Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:3]=1[C:4]([C:6]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([Cl:27])=[CH:8][N:7]=1)=O.[Si]([N:37]=[C:38]=[O:39])(C)(C)C.[OH-].[Na+]>C1COCC1.CC(O)=O.CO>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:11]2[C:6]([CH:4]3[C:3]4[C:2](=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:32])[NH:1][C:38](=[O:39])[NH:37]3)=[N:7][CH:8]=[C:9]([Cl:27])[CH:10]=2)(=[O:14])=[O:15])=[CH:17][C:18]=1[C:23]([F:26])([F:25])[F:24]
Reactant: Nc1cccc(Cl)c1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: C[Si](C)(C)N=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1Nc2cccc(Cl)c2C(c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)N1
Temperature: 75 °C
Reaction time: 12 h

Procedure:
N-(2-(2-Amino-6-chlorobenzoyl)-5-chloro-pyridin-3-yl)-4-chloro-3-(trifluoromethyl) benzenesulfonamide (26 mg, 0.05 mmol) in THF (2 mL) was treated with TMS-isocyanate (100 mg) and AcOH (0.5 mL) and then stirred at 75° C. for 12 h. To the mixture was added MeOH (0.5 mL), followed by NaOH (5 N, 1 mL), and the resultant mixture stirred at 75° C. for another 2 h. To the mixture was added AcOH (0.5 mL), and the mixture was purified through HPLC and dried (lyophilizer) to afford the title compound: 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 2H), 8.34 (d, 1 H), 8.14 (d, 1 H), 7.90 (dd, 1 H), 7.66 (d, 1 H), 7.46 (s, 1 H), 7.16 (t, 1 H), 6.90 (d, 2H), 6.81 (d, 1 H), 6.14 (d, 1 H); MS (ES) (M+H)+ expected 550.9, found 550.9.
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[CH3:13][C:14]1[CH:18]=[C:17]([CH3:19])[NH:16][C:15]=1/[CH:20]=[C:21]1\[C:22](=[O:30])[NH:23][C:24]2[C:29]\1=[CH:28][CH:27]=[CH:26][CH:25]=2>C1COCC1>[CH3:13][C:14]1[CH:18]=[C:17]([CH3:19])[NH:16][C:15]=1/[CH:20]=[C:21]1\[C:22](=[O:30])[N:23]([C:7]([Cl:10])=[O:6])[C:24]2[C:29]\1=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: Cc1cc(C)c(/C=C2\C(=O)Nc3ccccc32)[nH]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)Cl)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To the solution of triphosgene (7.2 gram, 24.2 mmol) in 500 mL of anhydrous THF was added 56 mL of thiethylamine in one portion and the resulting mixture was stirred at room temperature for 10 minutes. Solid 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole (5.768 gram, 24.2 mmol) was added in one portion to the above mixture. The reaction mixture was stirred at room temperature for 1 h and then cooled on ice bath to 0-4° C. Ice-cold 4M HCl aq. (1.5 L) was added in one portion upon vigorous stirring. The resulting suspension was further stirred for 10 min., and filtered. The solid was washed with ice-cold 4M HCl aq. and dried on the high vacuum oven overnight. The crude product was recrystallized from anhydrous benzene and filtered. The solid was then washed with cyclohexane and dried in a vacuum oven overnight to yield 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl chloride (5.531 gram, 76%). 1HNMR (400 MHz, DMSO-d6) δ 12.41 (s, br, 1H), 7.98 (m, 1H), 7.52 (m, 1H), 7.43 (s, 1H), 7.25 (m, 1H), 6.08 (d, br, J=2 Hz, 1H), 2.43 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1[CH2:13][CH2:12][CH2:11][CH2:10]1>C(N(CC)CC)C>[CH2:1]([N:8]1[CH2:4][C:3]2[C:11](=[CH:12][CH:13]=[CH:1][CH:2]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Product: c1ccc(CN2Cc3ccccc3C2)cc1

Procedure:
In Scheme 3, the bis-bromomethyl benzoic acid ester (26) is reacted with benzylamine in a polar aprotic solvent such as tetrahydrofuran (THF) in the presence of a non-interfering base such as triethylamine to give the N-benzyl dihydroisoindole intermediate (27). The ester group in intermediate (27) is then reduced to the corresponding alcohol using lithium aluminium hydride in THF to give the hydroxymethyldihydroisoindole intermediate (28). Debenzylation of the hydroxymethyldihydroisoindole intermediate (28) is then carried out by hydrogenation over palladium on charcoal catalyst in an alcohol (e.g. ethanol) solvent at a mildly elevated temperature (e.g. up to about 50°) to give the intermediate (29). Intermediate (29) is then converted to intermediate (20) by reaction with a reagent suitable for introducing a benzyloxycarbonyl (“Z”) group onto the nitrogen atom of the dihydroisoindole ring. For example, the intermediate (29) can be reacted with benzyl chloroformate in a polar non-protic solvent such as THF in the presence of a non-interfering base such as triethylamine to give intermediate (20).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].FC(F)(F)C(O)=O.[CH3:13][C:14]1[O:18][N:17]=[C:16]([C:19]2[N:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)=[O:34])=[C:28]([CH2:41][N:42]4[CH2:46][CH2:45][CH2:44][C:43]4=[O:47])[CH:27]=3)=[CH:21][CH:20]=2)[N:15]=1>>[CH3:13][C:14]1[O:18][N:17]=[C:16]([C:19]2[N:24]=[CH:23][C:22]([O:25][C:26]3[CH:27]=[C:28]([CH2:41][N:42]4[CH2:46][CH2:45][CH2:44][C:43]4=[O:47])[C:29]([NH:32][C:33]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)=[O:34])=[C:30]([N+:1]([O-:4])=[O:2])[CH:31]=3)=[CH:21][CH:20]=2)[N:15]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1nc(-c2ccc(Oc3ccc(NC(=O)c4ccccn4)c(CN4CCCC4=O)c3)cn2)no1
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2ccc(Oc3cc(CN4CCCC4=O)c(NC(=O)c4ccccn4)c([N+](=O)[O-])c3)cn2)no1
Temperature: 80 °C
Yield: 95.2 %

Procedure:
126 mg of potassium nitrate was added to a trifluoroacetic acid (3 ml) solution of 117 mg of N-{4-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl]oxy}-2-[(2-oxopyrrolidin-1-yl)methyl]phenyl}pyridine-2-carboxamide, and stirred under heat at 80° C. for 7 hours. Trifluoroacetic acid was evaporated away under reduced pressure, then chloroform was added to the residue, and washed with aqueous saturated sodium hydrogencarbonate solution. The organic layer was dried, and the solvent was evaporated away under reduced pressure to obtain 122 mg of N-{4-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl]oxy}-2-nitro-6-[(2-oxopyrrolidin-1-yl)methyl]phenyl}pyridine-2-carboxamide as a brown oil.
Reaction SMILES: [CH3:1][N:2]([CH3:59])[C@H:3]1[CH2:56][C@@H:55]([CH3:57])[O:54][CH:5]([O:6][C@@H:7]2[C@@H:23]([CH3:24])[C:22](=[O:25])[C@@H:21]([CH3:26])[C:20](=[O:27])[O:19][C@H:18]([CH2:28][CH3:29])[C@:17]3([CH2:30][OH:31])[C@H:13]([N:14]([CH2:33][CH2:34][CH2:35][CH2:36][N:37]4[CH:41]=[C:40]([C:42]5[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=5)[N:39]=[CH:38]4)[C:15](=[O:32])[O:16]3)[C@@H:12]([CH3:48])[C:11](=[O:49])[C@H:10]([CH3:50])[CH2:9][C@:8]2([O:52][CH3:53])[CH3:51])[C@@H:4]1[OH:58].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(OCC)(=O)C>[CH3:59][N:2]([CH3:1])[C@H:3]1[CH2:56][C@@H:55]([CH3:57])[O:54][CH:5]([O:6][C@@H:7]2[C@@H:23]([CH3:24])[C:22](=[O:25])[C@@H:21]([CH3:26])[C:20](=[O:27])[O:19][C@H:18]([CH2:28][CH3:29])[C@:17]3([CH:30]=[O:31])[C@H:13]([N:14]([CH2:33][CH2:34][CH2:35][CH2:36][N:37]4[CH:41]=[C:40]([C:42]5[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=5)[N:39]=[CH:38]4)[C:15](=[O:32])[O:16]3)[C@@H:12]([CH3:48])[C:11](=[O:49])[C@H:10]([CH3:50])[CH2:9][C@:8]2([O:52][CH3:53])[CH3:51])[C@@H:4]1[OH:58]
Reactant: CC[C@H]1OC(=O)[C@H](C)C(=O)[C@H](C)[C@@H](OC2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@H]2N(CCCCn3cnc(-c4cccnc4)c3)C(=O)O[C@]12CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC[C@H]1OC(=O)[C@H](C)C(=O)[C@H](C)[C@@H](OC2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@H]2N(CCCCn3cnc(-c4cccnc4)c3)C(=O)O[C@]12C=O
Reaction time: 3 h
Yield: 19 %

Procedure:
To (3aR,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyl-3a-(hydroxymethyl)-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (1 eq) in dichloromethane was added Dess-Martin Periodinane (1.1 eq). After stirring for 3 hours, more Dess-Martin Periodinane (1 eq) was added. After stirring for an additional 15 hours, the solution was diluted with ethyl acetate and was washed with 1:1 10% Na2S2O3/NaHCO3(sat), with NaCl(sat.), dried over MgSO4, filtered and concentrated. Purification by RP HPLC yielded (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyl-3a-formyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (19% yield) as a white solid. MH+(826.5).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([C:13]#[N:14])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:42][C:43]1[CH:56]=[CH:55][C:46]([O:47][C:48]2[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][CH:49]=2)=[CH:45][CH:44]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:13]([C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@H:9]([C:15](=[O:17])[NH:52][C:51]2[CH:50]=[CH:49][C:48]([O:47][C:46]3[CH:55]=[CH:56][C:43]([F:42])=[CH:44][CH:45]=3)=[CH:54][CH:53]=2)[CH2:10]1)#[N:14]
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](C#N)C[C@H]1C(=O)O
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
Product: CC(C)(C)OC(=O)N1C[C@H](C#N)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Step (a) A flask was charged with (2S,4R)-1-(tert-butoxycarbonyl)-4-cyanopyrrolidine-2-carboxylic acid (1.0 g, 4.16 mmol), HATU (1.74 g, 4.58 mmol), 4-(4-fluorophenoxy)aniline (0.844 g, 4.16 mmol), DIEA (4.8 mL, 27 mmol) and DMF (10 mL). The reaction mixture was stirred at ambient temperature for 30 minutes and then quenched with saturated sodium bicarbonate (aq., 20 mL). The mixture was extracted with ethyl acetate (60 mL) and the extract was washed with deionized water (30 mL), and then brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give (2S,4R)-tert-butyl 4-cyano-2-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidine-1-carboxylate. The crude mixture was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([N+:22]([O-])=O)=[C:5]([CH3:21])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:8]=1.O.NN>CCO>[NH2:22][C:4]1[NH:3][C:2]([CH3:1])=[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:8]=2)[C:5]=1[CH3:21]
Reactant: Cc1[nH]c([N+](=O)[O-])c(C)c1-c1ccnc(Nc2ccc(F)cc2)n1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1[nH]c(N)c(C)c1-c1ccnc(Nc2ccc(F)cc2)n1
Yield: 33.6 %

Procedure:
[4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine (45 mg, 0.14 mmol) was dissolved in EtOH (3 mL) and 10% Pd(C) catalyst (10 mg) was added, followed by hydrazine hydrate (48 μL of a 55% w/w aq solution, 0.84 mmol). The mixture was heated at reflux for 18 h. The cooled mixture was filtered through a pad of Celite filter aid and the filtrate was evaporated in vacuo. The residue was purified by SiO2 chromatography (20:1 EtOAc/2 M ammonia in MeOH) to afford the title compound (14 mg) as a yellow solid. M.p. 227–231° C. MS: [M+H]+=397.8 (C16H16FN5 requires 297.3). 1H-NMR (CDCl3) δ: 1.98 (s, 3H, CH3), 2.37 (s, 3H, CH3), 4.86 (br. s, 2H, NH2), 6.65 (d, 1H, J=4.9 Hz, pyrimidinyl-H), 7.03 (t, 2H, J=8.3 Hz, Ph-H), 7.49 (br. s, 2H, NH), 7.58–7.61 (m, 2H, Ph-H), 8.53 (d, 1H, J=4.9 Hz, pyrimidinyl-H).
Reaction SMILES: [CH2:1]([N:8]([CH3:12])[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20](F)[C:17]=1[C:18]#[N:19]>CN(C=O)C.CCOCC>[CH2:1]([N:8]([CH2:9][CH2:10][O:11][C:20]1[CH:21]=[CH:22][CH:23]=[C:16]([Cl:15])[C:17]=1[C:18]#[N:19])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c(F)cccc1Cl
Reactant: CN(CCO)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(CCOc1cccc(Cl)c1C#N)Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of N-benzyl-N-methylethanolamine (145 g) in dry DMF (500 ml) was added dropwise to a stirred suspension of sodium hydride (35.15 g of a 60% dispersion in mineral oil) in dry DMF (1000 ml) over 20 minutes under nitrogen. The mixture was heated on a steam bath for 30 minutes to give a solution. The solution was cooled to ambient temperature and a solution of 2-chloro-6-fluorobenzonitrile (136.7 g) in dry DMF (300 ml) was added over 30 minutes with stirring. The mixture was heated on a steam bath for 3 hours with stirring and distilled at approximately 13 mbar to remove 1 liter of DMF. The residue was cooled to ambient temperature and poured into ice (2 l), basified with 5M sodium hydroxide solution to pH 14 and extracted with dichloromethane to give an oil. This oil was dissolved in ether (2 l) and washed with water (4×200 ml). The ether solution was extracted with 2M hydrochloric acid (500 ml) which gave three layers in the separating funnel. The bottom two layers were run off and the top ether layer was extracted with 2M hydrochloric acid (2×250 ml). The combined acidic layers were basified with concentrated sodium hydroxide solution with cooling and then extracted with dichloromethane to give 2-[2-(N-benzyl-N-methylamino)ethoxy]-6-chlorobenzonitrile as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:26]#[C:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:23]=[CH:24][CH:25]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:1][C:2]1[C:7]2[C:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[CH:21]=3)=[C:27]([Si:28]([CH3:31])([CH3:29])[CH3:30])[NH:9][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccnc(Cl)c1I
Reactant: COc1cccc(C#C[Si](C)(C)C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-c2c([Si](C)(C)C)[nH]c3ccnc(Cl)c23)c1
Reaction time: 12 h

Procedure:
7.6 g (30 mmol) of 2-chloro-3-iodopyridin-4-ylamine from Example B1, 1.7 g (41 mmol) of lithium chloride and 15.9 g (120 mmol) of sodium carbonate are dissolved in 100 ml of DMF, and 8 g (39 mmol) of commercial (3-methoxyphenyl)ethynyltrimethylsilane and 4.9 g (6 mmol) of commercial Pd(dppf)2Cl2*H2Cl2 are added at 100° C. under nitrogen. The mixture is stirred at the temperature indicated for 12 h and subsequently poured at room temperature (RT) into water and extracted with ethyl acetate. The organic phase is concentrated and purified by chromatography over silica gel. The combined product fractions (5.3 g; 53%; pale-brown oil) are used for the subsequent reaction.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=O)[CH2:4][C@H:5]([NH:11]C(=O)OCC1C=CC=CC=1)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.B>O1CCCC1>[CH3:23][N:2]([CH3:1])[CH2:3][CH2:4][C@@H:5]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[NH2:11]
Reactant: CN(C)C(=O)C[C@H](NC(=O)OCc1ccccc1)c1cccs1
Agent: B
Solvent: C1CCOC1
Product: CN(C)CC[C@H](N)c1cccs1
Reaction time: 2 h

Procedure:
A solution of EXAMPLE 161B (400 mg) and borane in tetrahydrofuran (1M, 2.5 mL) in tetrahydrofuran (6 mL) was stirred for 24 hours. The reaction was quenched with methanol, taken up in pH 7 buffer solution, and extracted three times with ethyl acetate. The combined extracts were washed with brine and concentrated. The crude product was taken up in HBr in acetic acid (1.1 mL) and stirred for 2 hours. The reaction was poured into CH2Cl2 (50 mL) and washed with 1M NaOH solution. The organic layer was dried over Na2SO4, and concentrated.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:26]=[CH:25][C:14]3[N:15]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.CCN(C(C)C)C(C)C.[N:37]([CH:40]([CH3:42])[CH3:41])=[C:38]=[O:39]>CN1C(=O)CCC1>[CH:40]([NH:37][C:38]([N:21]1[CH2:22][CH2:23][CH2:24][C@H:19]([NH:18][C:16]2[S:17][C:13]3[CH:12]=[C:11]([O:10][C:8]4[CH:7]=[CH:6][N:5]=[C:4]([C:3]([NH:2][CH3:1])=[O:27])[CH:9]=4)[CH:26]=[CH:25][C:14]=3[N:15]=2)[CH2:20]1)=[O:39])([CH3:42])[CH3:41]
Reactant: CC(C)N=C=O
Reactant: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCNC4)sc3c2)ccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCN(C(=O)NC(C)C)C4)sc3c2)ccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
To the solution of (S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide (13 mg, 30 μmol) and DIPEA (17 μL, 100 μmol) in 300 μL of NMP was added 2-isocyanatopropane (5 μL, 50 μmol). The reaction solution was stirred at room temperature for 18 hours. The crude reaction solution was purified on prep HPLC and evaporated in vacuo to give (S)-4-(2-(1-(isopropylcarbamoyl)piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (5.9 mg, 12 μmol) as white powder. ES/MS m/z 469.2 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[N:13]=2)[NH:8][C:7]=1[CH3:27])=[O:5])[CH3:2].[H-].[Na+].Cl[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[N:13]=2)[N:8]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:7]=1[CH3:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)[nH]c2ncc(-c3cc(OC)c(OC)c(OC)c3)nc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2ncc(-c3cc(OC)c(OC)c(OC)c3)nc12
Reaction time: 0.25 h
Yield: 75.4 %

Procedure:
To a solution of 6-Methyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ethyl ester (108 mg) in 3 ml of DMF was added 60% NaH. After stirring 15 minutes, (2-Chloromethoxy-ethyl)-trimethyl-silane (108 mg) was added and the mixture stirred at rt for 14 h. The mixture was partitioned between water and diethylether. The organic phase was concentrated and purified by flash chromatography (9:1 Hexanes:Ethyl acetate). Obtain 110 mg of 6-Methyl-2-(3,4,5-trimethoxy-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([N:21]3[CH2:25][CH2:24][CH2:23][C@@H:22]3[CH3:26])[C:8]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][N:16]=[CH:15]4)=[N:9]2)=[CH:4][C:3]=1[C:27]([O:29]C)=[O:28].[OH-].[Na+].O>CO>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([N:21]3[CH2:25][CH2:24][CH2:23][C@@H:22]3[CH3:26])[C:8]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][N:16]=[CH:15]4)=[N:9]2)=[CH:4][C:3]=1[C:27]([OH:29])=[O:28]
Reactant: COC(=O)c1cc2nc(N3CCC[C@@H]3C)c(-c3ccc4[nH]ncc4c3)nc2cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)c(O)cc2nc1-c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
To a solution of (S)-methyl 7-hydroxy-2-(1H-indazol-5-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (120 mg, 0.30 mmol) in methanol (10 ml) was added NaOH (48 mg, 1.27 mmol) and water (1 ml). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (15 ml) and adjusted to pH 5 with hydrochloric acid (1N). The solids were collected by filtration to afford (S)-7-hydroxy-2-(1H-indazol-5-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid (65.6 mg, 56%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([S:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24]2)=[CH:19][CH:18]=1)[CH2:13][CH2:14][CH3:15]>C(Cl)Cl>[CH2:12]([S:16]([C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24]2)=[CH:21][CH:22]=1)=[O:9])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCSc1ccc(-n2[nH]c3ccccc3c2=O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCS(=O)c1ccc(-n2[nH]c3ccccc3c2=O)cc1
Reaction time: 0.25 h
Yield: 60.7 %

Procedure:
3-Chloroperbenzoic acid (150mg) was added to a stirred solution of 1,2-dihydro-2-(4-butylthiophenyl)-3H-indazol-3-one (250 mg) in methylene chloride (5 ml) at 0-5° C. Stirring was continued for 15 minutes after the addition was complete. The reaction mixture was then washed with water, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography using methylene chloride/ether (70:30 v/v) to give 1,2-dihydro-2-(4-butylsulphinylphenyl)-3H-indazol-3-one (Ex. 52) as a solid (160 mg), m.p. 168-169° C.
Reaction SMILES: [NH2:1][C:2]1([CH3:13])[C:7](=[O:8])[N:6]([CH2:9][CH3:10])[C:5](=[O:11])[NH:4][C:3]1=[O:12].[F:14][C:15]1[C:16]([F:28])=[C:17]([F:27])[C:18]([F:26])=[C:19]2C(=O)O[C:21](=[O:22])[C:20]=12.CN(C=O)C>O>[CH2:9]([N:6]1[C:7](=[O:8])[C:2]([NH:1][C:21](=[O:22])[C:20]2[CH:19]=[C:18]([F:26])[C:17]([F:27])=[C:16]([F:28])[C:15]=2[F:14])([CH3:13])[C:3](=[O:12])[NH:4][C:5]1=[O:11])[CH3:10]
Reactant: CCN1C(=O)NC(=O)C(C)(N)C1=O
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)NC(=O)C(C)(NC(=O)c2cc(F)c(F)c(F)c2F)C1=O
Temperature: 25 °C

Procedure:
A mixture of 5-amino-1-ethyl-5-methylbarbituric acid (0.37 g, 2 mmol), tetrafluorophthalic anhydride (0.44 g, 2 mmol) and DMF (14 mL) was stirred under reflux for 5 hours. The yellow solution was then allowed to cool down to room temperature and poured into water (50 mL). The precipitate that formed was collected by filtration and dried under reduced pressure to give 20f as white crystals.
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([O:6][P:7]([N:12]1[CH:18]2[CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:17]2)([O:9][CH2:10][CH3:11])=[O:8])[CH3:5]>C1COCC1.[Cu]I>[CH2:4]([O:6][P:7]([NH:12][CH:18]1[CH:13]([CH3:1])[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:17]1)([O:9][CH2:10][CH3:11])=[O:8])[CH3:5]
Reactant: CCOP(=O)(OCC)N1C2CCN(C(=O)OCc3ccccc3)CC21
Reactant: C[Mg]Br
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCOP(=O)(NC1CN(C(=O)OCc2ccccc2)CCC1C)OCC
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a suspension of CuI (0.3 equiv.) in anhydrous THF (0.1M) was added methyl magnesium bromide (3M solution in Et2O, 10 equiv.) at −40° C. The reaction was stirred for 30 min, followed by addition of benzyl 7-(diethoxyphosphoryl)-3,7-diazabicyclo[4.1.0]heptane-3-carboxylate (1.0 equiv.) in THF (0.1M) at −40° C. Allowed the reaction to warm to 10° C. over 5 h, then quenched with water and extracted with ethyl acetate. The organic phase was concentrated under vacuo and purified via silica gel column chromatography eluting with ethyl acetate and hexanes (50% to 100% ethyl acetate) to yield benzyl 3-(diethoxyphosphorylamino)-4-methylpiperidine-1-carboxylate in 35% yield. LCMS (m/z): 385.0 (MH+), Rt=3.38 min.