Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([N:26]1[C:34]2[C:29](=[N:30][CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=2)[N:28]([CH3:44])[C:27]1=[O:45])[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:33]=[C:34]6[N:26]([CH2:24][CH3:25])[C:27](=[O:45])[N:28]([CH3:44])[C:29]6=[N:30][CH:31]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CCn1c(=O)n(C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CCn1c(=O)n(C)c2ncc(-c3ccc4ncc5c(c4c3)n(-c3cn(C)nc3C)c(=O)n5C)cc21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 1-ethyl-3-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one (Stage 68.1.1) to give the title compound as a white solid. (HPLC: tR 2.47 min (Method A); M+H=469 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.14-8.08 (m, 3H), 8.01-7.94 (m, 1H), 7.62-7.58 (m, 1H), 7.58-7.54 (m, 1H), 3.94 (q, 2H), 3.89 (s, 3H), 3.57 (s, 3H), 3.37 (s, 3H), 1.97 (s, 3H), 1.28 (t, 3H))
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[N:31]1([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1>C1COCC1>[O:30]=[C:4]1[C:3](=[CH:2][NH:44][C:41]2[CH:42]=[CH:43][C:38]([CH2:37][CH2:36][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:39][CH:40]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5]1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: Nc1ccc(CCN2CCCC2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CCN4CCCC4)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 41 %

Procedure:
was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2 mL). To the resulting solution was added 4-(2-Pyrrolidin-1-yl-ethyl)-phenylamine (47.3 mg, 0.249 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture causing a black precipitate to form. The precipitate was vacuum filtered and the filtrate was then concentrated in vacuo and redissolved into ˜3 mL of EtOAc. Hexanes were added causing a yellow precipitate to form. The precipitate was then filtered and washed with ˜1 mL of i-prOH yielding 41% (0.058 g, 0.102 mmol) of the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]12C[CH:10]1[CH2:9][N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:7]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O)C.C(OC(C1[C@H](C2C=CC=CC=2)N(S(C2C=CC(C)=CC=2)(=O)=O)CC=1)=O)C.CC(C[AlH]CC(C)C)C.CO>C(Cl)Cl>[C:22]1([CH:7]2[C:6]([CH2:4][OH:3])=[CH:10][CH2:9][N:8]2[S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)C12CC1CN(S(=O)(=O)c1ccc(C)cc1)C2c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: CCOC(=O)C1=CCN(S(=O)(=O)c2ccc(C)cc2)[C@H]1c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CC=C(CO)C2c2ccccc2)cc1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To racemic intermediate 1, one enantiomer being (S)-2-phenyl-1-(toluene-4-sulfonyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl ester (1.8 g, 5.0 mmol), was dissolved in methylene chloride (60 mL) in a three necked flask equipped with an addition funnel and an internal thermometer. The mixture was cooled to −25° C., DIBAL (1M/toluene, 12.5 mL, 12.5 mmol) was added dropwise and the reaction stirred for an additional 0.5 hours. Methanol was added to the cold solution until gas evolution ceased and the solvents were then removed at reduced pressure. The residue was partitioned between a saturated solution of Rochelle's salt and methylene chloride. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was chromatographed on silica gel using a gradient of 20% to 60% ETOAc/Hexanes to yield the title compound as a sticky foam (1.6 g, 98% yield).
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:27][C:28]2([F:33])[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][C@@H:20]3[CH2:24][O:23]C(C)(C)[O:21]3)[N:15]=2)=[O:12])[C:7](=[O:34])[CH:6]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[F:1][C:2]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:27][C:28]2([F:33])[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][C@@H:20]([OH:21])[CH2:24][OH:23])[N:15]=2)=[O:12])[C:7](=[O:34])[CH:6]=1
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3(F)CCCC3)N3CC(Oc4c(F)cccc4F)=CC3=O)n2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=C(Nc1ccn(C[C@@H](O)CO)n1)C(CC1(F)CCCC1)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
A solution of 2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-3-(1-fluoro-cyclopentyl)-propionamide (0.330 g, 0.60 mmol) in methanol (6 mL) was treated with p-toluenesulfonic acid (0.017 g, 0.09 mmol). The reaction mixture was stirred at room temperature overnight. The solvents were removed under vacuum and ethyl acetate was added to the residue. The resulting mixture was washed with saturated sodium bicarbonate, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated which afforded 2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-3-(1-fluoro-cyclopentyl)-propionamide (0.260 g, 87%) as a light yellow solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.51-1.96 (m, 8H), 2.10-2.43 (m, 2H), 3.22-3.32 (m, 2H), 3.69-3.94 (m, 2H), 4.09 (dd, J=13.3, 3.3 Hz, 1H), 4.33 (d, J=18.3 Hz, 1H), 4.53 (d, J=18.3 Hz, 1H), 4.71 (t, J=5.3 Hz, 1H), 4.94 (d, J=5.1 Hz, 1H), 5.02 (s, 1H), 5.05-5.13 (m, 1H), 6.41 (s, 1H), 7.29-7.50 (m, 3H), 7.54 (s, 1H), 10.81 (s, 1H) HR-ES-MS m/z calculated for C24H27F3N4O5 [M+H]+, 509.2007 observed 509.2009.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][Si:27]([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(Nc1ccc(O)cc1)c1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of 4-bromo-N-(4-hydroxyphenyl)benzamide in DMF (1.3 M), 2.5 eq of imidazole and 1.2 eq of TBDMSCl were added and the solution stirred at RT for 30 minutes. The reaction mixture was diluted with EtOAc. The organic phase was washed with aqueous HCl (1N), saturated aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (95%); MS (ES+) m/z 406 (M+H)+, m/z 408 (M+H)+
Reaction SMILES: [Br:1][C:2]1[C:3]([C:17]([OH:19])=O)=[N:4][C:5]([Cl:16])=[CH:6][C:7]=1[N:8]([CH3:15])[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][CH2:54][C:55]1[C:56](=[O:63])[NH:57][C:58]([CH3:62])=[CH:59][C:60]=1[CH3:61]>CN(C=O)C.O>[Br:1][C:2]1[C:3]([C:17]([NH:53][CH2:54][C:55]2[C:56](=[O:63])[NH:57][C:58]([CH3:62])=[CH:59][C:60]=2[CH3:61])=[O:19])=[N:4][C:5]([Cl:16])=[CH:6][C:7]=1[N:8]([CH3:15])[CH:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1
Reactant: CN(c1cc(Cl)nc(C(=O)O)c1Br)C1CCOCC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
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: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2nc(Cl)cc(N(C)C3CCOCC3)c2Br)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.2 %

Procedure:
To a stirred solution of 3-bromo-6-chloro-4-[methyl(oxan-4-yl)amino]pyridine-2-carboxylic acid (73 mg, 0.21 mmol) in DMF (2 ml) were added DIPEA (56 μl, 0.31 mmol) and HATU (95 mg, 0.25 mmol) at 0° C. The reaction was stirred at 0° C. for 5 min after which time 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 52 mg, 0.31 mmol) was added and the reaction was stirred at room temperature for 16 h. The reaction mixture was then poured onto 50 ml of water, the aqueous phase was extracted with EtOAc (3×50 ml), washed with brine (50 ml) dried (Na2SO4) and evaporated to give an oil. The product was then purified using a 5 g silica Isolute column eluting with 0% to 4% MeOH in DCM and evaporated to give a glassy solid which was triturated with diethyl ether and filtered and dried in a vacuum oven at 40° C. for 24 h to afford the title compound as a white powder (50 mg, 41%). LC-MS 99%, m/z=483.1/485.0/486.9, 1H NMR (500 MHz, CDCl3) δ 10.94 (br. s, 1H), 8.14-7.98 (m, 1H), 6.83 (s, 1H), 5.92 (s, 1H), 4.55 (d, J=6.1 Hz, 2H), 4.15-3.94 (m, 2H), 3.93-3.70 (m, 1H), 3.40 (t, J=11.0 Hz, 2H), 2.78 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 1.99-1.82 (m, 2H), 1.79-1.64 (m, 2H).
Reaction SMILES: [NH:1]=[C:2]([NH:4][NH:5][C:6]([C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[N:12]=1)=O)[CH3:3].O>C(O)CO>[CH3:3][C:2]1[NH:4][N:5]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[N:12]=2)[N:1]=1
Reactant: CC(=N)NNC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)cs1
Solvent: O
Solvent: OCCO
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)n[nH]1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
A solution of N′-(1-iminoethyl)-4-(4-(trifluoromethoxy)phenyl)thiazole-2-carbohydrazide (10.0 g, 33.0 mmol) in ethylene glycol (20 mL) was stirred at 180° C. for 2 h. After cooling to RT, H2O (100 mL) was added and the mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure; the residue was purified by silica gel column chromatography (Petroleum ether:EtOAc=5:1) to afford the title compound as a white solid (9.6 g, 100%). MS (ES+) C13H9F3N4OS requires: 326. found: 327 [M+H]+; 1H NMR (500 MHz, DMSO) 8.27 (s, 1H), 8.15 (d, J=8.5 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 2.43 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][C:6](=[N:8][OH:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.Br[CH2:14][C:15]1[CH:44]=[CH:43][C:18]([CH2:19][O:20][C:21](=[O:42])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=2)=[O:31])=[CH:17][CH:16]=1>>[CH3:1][C:2]1([CH3:12])[CH2:7][CH:6]([N:8]([CH2:14][C:15]2[CH:44]=[CH:43][C:18]([CH2:19][O:20][C:21](=[O:42])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([CH2:40][N:8]([CH:6]4[CH2:7][C:2]([CH3:12])([CH3:1])[NH:3][C:4]([CH3:11])([CH3:10])[CH2:5]4)[OH:9])=[CH:36][CH:35]=3)=[O:31])=[CH:17][CH:16]=2)[OH:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1
Reactant: CC1(C)CC(=NO)CC(C)(C)N1
Reactant: O=C(CCCCCCCCC(=O)OCc1ccc(CBr)cc1)OCc1ccc(CBr)cc1
Product: CC1(C)CC(N(O)Cc2ccc(COC(=O)CCCCCCCCC(=O)OCc3ccc(CN(O)C4CC(C)(C)NC(C)(C)C4)cc3)cc2)CC(C)(C)N1

Procedure:
from 2,2,6,6-tetramethylpiperidin-4-one oxime and di-(4-bromomethylbenzyl)sebacate
Reaction SMILES: [F:1][C:2]1[C:12]([F:13])=[C:11]([F:14])[CH:10]=[CH:9][C:3]=1[NH:4][C@@H:5]([CH3:8])[CH2:6][OH:7].C(O[CH:18]=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])C>>[F:1][C:2]1[C:12]([F:13])=[C:11]([F:14])[CH:10]=[CH:9][C:3]=1[N:4]([CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C@@H:5]([CH3:8])[CH2:6][OH:7]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Product: CCOC(=O)C(=CN(c1ccc(F)c(F)c1F)[C@@H](C)CO)C(=O)OCC
Temperature: 100 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To the compound (103 mg) obtained in Example 51 was added diethyl ethoxymethylenemalonate (127 mg). Then the obtained mixture was stirred for 1 hour while heating to 100° C. under atmospheric pressure. Further, it was stirred at the same temperature for 1.5 hour under reduced pressure and then under atmospheric pressure for additional 16 hours. By analyzing reversed phase HPLC with the use of the compound of Example 63 as a specimen, the obtained product corresponded to 142 mg (78%) of the title compound.
Reaction SMILES: [OH:1][C:2]1([CH2:20][OH:21])[CH2:11][C:10]2[C:5](=[C:6]([O:14][CH3:15])[CH:7]=[CH:8][C:9]=2[O:12][CH3:13])[C:4]2([S:19][CH2:18][CH2:17][S:16]2)[CH2:3]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:21][CH2:20][C:2]1([OH:1])[CH2:11][C:10]2[C:5](=[C:6]([O:14][CH3:15])[CH:7]=[CH:8][C:9]=2[O:12][CH3:13])[C:4]2([S:16][CH2:17][CH2:18][S:19]2)[CH2:3]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(OC)c2c1CC(O)(CO)CC21SCCS1
Solvent: c1ccncc1
Product: COc1ccc(OC)c2c1CC(O)(COC(C)=O)CC21SCCS1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
1.6 g of rac-1',2',3',4'-tetrahydro-3'-hydroxy-3'-hydroxymethyl-5',8'-dimethoxyspiro[1,3-dithiolane-2,1'-naphthalene] were dissolved in 30 ml of dry pyridine and 1.5 g. of acetic anhydride were added to the solution. The mixture was left to stand at room temperature for 20 hours and then poured into ice-cold 5-M sulphuric acid. The resulting mixture was extracted with ethyl acetate, the extracts were washed with water and sodium hydrogen carbonate solution, dried and evaporated to give 1.8 g of rac-3'-acetoxymethyl-1',2',3',4'-tetrahydro-3'-hydroxy-5',8'-dimethoxyspiro[1,3-dithiolane-2,1'-naphthalene] in the form of a colourless oil which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([SH:18])[NH:11][C:12]=2[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1.[F:19][C:20]([F:24])=[C:21]([F:23])[F:22].O>CN(C)C=O.C(NC(C)C)(C)C.ClCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([S:18][C:21]([F:23])([F:22])[CH:20]([F:24])[F:19])[NH:11][C:12]=2[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:7]=1
Reactant: Sc1nc(-c2ccc(Cl)cc2)c(-c2cccs2)[nH]1
Reactant: FC(F)=C(F)F
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)C(F)(F)Sc1nc(-c2ccc(Cl)cc2)c(-c2cccs2)[nH]1

Procedure:
A solution of 6.9 g of 4-(4-chlorophenyl)-5-(2-thienyl)-1H-2-imidazolethiol in 40 ml of dimethylformamide and 1.5 ml of diisopropylamine was pressured in a bomb with 3 g of tetrafluoroethylene and shaken until there was no further pressure drop. The bomb contents were poured into water, the pH adjusted to 8 and the solution extracted with chloroform. The extract was dried and concentrated. It was chromatographed on silica gel (Silicar CC-4) to give 5.5 g of a cut which was dissolved in hot 1-chlorobutane. On cooling 4.5 g of product was obtained, m.p. 161.5°-163° C.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][C:5]=1[F:13].Cl.Cl[CH2:16][CH2:17][NH2:18].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:16][CH2:17][NH2:18])=[CH:6][C:5]=1[F:13]
Reactant: NCCCl
Reactant: Fc1cc2cc[nH]c2cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: CC#N
Product: NCCn1ccc2cc(F)c(Cl)cc21
Temperature: 25 °C
Reaction time: 36 h
Yield: 79.3 %

Procedure:
Tetra-n-butylammonium hydrogensulfate (0.1 g, 0.33 mmol), powdered sodium hydroxide (1.3 g, 33 mmol) and 6-chloro-5-fluoroindole (1.4 g, 8.3 mmol) were stirred at room tempera in acetonitrile (40 mL) for 1 h. 2-Chloroethylamine hydrochloride (1.45 g, 12.5 mmol) was then added in 1 portion and the reaction was heated to reflux and stirred for 36 h. After allowing to cool to room temperature the mixture was poured into water (100 mL) and extracted with ethyl acetate (3×70 mL). The combined organic extracts were washed with brine (1×100 mL), dried (magnesium sulfate), filtered and the solvent removed under vacuo to leave a crude oil. The oil was purified by flash column chromatography [SiO2; ethyl acetate-methanol-ammonium hydroxide, (90:9:1)] to give the product as an orange oil (1.4 g, 80%). IR νmax (film)/cm−1 3377, 3104, 2937, 2868, 1675, 1568, 1505, 1479, 1449, 1400, 1357, 1327, 1291, 1236, 1143, 1090, 1030, 994, 862, 817, 753, 717, 698, 678, 646, 633, 596 and 579; NMR δH (400 MHz; DMSO-d6) 7.79 (1H, d, J 7 Hz), 7.51 (1H, d, J 10 Hz), 7.50 (1H, d, J 3.5 Hz), 6.46 (1H, m), 4.13 (2H, t, J 6.3 Hz), 2.86 (2H, t, J 6.3 Hz), 1.52 (1H, br. s).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:7]([CH2:20][C:21](O)=[O:22])[C:6]=2[C:5]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[C:21](=[O:22])[CH2:20][N:7]3[C:6]=2[C:5]([CH:24]([CH2:25][CH3:26])[CH2:27][CH3:28])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(Cl)cc3Cl)n(CC(=O)O)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CC(=O)N3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of {4-chloro-2-[(2,4-dichlorophenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl}acetic acid (Reference Example 21; 294 mg, 0.667 mmol) in N,N-dimethylformamide (3 mL) were added triethylamine (0.11 mL, 0.800 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153 mg, 0.800 mmol), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water, and the suspension was stirred at room temperature for 1.5 hr. The resulting solid was collected by filtration and washed with water. The crystal was recrystallized from diisopropyl ether-n-hexane to give 160 mg (0.378 mmol, 57%) as a colorless crystal.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[OH:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[NH2:18]>>[OH:14][C:15]1[CH:16]=[C:17]([NH:18][S:10]([C:3]2[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=2[F:1])(=[O:12])=[O:11])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(N)cc1O
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1F
Product: COc1ccc(NS(=O)(=O)c2ccc(F)c(F)c2F)cc1O

Procedure:
The title compound was prepared in a manner similar to that described in Example 1 by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with 2,3,4-trifluorophenylsulfonyl chloride and replacing p-anisidine with 3-hydroxy-4-methoxyaniline. 1H-NMR (CDCl3): δ 7.55 (1H, m), 7.00 (1H, m), 6.70 (2H, m), 6.60 (2H, m), 5.61 (1H, s), 3.83 (3H, s). Anal. Calcd. for C13H10F3NO4S: C, 46.85; H, 3.02; N, 4.20; S, 9.62. Found: C, 46.79; H, 3.03; N, 4.24; S, 9.53.
Reaction SMILES: [CH2:1]([NH2:5])[C:2]([OH:4])=[O:3].C([O-])(O)=O.[Na+].[CH2:11]([C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19]([NH:29][CH3:30])=[C:20]2[S:25](Cl)(=[O:27])=[O:26])[CH2:12][CH2:13][CH3:14]>O.CC(C)=O>[CH2:11]([C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19]([NH:29][CH3:30])=[C:20]2[S:25]([NH:5][CH2:1][C:2]([OH:4])=[O:3])(=[O:27])=[O:26])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1cccc2c(S(=O)(=O)Cl)c(NC)ccc12
Reactant: NCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCc1cccc2c(S(=O)(=O)NCC(=O)O)c(NC)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Two mmoles of L-glycine and 3 mmoles of NaHCO3 were dissolved in 5 ml of water. A solution containing 1 mmol of 3 in acetone was slowly added. More acetone was added until the solution was clear. The mixture was stirred overnight at room temperature, and protected from light. Acetone was removed by flash evaporation and the remaining water solution was acidified to pH=4.5 to 5 by adding 2M citric acid. Then, NaCl was added until saturation and the solution was extracted with three portions of ethyl acetate (20 ml each). The extracts were combined, dried over MgSO4 and solution filtered Solvent was removed and residue purified by liquid chromatography on silica gel. A gradient of 0 to 5% methanol in dichloromethane was used as eluent. Fractions containing desired products were combined and solvents removed. The residue was triturated in 1:1 ether: petroleum ether. Precipitate was filtered out and dried in vacuum overnight thus affording 5-Butylmethylamino-naphtalene-1-sulfonyl-glycine (NST703).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([F:10])([F:9])[F:8])=[C:4]([C:11]([OH:13])=O)[CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:40]=[CH:41][CH:42]=1)[O:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([CH:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[N:33]=2)[N:30]=1.C(N(CC)CC)C>CN(C)C=O.O1CCCC1>[CH:37]1([C:35]([NH:34][C:32]2[N:33]=[C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]4[CH:22]=[C:21]([NH:20][C:11]([C:4]5[CH:3]=[C:2]([CH3:1])[O:6][C:5]=5[C:7]([F:8])([F:9])[F:10])=[O:13])[CH:42]=[CH:41][CH:40]=4)=[N:30][N:29]3[CH:31]=2)=[O:36])[CH2:38][CH2:39]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Cc1cc(C(=O)O)c(C(F)(F)F)o1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)c(C(F)(F)F)o1
Yield: 58.1 %

Procedure:
Using 5-methyl-2-(trifluoromethyl)-3-furancarboxylic acid (133.6 mg, 0.668 mmol), N,N-dimethylformamide (1 drop), oxalyl chloride (75 μL, 0.868 mmol), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (159 mg, 0.514 mmol), triethylamine (156 mg, 1.54 mmol) and tetrahydrofuran (15 mL) as starting materials and in the same manner as in Example 109, the title compound (145 mg, 58%) was obtained as a white powder.
Reaction SMILES: [C:1]1(=[O:13])[CH:9]2[CH:4]([CH:5]3[CH2:10][CH:8]2[CH2:7][C:6]3=[O:11])[C:3](=[O:12])[NH:2]1.[CH3:14][Mg]Br.C(O)(=O)C.O>C1COCC1.C(Cl)Cl.CO.CO.C(Cl)Cl>[OH:11][C:6]1([CH3:14])[CH2:7][CH:8]2[CH2:10][CH:5]1[CH:4]1[CH:9]2[C:1](=[O:13])[NH:2][C:3]1=[O:12]
Reactant: O=C1CC2CC1C1C(=O)NC(=O)C21
Reactant: C[Mg]Br
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC1(O)CC2CC1C1C(=O)NC(=O)C21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a −78° C. solution of rac-(3aS,4S,7S,7aR)-tetrahydro-1H-4,7-methanoisoindole-1,3,5(4H)-trione (1.08 g, 6.03 mmol) (Kossakowski, Jerzy; Zawadowski, Teodor; Balicka, Eliza., Acta Poloniae Pharmaceutica (1997), 54(6), 479-481) in 50 ml of anhydrous THF was added methylmagnesium bromide (5.02 ml of a 3 M solution in THF, 15.07 mmol). After 2 hr, an additional 3 mL of methylmagnesium bromide solution was added. After another 2 hr, an additional 2 mL of methylmagnesium bromide solution was added. After 6 hr total at −78° C., the cooling bath was removed and the reaction allowed to warm to room temperature. The reaction was quenched with acetic acid (1.725 ml, 30.1 mmol) (Carefully). 200 uL of water was added, and the mixture was diluted with CH2Cl2 and 2 mL MeOH. The mixture was dried over Na2SO4, filtered, and concentrated to give a white foam. The foam was dissolved in 5% MeOH/CH2Cl2 and filtered through a plug of silica to give the titled compound as an off-white solid.