Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:15][O:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH2:4][CH2:5][C:6]([CH3:14])([O:8][O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:7])[CH3:3].C(OOC(C1C=CC=CC=1)(C)C)(C1C=CC=CC=1)(C)C>>[CH3:3][C:2]([O:15][O:16][C:17]([CH3:20])([CH3:19])[CH3:18])([C:4]#[C:5][C:6]([CH3:7])([O:8][O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:14])[CH3:1]
Reactant: CC(C)(C)OOC(C)(C)CCC(C)(C)OOC(C)(C)C
Agent: CC(C)(OOC(C)(C)c1ccccc1)c1ccccc1
Product: CC(C)(C)OOC(C)(C)C#CC(C)(C)OOC(C)(C)C

Procedure:
2,5-dimethyl-2,5-di(t-butylperoxy)hexane; dicumylperoxide (DCP).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[F:7][C:8]([F:21])([F:20])[C:9]1[CH:10]=[C:11]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1)[NH2:12]>>[F:7][C:8]([F:20])([F:21])[C:9]1[CH:10]=[C:11]([NH:12][C:1](=[O:5])[C:2]([NH:12][C:11]2[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=[C:9]([C:8]([F:7])([F:20])[F:21])[CH:10]=2)=[O:3])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Into a 250 mnL Schlenk vessel was placed 100 mL of dry TBF, 3.50 g of oxalyl chloride and 12.4 g of 3,5-bis(trifluoromethyl)aniline. The mixture was refluxed under argon for 12 hours and then allowed to cool. All of the solvent was removed in vacuo to leave a pale brown solid. This was washed with hexane and toluene and pumped dry. Yield 10.33 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=O)=[S:10])=[CH:4][CH:3]=1.COC1C=CC(NC(NNC(C2SC=CC=2)=O)=S)=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)=[N:12][NH:11][C:9]2=[S:10])=[CH:4][CH:3]=1
Reactant: O=C(NNC(=S)Nc1ccc(Br)cc1)c1cccs1
Agent: COc1ccc(NC(=S)NNC(=O)c2cccs2)cc1
Product: S=c1[nH]nc(-c2cccs2)n1-c1ccc(Br)cc1
Yield: 57.9 %

Procedure:
By substituting 2 g of N1-(4-bromophenylaminothiocarbonyl)-N2-(thien-2-carbonyl)hydrazine for the N1-(4-methoxyphenylaminothiocarbonyl)-N2-(thien-2-carbonyl)hydrazine in the method of Example 97, 1.1 g of the title compound is obtained as an off-white solid.
Reaction SMILES: [K].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[S:15][C:14]([S:16](O)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:6]([F:20])[CH:5]=1)#[N:3].C(Cl)(=O)C(Cl)=O.C[N:28](C=O)C>C(OCC)(=O)C.[Cl-].[Na+].O>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[S:15][C:14]([S:16]([NH2:28])(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:6]([F:20])[CH:5]=1)#[N:3]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(Sc2ccc(S(=O)(=O)O)s2)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [K]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Sc2ccc(S(N)(=O)=O)s2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
The potassium salt of 5-[4-cyano-2-fluorophenylthio]thiophene-2-sulfonic acid (11.70 g, 33.12 mmol) was suspended in ethyl acetate and oxalyl chloride (8.41 g, 66.23 mmol) then cooled to -50° C., DMF (1.21 g, 16.56 mmol) was added dropwise and stirring at room temperature was continued overnight. The mixture was then cautiously diluted with 150 ml of brine. After washing the organic layer with H2O, 50 ml of concentrated NH4OH was added and the mixture was stirred for 2 hours. The solution was made acidic with HCl and diluted with water. The layers were separated and the organic phase was dried over MgSO4, filtered and concentrated to dryness to give 4.83 g of solid.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[CH:14]=[C:13]([CH:16]([CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:17](O)=[O:18])[CH:12]=[CH:11][C:10]=2[S:9](=[O:28])(=[O:27])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[NH2:29][C:30]1[S:31][CH:32]=[CH:33][N:34]=1.C(N(CC)C(C)C)(C)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][N:2]1[C:15]2[CH:14]=[C:13]([CH:16]([CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:17]([NH:29][C:30]3[S:31][CH:32]=[CH:33][N:34]=3)=[O:18])[CH:12]=[CH:11][C:10]=2[S:9](=[O:28])(=[O:27])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: Nc1nccs1
Reactant: CN1c2ccccc2S(=O)(=O)c2ccc(C(CC3CCOCC3)C(=O)O)cc21
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1c2ccccc2S(=O)(=O)c2ccc(C(CC3CCOCC3)C(=O)Nc3nccs3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg of 2-(10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-3-(tetrahydropyran-4-yl)propionic acid, 74.8 mg of commercially available 2-aminothiazole and 220 μl of N,N-diisopropylethylamine are dissolved in 10 ml of dimethylformamide. 212 mg of TOTU are added, and the mixture is stirred at room temperature overnight. The reaction mixture is then diluted by addition of 50 ml of ethyl acetate and washed five times with in each case 30 ml of saturated sodium bicarbonate solution. The organic phase is dried over MgSO4, and the solvent is then removed under reduced pressure. The residue is purified by RP-HPLC. This gives 141 mg of 2-(10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylpropionamide as a colorless lyophilisate.
Reaction SMILES: [CH2:1]([CH:5]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:6][O:7][C:8]1[C:17]2[CH:16]=[C:15]3[S:18][CH:19]=[CH:20][C:14]3=[C:13]([O:21][CH2:22][CH:23]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:12]=2[CH:11]=[C:10]2[S:34][CH:35]=[CH:36][C:9]=12)[CH2:2][CH2:3][CH3:4].C([Li])CCC.[Sn:48](Cl)([CH3:51])([CH3:50])[CH3:49].O>C1COCC1.CCCCCC>[CH2:1]([CH:5]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:6][O:7][C:8]1[C:9]2[CH:36]=[C:35]([Sn:48]([CH3:51])([CH3:50])[CH3:49])[S:34][C:10]=2[CH:11]=[C:12]2[C:17]=1[CH:16]=[C:15]1[C:14](=[C:13]2[O:21][CH2:22][CH:23]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:20]=[C:19]([Sn:48]([CH3:51])([CH3:50])[CH3:49])[S:18]1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCCCC(CCCC)COc1c2ccsc2cc2c(OCC(CCCC)CCCCCC)c3ccsc3cc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCCCCCC(CCCC)COc1c2cc([Sn](C)(C)C)sc2cc2c(OCC(CCCC)CCCCCC)c3cc([Sn](C)(C)C)sc3cc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
A solution in which 0.48 g of 4,9-bis(2-butyloctyloxy)-1,6-dithia-dicyclopenta[b,g]-naphthalene (0.78 mmol) prepared in Example 2 was dissolved in 20 mL of dry THF was cooled to −78° C., 1.9 mL of n-butyllithium (2.5M solution in hexane, 4.72 mmol) was added thereto. The reaction solution was stirred for 30 minutes and then stirred again at room temperature for 30 minutes. The reaction solution was cooled to −78° C. again, and 4.72 mL of Me3SnCl (1M solution in hexane, 4.72 mmol) was slowly dropped therein. After the reaction solution was stirred again for 30 minutes, a temperature of the reaction solution was raised to room temperature, and the reaction solution was stirred for 12 hours. Water was added to the reaction solution, and a solvent layer was separated. The separated solvent layer was condensed, diluted with hexane, washed with distilled water, dried over Na2SO4, followed by filtering. Then, the obtained filtrate was condensed. The condensed filtrate was recrystallized using isopropanol, thereby obtaining 0.5 g of the title compound (68%) as a yellow solid.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[O-:13][C:14]#[N:15].[Na+]>C(O)(=O)C>[CH:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[C:14]([NH2:15])=[O:13])([CH3:3])[CH3:2]
Reactant: N#C[O-]
Reactant: COc1ccc(NC(C)C)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(N(C(N)=O)C(C)C)cc1

Procedure:
To a solution of 4.47 g (27.1 mmol) isopropyl-(4-methoxy-phenyl)-amine in 70 ml acetic acid are added in small portions 1.72 g (25.4 mmol) sodium cyanate while keeping the temperature below 15° C. by means of an ice bath. After stirring for 2 h at room temperature the acetic acid is evaporated and the residue is taken up in dichloromethane and washed with aqueous sodium hydroxide solution (1M). The organic phase is evaporated and the crude product is purified by recrystallization from dichloromethane/hexanes to yield 1-isopropyl-1-(4-methoxy-phenyl)-urea.
Reaction SMILES: [C:1]([Si:5]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:6][CH2:7][C:8]([CH3:15])([CH3:14])[C:9](=O)[CH2:10][C:11]#[N:12])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:29]([O:36][C:37]1[CH:38]=[C:39]([NH:43][NH2:44])[CH:40]=[CH:41][CH:42]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C>C(O)C.CCOC(C)=O>[CH2:29]([O:36][C:37]1[CH:38]=[C:39]([N:43]2[C:11]([NH2:12])=[CH:10][C:9]([C:8]([CH3:15])([CH3:14])[CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:44]2)[CH:40]=[CH:41][CH:42]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)CC#N
Reactant: NNc1cccc(OCc2ccccc2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(N)n(-c2cccc(OCc3ccccc3)c2)n1
Yield: 107 %

Procedure:
A solution of Intermediate 153b (1.00 g, 2.63 mmol) in ethanol (IMS grade, 20 mL) was treated with 3-benzyloxyphenylhydrazine hydrochloride (0.66 mL, 2.63 mmol) then DIPEA (0.46 mL, 2.63 mmol) and the mixture was heated to reflux for 114 h. The cooled reaction mixture was diluted with EtOAc and a saturated aqueous sodium bicarbonate solution and the mixture was filtered and the phases separated. The aqueous layer was extracted with EtOAc (×2) and the combined organic phase was washed with brine, dried (Na2SO4), and concentrated in vacuo to give an orange oil (1.62 g). The gum was purified by FCC, using 0-20% EtOAc in cyclohexane, to give the title compound as a yellow oil (1.21 g, 80%). LCMS (Method 3): Rt 5.40 min, m/z 576.5 [MH+].
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]([CH3:37])([CH3:36])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:35])[CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]([OH:34])([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[CH:7][CH:6]=1.[OH-].[Na+].[ClH:41]>CO>[ClH:41].[OH:34][C:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([CH3:37])([CH3:36])[C:3]([OH:38])=[O:2])=[CH:6][CH:7]=2)=[O:35])[CH2:16][CH2:17]1
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C(=O)O)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 68 °C

Procedure:
Dissolve 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetic acid methyl ester (0.131 mol) in methanol (2.5 L) and add 10% sodium hydroxide (769 mL, 1.92 mol). Stir at reflux for 1.5 hours, cool to 68° C. and evaporate the solvent in vacuo to a residue. Add chloroform (1 L) and stir until the solids are dissolved. Separate the organic phase and extract the aqueous phase with chloroform (3×300 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo to give a residue. Treat the residue with ethereal HCl, filter and dry to give the title compound.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[O:13][CH:14]([CH3:16])[CH3:15].[OH-].[Na+]>C1COCC1>[C:10]([C:8]1[CH:7]=[CH:6][C:5]([O:13][CH:14]([CH3:16])[CH3:15])=[C:4]([CH:9]=1)[C:3]([OH:17])=[O:2])(=[O:12])[CH3:11]
Reactant: COC(=O)c1cc(C(C)=O)ccc1OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OC(C)C)c(C(=O)O)c1
Temperature: 80 °C

Procedure:
To 25.8 mmol 5-acetyl-2-isopropoxy-benzoic acid methyl ester in 100 ml THF was 400 mmol 2 M aq NaOH, and the mixture was heated at 80° C. for 2 h. The mixture en cooled to RT and extracted twice with ether. The aqueous phase was acidified with q hydrochloric acid and extracted 3 times with ethyl acetate. The combined organic were dried with Na2SO4. Evaporation in vacuo followed by trituration in ether ed the title compound. MS (m/e): 221.2 ([M−H]−, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=O)[CH:19]([CH3:21])[CH3:20])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[S:32])[CH:19]([CH3:21])[CH3:20])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)C(=O)Nc1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)C(=S)Nc1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Temperature: 110 °C
Yield: 46.3 %

Procedure:
To N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)isobutyramide (50 mg, 0.16 mmol) in toluene (2 mL) at 110° C. was added Lawesson's reagent (35 mg, 0.09 mmol). The resulting solution was heated at 110° C. for 7 h. After cooling, the solution was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, then dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 20:80 v/v to afford 13.8 mg (26%) of the title compound (LCMS RT=7.36 min, MH+331.2)
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:32][CH2:33][C:34]#[CH:35])[C:27]=1[O:28][CH2:29][C:30]#[CH:31])[CH:23]=[O:24].C(O)C>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:32][CH2:33][C:34]#[CH:35])[C:27]=1[O:28][CH2:29][C:30]#[CH:31])[C:23]([OH:3])=[O:24]
Reactant: C#CCOc1cc(C=O)cc(Cl)c1OCC#C
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: C#CCOc1cc(C(=O)O)cc(Cl)c1OCC#C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Jones reagent (e.g. an aqueous sulfuric acid solution of chromium trioxide) was added to a solution of 3-chloro-4,5-dipropargyloxybenzaldehyde (18.0 g) in acetone (100 ml) under stirring at a temperature below 20° C. The addition was stopped when the reaction mixture became red, and stirring was continued at 20° C. for 1 hour. The reaction mixture was poured into ice-water containing ethanol (100 ml) and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane to give 3-chloro-4,5-dipropargyloxybenzoic acid (16.2 g). m.p. 158°-159° C.
Reaction SMILES: [C:1](=[N:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[CH3:23])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:1](=[N:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[CH2:23][Br:24])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C#N)ccc1N=C(c1ccccc1)c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc(N=C(c2ccccc2)c2ccccc2)c(CBr)c1
Yield: 56.9 %

Procedure:
To a solution of 4-(benzhydrylidene-amino)-3-methyl-benzonitrile (1.36 g, 4.27 mmol) in 40 mL of CCl4 is added N-bromosuccinimide (0.84 g, 4.7 mmol) and benzoyl peroxide (0.22 g, 0.64 mmol). The solution is heated to reflux for 16 h. The solution is cooled to ambient temperatures. The solution is diluted with CH2Cl2. The solution is washed with 1N NaOH and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude material is purified by column chromatography eluting with a gradient of 5% EtOAc/hexanes to 10% EtOAc/hexanes. The title compound (0.91 g, 2.43 mmol) is obtained as an oil.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.[H-].[Na+].CN(C)C=O.Cl[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[N+:24]([O-:26])=[O:25]>C(O)(=O)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([S:1][C:2]2[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=2)=[C:17]([N+:24]([O-:26])=[O:25])[CH:18]=1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Cn1ccnc1S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc(Sc2nccn2C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
To a mixture of 2-mercapto-1-methylimidazole (1.14 g, 10 mmoles), 0.6 of 60% sodium hydride in mineral oil and 20 ml of N,N-dimethylformamide was added 1.88 g (10 mmoles) of 4-chloro-3-nitroanisole. The mixture was stirred at room temperature for 0.5 hours and then heated at 90°-100° C. for 4 hours. After cooling in an icebath, 0.5 ml of acetic acid was added and the mixture was partitioned between dichloromethane and dilute sodium bicarbonate. The organics were concentrated on a steam bath to a small volume and the residue was chromatographed on silica gel using ethyl acetate as the eluent. The fractions containing the product were combined and concentrated to give 1.0 g (38%) of the product, mp 117°-120° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[C:19]([O:24]C)=[N:20][CH:21]=[CH:22][CH:23]=3)[N:12]=2)[CH3:9])=[N:6][CH:7]=1>Br.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[C:19](=[O:24])[NH:20][CH:21]=[CH:22][CH:23]=3)[N:12]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncccc1Nc1nccc(N[C@@H](C)c2ccc(F)cn2)n1
Agent: Br
Solvent: O
Product: C[C@H](Nc1ccnc(Nc2ccc[nH]c2=O)n1)c1ccc(F)cn1
Temperature: 100 °C
Yield: 40.9 %

Procedure:
A suspension of (S)—N4-(1-(5-fluoropyridin-2-yl)ethyl)-N2-(2-methoxypyridin-3-yl) pyrimidine-2,4-diamine (Preparation 1 b, 11 mg, 0.03 mmol) in 48% aqueous hydrogen bromide solution (2 mL) was stirred and heated to 100° C. for 5 hours. After cooling to ambient temperature, the reaction mixture was diluted with water and extracted with dichloromethane. The pH of the aqueous phase was then adjusted to ca. 8 with 2M aqueous sodium hydroxide solution and extracted (×3) with dichloromethane. The combined organic extracts were washed with water and brine, dried (MgSO4), filtered and the solvent evaporated under reduced pressure to yield the title compound (4 mg, 38%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](O)=[O:9])[CH:3]=1.[NH2:11][C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][CH:13]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH3:21][O:20][C:18]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:11][C:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)=[O:9])[N:17]=1)=[O:19]
Reactant: COC(=O)c1cccc(N)n1
Reactant: O=C(O)c1cc(Cl)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)c1cccc(NC(=O)c2cc(Cl)ccn2)n1
Yield: 93 %

Procedure:
A solution of 4-chloro-pyridine-2-carboxylic acid (16.3 g, 103 mmol), methyl 6-aminopicolinate (3.0 g, 18.6 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 41.1 g, 108 mmol), and N-methyl morpholine (12.5 mL, 108 mmol) in N,N-dimethylformamide was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, and the residue suspended in acetonitrile. The solid thus obtained was isolated by filtration, washed with water (80 mL), acetonitrile (80 mL) and diethyl ether (80 mL) and dried under reduced pressure to afford 6-[(4-chloro-pyridine-2-carbonyl)-amino]-pyridine-2-carboxylic acid methyl ester as a white powder (25.6, 93% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][S:15][C:11]=2[C:10](I)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([Si:21]([CH3:43])([CH3:42])[O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:27](B(O)O)=[CH:26]2)([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C(OCC)(=O)C>[C:35]([O:34][C:32]([N:28]1[C:29]2[C:25](=[CH:24][C:23]([O:22][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:42])[CH3:43])=[CH:31][CH:30]=2)[CH:26]=[C:27]1[C:10]1[C:11]2[S:15][CH:14]=[CH:13][C:12]=2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[N:9]=1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)n1nc(I)c2sccc21
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(O[Si](C)(C)C(C)(C)C)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Yield: 61 %

Procedure:
To a solution of 3-iodo-thieno[3,2-c]pyrazole-1-carboxylic acid tert-butyl ester (200 mg, 0.57 mmol, Example 5B) and bis-(diphenylphosphinoferrocene)-dichloro palladium (complex with dichloromethane 1:1, 21 mg, 0.03 mmol) in 1,4-dioxane (5 mL) is added 5-(tert-butyl-dimethyl-silanoxy)-1-(tert-butoxycarbonyl)-1H-indole-2-boronic acid (335 mg, 0.86 mmol, prepared as described in Example 4-6 of International Patent Application Publication No. WO 02/32861) followed by a solution of cesium carbonate (741 mg, 2.28 mmol) in water (2 mL). The mixture is stirred at reflux for 15 minutes. Then it is diluted with ethyl acetate and washed with water and brine. The organic layer is dried over magnesium sulfate and concentrated. The residue is chromatographed through silica gel (n-heptane-ethyl acetate, 95:05 as eluant) to afford 200 mg (61%) of 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-(tert-butyl-dimethyl-silanoxy)-indole-1-carboxylic acid tert-butyl ester as a white foam. LC/MS: RT=4.29 minutes, 570.1 m/e.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:6]2[NH:7][C:8]([C:14]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:15]=3[N:16]=[C:17]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])[C:18]([CH3:24])=[N:19]4)=[CH:9][C:10]=2[C:11](O)=[O:12])[CH2:5][CH2:4]1.C(Cl)Cl.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CCOC(C)=O.CN(C=O)C>[CH3:24][C:18]1[C:17]([NH:25][CH2:26][C:27]([F:29])([F:30])[F:28])=[N:16][C:15]2[C:20](=[CH:21][CH:22]=[CH:23][C:14]=2[C:8]2[NH:7][C:6]3[C:3]4([CH2:5][CH2:4]4)[NH:2][C:11](=[O:12])[C:10]=3[CH:9]=2)[N:19]=1
Reactant: Cc1nc2cccc(-c3cc(C(=O)O)c(C4(N)CC4)[nH]3)c2nc1NCC(F)(F)F
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)C3(CC3)NC4=O)c2nc1NCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 8.8 %

Procedure:
1-(3-carboxy-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrolo-2-yl)cyclopropanaminium chloride (381b, 800 mg, 1.81 mmol) was treated with DCM (15 mL) and DMF (15.00 mL) followed by DIEA (1.27 mL, 7.24 mmol) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (1131 mg, 2.17 mmol). The reaction mixture was then stirred at RT for 15 min. It was diluted with EtOAc (100 mL) and washed with a saturated solution of NaHCO3, and brine (3×50 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (0-20% MeOH in DCM) twice to give 2′-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (381) (62 mg, 0.16 mmol, 9% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.60 (1H, s), 7.87 (1H, d, J=6.8 Hz), 7.72 (1H, t, J=6.3 Hz), 7.62-7.70 (2H, m), 7.44 (1H, t, J=7.8 Hz), 6.90-6.97 (1H, m), 4.31-4.45 (2H, m), 2.59 (3H, s), 1.36-1.45 (2H, m), 1.26 (2H, d, J=5.9 Hz). 19F NMR (376 MHz, DMSO-d6) δ ppm −69.21 (1F, s), −69.64 (1F, s), −71.10 (1F, s). m/z (ESI, +ve ion) 388.0 (M+H)+.