Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[F:14][C:15]1[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=1[O:17][S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19]>C(Cl)Cl>[CH3:13][O:12][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N:3]=[C:2]([NH:1][C:22]([NH:21][S:18]([O:17][C:16]2[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=2[F:14])(=[O:20])=[O:19])=[O:23])[N:11]=1
Reactant: COc1nc(N)nc2nccnc12
Reactant: O=C=NS(=O)(=O)Oc1ccccc1F
Solvent: ClCCl
Product: COc1nc(NC(=O)NS(=O)(=O)Oc2ccccc2F)nc2nccnc12
Reaction time: 0.17 h

Procedure:
0.88 g (0.005 mol) of 2-amino-4-methoxypteridine were suspended in 40 ml of methylene chloride and 1.2 g (0.0055 mol) of 2-fluorophenoxysulfonyl isocyanate were added thereto rapidly to obtain a clear solution. The solution was heated to reflux for a short time, thereafter stirred for 10 minutes and then was concentrated by evaporation to dryness. The residue was treated with diisopropyl ether and a little acetone and the mixture was vacuum filtered. The product was dried to obtain 1.95 of N-(4-methoxypteridin-2-yl)-N'-(2-fluorophenoxysulfonyl)-urea in the form of light yellow crystals melting at 135° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](O)=[O:20]>CCOCC.C1COCC1>[Cl:15][C:16]1[CH:17]=[C:18]([C:19](=[O:20])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cccc(Br)c1
Reactant: O=C(O)c1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc(C(=O)c2cccc(Cl)c2)c1
Temperature: -20 °C
Reaction time: 2 h
Yield: 105.4 %

Procedure:
0.2 mol of butyl-lithium (a suspension in ether, containing 1.8 mol/liter) is placed in a 500 cm3 flask; it is cooled to -20° C. and 37.4 g (0.2 mol) of meta-bromoanisole diluted with 50 cm3 of anhydrous ether are added dropwise; when the addition has ended, the mixture is stirred for 10 to 15 minutes at the same temperature and 15.7 g (0.1 mol) of meta-chlorobenzoic acid dissolved in the minimum amount of THF are added dropwise; the temperature is allowed to return to ambient temperature and the reaction mixture is stirred for 2 hours under these conditions; it is then poured onto water, the ether is decanted and the aqueous phase is extracted with ether; the combined ether phases are washed with sodium bicarbonate and then with water, dried, decolorised and concentrated in vacuo. 26 g of a solid melting at 52° C. are obtained.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][NH:4]1.C(N(CC)CC)C.[C:23](=[S:25])=[S:24].Cl>CS(C)=O>[OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][N:4]1[C:23]([SH:25])=[S:24]
Reactant: OC[C@@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: S=C=S
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: OC[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=S)S
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
(3S)-3-Hydroxymethyl-1,2,3,4-tetrahydro-β-carboline (2.02 g) is dissolved in dimethylsulfoxide (10 ml), and thereto are added triethylamine (1.67 ml) and CS2 (0.72 ml), and the mixture is stirred at room temperature for 3 hours. The reaction mixture is poured onto ice-water and is neutralized with 10% HCl. The precipitated crystals are collected by filtration, washed with water and then recrystallized from methanol to give the title compound (1.46 g, 60%) as colorless needles, m.p. 225°-227° C. IR νmaxNujol (cm-1): 3480, 3340; Mass m/e: 278 (M+), 244 (M+ --H2S); [α]D20 +170.0° (c=1.0, methanol).
Reaction SMILES: [C:1]([O:5][NH:6][C:7](=[O:31])[CH:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:38](Br)[C:39]#[CH:40]>CN(C=O)C>[C:1]([O:5][NH:6][C:7](=[O:31])[CH:8]([NH:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:24][CH:25]=1)(=[O:19])=[O:18])[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:40][C:39]#[CH:38])=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCBr
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)NOC(C)(C)C)c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1ccc(C(NS(=O)(=O)c2ccc(OCC#CC)cc2)C(=O)NOC(C)(C)C)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 321.6 mg (0.72 mmol) of ′N-(tert-butoxy)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-(4-hydroxyphenyl)acetamide from Example 176 in 3 ml DMF at 0° C. was added 199 mg (1.44 mmol) of K2CO3. The reaction mixture was stirred for 15 min, 94.4 mg (0.79 mmol) of propargyl bromide was added, and reaction mixture was stirred at room temperature overnight. DMF was removed in vacuo. The residue was diluted with ethyl acetate, washed with 1N HCl solution, water and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was chromatographed on silica gel, eluting with hexane/ethyl acetate (5:1, 4:1 then 3:1) to provide 75 mg (17%) of ′N-(tert-butoxy)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-[4-(2-propynyloxy)phenyl]acetamide as a white solid. Electrospray Mass Spec 485.4 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][NH2:9])=[N:4][CH:5]=[CH:6][N:7]=1.ClC1C(Cl)=NC=CN=1.NN.[C:20](OCC)(OCC)(OCC)[CH2:21][CH3:22]>>[Cl:1][C:2]1[C:3]2[N:4]([C:20]([CH2:21][CH3:22])=[N:9][N:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CCOC(CC)(OCC)OCC
Reactant: NNc1nccnc1Cl
Agent: Clc1nccnc1Cl
Agent: NN
Product: CCc1nnc2c(Cl)nccn12
Temperature: 25 °C

Procedure:
To 3-chloro-2-hydrazinopyrazine (3.0 g, 20.75 mmol), prepared from 2,3-dichloropyrazine and hydrazine using a procedure analogous to that described in the literature (Huynh-Dinh et al, J. Org. Chem. 1979, 44, 1028), was added 8 mL of triethyl orthopropionate. After refluxing for 10 h, the reaction was cooled down to ambient temperature and the precipitate was filtered. The solid was purified by flash chromatography (100% ethyl acetate, then 10% methanol in ethyl acetate) to give 2.73 g of the title compound as a solid. 1H NMR (500 MHz, CDCl3) δ 1.54 (t, 3H, J=7.6 Hz), 3.16 (q, 2H, J=7.8 Hz), 7.70 (d, 1H, J=4.5 Hz), 7.83 (d, 1H, J=4.8 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:26]=2)=[O:24])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[CH3:14][C:3]1[CH:4]=[C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH:6]=[CH:7][C:2]=1[C:17]1[C:16]([CH3:15])=[CH:21][CH:20]=[C:19]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([N:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)[CH:26]=2)=[O:24])[CH:18]=1
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1nnc(-c2ccc(-c3cc(NC(=O)c4ccnc(N5CCCC5)c4)ccc3C)c(C)c2)o1

Procedure:
Example 10 was prepared using 2-(4-bromo-3-methylphenyl)-5-methyl-1,3,4-oxadiazole and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)phenyl]-2-(1-pyrrolidinyl)-4-pyridinecarboxamide (Intermediate 20).
Reaction SMILES: I[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C:18](=[CH:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[CH3:24].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[N:37]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[N:35]=[C:34]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[N:33]=1>>[CH3:24][C@@H:5]1[CH2:6][C@@H:7]2[C@:21]([CH3:22])([CH2:20][CH:19]=[C:18]3[C@H:8]2[CH2:9][CH2:10][C:11]2[C@:16]3([CH3:17])[CH:15]=[CH:14][C:13](=[O:23])[CH:12]=2)[C@H:4]1[C:3](=[O:25])[CH2:2][N:47]1[CH2:48][CH2:49][N:44]([C:34]2[N:35]=[C:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[N:37]=[C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)[N:33]=2)[CH2:45][CH2:46]1
Reactant: c1ccc(-c2nc(-c3ccccn3)nc(N3CCNCC3)n2)nc1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CI
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CN1CCN(c2nc(-c3ccccn3)nc(-c3ccccn3)n2)CC1

Procedure:
Following the general procedure of EXAMPLES 1-6A, 7, 8, 11-19, 83 and 126, and making non-critical variations but starting with 21-iodo-16α-methylpregna-1,4,9(11)-triene-3,20-dione (PREPARATION S-22) and 4-[4,6-bis(2-pyridinyl)-1,3,5-triazin-2-yl]piperazine (PREPARATION A-49) the title compound is obtained.
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1.[SH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C[O-].[Na+].O>CO>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][S:13][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1)[CH3:19]
Reactant: Clc1nc(-c2ccccc2)no1
Reactant: CCOC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CSc1nc(-c2ccccc2)no1
Reaction time: 3 h
Yield: 75 %

Procedure:
5-chloro-3-phenyl-1,2,4-oxadiazole (36 parts) was added portionwise to a solution of ethyl mercaptoacetate (24 parts) and sodium methoxide (11 parts) in methanol (500 parts). The temperature rose to about 50° C. and the mixture was allowed to stand for three hours. The product was poured into an excess of cold water, and extracted with benzene, washed with water and the solvent then evaporated off. Recrystallisation gave ethyl(3-phenyl-1,2,4-oxadiazol-5-ylthio)acetate (40 parts, 75% yield), melting point 50-52° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:10]([F:22])=[C:11]([F:21])[CH:12]=[C:13]2[C:18]=1[C:17](=[O:19])[NH:16][N:15]=[C:14]2[CH3:20].C1C(=O)N([I:30])C(=O)C1>CC(O)=O.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([I:30])[CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:10]([F:22])=[C:11]([F:21])[CH:12]=[C:13]2[C:18]=1[C:17](=[O:19])[NH:16][N:15]=[C:14]2[CH3:20]
Reactant: Cc1n[nH]c(=O)c2c(Nc3ccccc3Cl)c(F)c(F)cc12
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1n[nH]c(=O)c2c(Nc3ccc(I)cc3Cl)c(F)c(F)cc12
Temperature: 85 °C
Yield: 18.5 %

Procedure:
A mixture of 8-(2-chlorophenylamino)-6,7-difluoro-4-methyl-2H-phthalazin-1-one (30 mg, 0.093 mmol) and NIS (24 mg, 0.11 mmol) in AcOH-THF (2 mL/0.5 mL) was heated at 85° C. for 3 minutes The reaction mixture was concentrated in vacuo and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that was purified by silica gel flash column chromatography (100% hexanes to 15% EtOAc in hexanes) to afford 8-(2-chloro-4-iodophenylamino)-6,7-difluoro-4-methyl-2H-phthalazin-1-one (7.7 mg, 17%). MS APCI (−) m/z 446, 448 (M-, Cl pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 10.96 (s, 1H), 7.86 (s, 1H), 7.60 (d, 1H), 7.53 (dd, 1H), 6.94 (t, 1H), 2.47 (s, 3H).
Reaction SMILES: [CH:1]([NH:4][OH:5])([CH3:3])[CH3:2].[CH:6]([C:8]1[O:12][C:11]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:10][CH:9]=1)=O.[Na]>CO>[CH:1]([N+:4]([O-:5])=[CH:6][C:8]1[O:12][C:11]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:10][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)NO
Reactant: O=Cc1ccc(S(=O)(=O)O)o1
Agent: [Na]
Solvent: CO
Product: CC(C)[N+]([O-])=Cc1ccc(S(=O)(=O)O)o1
Reaction time: 24 h
Yield: 75 %

Procedure:
N-Isopropylhydroxylamine (from Example A above) and 5-formylfuran-2-sulfonic acid, sodium salt hydrate (5.94 g) were refluxed in methanol (200 mL) for 24 hours. Another portion of N-isopropylhydroxylamine was added and the reaction stirred for 24 hours. The solvent was stripped to provide a pale yellow solid which was recrystallized from ethyl acetate to afford 5.72 g (75% yield) of the title compound, m.p.=230° C. (decomposed). HPLC analysis showed a major product of 88% by area. Depending upon the pH, the title compound was present as the free acid, or, if in the presence of sodium cations and a higher pH, as the sodium salt. Other salt forms can be prepared by changing the cation.
Reaction SMILES: O=[C:2]([CH:8]1[C:17](=O)[C:16]2[C:11](=[CH:12][C:13]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:14][CH:15]=2)[S:10][CH2:9]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(OC([NH:31][NH:32][CH:33]1[CH2:38][CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]1)=O)(C)(C)C.Cl>CCO>[NH:35]1[CH2:36][CH2:37][CH2:38][CH:33]([N:32]2[C:17]3[C:16]4[CH:15]=[CH:14][C:13]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=4[S:10][CH2:9][C:8]=3[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:31]2)[CH2:34]1
Reactant: CC(C)(C)OC(=O)NNC1CCCN(C(=O)OC(C)(C)C)C1
Reactant: CCOC(=O)C(=O)C1CSc2cc(OC(F)(F)F)ccc2C1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1nn(C2CCCNC2)c2c1CSc1cc(OC(F)(F)F)ccc1-2
Temperature: 75 °C
Yield: 84.2 %

Procedure:
To a solution of ethyl oxo[4-oxo-7-(trifluoromethoxy)-3,4-dihydro-2H-thiochromen-3-yl]acetate (3.00 g; 8.61 mmol; 1 eq.) and tert-butyl 3-[2-(tert-butoxycarbonyl)hydrazino]piperidine-1-caroxylate (4.08 g; 12.92 mmol; 1.50 eq.) in EtOH (80 ml) is added HCl (4M in dioxane, 42.38 mL) were added in a dropwise fashion. Reaction mixture is heated at 75° C. for 5 h after which it is concentrated under vacuum, partitioned between NaHCO3 sat (pH 7-8) and EtOAc. Organic layer is washed NaHCO3 sat and brine, dried over MgSO4 to give 3.1 g (88%) of the title compound as a brown solid. 1H NMR (DMSO, 300 MHz): δ 7.77 (d, J=9.43 Hz, 1H), 7.62 (s, 1H), 7.39 (d, J=7.7 Hz, 1H), 4.61-4.46 (m, 1H), 4.40-4.26 (m, 2H), 4.17 (s, 1H), 4.09-3.98 (m, 1H), 3.19-3.06 (m, 1H), 2.97-2.82 (m, 2H), 2.17-2.05 (m, 2H), 1.99 (s, 1H), 1.80-1.67 (m, 1H), 1.67-1.45 (m, 1H), 1.32 (t, J=7.0 Hz, 3H), 1.18 (t, J=6.9 Hz, 1H).
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([CH:15]=[O:16])=[N:10]2.O>C1COCC1>[Br:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([CH:15]([OH:16])[CH3:1])=[N:10]2
Reactant: C[Mg]Br
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2nc1C=O
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1nc2cccc(Br)c2nc1NC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 92.2 %

Procedure:
Methylmagnesium bromide (Aldrich) (3.0M in Et2O; 2.23 mL, 6.70 mmol) was added to a solution of 5-bromo-3-(tert-butylamino)quinoxaline-2-carbaldehyde (306a) (983.0 mg, 3.19 mmol) in THF (15.0 mL) at 0° C., and the resulting solution was stirred at 0° C. for 5 min. Water (5 mL) was added, and the resulting mixture was partitioned between saturated aq. NaHCO3 (80 mL) and EtOAc (120 mL). The organic layer was separated and sequentially washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-40% EtOAc/hexanes) furnished 1-(5-bromo-3-(tert-butylamino)quinoxalin-2-yl)ethanol (952 mg, 2.94 mmol, 92% yield) as a light-yellow solid (following trituration with hexanes). 1H NMR (400 MHz, CDCl3) δ ppm 7.83 (1H, dd, J=7.6, 1.4 Hz), 7.75 (1H, dd, J=8.2, 1.4 Hz), 7.19 (1H, t, J=7.9 Hz), 5.74 (1H, br. s.), 5.01 (1H, q, J=6.7 Hz), 3.55 (1H, br. s.), 1.63 (9H, s), 1.59 (3H, d, J=6.7 Hz). m/z (EST, +ve) 324.1/326.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:13])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([Cl:12])[CH:8]=[CH:7][CH:6]=2.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(O)(O)=O>CC#N.O>[Cl:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:2]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:15]([F:26])([F:25])[F:14])[C:3]([CH3:13])=[N:4]2
Reactant: Cc1nc2cccc(Cl)c2nc1Cl
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: O=C(O)O
Solvent: CC#N
Solvent: O
Product: Cc1nc2cccc(Cl)c2nc1-c1ccccc1C(F)(F)F
Temperature: 100 °C
Reaction time: 13.5 h

Procedure:
A mixture of 3,5-dichloro-2-methylquinoxaline (1.1209 g, 5.261 mmol), 2-(trifluoromethyl)phenylboronic acid (1.099 g, 5.787 mmol), tetrakis(triphenyl-phosphine)palladium (0.3040 g, 0.2630 mmol), and sodium carbonate anhydrous (2.788 g, 26.30 mmol) in 53 mL of CH3CN—H2O (3:1) was stirred at 100° C. After 13.5 h, the mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (50 mL×3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a red syrup. The red syrup was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 20 min as eluent to give 5-chloro-2-methyl-3-(2-(trifluoromethyl)phenyl)quinoxaline as a red solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09 (1H, dd, J=8.4, 1.4 Hz), 8.02 (1H, dd, J=7.6, 1.2 Hz), 7.98 (1H, d, J=7.8 Hz), 7.73-7.92 (4H, m), 2.47 (3H, s); LC-MS (ESI) m/z 323.0 [M+H]+.
Reaction SMILES: [C:1](#[N:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:7][OH:8].[ClH:9]>COC(C)(C)C>[ClH:9].[C:1](=[NH:6])([O:8][CH3:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CO
Reactant: CCCCC#N
Agent: Cl
Solvent: COC(C)(C)C
Product: CCCCC(=N)OC
Temperature: 5 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A 10 gallon, glass-lined fixed reactor was charged with 7.0 kg (84.6 mol) of valeronitrile and 2.96 kg (92.2 mol, 1.1 eq) of methanol. The solution was stirred with cooling to about 5° C. under an atmosphere of nitrogen. A flow of hydrogen chloride gas from a gas cylinder was bubbled into the solution below the surface of the mixture at a rate such that the reaction temperature did not exceed 15° C. After about one hour, 3.67 kg (101 tool, 1.19 eq) of hydrogen chloride had been disbursed from the gas cylinder and addition was stopped. Stirring was continued for an additional 18 h at 0° C. Tert-butyl methyl ether (9.7 kg) was added to the suspension and stirring was continued for 3 h at 0° C. The slurry was then centrifuged under an atmosphere of nitrogen. After drying overnight under nitrogen and for several hours under reduced pressure at ambient temperature the product weighed 9.66 kg (76% yield uncorrected for purity) and had amp of 91°-92° C. The crude product was hygroscopic and was stored in sealed bottles under nitrogen at -5° C.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]2[C:5]([CH:6]([NH:15][C:16]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH:21]=[N:22][NH:23]4)=[O:17])[CH2:7][C:8]3([O:12]2)[CH2:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=1.[H-].[Na+].S(OC)(O[CH3:34])(=O)=O>CN(C)C=O>[F:1][C:2]1[CH:14]=[C:13]2[C:5]([CH:6]([NH:15][C:16]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH:21]=[N:22][N:23]4[CH3:34])=[O:17])[CH2:7][C:8]3([O:12]2)[CH2:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc2[nH]ncc12)NC1CC2(CCC2)Oc2cc(F)ccc21
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc2c(NC(=O)NC3CC4(CCC4)Oc4cc(F)ccc43)cccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of Example 3D (483 mg, 1.32 mmol) in N,N-dimethylformamide (5 mL) was treated with 60% NaH (65 mg, 1.63 mmol), and the mixture was stirred at room temperature for 45 min. Dimethyl sulfate (0.14 mL, 1.48 mmol) was then added, and the reaction was allowed to stir for 1 h. Concentration in vacuo, followed by silica gel chromatography (98:2 CH2Cl2-methanol, eluent), afforded the title compound as an off-white solid, 121 mg (24%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.74 (s, 1H), 8.03 (s, 1H), 7.72 (d, J=7.1 Hz, 1H), 7.29 (m, 2H), 7.16 (d, J=8.5 Hz, 1H), 6.77 (m, 2H), 6.66 (dd; J=10.5, 7.8 Hz; 1H), 4.97 (m, 1H), 4.01 (s, 3H), 2.40 (m, 1H), 2.12-2.30 (m, 4H), 1.65-1.99 (m, 3H). MS (ESI+) m/z 381 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10](Cl)[C:5]2=[N:4][CH:3]=1.[CH:12]([NH2:15])([CH3:14])[CH3:13]>>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:15][CH:12]([CH3:14])[CH3:13])[C:5]2=[N:4][CH:3]=1
Reactant: Clc1nccn2c(Br)cnc12
Reactant: CC(C)N
Product: CC(C)Nc1nccn2c(Br)cnc12

Procedure:
(3-Bromo-imidazo[1,2-a]pyrazin-8-yl)-isopropyl-amine was prepared by a process analogous to that described in Example 2 starting from 3-bromo-8-chloro-imidazo[1,2-a]pyrazine and isopropylamine.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH2:18][CH2:19][C:20]1([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)[CH2:30][CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH2:12][CH2:13][O:14][C:15](=[O:17])[CH3:16])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].C(N(CC)CC)C.[O:49]1[CH:53]=[CH:52][CH:51]=[C:50]1[C:54](Cl)=[O:55].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:1]([O:4][CH2:5][C:6]([CH2:18][CH2:19][C:20]1([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([N:34]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)[C:54]([C:50]3[O:49][CH:53]=[CH:52][CH:51]=3)=[O:55])[CH2:30][CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH2:12][CH2:13][O:14][C:15](=[O:17])[CH3:16])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC(CCC1(CCN2CCC(Nc3ccc(C)cc3)CC2)CCCCC1)(COC(C)=O)COC(C)=O
Reactant: O=C(Cl)c1ccco1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCC(CCC1(CCN2CCC(N(C(=O)c3ccco3)c3ccc(C)cc3)CC2)CCCCC1)(COC(C)=O)COC(C)=O
Reaction time: 17 h

Procedure:
To a solution of 2-(acetoxymethyl)-2-[2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]ethyl]-1,4-diacetoxybutane (synthesized in Example 13) (324 mg) dissolved in dichloromethane (4 mL) was added triethylamine (0.16 mL). 2-Furoyl chloride (0.084 mL) was added to the solution under ice cooling, and the temperature was then allowed to rise to room temperature. The solution was stirred for 17 hours. A 10% aqueous citric acid solution was added to the solution and the solution was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (1:1)] to give the title compound (356 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=3)(=[O:16])=[O:15])[CH2:10][CH:9]1[CH2:27][C:28](O)=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:43][S:44]([NH2:47])(=[O:46])=[O:45].C1CCN2C(=NCCC2)CC1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=3)(=[O:15])=[O:16])[CH2:10][CH:9]1[CH2:27][C:28](=[O:29])[NH:47][S:44]([CH3:43])(=[O:46])=[O:45])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1CC(=O)O
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1CC(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In tetrahydrofuran (10 ml) was dissolved 1-tert-butoxycarbonyl-2-carboxymethyl-4-[(5-chloroindol-2-yl)sulfonyl]piperazine (1.00 g), followed by the addition of carbonyldiimidazole (1.06 g). The resulting mixture was heated overnight under reflux. After cooling to room temperature, methanesulfonamide (415 mg) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.64 ml) were added, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. Dichloromethane was added to the residue and the resulting mixture was washed successively with 1N hydrochloric acid, and saturated aqueous NaCl solution. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (Φ3.0×10.0 cm, dichloromethane:methanol=100:1), whereby the title compound (518 mg, 44%) was obtained as colorless foam.