Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([S:37]([N:40]1[CH2:45][CH2:44][N:43]3[CH:46]=[CH:47][CH:48]=[C:42]3[CH:41]1[CH2:49][C:50]([OH:52])=O)(=[O:39])=[O:38])[CH:31]=[CH:30]2.[NH:53]1[CH2:57][CH2:56][N:55]=[C:54]1[C:58]1[CH:63]=[CH:62][C:61]([CH2:64][CH2:65][NH2:66])=[CH:60][CH:59]=1.CCN(C(C)C)C(C)C>C1COCC1>[NH:55]1[CH2:56][CH2:57][N:53]=[C:54]1[C:58]1[CH:59]=[CH:60][C:61]([CH2:64][CH2:65][NH:66][C:50](=[O:52])[CH2:49][CH:41]2[N:40]([S:37]([C:32]3[CH:31]=[CH:30][C:29]4[C:34](=[CH:35][CH:36]=[C:27]([O:26][CH3:25])[CH:28]=4)[CH:33]=3)(=[O:38])=[O:39])[CH2:45][CH2:44][N:43]3[CH:46]=[CH:47][CH:48]=[C:42]23)=[CH:62][CH:63]=1
Reactant: NCCc1ccc(C2=NCCN2)cc1
Reactant: COc1ccc2cc(S(=O)(=O)N3CCn4cccc4C3CC(=O)O)ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cc(S(=O)(=O)N3CCn4cccc4C3CC(=O)NCCc3ccc(C4=NCCN4)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 35 %

Procedure:
HATU (563 mg, 1.48 mmol, 2.0 eq.) was added to a mixture of 2-(2-(6-methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid (S-2) (297 mg, 0.74 mmol, 1.0 eq.), 2-(4-(4,5-Dihydro-1H-imidazol-2-yl)phenyl)ethanamine (A49) (140 mg, 0.74 mmol, 1.0 eq.), and DIPEA (0.39 ml, 2.22 mmol, 3.0 eq.) in THF (10 ml) at 0° C. and the resulting reaction mixture was stirred at RT for 14 h. The solvent was evaporated under reduced pressure, the residue dissolved in DCM (30 ml) and washed with saturated ammonium chloride solution (15 ml), saturated sodium bicarbonate solution (15 ml), water (15 ml) and brine (15 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to yield the crude product which was purified by column chromatography (neutral alumina; 1% MeOH/DCM) to afford the desired product as an off-white solid. Yield: 35% (140 mg, 0.245 mmol); MS, Rt=3.3 min; m/z=572.5 [MH]+
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.O1CCOCC1.C(OC([N:34]1[CH:38]=[CH:37][CH:36]=[C:35]1B(O)O)=O)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[S:6][C:2]=2[C:35]2[NH:34][CH:38]=[CH:37][CH:36]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: Clc1ccc(Cc2nc(-c3ccncc3)sc2Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Clc1ccc(Cc2nc(-c3ccncc3)sc2-c2ccc[nH]2)cc1
Temperature: 130 °C
Yield: 28.8 %

Procedure:
To a solution of 5-bromo-4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole (94.0 mg, 0.257 mmol) in 4:1 dioxane:water (3.0 mL) was added 1-(t-butoxycarbonyl)pyrrole-2-boronic acid (57 mg, 0.27 mmol), cesium carbonate (251 mg, 0.771 mmol), and tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.026 mmol). The solution was degassed with argon and heated in a microwave reactor at 130° C. for 105 minutes. The reaction was concentrated in vacuo and the residue taken up in DCM (25 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with DCM (2×10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=0/100→80/20) followed by HPLC purification (formic acid method) to give 26 mg of the title compound as a yellow solid (29% yield). LC/MS (FA) ES+ 352. 1H NMR (300 MHz, d4-MeOH) δ: 8.62-8.60 (m, 2H), 7.90-7.88 (m, 2H), 7.66-7.55 (m, 1H), 7.26-7.24 (m, 2H), 7.20-7.17 (m, 2H), 6.92 (dd, 1H, J=2.7, 1.5 Hz), 6.32 (dd, 1H, J=3.5, 1.5 Hz), 6.21 (dd, 1H, J=3.5, 2.7 Hz), 4.28 (s, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C@H:15]2[CH2:18][C@H:17]([O:19][CH3:20])[CH2:16]2)[C:13]2[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:22]1[CH:23]=[CH:24][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([C@H:15]3[CH2:18][C@@H:17]([O:19][CH3:20])[CH2:16]3)[C:13]=2[CH:21]=1
Reactant: CO[C@H]1C[C@H](n2c([C@H](C)NC(=O)OC(C)(C)C)nc3ccc(F)cc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H]1C[C@@H](n2c([C@H](C)N)nc3ccc(F)cc32)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of {(S)-1-[6-fluoro-1-(trans-3-methoxycyclobutyl)1Hbenzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester (0.125 g, 0.34 mmol) in DCM (3 mL) was added TFA (2 mL) and the mixture stirred at RT for 1.5 h. The volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The crude material was used in the following step without further purification. Yellow oil (85 mg, 95%). LCMS (Method J): RT 1.60 min [M+H]+ 264.23. 610116410
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH2:25].[Br:31][CH2:32][C:33](O)=[O:34]>CN(C=O)C>[Br:31][CH2:32][C:33]([NH:25][C:24]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:23]=1[F:22])=[O:34]
Reactant: O=C(O)CBr
Reactant: Nc1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CBr)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
WSC (2.1 g, 11 mmols) and HOBt (1.49 g, 11 mmols) were added to a DMF (30 ml) solution of 2,4-difluroaniline (1.29g, 10 mmols) an bromoacetic acid (2.08 g, 15 mmols), and stirred at room temperature for 12 hours. The reaction mixture was extracted with ether. The organic layer was washed with water, 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through silica gel column chromatography (developer: hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane to obtain 1.7 g (yield: 68%) of 2-bromo-N-(2,4-difluorophenyl)acetamide as colorless needle-like crystals.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][O:21][C:22]3[N:26]=[CH:25][NH:24][N:23]=3)[CH:13]=2)=[O:9])=[N:5][C:4]2[CH:27]=[N:28][N:29]([CH2:30][CH2:31][O:32][C:33]3[CH:42]=[CH:41][C:36]([C:37]([O:39]C)=[O:38])=[CH:35][CH:34]=3)[C:3]1=2.[OH-].[Na+].C1COCC1.CO>O>[O:1]=[C:2]1[NH:7][C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][O:21][C:22]3[N:26]=[CH:25][NH:24][N:23]=3)[CH:13]=2)=[O:9])=[N:5][C:4]2[CH:27]=[N:28][N:29]([CH2:30][CH2:31][O:32][C:33]3[CH:34]=[CH:35][C:36]([C:37]([OH:39])=[O:38])=[CH:41][CH:42]=3)[C:3]1=2
Reactant: COC(=O)c1ccc(OCCn2ncc3nc(C(=O)NCc4cccc(OCCOc5nc[nH]n5)c4)[nH]c(=O)c32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCCn2ncc3nc(C(=O)NCc4cccc(OCCOc5nc[nH]n5)c4)[nH]c(=O)c32)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
A mixture of methyl 4-({2-[7-oxo-5-({[(3-{[2-(1H-1,2,4-triazol-3-yloxy)ethyl]oxy}phenyl)methyl]amino}carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethyl}oxy)benzoate obtained in Example 47 (164 mg, 0.285 mmol), 4N aqueous sodium hydroxide solution (0.250 mL), THF (2 mL), methanol (2 mL) and water (2 mL) was stirred at 90° C. for 2 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with water (20 mL), and acidified with 1N hydrochloric acid (1.5 mL). The precipitated solid was collected by filtration, and washed with water (4 mL×2) and methanol (4 mL). The obtained solid was recrystallized from methanol to give the title compound as a white powder (120 mg, 75%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:21]1[S:25][C:24]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)=[N:23][CH:22]=1)CCC>>[CH3:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:6]2[N:7]=[C:2]([C:21]3[S:25][C:24]([C:26]4[CH:27]=[CH:28][C:29]([C:30]#[N:31])=[CH:32][CH:33]=4)=[N:23][CH:22]=3)[CH:3]=[CH:4][CH:5]=2)[CH:14]=1
Reactant: Cc1ccnc(Nc2cccc(Br)n2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(-c2ccc(C#N)cc2)s1
Product: Cc1ccnc(Nc2cccc(-c3cnc(-c4ccc(C#N)cc4)s3)n2)c1

Procedure:
By following essentially the same procedure in preparative example 020 and starting with 6-bromo-N-(4-methylpyridin-2-yl)pyridin-2-amine (100 mg 0.38 mmol) and 4-(5-(tributylstannyl)thiazol-2-yl)benzonitrile (328 mg, 0.69 mmol), the 4-(5-(6-(4-methylpyridin-2-ylamino)pyridin-2-yl)thiazol-2-yl)benzonitrile was obtained and purified by dry flash chromatography over SiO2 eluting with EtOAc/Cyclohexane 50/50-MeOH (5%) and by trituration with Et2O (51 mg, 37%). 1H NMR (300 MHz, DMSO-d6) δ 9.77 (br s, 1H), 8.65 (s, 1H), 8.20-8.10 (m, 3H), 8.00 (d, J=8.4 Hz, 2H), 7.93 (br s, 1H), 7.75 (t, J=7.9 Hz, 1H), 7.55 (d, J=7.4 Hz, 1H), 7.50 (d, J=8.3 Hz, 1H), 6.80 (d, J=5.1 Hz, 1H), 2.39 (s, 3H). (APCI+) m/z 370 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[CH3:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:42]=[CH:43][C:44]([CH3:45])=[C:23]([NH:22][C:8]([C:7]5[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][CH:6]=5)=[O:10])[CH:24]=4)=[N:32][N:31]3[CH:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: CCn1nccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCn1nccc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1C
Yield: 76 %

Procedure:
In the same manner as in Example 259 and using 1-ethyl-1H-pyrazole-5-carboxylic acid (110 mg, 0.80 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (83 μL, 0.97 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (210 mg, 75%) was obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]=1.[Br:19][CH2:20][CH2:21]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(CC)=O>[Br:19][CH2:20][CH2:21][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:9]=1
Reactant: Oc1ccccc1-c1nc(-c2ccccc2)no1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: BrCCOc1ccccc1-c1nc(-c2ccccc2)no1

Procedure:
1.85 g of 5-(2-hydroxyphenyl)-3-phenyl-1,2,4-oxadiazole are dissolved in 80 ml of methylethylketone, mixed with 5 ml of 1,2-dibromoethane, 6 g of potassium carbonate and 0.1 g of potassium iodide. The mixture is refluxed for 12 hours and after cooling the precipitate is filtered off. The organic phase is evaporated down in vacuo and chromatographed on silica gel first with toluene, then with dichloromethane as eluant. Yield: 2.3 g (86% of theory).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][Cl:19]>CN(C)C=O>[Cl:19][CH2:18][CH2:17][CH2:16][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:12])([CH3:1])[C:3]1=[O:11]
Reactant: CC1(C)C(=O)Nc2ccccc21
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(CCCCl)c2ccccc21
Temperature: 25 °C
Yield: 87.6 %

Procedure:
A solution of 3,3-dimethylindolin-2-one (1.843 g, 11.43 mmol, 1 equiv) in N,N-dimethylformamide was cooled to 0° C. Sodium hydride (60% dispersion) (503 mg, 12.58 mmol, 1.1 equiv) was slowly added and the reaction was stirred as such until all bubbling had stopped. 1-bromo-3-chloropropane (3.37 ml, 34.3 mmol, 3 equiv) was added to the reaction mixture in one portion. The reaction was allowed to warm to ambient temperature and stirred as such for 16 h. The crude mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, concentrated, and the residue was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.5, gradient—5%-30% ethyl acetate in hexanes) to afford the title compound as a light orange oil (2.38 g, 87%); 1H NMR (400 MHz, DMSO-d6): δ 1.26 (s, 6H); 1.98-2.14 (m, 2H); 3.65 (t, 2H, J=6 and 6.8 Hz); 3.77-3.81 (m, 2H); 7.02-7.07 (m, 2H); 7.24-7.28 (m, 1H); 7.33-7.35 (m, 1H); MS for C13H16ClNO m/z 237.99 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][O:8][C:9](=[O:33])[CH2:10][CH2:11][CH2:12][CH:13](Br)[CH:14]1[O:31][C@H:17]2[CH2:18][C@@H:19]([OH:30])[C@H:20](/[CH:21]=[CH:22]/[C@@H:23]([OH:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C@H:16]2[CH2:15]1)[CH2:4][CH3:5])[CH3:2].Cl.P([O-])([O-])([O-])=O>>[CH2:1]([N:3]([CH2:6][CH2:7][O:8][C:9](=[O:33])[CH2:10][CH2:11][CH2:12]/[CH:13]=[C:14]1/[CH2:15][C@@H:16]2[C@@H:20](/[CH:21]=[CH:22]/[C@@H:23]([OH:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C@H:19]([OH:30])[CH2:18][C@@H:17]2[O:31]/1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(C(Br)CCCC(=O)OCCN(CC)CC)O[C@H]2C[C@H]1O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2C/C(=C/CCCC(=O)OCCN(CC)CC)O[C@H]2C[C@H]1O
Yield: 28.8 %

Procedure:
123 mg of (13E)-(5RS,6RS,9α,11α,15S)-5-bromo-6,9-epoxy-11,15-dihydroxyprost-13-enoic acid 2-(N,N-diethylamino)ethyl ester (prepared as described in Example 1) and 0.4 ml of DBU (1,5-diazabicyclo[5.4.0]-undecene-5) were stirred at 50°-60° C. for 3 hours under a nitrogen atmosphere. The solution obtained was cooled to 0°-5° C., 2.5 ml of 1 N hydrochloric acid and 2 ml of a phosphate buffer with a pH of 6.86 cooled to 0°-5° C., were added, and the mixture was extracted with diethyl ether. The extract was washed with water and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using as eluent a mixture of diethyl ether and acetone (6:1) containing 0.1% v/v of triethylamine to give 30 mg of the title compound having the following physical characteristics.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:17])[C:4]1[CH:14]=[C:13]([NH:15][CH3:16])[C:7]([C:8](OCC)=[O:9])=[CH:6][N:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][O:2][N:3]([CH3:17])[C:4]1[N:5]=[CH:6][C:7]([CH2:8][OH:9])=[C:13]([NH:15][CH3:16])[CH:14]=1
Reactant: CCOC(=O)c1cnc(N(C)OC)cc1NC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1cc(N(C)OC)ncc1CO
Reaction time: 0.33 h
Yield: 77.1 %

Procedure:
To a solution of ethyl 6-(methoxy(methyl)amino)-4-(methylamino)nicotinate (6 g, 25 mmol) in THF (60 mL) at 0° C. was added LiAlH4 (1.9 g, 50.2 mmol) in portions under N2 atmosphere. After 20 min, the reaction was quenched by addition of water followed by aqueous 2N NaOH. The resultant suspension was filtered and the filtrate was concentrated in vacuo to afford (6-(methoxy(methyl)amino)-4-(methylamino)pyridin-3-yl)methanol (3.8 g, 77.6% yield), which was used without further purification. 1H NMR (400 MHz, DMSO-d6): δ 7.61 (s, 1 H), 6.08 (s, 1 H), 5.86 (m, 1 H), 4.88 (t, J=5.2 Hz, 1 H), 4.30 (d, J=5.2 Hz, 2 H), 3.64 (s, 3 H), 3.04 (s, 3 H), 2.73 (d, J=4.8 Hz, 3 H); MS (ESI) m/z: 198.2 (M+H+).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:14]([NH:16][C:17]3[S:18][C:19]([CH:22]=O)=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:31]O.Cl.CC(OC(C)=O)=O>N1C=CC=CC=1>[C:22]([C:19]1[S:18][C:17]([NH:16][C:14](=[O:15])[CH:13]([C:10]2[CH:11]=[CH:12][C:7]([S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:5])=[O:6])=[CH:8][CH:9]=2)[CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[N:21][CH:20]=1)#[N:31]
Reactant: NO
Reactant: O=Cc1cnc(NC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cnc(NC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A stirred solution of 2-(4-cyclopropanesulfonylphenyl)-N-(5-formylthiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide (EXAMPLE 86, 369 mg, 0.82 mmol) in pyridine (1.53 mL) was treated with H2NOH.HCl (63 mg, 0.91 mmol) at 0° C. The mixture was stirred at 20° C. for 3 h, before being warmed up to 60° C. and treated with Ac2O (155 μL, 1.65 mmol). After 3 h, the mixture was cooled to 20° C., before being concentrated in vacuo and treated with CH2Cl2 (6 mL) and H2O (6 mL). The aqueous phase was acidified to pH 3 with 10% aqueous citric acid. The organic layer was separated, then the aqueous layer was further extracted with CH2Cl2 (2×10 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated to give a residue that was purified by column chromatography (IH-EtOAc, 1:3) to furnish the title compound: RTA=3.40 min; m/z (ES+)=487.4 [M+MeCN+H]+.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH2:15]([O:17][C:18](=[O:41])[CH2:19][O:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28](=O)[NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=1)[CH3:16]>N1C=CC=CC=1.O.C(OCC)(=O)C>[CH2:15]([O:17][C:18](=[O:41])[CH2:19][O:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28](=[S:2])[NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=1)[CH3:16]
Reactant: CCOC(=O)COc1cc(F)ccc1C(=O)NCc1cccc([N+](=O)[O-])c1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(F)ccc1C(=S)NCc1cccc([N+](=O)[O-])c1
Temperature: 115 °C
Yield: 176.8 %

Procedure:
In a flame dried flask under a nitrogen atmosphere, a suspension of phosphorus pentasulfide (0.77 g, 1.73 mmol) in pyridine (6.9 mL) was treated with [5-fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid ethyl ester (Example 27, 1.3 g, 3.45 mmol) and heated to 115° C. for 4 h. After cooling to room temperature, the mixture was diluted with water and ethyl acetate. The organic layer was washed successively with 2 N HCl and saturated NaCl, dried over MgSO4, and concentrated. The dark orange solid was filtered through a short pad of silica and again concentrated to give [5-fluoro-2-(3-nitro-benzylthiocarbamoyl)-phenoxy]-acetic acid ethyl ester as an orange solid (1.2 g, 89%): mp 118° C.; Rf 0.43 (40% ethyl acetate in heptane); 1H NMR (DMSO-d6 300 MHz) δ 10.71 (s, 1 H), 8.23 (s, 1 H), 8.12 (d, J=8.1 Hz, 1 H), 7.83 (d, J=7.8 Hz, 1 H), 7.71–7.60 (m, 2 H), 7.04 (dd, J1=11.1 Hz, J2=2.4 Hz, 1 H), 6.87 (dt, J1=8.4 Hz, J2=2.4 Hz, 1 H), 5.07 (d, J=3.3 Hz, 2 H), 4.89 (s, 2 H), 4.13 (q, J=6.7 Hz, 2 H), 1.17 (t, J=5.7 Hz, 3 H). ESI-LC/MS m/z calcd for C18H17FN2O5S: 394.1. Found 393.0 (M+1)+. Anal. calcd for C18H17FN2O5S: C, 55.09; H, 4.37; N, 7.14. Found C, 54.98; H, 4.36; N, 7.08.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12](Cl)=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:20]#[N:21].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C1(C)C=CC=CC=1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:20]#[N:21]
Reactant: CN1CCNCC1
Reactant: N#Cc1cnc2cc(Cl)c([N+](=O)[O-])cc2c1Nc1ccc(F)c(Cl)c1
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CN1CCN(c2cc3ncc(C#N)c(Nc4ccc(F)c(Cl)c4)c3cc2[N+](=O)[O-])CC1

Procedure:
A stirred mixture of 4-(3-chloro-4-fluoroanilino)-7-chloro-6-nitro-3-quinolinecarbonitrile (1.88 g, 5.0 mmol), N-methylpiperazine (5 ml, 45 mmol), and 10 ml of toluene was refluxed for 45 m, evaporated to remove volatile matter, and stirred in water with potassium carbonate (2.75 g). The resulting solid was filtered, washed with water, and dried to give 2.26 g. An acetone solution was passed onto a pad of silica gel; elution with 50:2:1 acetone-MeOH-TEA and evaporation gave a red solid, mp 240-246°; ms 441.2 (M+H)+, 221.2 (M+2H)+2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.O[CH2:27][CH2:28][C:29](=[O:31])[CH3:30].N>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:27][CH2:28][C:29](=[O:31])[CH3:30])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2O)cc1
Reactant: CC(=O)CCO
Agent: N
Product: CC(=O)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 460 starting with 2-(4-fluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 4-hydroxy-2-butanone in place of acetol. (yield: 85.0 mg, 20%). mp 133-136° C.; 1H NMR (300 MHz, CDCl3) δ 2.04 (s, 3H), 2.80 (t, J=9 Hz, 2H), 3.13 (s, 3H), 4.76 (t, J=9 Hz, 2H), 7.20 (t, J=9 Hz, 2H), 7.55 (m, 2H), 7.75 (d, J=9 Hz, 2H), 7.91 (s, 1H), 8.05 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 431 (M+H)+, 448 (M+NH4)30 . Anal. calc. for C21 H19FN2O5S: C, 58.60; H, 4.42; N, 6.52. Found: C, 58.87; H, 4.55; N, 6.51.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28](O)=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].FC(F)(F)C(O)=O.[CH3:38][S:39]([CH2:42][CH2:43][NH2:44])(=[O:41])=[O:40].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.C(N(CC)CC)C>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([NH:44][CH2:43][CH2:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CS(=O)(=O)CCN
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[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: ClCCl
Product: CS(=O)(=O)CCNC(=O)c1ccc2c(n1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.8 %

Procedure:
In a dried reaction flask, the crude 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (Compound 1) (0.4 g, about 0.9 mmol), the crude 2-(methylsulfonyl)ethylamine trifluoroacetate (1.258 g, about 4.06 mmol), DIEA (0.86 mL, 4.97 mmol), HATU (1.742 g, 4.581 mmol) and triethylamine (1.08 mL, 7.743 mmol) were added a mixed solvent of DMF (4.5 mL) and dichloromethane (4.5 mL). The mixture was stirred at room temperature for 24 hr, and was concentrated at reduced pressure. Water was added to the residue and the mixture was filtered to produce a crude yellow solid, which was then washed with methanol to produce a purified product (0.378 g) in 79.8% yield.