-sulfonyl chloride (37.2 mg, 0.22 mmol, 1.50 equip), and triethylamine (44.6 mg, 0.44 mmol, 3.01 equip). The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 6-[bis(4-chlorophenyl)methyl]-4-[[1-(pyrrolidine-1-sulfonyl)piperidin-4-yl]amino]quinolin-2-ol as an off-white solid.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].[NH2:21][CH:22]1[C:42](=[O:43])[N:24]2[C:25]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])=[CH:26][CH2:27][S:28][C@H:23]12.CN(C)C=O.P(Cl)(Cl)(Cl)=O>O.O1CCCC1>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]([NH:21][CH:22]2[C:42](=[O:43])[N:24]3[C:25]([C:29]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=4)=[O:30])=[CH:26][CH2:27][S:28][C@H:23]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: CCOC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(NC=O)n1
Yield: 90.9 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetic acid (syn isomer, 1.35 g.), 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (1.54 g.), N,N-dimethylformamide (393 mg.), phosphoryl chloride (825 mg.), tetrahydrofuran (21.2 ml.), acet(3.9 ml.) and water (3.9 ml.) were treated in a similar manner to that of Example 15-(1) to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer 2.52 g.).
Reaction SMILES: [O:1]=[C:2]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][C:26]2=[O:35])[CH2:21][CH2:20]1)[CH2:3][CH:4]([CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:5](O)=[O:6].[N:36]1([CH2:48][C:49]([O:51][CH3:52])=[O:50])[CH2:41][CH2:40][CH:39]([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:38][CH2:37]1>>[O:1]=[C:2]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][C:26]2=[O:35])[CH2:23][CH2:24]1)[CH2:3][CH:4]([CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:5]([N:45]1[CH2:46][CH2:47][CH:42]([CH:39]2[CH2:40][CH2:41][N:36]([CH2:48][C:49]([O:51][CH3:52])=[O:50])[CH2:37][CH2:38]2)[CH2:43][CH2:44]1)=[O:6]
Reactant: O=C(O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)Cc1ccc2c(c1)CCCC2
Reactant: COC(=O)CN1CCC(C2CCNCC2)CC1
Product: COC(=O)CN1CCC(C2CCN(C(=O)C(CC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)Cc3ccc4c(c3)CCCC4)CC2)CC1

Procedure:
Prepared analogously to Example 76e) from 4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-2-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-butanoic acid and methyl [4,4′]bipiperidinyl-1-yl-acetate.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[C:6]1[CH:10]=[CH:9][S:8][CH:7]=1.[C:21]([CH2:23][NH:24][C:25](=[O:32])[C@@H:26]([OH:31])[CH2:27][CH:28]([CH3:30])[CH3:29])#[N:22].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.O>ClCCl>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([CH:5]([C:6]2[CH:10]=[CH:9][S:8][CH:7]=2)[O:31][C@@H:26]([CH2:27][CH:28]([CH3:29])[CH3:30])[C:25]([NH:24][CH2:23][C:21]#[N:22])=[O:32])=[CH:16][CH:15]=1
Reactant: CC(C)C[C@H](O)C(=O)NCC#N
Reactant: N=C(OC(c1ccc(Br)cc1)c1ccsc1)C(Cl)(Cl)Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: O
Solvent: ClCCl
Product: CC(C)C[C@H](OC(c1ccc(Br)cc1)c1ccsc1)C(=O)NCC#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-bromophenyl)(thien-3-yl)methyl 2,2,2-trichloroethanimidoate from step 2 (970 mg, 2.36 mmol) in dichloromethane (12 mL) was added (2S)-N-(cyanomethyl)-2-hydroxy-4-methylpentanamide (402 mg, 2.36 mmol) and camphorsulfonic acid (137 mg, 0.59 mmol). The reaction was stirred overnight at room temperature and the resulting mixture was poured into water. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried and evaporated and the crude residue was chromatographed on silica gel using 50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([I:17])=[C:12]([CH:16]=1)[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:18]([O:25][CH2:26][C@@H:27]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][NH:28]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>>[Si:18]([O:25][CH2:26][C@@H:27]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][N:28]1[C:13]([C:12]1[CH:16]=[C:8]([CH:9]=[CH:10][C:11]=1[I:17])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)c1ccc(I)c(C(=O)O)c1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1Cc2ccccc2CN1
Product: CC(C)(C)OC(=O)c1ccc(I)c(C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)c1
Yield: 53.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 223A, 5-(tert-butoxycarbonyl)-2-iodobenzoic acid (1.67 g, 4.81 mmol) and (S)-3-((tert-butyldimethylsilyloxy)methyl)-1,2,3,4-tetrahydroisoquinoline (1.6 g, 5.8 mmol) were converted to the title compound (1.57 g, 54%). MS(ESI+) m/z 608.1 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]1([C:20]2[O:24][C:23]([NH2:25])=[N:22][N:21]=2)[CH2:19][CH2:18]1>>[CH:17]1([C:20]2[O:24][C:23]([NH:25][C:8](=[O:9])[CH:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:22][N:21]=2)[CH2:19][CH2:18]1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: Nc1nnc(C2CC2)o1
Product: O=C(Nc1nnc(C2CC2)o1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 159-160° C. and MS: m/e=320.3 (M+H+) was prepared in accordance with the general method of example 44a from 2,2-diphenylacetic acid chloride and 5-cyclopropyl-[1,3,4]oxadiazol-2-ylamine.
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]([F:16])([F:15])[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]O>C1(C)C=CC=CC=1>[F:5][C:6]([F:16])([F:15])[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][Br:2]
Reactant: OCc1ccccc1C(F)(F)F
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccccc1CBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 30 ml of phosphorus tribromide in 60 ml of absolute toluene was added dropwise at 20°-30° C. to a solution of 14 g of o-trifluoromethylbenzyl alcohol in 80 ml of absolute toluene. Subsequently, the reaction mixture was stirred at room temperature for 2 hours, the toluene was distilled under reduced pressure, the residue was dissolved in methylene chloride, treated with water and the mixture was adjusted to pH 8.0 with potassium hydrogen carbonate. The aqueous phase was extracted three times with CH2Cl2 and the organic phases were washed twice with water and once with saturated NaCl solution, dried over Na2SO4 and evaporated under reduced pressure. o-Trifluoromethylbenzyl bromide was obtained as the residue.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][C:17]4[CH:18]=[C:19]([NH2:24])[C:20]([NH2:23])=[CH:21][CH:22]=4)=[N:14][N:15]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:25](O)=O>>[N:23]1[C:20]2[CH:21]=[CH:22][C:17]([CH2:16][C:13]3[N:11]4[N:12]=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH:8]=[CH:9][C:10]4=[N:15][N:14]=3)=[CH:18][C:19]=2[NH:24][CH:25]=1
Reactant: Nc1ccc(Cc2nnc3ccc(-c4ccccc4)nn23)cc1N
Reactant: O=CO
Product: c1ccc(-c2ccc3nnc(Cc4ccc5nc[nH]c5c4)n3n2)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
A suspension of 4-(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-benzene-1,2-diamine (20 mg, 0.063 mmol) in formic acid (0.5 mL) was stirred at 100° C. for 5 h. The reaction mixture was cooled to room temperature and filtered through a 0.45 micron filter. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC on Xbridge prep C18 column (5 microns, 19×150 mm) using a formic acid buffered gradient of acetonitrile in water to return the title compound as an off-white solid (15 mg, 0.046 mmol, 73% yield). Analytical data presented in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:30][CH2:31][CH3:32])=[N:25][C:26]([CH3:29])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:35][S:36]([CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:38])=[O:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:44]3[CH2:43][CH2:42][N:41]([CH2:40][CH2:39][S:36]([CH3:35])(=[O:37])=[O:38])[CH2:46][CH2:45]3)=[O:21])[C:10]([C:23]3[C:24]([O:30][CH2:31][CH3:32])=[N:25][C:26]([CH3:29])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1nc(C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Product: CCOc1nc(C)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 16) was reacted with 1-(2-methanesulfonyl-ethyl)piperazine dihydrochloride (example 3) to give cis-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C30H34N6O4SCl2 [(M+H)+] 645.1812, observed 645.1814.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].C(O)CO.CN(C)C=O.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[SH:48]>[Cu]I>[CH3:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[S:48][C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Reactant: COc1ccccc1S
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: OCCO
Solvent: CN(C)C=O
Product: COc1ccccc1Sc1ccc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nn12
Temperature: 120 °C

Procedure:
Into a sealed tube was added (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (0.320 g, 0.826 mmol), Sodium tert-butoxide (238 mg, 2.48 mmol), Copper(I) iodide (16 mg, 0.083 mmol), 1,2-Ethanediol (92.6 uL, 1.66 mmol), N,N-Dimethylformamide (12 mL, 150 mmol), and finally 2-Methoxy-benzenethiol (0.174 g, 1.24 mmol). The reaction was heated at 120° C. overnight. The reaction was partitioned with DCM and water. The organic was separated, washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 10% methanol). The collected fractions afforded [7-(2-Methoxy-phenylsulfanyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine an orange solid (9 mg, 2.5%). MP 171-172° C. LCMS (E/I+) 447.24 (M+H). NMR 1H (DSMO-d6)-9.27 (s, 1H), 8.97 (s, 1H), 7.35 (d, 2H, J=9.00 Hz), 7.08-7.20 (m, 2H), 6.97 (d, 1H, J=4.68 Hz), 6.92 (d, 1H, J=4.57 Hz), 6.75 (t, 1H, J=6.72 Hz), 6.68 (d, 2H, J=9.08 Hz), 6.36 (dd, 1H, JJ=1.40, 6.41 Hz), 3.91 (s, 3H), 3.01 (t, 4H, J=4.72 Hz), 2.43 (t, 4H, J=4.68 Hz), 2.21 (s, 3H).
Reaction SMILES: C(OC([CH:6]1[C:15](=[O:16])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Br:17])[O:7]1)=O)C.FC(F)(F)C(O)=O>CO.Cl.O>[Br:17][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[CH2:14][C:15](=[O:16])[CH2:6][O:7]2
Reactant: CCOC(=O)C1Oc2cccc(Br)c2CC1=O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: O=C1COc2cccc(Br)c2C1
Reaction time: 18 h
Yield: 52.9 %

Procedure:
A suspension of 2-ethoxycarbonyl-5-bromo-3-chromanone (300 mg, 1 mMol) in methanol (5 mL) and 10% hydrochloric acid (3 mL) was heated at reflux for 2 hours. All of the solid had not dissolved; therefore, trifluoroacetic acid (1 mL) was added, and heating was continued for 18 hours. The reaction mixture was diluted with water and extracted well with diethyl ether. The ether phases were combined, dried over sodium sulfate, and concentrated in vacuo to give a yellow glass. Purification by flash chromatography (1:1 hexane:ether) gave the title compound as a light yellow glass (120 mg, 53%).
Reaction SMILES: [N:1]1[NH:2][N:3]=[CH:4][CH:5]=1.N#N.Br[C:9]1[C:10]([C:16]#[N:17])=[N:11][CH:12]=[CH:13][C:14]=1[CH3:15].CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I.O>[CH3:15][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([C:16]#[N:17])[C:9]=1[N:2]1[N:3]=[CH:4][CH:5]=[N:1]1
Reactant: Cc1ccnc(C#N)c1Br
Reactant: c1cn[nH]n1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: N#N
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccnc(C#N)c1-n1nccn1
Temperature: 120 °C
Yield: 40.3 %

Procedure:
In a microwave vial was dissolved 2H-1,2,3-triazole (0.22 mL, 3.8 mmol) and CuI (26 mg) in DMF (4 mL). The reaction mixture was degassed with N2 and 3-bromo-4-methylpicolonitrile (300 mg, 1.5 mmol) was added followed by trans-N,N′-dimethyl-1,2-cyclohexanediamine (41 μL, 0.3 mmol) and Cs2CO3 (844 mg, 2.6 mmol). The reaction mixture was heated at 120° C. for 1 h in a microwave reactor. Then H2O was added and the mixture extracted with EtOAc. The combined organic layers were dried (MgSO4). Purification via silica gel chromatography (0-50% EtOAc in heptane) gave the title compound (112 mg, 27%). MS (ESI) mass calcd. for C9H7N5, 185.2; m/z found 186 [M+H]+.
Reaction SMILES: [CH2:1]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:38](Cl)([Cl:40])=[O:39]>C1(C)C=CC=CC=1>[CH2:20]([N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:38]([Cl:40])=[O:39])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: O=C(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)Cl
Temperature: 100 °C

Procedure:
Distearyl carbamoyl chloride was prepared by charging 2.1 kg of toluene into a flask and then simultaneously adding 1.8kg of melted distearyl amine and 0.5 kg of phosgene under agitation at 55°-60°C. The temperature was then raised to 100°C. The reaction was carried out under slight vacuum and reflux. When the conversion was almost 100%, corresponding to a yield of about 1.8 kg distearyl carbamoyl chloride, toluene and phosgene were evaporated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.O=[S:19](Cl)Cl>ClCCl>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[C:4]([CH:3]=1)=[N:10][S:19][N:9]=2
Reactant: O=S(Cl)Cl
Reactant: Nc1cc(F)c(F)cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1cc2nsnc2cc1F
Temperature: 25 °C
Yield: 58.1 %

Procedure:
To a solution of 4,5-difluorobenzene-1,2-diamine (2.0 g, 0.014 mol) and triethylamine (7.8 mL, 0.056 mol) in dichloromethane (80 mL) was added SOCl2 (4.04 mL, 0.055 mol) dropwise at room temperature. The resulting reaction mixture was heated to reflux overnight. The reaction mixture was then allowed to cool to room temperature, and quenched with water carefully. The resulting mixture was extracted with dichloromethane, dried over Na2SO4 and concentrated on a rotary evaporator to give a white solid as the crude compound. The crude product was purified by flash column chromatography (silica gel, hexanes) to afford 5,6-difluorobenzo[1,2,5]thiadiazole as a white crystalline solid (1.4 g, 58% yield). 1H NMR (CDCl3 500 MHz): δ: 7.76 (t, 2H, J=8.5 Hz). 13C NMR (CDCl3, 500 MHz): δ 154.94, 154.78, 152.86, 152.70, 150.89, 150.85, 150.81, 106.26, 106.21, 106.14, 106.09. Anal. calcd. for (C6H2F2N2S): C, 41.86; H, 1.17; N, 16.27. Found: C, 41.41; H, 1.22; H, 15.87. m.p: 64-65° C.