Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[N:8]=[C:9]3[N:19]([CH:20]=2)[CH2:18][CH2:17][O:16][C:15]2[C:10]3=[CH:11][CH:12]=[C:13]([C:21]3[CH:22]=[N:23][N:24]([CH3:32])[C:25]=3[CH:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[CH:14]=2)[N:4]([CH:33]([CH3:35])[CH3:34])[N:3]=1.Br[C:37]([CH3:44])([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39].O>CC#N>[CH3:43][C:37]([N:28]1[CH2:29][CH2:30][CH2:31][CH:26]([C:25]2[N:24]([CH3:32])[N:23]=[CH:22][C:21]=2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[C:9]2[N:19]([CH:20]=[C:7]([C:5]4[N:4]([CH:33]([CH3:35])[CH3:34])[N:3]=[C:2]([CH3:1])[N:6]=4)[N:8]=2)[CH2:18][CH2:17][O:16]3)[CH2:27]1)([CH3:44])[C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C)c4C4CCCNC4)cc2OCC3)n(C(C)C)n1
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(C)(C)N1CCCC(c2c(-c3ccc4c(c3)OCCn3cc(-c5nc(C)nn5C(C)C)nc3-4)cnn2C)C1
Temperature: 60 °C
Yield: 47 %

Procedure:
A mixture of 4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-12-[1-methyl-5-(piperidin-3-yl)-1H-pyrazol-4-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1 (14),2,4,10,12-pentaene (60 mg, 0.127 mmol), ethyl 2-bromo-2-methylpropanoate (247.65 mg, 1.27 mmol), Ag2O (294 mg, 1.27 mmol), H2O (0.1 ml) and CH3CN (1.5 ml) in a seal tube was heated at 60° C. for 8 h. The solid was filtered off and the filtrate was purified by Combiflash eluting with a 0-70% gradient of CH3CN in 0.3% NH4HCO3 to afford ethyl 2-methyl-2-[3-(1-methyl-4-{4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-12-yl}-1H-pyrazol-5-yl)piperidin-1-yl]propanoate (35 mg, 47% yield). LCMS (ESI) m/z: 589.3 [M+H+]
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[C:47]1([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[CH2:53][N:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.Br[C:67]1[CH:95]=[CH:94][C:70]([CH2:71][N:72]2[C:76]3[CH:77]=[C:78]([CH3:81])[CH:79]=[CH:80][C:75]=3[N:74]([CH2:82][CH2:83][CH2:84][O:85][C:86]3[CH:91]=[CH:90][C:89]([F:92])=[CH:88][CH:87]=3)[C:73]2=[NH:93])=[CH:69][CH:68]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:47]1([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[CH2:53][N:54]1[CH2:55][CH2:56][N:57]([C:67]2[CH:95]=[CH:94][C:70]([CH2:71][N:72]3[C:76]4[CH:77]=[C:78]([CH3:81])[CH:79]=[CH:80][C:75]=4[N:74]([CH2:82][CH2:83][CH2:84][O:85][C:86]4[CH:87]=[CH:88][C:89]([F:92])=[CH:90][CH:91]=4)[C:73]3=[NH:93])=[CH:69][CH:68]=2)[CH2:58][CH2:59]1
Reactant: Cc1ccc2c(c1)n(Cc1ccc(Br)cc1)c(=N)n2CCCOc1ccc(F)cc1
Reactant: c1ccc(-c2ccccc2CN2CCNCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)n(Cc1ccc(N3CCN(Cc4ccccc4-c4ccccc4)CC3)cc1)c(=N)n2CCCOc1ccc(F)cc1
Temperature: 130 °C
Yield: 10.9 %

Procedure:
3-(4-Bromo-benzyl)-1-[3-(4-fluoro-phenoxy)-propyl]-5-methyl-1,3-dihydrobenzoimidazol-2-ylideneamine, hydrobromide salt (20 mg, 0.036 mmol) was partitioned between aqueous NaOH and EtOAc. The organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure to provide 3-(4-bromo-benzyl)-1-[3-(4-fluoro-phenoxy)-propyl]-5-methyl-1,3-dihydrobenzoimidazol-2-ylideneamine (0.036 mmol). To a degassed solution of Pd(OAc)2 (0.04 mg, 0.16 □mol) and BINAP (0.44 mg, 0.71 mmol) in toluene (8 ml) at 40° C. was added 1-biphenyl-2-ylmethyl-piperazine (18 mg, 0.071 mmol) followed by 3-(4-bromo-benzyl)-1-[3-(4-fluoro-phenoxy)-propyl]-5-methyl-1,3-dihydrobenzoimidazol-2-ylideneamine (0.036 mmol) and sodium t-butoxide (4.8 mg, 0.05 mmol). The suspension was then heated to 130° C. where it was maintained for 20 h. After this time, the mixture was filtered and then the filtrate was partitioned between H2O and EtOAc. The organic phase was separated and concentrated under reduced pressure to provide the crude product. Purification by preparative HPLC gave 3-[4-(4-biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-1-[3-(4-fluoro-phenoxy)-propyl]-5-methyl-1,3-dihydro-benzoimidazol-2-ylideneamine (2.5 mg, 11%). HPLC-MS 640 [M+1]+, 320 (100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl.Cl[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]Cl>C1(C)C(C)=CC=CC=1.[OH-].[Na+]>[C:5]([C:4]1[CH:3]=[C:2]([N:1]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: ClCCNCCCl
Reactant: N#Cc1cccc(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: N#Cc1cccc(N2CCNCC2)c1
Temperature: 155 °C
Reaction time: 5 h
Yield: 32.7 %

Procedure:
3-Aminobenzonitrile (6.1 g, 52 mmol) and bis(2-chloroethyl)amine hydrochloride (10 g, 57 mmol) were dissolved in xylene (100 ml), and the resulting solution was stirred at 150 to 160° C. for 5 hours. Supernatant fluid of the reaction solution was discarded, the remaining residue was dissolved in sodium hydroxide aqueous solution (1 N) and then the reaction product was extracted therefrom with ethyl acetate. The extract was washed with saturated brine, and then the compound obtained by the evaporation of the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 3.2 g of the title compound (17 mmol, 34% in yield). A portion of the thus obtained compound was made into hydrochloric acid salt by treating it with hydrochloric acid-saturated methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=1.C1C(=O)N([Br:28])C(=O)C1>C(O)(=O)C>[Br:28][C:3]1[C:2]([F:1])=[CH:7][C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:11])[CH3:12])=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:4]=1
Reactant: CC(C)(C)C(=O)Nc1cc(F)ccc1-c1ccccn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)Nc1cc(F)c(Br)cc1-c1ccccn1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of N-(5-fluoro-2-(pyridin-2-yl)phenyl)pivalamide (19.0 g, 69.83 mmol) in acetic acid (140.0 mL) was added NBS (24.86 g, 139.66 mmol) at 0° C. The resulted mixture was stirred at 50° C. for 1 h. After completion of reaction (by TLC), the mixture was poured onto 100 mL of crushed ice and extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and solvent evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 2% EtOAc:hexane to obtain the desired product as an off white solid (17.50 g, 72%).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[CH:4]=1.Cl.[NH+]1C=CC=CC=1>>[C:13]1([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]3)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc2cc(-c3ccccc3)ccc2c1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: Oc1ccc2cc(-c3ccccc3)ccc2c1

Procedure:
The title compound was prepared by reacting 2-methoxy-6-phenylnaphthalene (0.54 g, 2.30 mmol) with of pyridinium HCl (10 g) at 190° C. according to method B to yield 0.32 g (63%) of a light pink solid: mp 169-170° C.; 1H NMR (DMSO-d6): δ 7.12 (1H, dd, J=2.56 Hz, J=8.54 Hz), 7.16 (1H, d, J=2.56 Hz), 7.35-7.38 (1H, m), 7.47-7.50 (2H, m), 7.73 (1H, dd, J=1.71 Hz, J=8.54 Hz), 7.76-7.79 (3H, m), 7.85 (1H, d, J=8.54 Hz), 8.08 (1H, d, J=1.28 Hz), 9.82 (1H, s); MS (ESI) m/z 219 (M−H)−.
Reaction SMILES: Cl.[C:2]([CH2:4][C:5](=[NH:8])[O:6][CH3:7])#[N:3].[N:9]#[C:10]N>C1C=CC=CC=1>[C:10]([N:8]=[C:5]([O:6][CH3:7])[CH2:4][C:2]#[N:3])#[N:9]
Reactant: COC(=N)CC#N
Reactant: N#CN
Agent: Cl
Solvent: c1ccccc1
Product: COC(CC#N)=NC#N
Yield: 91.8 %

Procedure:
2.69 g of methyl cyanoacetimidate hydrochloride, 1.68 g of cyanamide and 5.0 g of molecular sieve (type 4A, 60 mesh through) were suspended in 30 ml of benzene and the suspension was made to react for 5 hours at 25°C under stirring. After reaction, insoluble materials were filtered off and then the filtrate was concentrated to dryness in vacuo to give 2.26 g of methyl N-cyanocyanoacetimidate (yield 91.2%) mp 45.5°C.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]([OH:11])[CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][NH:19][CH3:20]>C(O)C>[CH3:18][N:19]([CH3:20])[CH2:9][CH:8]([OH:11])[CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(CBr)C(c1ccccc1)c1ccccc1
Reactant: CNC
Solvent: CCO
Product: CN(C)CC(O)C(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 75 %

Procedure:
1,1-Diphenyl-3-bromopropan-2-ol (500 mg.) prepared as described in Example 20 was treated with excess dimethylamine in ethanol and the solution allowed to stand overnight. Solvent was removed by evaporation and the residue dissolved in dilute hydrochloric acid and ether. Basification of the acid extract and isolation through ether in the usual manner gave 3-dimethylamino-1,1-diphenyl-propan-2-ol (330 mg., 75%), m.p. 72° - 73°.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:38]([CH:41]([CH:45]([CH3:47])[CH3:46])[C:42](Cl)=[O:43])([CH3:40])[CH3:39]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:42](=[O:43])[CH:41]([CH:45]([CH3:47])[CH3:46])[CH:38]([CH3:40])[CH3:39])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)C(C(=O)Cl)C(C)C
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CC(C)C(C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21)C(C)C
Yield: 16.2 %

Procedure:
A procedure similar to that described in Example 4, above, was followed, but using 1.0 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and 888 mg (5.5 mmol) of 2-isopropyl-3-methylbutyryl chloride, to provide 198 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:13](=[O:15])[CH3:14].ClC1C=CC=C(C(OO)=[O:24])C=1>ClCCl.C(Cl)(Cl)Cl>[N+:9]1([O-:24])[CH:10]=[CH:11][CH:12]=[CH:7][CH:8]=1.[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:13](=[O:15])[CH3:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CC(=O)c1nc(-c2cccnc2)[nH]c1C
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: [O-][n+]1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 5.0 g (0.025 mole) amount of 1-[5-methyl-2-(3-pyridinyl)-1H-imidazol-4-yl]ethanone was dissolved in 500 ml of dichloromethane and 250 ml of chloroform. Then 5.0 g (0.025 mole) of m-chloroperbenzoic acid (86-90%) was added. The solution was stirred at room temperature and after one hour a precipitate began to form. Stirring was continued for 23 hours. The precipitate was collected by filtration, washed with 50 ml of dichloromethane and air dried. The precipitate was recrystallized from ethanol and gave 1.3 g of the desired product as a white solid, mp 288°-292° C. (dec.).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.Cl[C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[N:27]=[CH:28][NH:29]2>>[N:33]1[C:25]([NH:2][C:3]2[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=2)[CH2:6][NH:7][C:8]2[C:17]3[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)=[C:26]2[C:30]([NH:29][CH:28]=[N:27]2)=[N:31][CH:32]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Agent: Cl
Product: NC(=O)c1cccc2c(NCc3cccc(Nc4ncnc5[nH]cnc45)c3)ncnc12
Reaction time: 3 h

Procedure:
The title compound was prepared according to Example 549 starting 4-(3-Amino-benzylamino)-quinazoline-8-carboxylic acid amide hydrochloride and 6-Chloro-9H-purine. Reaction conditions: 120° C. in the microwave for 3 h:
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:16][C:17]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[NH:18])[CH:13]=2)[N:8](CC2C=CC(OC)=CC=2)[C:7]1=[O:33].C1(OC)C=CC=CC=1.[ClH:43]>FC(F)(F)C(O)=O.CO.C(Cl)Cl.C(Cl)Cl.CCOCC>[ClH:43].[ClH:43].[CH3:34][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:16][C:17]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[NH:18])[CH:13]=2)[NH:8][C:7]1=[O:33]
Reactant: COc1ccc(CN2C(=O)C(CCCN(C)C)Cc3cc(NC(=N)c4cccs4)ccc32)cc1
Agent: Cl
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCCC1Cc2cc(NC(=N)c3cccs3)ccc2NC1=O
Temperature: 60 °C
Yield: 51.3 %

Procedure:
A solution of N-(3-(3-(dimethylamino)propyl)-1-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximidamide (50 mg, 0.1 mmol) and anisole (23 μL, 0.2 mmol) in 7.5 mL trifluoroacetic acid was stirred at room temperature for 2 hours then heated at 60° C. for 22 hours. A TLC analysis indicated that only starting material is present. The mixture was concentrated and treated with 3N HCl and ethanol (5 mL) then heated at 60° C. for 4 hours. The yellow solution was treated with saturated NaHCO3 then extracted with 3×20 mL CH2Cl2. The combined organic layers were dried with MgSO4, filtered and concentrated to give a yellow residue. This residue was subjected to flash chromatography on silica gel using 5% 2M NH3 in MeOH/CH2Cl2 to give a light yellow solid. This compound was dissolved in CH2Cl2 (5 mL) and treated with 1 mL of a 1M HCl solution in Et2O to form a precipitate. The slurry was concentrated to give a yellow solid (22 mg, 51.3%). An HPLC analysis indicated that the product is >99% pure. An HPLC analysis indicated that the product is >99% pure. 1H-NMR (CD3OD) δ: 7.96-7.95 (d, J=4.5 Hz, 2H), 7.31 (pseudo t, J=4.2 Hz, 1H), 7.24 (br s, 1H), 7.17 (dd, J=1.5, 8.1 Hz, 1H), 7.00 (d, J=5.9 Hz, 1H), 3.17-3.10 (m, 2H), 2.85 (s, 6H), 2.91-2.83 (m, 2H) 2.67-2.60 (m, 1H), 1.91-1.56 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1C=CC=C([N+]([O-])=O)C=1C)([O-])=O.[NH2:14][C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[C:17]([N+:22]([O-:24])=[O:23])[C:16]=1[CH3:25].N#CBr>>[NH2:1][C:4]1[NH:14][C:15]2[C:16]([CH3:25])=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=2[N:21]=1
Reactant: Cc1c([N+](=O)[O-])ccc(N)c1N
Reactant: Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: N#CBr
Product: Cc1c([N+](=O)[O-])ccc2nc(N)[nH]c12

Procedure:
This compound is prepared by a combination of Schemes 1 and 4. Commercially available 2,6-dinitrotoluene is converted to 2,3-diamino-6-nitrotoluene according to scheme 2. Reaction with cyanogen bromide affords 2-amino-4-methyl-5-nitrobenzimidazole. After protection of the amino group with a tert-butoxycarbonyl group, the compound is reduced by hydrogenation (palladium-on-carbon) and brominated (bromine, sodium acetate, acetic acid) to afford 5-amino-6-bromo-2-tert-butoxycarbonylamino-4-methylbenzimidazole. The formation of the 5-(2-imidazolinylamino) group is completed in the usual fashion and the tert-butoxycarbonyl group is cleaved by treatment with hydrobromic acid to afford 2-amino-6-bromo-5-(2-imidazolinylamino)-4-methylbenzimidazole.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][CH:59]1[CH2:62][N:61]([C:63](=[O:65])[CH3:64])[CH2:60]1>>[C:63]([N:61]1[CH2:62][CH:59]([NH:58][C:27](=[O:29])[C:26]2[CH:30]=[CH:31][C:23]([NH:22][C:20]3[N:19]=[CH:18][C:9]4[N:10]([CH3:17])[C:11](=[O:16])[C:12]([F:14])([F:15])[CH2:13][N:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[C:8]=4[N:21]=3)=[C:24]([O:32][CH3:33])[CH:25]=2)[CH2:60]1)(=[O:65])[CH3:64]
Reactant: CC(=O)N1CC(N)C1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CN(C(C)=O)C2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-(3-aminoazetidin-1-yl)ethanone. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (t, J=12.4 Hz, 1 H) 1.34-1.45 (bq, 2 H) 1.57-1.68 (m, 3 H) 1.78 (s, 3 H) 1.84 (m, 3 H) 3.32 (s, 3 H) 3.88 (m, 1 H) 3.95 (s, 3 H) 4.03-4.12 (m, 4 H) 4.42 (t, J=8.2 Hz, 1 H) 4.45-4.51 (m, 1 H) 4.68 (q, J=6.8 Hz, 3 H) 7.51 (dd, J=8.3, 1.8 Hz, 1 H) 7.54 (d, J=1.5 Hz, 1 H) 7.93 (s, 1 H) 8.22 (s, 1 H) 8.30 (d, J=8.3 Hz, 1 H) 8.89 (d, J=6.8 Hz, 1 H). [M+H] calc'd for C27H33F2N7O4 558; found 558.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:18]#[N:19])=[CH:13][CH:12]=2.B(Br)(Br)[Br:21].C(Cl)Cl.C([O-])(O)=O.[Na+]>ClCCCl>[Br:21][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=2)[NH:10][C:9]=1[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[OH:2]
Reactant: BrB(Br)Br
Reactant: COc1ccncc1-c1cc2cc(C#N)ccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: N#Cc1ccc2[nH]c(-c3cnccc3O)c(Br)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask is charged with 2-(4-methoxy-pyridin-3-yl)-1H-indole-5-carbonitrile (Example 90, 190 mg, 0.80 mmol) and DCE (8 mL), and 1.0 M BBr3 in DCM (4.8 mL, 4.8 mmol) is added. The mixture is stirred at room temperature overnight. The reaction mixture is poured into saturated aqueous NaHCO3 and extracted with DCM. The aqueous phase is concentrated, acidified with 1M HCl in water and concentrated in vacuo. The residue is purified with an Xbridge C18 eluting with a 1:9 to 9:1 acetonitrile-water gradient to give 3-bromo-2-(4-hydroxy-pyridin-3-yl)-1H-indole-5-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.40 (d, J=7.1 Hz, 1H), 7.48 (dd, J=8.5, 1.6 Hz, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.81 (dd, J=7.1, 1.3 Hz, 1H), 7.86 (d, J=1.0 Hz, 1H), 8.67 (d, J=1.3 Hz, 1H). HRMS (ESI) m/z 313.9932 [(M+H) calcd for C14H9BrN3O: 313.9929].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[S:10]([NH:13][C:14]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]2[C:17]([CH:18]3[CH2:28][CH:19]3[CH2:20][O:21]2)=[CH:16][CH:15]=1)(=[O:12])=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:53]([N:55]1[CH2:59][CH2:58][CH2:57][C@H:56]1[C:60](O)=[O:61])[CH3:54].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:53]([N:55]1[CH2:59][CH2:58][CH2:57][C@H:56]1[C:60]([CH:2]([NH2:1])[C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[S:10]([NH:13][C:14]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]2[C:17]([CH:18]3[CH2:28][CH:19]3[CH2:20][O:21]2)=[CH:16][CH:15]=1)(=[O:11])=[O:12])=[O:61])[CH3:54]
Reactant: CCN1CCC[C@H]1C(=O)O
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CN)ccc2c1OCC1CC21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CCC[C@H]1C(=O)C(N)c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-(2-aminomethyl-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 102, 0.515 g), HATU (0.483 g), (S)—N-ethylpyrrolidine-2-carboxylic acid (Intermediate 106, 0.182 g) and N,N-di-isopropyl-N-ethylamine (0.328 g) in dry DMF (25 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum and the residue was diluted with water and extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM, with a gradient of 1-2% to give methyl (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-2-yl)cabonyl-aminomethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.505 g) as a glassy solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][NH:5][C:4](=[O:14])[CH:3]=1.CS(C1C=CNC(=O)C=1)(=O)=O.CS(O[CH:31]1[CH2:36][CH2:35][N:34]([C:37]2[N:42]=[CH:41][C:40]([CH2:43][CH2:44][CH3:45])=[CH:39][N:38]=2)[CH2:33][CH2:32]1)(=O)=O.CS(OC1CCN(C(OC(C)(C)C)=O)CC1)(=O)=O>>[C:8]1([C:7]2[C:2]([O:1][CH:31]3[CH2:36][CH2:35][N:34]([C:37]4[N:38]=[CH:39][C:40]([CH2:43][CH2:44][CH3:45])=[CH:41][N:42]=4)[CH2:33][CH2:32]3)=[CH:3][C:4](=[O:14])[NH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCc1cnc(N2CCC(OS(C)(=O)=O)CC2)nc1
Reactant: O=c1cc(O)c(-c2ccccc2)c[nH]1
Agent: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: CS(=O)(=O)c1cc[nH]c(=O)c1
Product: CCCc1cnc(N2CCC(Oc3cc(=O)[nH]cc3-c3ccccc3)CC2)nc1

Procedure:
The compound in Step C was prepared according to the procedures described in Example 1 substituting 4-hydroxy-5-phenylpyridin-2(1H)-one for 4-hydroxy-1-(4-(methylsulfonyl)pyridine-2(1H)-one and 1-(5-propylpyrimidin-2-yl)piperidin-4-yl methanesulfonate for tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate in Step D. MS (ESI) 391 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([S:15](F)(=[O:17])=[O:16])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][C:7]=2[CH:14]=1.O1CCCC1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1.O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O.C(OCC)C>[F:24][C:25]1[CH:30]=[CH:29][C:28]([S:15]([C:4]2[C:3]([O:2][CH3:1])=[CH:14][C:7]3[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=3[CH:5]=2)(=[O:17])=[O:16])=[CH:27][CH:26]=1
Reactant: COc1cc2c(cc1S(=O)(=O)F)CCN(C)CC2
Reactant: Fc1ccc([Mg]Br)cc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cc1S(=O)(=O)c1ccc(F)cc1)CCN(C)CC2
Reaction time: 8 h
Yield: 51 %

Procedure:
The sulfonyl fluoride D4 from Description 4 (25 g) was dissolved it dry tetrahydrofuran (250 mL) and 4-fluorophenylmagnesium bromide in tetrahydrofuran (2.5 equivalents) added over 15 min with ice bath cooling, an exotherm only apparent during the first part of the addition. Stirred overnight without cooling then added over 10 min to a solution of sodium potassium tartrate tetrahydrate (250 g) in water (450 mL) with stirring. Diethyl ether was added (400 mL) and the organic layer separated, dried, evaporated, and crystallised from diethyl ether to give crystalline fluorophenyl sulfone D5 17 g (51%).