Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:10]2[C:9]3[CH:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:8]=3[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[N:5]=[CH:4][CH:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:15]([C:12]1[N:13]=[CH:14][C:8]2[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]3[N:5]=[CH:4][CH:3]=[C:2]([NH:25][CH:26]4[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]4)[C:10]=3[C:9]=2[CH:11]=1)#[N:16]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(Cl)ccnc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)CC1
Temperature: 110 °C
Yield: 60 %

Procedure:
A mixture of 4-chloro-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile with 4-chloro-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (6.5:1, 85 mg, 0.24 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (240 mg, 1.2 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20 mg, 0.04 mmol), tris(dibenzylideneacetone)dipalladium(0) (16 mg, 0.02 mmol), and cesium carbonate (150 mg, 0.47 mmol) in 1,4-dioxane (2 mL) was sealed and heated at 110° C. for 2 h. The mixture was diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 40 g, ISCO, 5-75% ethyl acetate in heptane) to afford the title compound as a yellow solid (80 mg, 60%).
Reaction SMILES: C([N:5]([C:13]1[C:17]([CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:16][NH:15][C:14]=1[C:25]([O:27]C)=O)[C:6]([NH:8]C(OC)=O)=[NH:7])(OC)=O.[OH-].[Na+].C(O)(=O)C>CO>[NH2:7][C:6]1[NH:8][C:25](=[O:27])[C:14]2[NH:15][CH:16]=[C:17]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:13]=2[N:5]=1
Reactant: COC(=O)NC(=N)N(C(=O)OC)c1c(Cc2cccnc2)c[nH]c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1nc2c(Cc3cccnc3)c[nH]c2c(=O)[nH]1
Yield: 88 %

Procedure:
Methyl 3-(N,N′-bis-carbomethoxyguanidinyl)-4-(3-pyridylmethyl)-1H-pyrrole-2-carboxylate, obtained from Example 26 (15.0 g, 0.04 mol), methanol (100 mL) and sodium hydroxide pellets (3.7 g, 0.9 mol) were stirred together and boiled under reflux for 18 hours. The mixture was cooled, neutralized with acetic acid (5.4 g. 0.09 mol) and the solid collected by filtration. The product was washed in turn with methanol (20 mL), water (200 mL) and methanol (30 mL) and dried at 110° C. overnight to give 8.2 g (88%) of an off-white powder, mp>300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:32])([C:26]2[N:27]([CH3:31])[CH:28]=[N:29][CH:30]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[C:20]2[S:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:35]I>C1COCC1.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:32])([C:26]2[N:27]([CH3:31])[CH:28]=[N:29][CH:30]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:35])[C:14](=[O:19])[CH:13]=[C:12]3[C:20]2[S:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: Cc1ccc(-c2cc(=O)[nH]c3ccc(C(O)(c4ccc(Cl)cc4)c4cncn4C)cc23)s1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(=O)n(C)c3ccc(C(O)(c4ccc(Cl)cc4)c4cncn4C)cc23)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.7 %

Procedure:
To a solution of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(5-methyl-thiophen-2-yl)-1H-quinolin-2-one (115 mg, 0.248 mmol) in THF (6.6 ml) was added a 40% aqueous NaOH (3.3 ml), benzyltriethylammonium chloride (28 mg. 0.124 mmol) and a solution of methyl iodide (0.017 ml, 0.273 mmol) in THF (0.05 ml). The reaction mixture was stirred at ambient temperature for 1.5 hours after which time it was partitioned between ethyl acetate and 10% aqueous potassium carbonate. The organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to give the crude product. It was chromatographed on silica gel with MeOH—CHCl3—NH4 (1:99:0.1) as eluents to afford the title compound as a white solid (68 mg, 0.143 mmol, 58% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].[Cl:18][C:19]1[CH:20]=[C:21]([C:26]2[S:27][CH:28]=[C:29]([CH2:31]Cl)[N:30]=2)[CH:22]=[CH:23][C:24]=1[F:25].ClC1C=C(C=CC=1F)C(N)=S.ClCC(CCl)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:31][C:29]2[N:30]=[C:26]([C:21]3[CH:22]=[CH:23][C:24]([F:25])=[C:19]([Cl:18])[CH:20]=3)[S:27][CH:28]=2)=[CH:8][C:7]=1[CH3:13]
Reactant: Fc1ccc(-c2nc(CCl)cs2)cc1Cl
Reactant: CCO[C@@H](Cc1ccc(O)cc1C)C(=O)OC
Agent: NC(=S)c1ccc(F)c(Cl)c1
Agent: O=C(CCl)CCl
Agent: O=C([O-])[O-]
Product: CCO[C@@H](Cc1ccc(OCc2csc(-c3ccc(F)c(Cl)c3)n2)cc1C)C(=O)OC

Procedure:
In analogy to the procedure described in example 14 b], (2S)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester was reacted with 2-(3-chloro-4-fluoro-phenyl)-4-chloromethyl-thiazole (prepared from 3-chloro-4-fluoro-thiobenzamide and 1,3-dichloroacetone in analogy to the procedure described in example 4 a]) in the presence of cesium carbonate and potassium iodide to yield (2S)-3-{4-[2-(3-chloro-4-fluoro-phenyl)-thiazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid methyl ester as yellow liquid.
Reaction SMILES: [CH:1]1([CH2:6][O:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:28])=[C:23]([CH:27]=2)[C:24]([OH:26])=O)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH:1]1([CH2:6][O:7][NH:8][C:9](=[O:10])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:28])=[C:23]([C:24]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:26])[CH:27]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(CNc2ccccc2C(=O)NOCC2CCCC2)ccc1F
Product: O=C(NOCC1CCCC1)c1ccccc1NCc1ccc(F)c(C(=O)N2CCOCC2)c1

Procedure:
Prepared by a similar procedure as described for the preparation of Example 499, starting from 5-[(2-cyclopentylmethoxycarbamoyl-phenylamino)methyl]-2-fluoro-benzoic acid (Example 496) and morpholine.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([CH:15]([CH3:17])[CH3:16])[C:6]([S:11]([O-:14])(=[O:13])=[O:12])=[CH:7][CH:8]=[CH:9][CH:10]=1.[Na+].[CH:19](Cl)(Cl)Cl>CN(C=O)C>[C:5]1([CH:15]([CH3:17])[CH3:16])[C:6]([S:11]([O:14][CH3:19])(=[O:13])=[O:12])=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: ClC(Cl)Cl
Reactant: CC(C)c1ccccc1S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COS(=O)(=O)c1ccccc1C(C)C
Yield: 44 %

Procedure:
594.9 g (5.0 mol) of thionyl chloride were initially introduced together with 1 g of DMF, and 222.2 g (1.0 mol) of sodium cumenesulfonate were slowly added in portions starting at room temperature. The mixture was stirred at reflux for 16 hours and 250 ml of chloroform were added after cooling. Following filtration, excess thionyl chloride was stripped off together with the chloroform under reduced pressure. 250 ml of methanol were added, and a pH of 7.0 was established using 25% strength sodium hydroxide solution at 25° C. The mixture was then stirred out with dichloromethane, the organic phase was concentrated on a rotary evaporator, and the residue obtained was subjected to fractional distillation under reduced pressure. At 102° C. and 0.03 mbar, 96.9 g (0.44 mol) of methyl cumenesulfonate were isolated in the form of a clear liquid, corresponding to a yield of 44%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](=O)[CH:8]([CH3:10])[CH3:9])[S:5][CH:6]=1.O.NN.Cl>C(O)CO.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][CH:8]([CH3:10])[CH3:9])[S:5][CH:6]=1
Reactant: CC(C)C(=O)c1cc(Br)cs1
Agent: Cl
Agent: NN
Solvent: OCCO
Solvent: O
Product: CC(C)Cc1cc(Br)cs1
Temperature: 160 °C
Yield: 24.9 %

Procedure:
1-(4-bromo-2-thienyl)-2-methyl-1-propanone (816 mg, 3.52 mmol) was diluted in ethylene glycol (3 mL). Hydrazine monohydrate (0.46 mL, 9.5 mmol, 2.7 eq) was added, and the mixture was heated to 160° C. for 1.5 h behind a blast shield. The mixture was cooled to rt, and diluted with water. 6 M aqueous HCl was added until pH was acidic (pH paper), and the mixture was extracted three times with hexanes. The combined organics were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by biotage, 25M+ column, eluting with 5% ethyl acetate in hexanes. Fractions containing the desired product were concentrated in vacuo to afford the title compound as light yellow oil (192 mg, 25%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:21]=[O:22])=[N:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(=CC)C.P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+].C[Si](C=[N+]=[N-])(C)C.C[C:46](O)=[O:47]>O.CC(O)(C)C>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:21]([O:47][CH3:46])=[O:22])=[N:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:19])[CH3:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)O
Reactant: C[Si](C)(C)CCOCn1nc(C=O)c2ccc([N+](=O)[O-])cc21
Agent: CC=C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: O=P([O-])(O)O
Solvent: O
Solvent: CC(C)(C)O
Product: COC(=O)c1nn(COCC[Si](C)(C)C)c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
6-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbaldehyde (1.72 g, 5.35 mmol, Preparation #N.1) was added to a solution of 2-methyl-2-butene (2.0 M in THF, 26.8 mL, 53.5 mmol) and t-BuOH (48.2 mL) under N2. A solution of sodium dihydrogen phosphate (3.35 g, 27.9 mmol) and sodium chlorite (1.50 g, 16.6 mmol) in water (16.1 mL) was added and the mixture was stirred at rt for about 3 h. The mixture was concentrated under reduced pressure. DCM (50 mL) and aqueous 1 N HCl (20 mL) were added and the layers separated. The aqueous layer was extracted with DCM (15 mL). The combined organic layers were washed with brine (10 mL), dried over Na2CO3, filtered, and concentrated under vacuum. The solid was dissolved in a mixture of THF (64.3 mL) and MeOH (16.1 mL). (Trimethylsilyl)diazomethane (2 M in Et2O, 4.01 mL, 8.03 mmol) was added drop-wise. After about 2 h, AcOH (1 mL) was added and the mixture was stirred for about 14 h. The mixture was concentrated under reduced pressure. DCM (100 mL) was added and the mixture was washed with an aqueous solution of saturated NaHCO3 (25 mL) and the layers separated. The organic layer was washed with brine (10 mL), dried over Na2CO3, filtered and concentrated in vacuo. The residue was purified by column chromatography (80 g silica gel) eluting with 10 to 20% EtOAc/heptane to provide methyl 6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carboxylate (1.66 g, 88%): LC/MS (Table 2, Method c) Rt=2.99 min.; MS m/z: 352 (M+H)+, 369 (M+H2O)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1B(O)O.Br[C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[N:19][NH:20]2)=[C:16]([NH:23][C:24]([C:26]2[N:27]=[C:28]([CH3:31])[S:29][CH:30]=2)=[O:25])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CO.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:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[N:19][NH:20]2)=[C:16]([NH:23][C:24]([C:26]2[N:27]=[C:28]([CH3:31])[S:29][CH:30]=2)=[O:25])[CH:15]=1
Reactant: Cc1nc(C(=O)Nc2cc(Br)cc3[nH]ncc23)cs1
Reactant: OB(O)c1cc2ccccc2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(C(=O)Nc2cc(-c3cc4ccccc4o3)cc3[nH]ncc23)cs1
Temperature: 150 °C
Yield: 3.2 %

Procedure:
To a solution of 1-benzofuran-2-ylboronic acid (24 mg, available from Lancaster Synthesis) in 1,4-dioxane (1 ml) was added a solution of .N-(6-bromo-1H-indazol-4-yl)-2-methyl-1,3-thiazole-4-carboxamide (34 mg) in 1,4-dioxane (1 ml). A solution of potassium carbonate (17 mg) in water (0.2 ml) was then added, followed by Pd(dppf)Cl2 (10 mg). The reaction vessel was sealed and heated under microwave irradiation in CEM Discover at 150° C. for 30 min. The mixture was cooled and the solvent was evaporated in vacuo using the Genevac to give the crude products. The sample was loaded in methanol and applied to a reverse phase (C18) cartridge (500 mg) and eluted using MeCN/TFA 0.1% (3×3 ml). The appropriate fractions were combined and dried under a stream of nitrogen then the residue was dissolved in (3:1, DMSO:MeOH, 0.5 ml) and purified by mass directed preparative HPLC (Method C) to afford the title compound (1.2 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[N:3]=1.[C:26]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Sn](CCCC)(CCCC)CCCC)[N:41]=2)[CH:35]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27].CCCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:26]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[N:41]=[C:42]([C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)[CH:5]=[C:4]([CH2:18][O:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][O:21]4)[N:3]=3)[CH:43]=[CH:44][CH:45]=2)[CH:35]=1)(=[O:32])=[O:33])([CH3:29])([CH3:27])[CH3:28]
Reactant: FC(F)(F)c1ccc(-c2cc(Br)nc(COC3CCCCO3)c2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2cccc(S(=O)(=O)NC(C)(C)C)c2)n1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(COC4CCCCO4)n3)n2)c1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A stirred mixture of 2-bromo-6-(tetrahydro-pyran-2-yloxymethyl)-4-(4-trifluoromethyl-phenyl)-pyridine (Example A.65) (0.400 g, 0.894 mmol), N-tert-butyl-3-(6-tributylstannanyl-pyridin-2-yl)-benzenesulfonamide (Example F.6) (0.518 g, 0.894 mmol), tetrakis(triphenyl-phosphine)palladium (0.052 g, 5 mol %) in toluene (5 mL) was heated under reflux conditions for 18 h. After cooling to rt, the reaction mixture was directly subjected to silica gel column chromatography with n-heptane/ethyl acetate to give the N-tert-butyl-3-[6′-(tetrahydro-pyran-2-yloxymethyl)-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonamide (550 mg, 98%) as a light yellow oil. MS (ISP) 626.0 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[F:21][C:22]([F:35])([F:34])[O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:22]([F:21])([F:34])[F:35])=[CH:29][CH:28]=2)(=[O:32])=[O:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (521 mg, 2.8 mmol) in DCM (6 ml) was added NEt3 (547 μl, 3.92 mmol, 1.4 eq.) and 4-trifluoromethoxy-benzenesulfonyl chloride (880 mg, 3.36 mmol, 1.2 eq.). The reaction mixture was stirred at room temperature for 12 hrs. The excess of sulfonyl chloride was quenched by addition of trisamine resin (150 mg), and subsequent stirring for 2 hrs. The resin was then filtered off, and NaHCO3 sat (5 ml) was added. Filtration of the resulting mixture through hydrophobic catridge and subsequent removal of the solvent under reduced pressure afforded the desired 4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester in quantitative yield.
Reaction SMILES: [OH-].[Na+].[NH2:3][C@@H:4]([C:9]([OH:11])=[O:10])[C:5]([CH3:8])([CH3:7])[CH3:6].[OH-].[NH4+].N>>[NH2:3][CH:4]([C:9]([OH:11])=[O:10])[C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[C@@H](N)C(=O)O
Agent: N
Agent: [NH4+]
Agent: [Na+]
Product: CC(C)(C)C(N)C(=O)O
Reaction time: 12 h

Procedure:
A process was developed to racemize D-tert-leucine so that it can be recycled. Use of acids, although caused racemization, resulted in salt formation. It was tedious to obtain free amino acid from such salts. The same drawback was observed when a strong base such as sodium hydroxide was used. However, treating D-tert-leucine with ammonium hydroxide resulted in complete racemization. The reaction has to be conducted at about 80° C. for about 12 hours in an autoclave to prevent the escape of ammonia. The solvent is removed at 55° C. (±5) under reduced pressure to obtain DL-tert-leucine. After the reaction, although ammonium salt of DL-tent-leucine is obtained, during the removal of the solvent, ammonia also is eliminated and free amino acid is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]1(B(O)O)[CH2:13][CH2:12]1.C1(C)C(C)=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CCCCCC.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.C(OC(=O)C)C>[CH:11]1([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: OB(O)C1CC1
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: [K+]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=[N+]([O-])c1cnccc1C1CC1
Temperature: 130 °C
Yield: 736.3 %

Procedure:
4-Chloro-3-nitropyridine (100 mg, 0.630 mmol) and cyclopropyl boronic acid (10.0 mg, 0.091 mmol) were added to a solution of xylene (3 mL) previously purged with argon (10 minutes). The reaction mixture was purged with argon for a further 15 minutes, followed by the addition of potassium carbonate (174.35 mg, 1.26 mmol) and Pd(PPh3)4 (34.5 mg, 0.063 mmol). The resulting mixture was heated to reflux at 130° C. overnight. The reaction was monitored by TLC (30% ethylacetate in hexane). The reaction mixture was cooled and concentrated to afford the crude product. Purification by column chromatography on silica gel (15% ethyl acetate in hexane) afforded 110 mg of the product (100% yield). LCMS Purity: 99%, m/z=165 (M+1)
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH2:6][N:5](C(OCC2C=CC=CC=2)=O)[CH2:4]1)[CH3:2].Br>CCOCC.O.C(Cl)Cl>[CH2:1]([C@H:3]1[CH2:4][NH:5][CH2:6][C@H:7]1[C:8]1[N:12]2[C:13]3[CH:19]=[CH:18][N:17]([S:20]([C:23]4[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=4)(=[O:21])=[O:22])[C:14]=3[N:15]=[CH:16][C:11]2=[N:10][CH:9]=1)[CH3:2]
Reactant: CC[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1c1cnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: Br
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: CC[C@H]1CNC[C@H]1c1cnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of (cis)-benzyl 3-ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidine-1-carboxylate (0.838 g, 1.541 mmol, prepared using E from Example #36 Step D with TFA, N, R, S.1 with Example #3 Step E, and T with Lawesson's reagent) was added a solution of HBr (2.50 mL, 15.19 mmol, 33% in acetic acid). The reaction mixture was stirred at ambient temperature for about 1 h. The reaction was diluted with Et2O (50 mL) and water (20 mL). The layers were stirred for about 3 min and the organic layer was decanted then the procedure was repeated 5 times. The aqueous layer was cooled to about 0° C. was basified with saturated aqueous NaHCO3 solution (10 mL) to about pH 7. The aqueous layer was extracted with EtOAc (3×50 mL), combined, and dried over anhydrous Na2SO4, filtered and concd to give a brown solid. The solid was dissolved in DCM (50 mL) and washed with water (3×20 mL), dried over anhydrous Na2SO4, filtered and coned to afford 8-((cis)-4-ethylpyrrolidin-3-yl)-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (0.453, 61%) as a brown residue: LC/MS (Table 1, Method a) Rt=1.73 min; MS m/z: 410 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH3:14])[CH2:10][C@@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]2=[O:31])=[CH:21][C:20]=1[F:32].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.C(N(CC)CC)C>C(Cl)(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH3:14])[CH2:10][C@@H:9]1[C:15](=[O:17])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]2=[O:31])=[CH:21][C:20]=1[F:32])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CO[C@@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Nc1ccc(N2CCCCC2=O)cc1F
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CO[C@@H]1C[C@H](C(=O)Nc2ccc(N3CCCCC3=O)cc2F)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
Into a solution of 6 (0.250 g, 1.02 mmol) in CHCl3 (10 mL) was added 7 (0.212 g, 1.02 mmol), EEDQ (0.302 g, 1.22 mmol), and triethylamine (0.213 mL, 1.53 mmol). The solution was stirred at reflux for 19 h before cooling to RT and adding EtOAc. The solution was washed sequentially with 10% aq. citric acid, 1N NaOH, water, and brine, before drying over MgSO4 and concentrating under reduced pressure. The crude material was purified by flash chromatography to reveal 8 (0.329 g, 74%) as a tan foam. MS: APCI (AP+): 436.1 (M)+, (AP−): 434.1 (M)−.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([CH3:22])=[N:19][C:18]=2[CH:23]=1.IC>C1COCC1.C(OCC)(=O)C>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([CH2:22][CH3:1])=[N:19][C:18]=2[CH:23]=1
Reactant: Cc1nc2cc(Br)ccc2s1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: CCOC(C)=O
Product: CCc1nc2cc(Br)ccc2s1
Reaction time: 0.33 h

Procedure:
A 0° C. solution of diisopropylamine (340 μL, 2.41 mmol) in THF (3 mL) was treated with 2.5M n-butyllithium in hexanes (0.88 mL), stirred for 20 minutes, added to a −78° C. solution of 5-bromo-2-methyl-1,3-benzothiazole (250 mg, 1.10 mmol) in THF (3 mL), stirred for 30 minutes, treated with iodomethane (340 μL, 5.50 mmol), and stirred for 1 hour. The mixture was diluted with ethyl acetate (50 mL), washed sequentially with 1M HCl (5 mL), water (5 mL), and brine (5 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 30% hexanes/dichloromethane to provide the desired product. MS (DCI) m/e 242 (M+H)+.