Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C@@:5]2([CH2:9][CH2:8][NH:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=3)[C:17]2=[O:27])=[CH:12][CH:11]=1.Br[CH2:29][CH2:30][CH2:31][F:32].C(=O)([O-])O.[Na+].CN1C(=O)CCC1>O.C(OCC)(=O)C>[F:32][CH2:31][CH2:30][CH2:29][N:7]1[CH2:8][CH2:9][C@@:5]2([CH2:1][N:2]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:25][CH2:24][C:23]5[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=5)[C:17]4=[O:27])=[CH:12][CH:11]=3)[CH2:3][CH2:4]2)[CH2:6]1
Reactant: FCCCBr
Reactant: O=C1c2ccc(O)cc2CCN1c1ccc(N2CC[C@]3(CCNC3)C2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1c2ccc(O)cc2CCN1c1ccc(N2CC[C@]3(CCN(CCCF)C3)C2)cc1
Temperature: 50 °C

Procedure:
A mixture of 2-[(S)-4-(2,7-diaza-spiro[4.4]non-2-yl)-phenyl]-6-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (0.20 g), 1-bromo-3-fluoro-propane (76 mg), sodium hydrogencarbonate (10 mg) and NMP (5 mL) was heated at 50° C. for 15 hours. The reaction mixture was distributed between ethyl acetate and water. The organic phase was dried over magnesium sulfate and concentrated. The raw product was purified by preparative HPLC. In this way the product was obtained with molecular weight 423.54 (C25H30FN3O2); MS (ESI): 424 (M+H+).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:23]=[CH:22][C:7]([CH2:8][CH:9]2[CH2:14][CH2:13][CH:12]([NH:15][C@H:16]3[C@H:20]([NH2:21])[CH2:19][O:18][CH2:17]3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:31]([C:34]1[CH:35]=[C:36]([N:40]=[C:41]=[O:42])[CH:37]=[CH:38][CH:39]=1)(=[O:33])[CH3:32]>ClCCl>[C:31]([C:34]1[CH:35]=[C:36]([NH:40][C:41]([NH:21][C@H:20]2[C@H:16]([NH:15][CH:12]3[CH2:11][CH2:10][CH:9]([CH2:8][C:7]4[CH:6]=[CH:5][C:4]([F:3])=[CH:23][CH:22]=4)[CH2:14][CH2:13]3)[CH2:17][O:18][CH2:19]2)=[O:42])[CH:37]=[CH:38][CH:39]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)c1cccc(N=C=O)c1
Reactant: N[C@@H]1COC[C@H]1NC1CCC(Cc2ccc(F)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cccc(NC(=O)N[C@@H]2COC[C@H]2NC2CCC(Cc3ccc(F)cc3)CC2)c1
Yield: 66.1 %

Procedure:
To a stirring solution of (3S,4S)-N3-[4-(4-fluorobenzyl)cyclohexyl]tetrahydro-3,4-furandiamine dihydrochloride (20 mg, 0.055 mmol) and triethylamine (100 μL, 0.72 mmol) in dichloromethane (1 mL) was added 3-acetylphenyl isocyanate (7.1 mg, 0.050 mmol). The resulting solution was immediately concentrated, and the resulting residue was purified by flash column chromatography (100% ethyl acetate then 5% triethylamine in ethyl acetate then 10% methanol in ethylacetate containing 5% triethylamine) to yield the desired urea (15 mg, 60%) as an oily white solid. MS (ESI) 454 (M+H).
Reaction SMILES: Cl.[CH2:2]([C:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:8][C:7]=2[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]=1)[CH3:3].Cl.Br[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:2]([C:4]1[C:12]2[C:7](=[N:8][C:9]([CH:14]3[CH2:15][CH2:16][N:17]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:18][CH2:19]3)=[N:10][C:11]=2[OH:13])[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]=1)[CH3:3]
Reactant: Brc1ccncc1
Reactant: CCc1nn(-c2ccccc2)c2nc(C3CCNCC3)[nH]c(=O)c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1nn(-c2ccccc2)c2nc(C3CCN(c4ccncc4)CC3)nc(O)c12
Temperature: 130 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-ethyl-1-phenyl-6-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one hydrochloride (200 mg, 0.56 mmol, 1.00 equiv) in N,N-dimethylformamide (40 mL) at room temperature. To the resulting mixture was then added 4-bromopyridine hydrochloride (131 mg, 0.68 mmol, 1.10 equiv), in portions at room temperature, followed by triethylamine (188 mg, 1.86 mmol, 3.00 equiv), in portions at room temperature. The resulting solution was stirred overnight at 130° C. The resulting mixture was concentrated under vacuum. The resulting residue (150 mg) was purified by Prep-HPLC with the following conditions (Gilson Pre-HPLC): Column, SHISEIDO, CAPCELL PAK C18, 20 mm ID*250 mm, 5 u; mobile phase, methanol/H2O; Detector, UV 254 nm, to yield 3-ethyl-1-phenyl-6-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[CH:21][C:20]([CH2:23][C:24]([NH2:26])=[O:25])=[C:19]([NH:27][CH2:28][C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=4)[CH:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].O.[CH3:44][NH2:45].C(O)C>>[F:35][C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([F:36])[CH:32]=1)[CH2:28][NH:27][C:19]1[CH:18]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:45][CH3:44])[CH2:5][CH2:6]3)=[CH:15][CH:14]=2)[N:22]=[CH:21][C:20]=1[CH2:23][C:24]([NH2:26])=[O:25]
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCN(CCCl)CC3)cc2)cc1NCc1cc(F)cc(F)c1
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CNCCN1CCN(c2ccc(Nc3cc(NCc4cc(F)cc(F)c4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
42 mg of 6-({4-[4-(2-chloroethyl)piperazin-1-yl]phenyl}amino)-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide (the compound of Example 250) was dissolved in a 30% methylamine-ethanol solution, to which 23 mg of potassium carbonate was added, and stirred at 80° C. for 8 hours. After cooling, water was added to the reaction mixture, extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel thin layer chromatography (chloroform:ammonia methanol=10:1), and crystallized by adding ether to obtain 8 mg (15%) of the title compound as a slight yellow solid.
Reaction SMILES: Cl[CH:2]([F:12])[C:3](=O)[C:4](=[N:9][OH:10])[C:5]([O:7][CH3:8])=[O:6].[NH2:13][C:14]([NH2:16])=[S:15].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CN(C)C(=O)C.O>[NH2:16][C:14]1[S:15][C:2]([F:12])=[C:3](/[C:4](=[N:9]/[OH:10])/[C:5]([O:7][CH3:8])=[O:6])[N:13]=1
Reactant: NC(N)=S
Reactant: COC(=O)C(=NO)C(=O)C(F)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)/C(=N\O)c1nc(N)sc1F
Temperature: 300 °C
Reaction time: 12 h
Yield: 25.1 %

Procedure:
To a solution of methyl 4-chloro-4-fluoro-2-(hydroxyimino)-3-oxobutyrate (7.8 g) in N,N-dimethylacetamide (80 ml) was added thiourea (15 g) under stirring at 300° C. and then the stirring was continued for 12 hours at the same temperature. The resulting solution was powered into a mixture of ethyl acetate (300 ml) and water (400 ml), and adjusted to pH 3.0 with saturated aqueous sodium hydrogencarbonate. The separated organic phase was washed with water (400 ml), and brine (400 ml), and dried with magnesium sulfate and evaporated in vacuo to give methyl 2-(2-amino-5-fluorothiazol-4-yl)-2-(Z)-(hydroxyimino)acetate (2.17 g).
Reaction SMILES: [OH:1][C:2]1([C:15](O)=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[CH2:43]([O:50][C:51](=[O:57])[C@@H:52]1[CH2:56][CH2:55][CH2:54][NH:53]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:43]([O:50][C:51](=[O:57])[C@@H:52]1[CH2:56][CH2:55][CH2:54][N:53]1[C:15]([C:2]1([OH:1])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:16])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: O=C(O)C1(O)c2ccccc2-c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 9-hydroxy-9-fluorene carboxylic acid (5.04 g, 22.3 mmol) in N,N-dimethylformamide (30 mL), cooled to 0° C. under nitrogen, was added (O-7-azabenzotriazol-1-y)-1,1,3,3-tetramethyluronium hexafluorophosphate, (9.32 g, 24.5 mmol), L-proline benzyl ester hydrochloride (5.93 g, 24.5 mmol), and N,N-diisopropylethylamine (8.5 mL, 48.8 mmol). The mixture was stirred at 0° C. for 3 hours, then concentrated and purified on silica gel (ethyl acetate-hexane, 1:2) to give 9-hydroxy-9-fluorenylcarbonyl-L-proline benzyl ester. HPLC=96%, R.T.=3.7 min, method A; M+1=414.1.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([Cl:7])[C:3]=1[Cl:8].[F:9][C:10]([F:17])([F:16])[S:11]([O:14]C)(=[O:13])=[O:12]>CCOCC>[F:9][C:10]([F:17])([F:16])[S:11]([O-:14])(=[O:13])=[O:12].[CH3:10][N+:5]1[S:6][C:2]([Cl:1])=[C:3]([Cl:8])[C:4]=1[Cl:7]
Reactant: Clc1nsc(Cl)c1Cl
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: CCOCC
Product: C[n+]1sc(Cl)c(Cl)c1Cl
Product: O=S(=O)([O-])C(F)(F)F
Yield: 26 %

Procedure:
Trichloroisothiazole (9.4 g, 0.05 mol) and 9 ml of methyl trifluoromethane sulfonate were heated at 65° for 30 min. After cooling, ether (150 ml) was added and the solid collected to yield 4.6 g (26%) of product, mp 118-120. Spectral data (NMR & IR) were consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[N:15]=[C:5]2[C:6](Br)=[CH:7][CH:8]=[C:9]([C:10]([OH:13])([CH3:12])[CH3:11])[N:4]2[N:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O1CCOCC1.O>[NH2:1][C:2]1[N:15]=[C:5]2[C:6]([C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=3)=[CH:7][CH:8]=[C:9]([C:10]([OH:13])([CH3:12])[CH3:11])[N:4]2[N:3]=1
Reactant: CC(C)(O)c1ccc(Br)c2nc(N)nn12
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(O)c1ccc(-c2ccc(Cl)cc2)c2nc(N)nn12
Temperature: 25 °C

Procedure:
To a solution of 2-(2-amino-8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-propan-2-ol (contaminated with ketone) (120 mg, 0.443 mmol) and 4-chlorophenyl boronic acid (155 mg, 0.987 mmol) in dioxane (6 mL) was added aqueous solution of Na2CO3 (2 M, 0.72 mL) and degassed with argon for 5 minute. To this was added PdCl2 (dppf)2.CH2Cl2 (30.34 mg, 0.04 mmol) and stirred at 90° C. for 90 minutes. The reaction mixture was cooled to room temperature and water (20 mL) was added. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue was purified by silica gel chromatography using ethyl acetate/hexane as eluent. The title compound was obtained as an off white solid (65 mg, 48%) which was contaminated with 1-[2-amino-8-(4-chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-ethanone.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([CH2:14][CH3:15])([F:13])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[H-].[Na+].[CH3:24]I>CC(N(C)C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:24])[C:10](=[O:12])[C:9]([CH2:14][CH3:15])([F:13])[CH2:8][N:7]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[C:6]=2[N:21]=1
Reactant: CI
Reactant: CCC1(F)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCC1(F)CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a solution of 2-chloro-9-cyclopentyl-7-ethyl-7-fluoro-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (890 mg, 2.85 mmol) in 10 mL of DMA was added sodium hydride (60% dispersion in mineral oil, 116 mg, 2.9 mmol) at 0° C., followed by the dropwise addition of methyl iodide (0.18 mL, 2.9 mmol). The reaction mixture was warmed up to rt and stirred for 1 h. The whole was poured into ice-water, extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4. The solution was concentrated in vacuo followed by precipitation from ether/EtOA to afford the product (750 mg, 80% yield) as light tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.90 (t, J=7.3 Hz, 3H) 1.55-1.98 (m, 10H) 3.28 (s, 3H) 3.70-3.93 (m, 2H) 4.74 (t, J=7.9 Hz, 1H) 8.25 (s, 1H). [M+H] calc'd for C15H20ClFN4O, 327. found 327.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:48][C:49]1[CH:111]=[CH:110][C:52]([C:53]([NH:55][C:56]2[CH:57]=[C:58]3[C:63](=[CH:64][CH:65]=2)[N:62]=[C:61]([N:66]2[CH2:71][C@@H:70]([NH:72][C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH2:69][C@@H:68]([NH:80][C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[CH2:67]2)[C:60]([N:88]2[CH2:93][C@@H:92]([NH:94][C:95]([O:97][C:98]([CH3:101])([CH3:100])[CH3:99])=[O:96])[CH2:91][C@@H:90]([NH:102][C:103]([O:105][C:106]([CH3:109])([CH3:108])[CH3:107])=[O:104])[CH2:89]2)=[N:59]3)=[O:54])=[CH:51][CH:50]=1>CN(C=O)C.CCOC(C)=O>[C:76]([O:75][C:73]([NH:72][C@@H:70]1[CH2:69][C@H:68]([NH:80][C:81]([O:83][C:84]([CH3:85])([CH3:86])[CH3:87])=[O:82])[CH2:67][N:66]([C:61]2[C:60]([N:88]3[CH2:93][C@@H:92]([NH:94][C:95]([O:97][C:98]([CH3:101])([CH3:100])[CH3:99])=[O:96])[CH2:91][C@@H:90]([NH:102][C:103]([O:105][C:106]([CH3:108])([CH3:107])[CH3:109])=[O:104])[CH2:89]3)=[N:59][C:58]3[C:63](=[CH:64][CH:65]=[C:56]([NH:55][C:53]([C:52]4[CH:110]=[CH:111][C:49]([NH:48][C:12]([C:3]5[CH:4]=[CH:5][C:6]6[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=6)[C:2]=5[OH:1])=[O:14])=[CH:50][CH:51]=4)=[O:54])[CH:57]=3)[N:62]=2)[CH2:71]1)=[O:74])([CH3:77])([CH3:78])[CH3:79]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc3ccc(NC(=O)c4ccc(N)cc4)cc3nc2N2C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C2)C1
Reactant: O=C(O)c1ccc2ccccc2c1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc3ccc(NC(=O)c4ccc(NC(=O)c5ccc6ccccc6c5O)cc4)cc3nc2N2C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C2)C1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 12.5 %

Procedure:
1-Hydroxy-naphthalene-2-carboxylic acid (142) (0.016 g, 0.085 mmol) was dissolved in DMF (0.8 mL) and HBTU (0.032 g, 0.085 mmol) followed by iPr2EtN (0.022 mL, 0.128 mmol) were added. The mixture was shaken at room temperature for 25 minutes. 4-Amino-N-(2,3-bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-quinoxalin-6-yl)-benzamide (252) (0.06 g, 0.068 mmol) was added and the mixture was shaken at room temperature for 16 h. The mixture was diluted with EtOAc, washed with sodium bicarbonate and brine via extraction, dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of hexane and EtOAc gave the desired product (253) (0.009 g, 0.0085 mmol, 12.5% yield). LC-MS (ESI): (exact mass: 1060.54, mol. wt: 1061.23) m/e=1062.0 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[O:14][CH2:15][C:16]([CH3:18])([CH3:17])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:21])[C:5]([C:19]#[N:20])=[CH:6]3.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][CH2:30][NH2:31]>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:31][CH2:30][CH2:29][CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)[C:9]2[O:14][CH2:15][C:16]([CH3:18])([CH3:17])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:21])[C:5]([C:19]#[N:20])=[CH:6]3
Reactant: NCCCc1ccccn1
Reactant: CC1(C)COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Solvent: CS(C)=O
Product: CC1(C)COc2c(NCCCc3ccccn3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 120 °C
Yield: 29.1 %

Procedure:
To a solution of 12 (250 mg, 0.86 mmol) in 4 ml of DMSO, 268 mg (1.98 mmol) of 3-(pyridin-2-yl)propan-1-amine were added. The reaction mixture was heated to 120° C. for 5 h. After cooling, the reaction mixture was freeze dried to remove DMSO and the remaining solid was purified by preparative HPLC to give the title compound as a yellow solid (102 mg, 29% yield).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH3:6][O:7][CH:8](OC)[CH2:9][CH:10](OC)OC.C(OC(=O)C)(=O)C>>[CH3:6][O:7][CH:8]=[CH:9][CH:10]=[C:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#CCC#N
Reactant: COC(CC(OC)OC)OC
Solvent: CC(=O)OC(C)=O
Product: COC=CC=C(C#N)C#N

Procedure:
A solution of 2.0 g. (31 m moles) of malononitrile and 5 g. (31 m moles) of 1,1,3,3-tetramethoxypropane in 12 ml. of acetic anhydride is heated to reflux for 24 hrs. The reaction mixture is distilled separating the lower boiling by-products and solvent from the product. The product fraction is diluted with water and the resulting precipitate is filtered and recrystallized from isopropanol-water, 1.0 g., m.p. 74°-76° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[N:29]([CH3:30])[CH:28]=[N:27][CH:26]=3)=[O:24])[CH:21]=2)[N:16]=[C:15]([O:31][CH3:32])[C:14]=1[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1>C1COCC1>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[N:29]([CH3:30])[CH:28]=[N:27][CH:26]=3)([C:2]3[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([O:31][CH3:32])[C:14]=1[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([S:40]([CH3:43])(=[O:41])=[O:42])=[CH:38][CH:39]=1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: COc1nc2ccc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1ccc(S(C)(=O)=O)cc1
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Isopropyl magnesium chloride LiCl complex (1.3 M in THF, 0.7 mL, 0.904 mmol) was added dropwise to a solution of 5-bromo-2-(trifluoromethyl)pyridine (0.2 g, 0.904 mmol) in dry THF 5 mL) at 0° C. The mixture was stirred at 0° C. for five minutes then at room temperature for 30 minutes. A suspension of (4-chloro-2-methoxy-3-(4-(methylsulfonyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (0.085 g, 0.181 mmol, Intermediate 38: step b) in THF (5 mL) was added rapidly at 0° C. and the reaction mixture was stirred and allowed to warm to room temperature. The homogeneous amber solution was stirred at room temperature for 4 hours, then heated at 45° C. for 12 hours. Once cooled the reaction mixture was quenched with saturated aqueous NH4Cl, diluted with H2O and extracted with EtOAc (2×). The EtOAc extracts were washed with brine, dried (Na2SO4), filtered, evaporated in vacuo and chromatographed (DCM/MeOH) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.80 (s, 1H), 8.15 (d, J=2.0 Hz, 1H), 7.87-8.00 (m, 1H), 7.78-7.87 (m, 3H), 7.65 (d, J=8.1 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.46 (d, J=8.6 Hz, 2H), 7.32 (s, 1H), 6.33 (s, 1H), 5.30 (s, 1H), 4.37 (s, 2H), 4.08 (s, 3H), 3.36 (s, 3H), 3.01 (s, 3H); MS (ESI) 617.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:22][CH3:23])[C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][CH3:21])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].Br[CH2:25][CH2:26][O:27][CH3:28].C([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:22][CH3:23])[C@H:14]2[CH2:19][CH2:18][C@H:17]([N:20]([CH2:25][CH2:26][O:27][CH3:28])[CH3:21])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COCCBr
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)[C@H]1CC[C@H](NC)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)CCOC)CC1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a stirred solution of crude methyl 5-bromo-3-(ethyl((trans)-4-(methylamino)cyclohexyl)amino)-2-methylbenzoate (25 g, 65.44 mmol), 1-bromo-2-methoxyethane (18.19 g, 130.8 mmol) in acetonitrile (250 mL), K2CO3 (18.06 g, 130.8 mmol) and KI (6.51 g, 39.21 mmol) were added. The resulting reaction mass was stirred at 65° C. for 16 h. On completion, reaction mixture was diluted with water (300 mL) and extracted with DCM (500 mL×3). The combined organic layers were washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to afford the title compound (20 g, 69.3% yield).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])=[CH:10][CH:9]=2)[N:6]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CS(O)(=O)=O>C(O)CCC>[C:16]1([S:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][C:5]3[N:6]=[C:2]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[S:3][CH:4]=3)=[CH:9][CH:10]=2)=[O:15])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(c1ccccc1)c1ccc(Cc2csc(Br)n2)cc1
Reactant: C1CNCCN1
Agent: CS(=O)(=O)O
Solvent: CCCCO
Product: O=S(c1ccccc1)c1ccc(Cc2csc(N3CCNCC3)n2)cc1
Yield: 94 %

Procedure:
A solution of 6.4 g of 2-bromo-4-(4-phenylsulfinylbenzyl)thiazole (M. P. Kofler: 102° C.) and 6.5 g of anhydrous piperazine in 200 ml of butanol was refluxed for ten hours. Then, the solvent was evaporated and the thus obtained raw oil was taken off with 200 ml of a N solution of CH3SO3H. The insoluble matter was extracted twice with, each time, 20 ml of ether, then alkalized with K2CO3. The thus salted out oil was extracted twice with, each time, 50 ml of chloroform. The chloroform solution was washed with water, dried and evaporated. There was obtained 6.1 g of 1-[4-(4-phenylsulfinylbenzyl)-2-thiazolyl]piperazine, as semicrystallized product.
Reaction SMILES: O[CH:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:5](=[O:19])[N:4]([C:20]2[CH2:21][O:22][C:23](=[O:25])[CH:24]=2)[CH:3]1[CH3:26].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:51]I>C1(C)C=CC=CC=1>[I:51][CH:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:5](=[O:19])[N:4]([C:20]2[CH2:21][O:22][C:23](=[O:25])[CH:24]=2)[CH:3]1[CH3:26]
Reactant: CC1C(O)C2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1C1=CC(=O)OC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC1C(I)C2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1C1=CC(=O)OC1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
To a solution of the compound of step C (370 mg, 1.01 mmol) in toluene (20 mL) at rt was added PPh3 (397 mg, 1.515 mmol), imidazole (137 mg, 2.02 mmol), and I2 (384 mg, 1.515 mmol). The mixture was stirred for 10 h at 100° C., and quenched with NaHCO3 aqueous solution. The organic layer was diluted with DCM, separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried (MgSO4) and purified by column chromatography (0-100% EtOAc/hex) to give the title compound. LC/MS: [(M+1−56)]+=421
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([O:12][C:13]1[CH:29]=[CH:28][C:16]2[NH:17][C:18]([NH:20]C(OC(C)(C)C)=O)=[N:19][C:15]=2[CH:14]=1)(=[O:11])=[O:10].FC(F)(F)C(O)=O>ClCCl.CCCCC>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:9]([O:12][C:13]1[CH:29]=[CH:28][C:16]2[NH:17][C:18]([NH2:20])=[N:19][C:15]=2[CH:14]=1)(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)Nc1nc2cc(OS(=O)(=O)c3c(Cl)cccc3Cl)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCC
Solvent: ClCCl
Product: Nc1nc2cc(OS(=O)(=O)c3c(Cl)cccc3Cl)ccc2[nH]1
Reaction time: 24 h
Yield: 40.9 %

Procedure:
To a solution of 250 mg of 2-[(tert-butoxycarbonyl)amino]-1H-benzimidazol-5-yl 2,6-dichlorobenzenesulfonate in 20 cm3 of dichloromethane are added 746 mg of trifluoroacetic acid. After stirring overnight at a temperature in the region of 20° C., 746 mg of trifluoroacetic acid are added. After stirring for 24 hours, the reaction medium is concentrated to dryness under reduced pressure (2 kPa) and then taken up in 40 cm3 of saturated aqueous sodium hydrogen carbonate solution. The aqueous phase is extracted with five times 60 cm3 of dichloromethane and the combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa). After flash chromatography on a column of silica [eluent: dichloromethane/methanol (90/10 by volume)], the resin obtained is solidified in 5 cm3 of pentane and the solid obtained is filtered off by suction and then washed with three times 2 cm3 of pentane and dried under reduced pressure over phosphorus pentoxide. 80 mg of 2-amino-1H-benzimidazol-5-yl 2,6-dichlorobenzenesulfonate are obtained in the form of a beige-coloured powder, the characteristics of which are as follows: