Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH3:38][S:39]([N:42]1[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]1)(=[O:41])=[O:40]>C1COCC1>[F:36][C:30]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[N:10]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:48][CH:45]3[CH2:46][CH2:47][N:42]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:43][CH2:44]3)[N:7]=2)[C:20]=1[F:37])(=[O:28])=[O:27]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(Nc2nccc(-c3sc(N4CCOCC4)nc3-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)n2)CC1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.2 g, 0.352 mmol) and 1-(methylsulfonyl)-4-piperidinamine (0.314 g, 1.76 mmol) in THF (1 mL) the title compound was obtained as a white solid (0.14 g, 0.197 mmol, 56.0% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.75 (s, 1H), 7.90 (d, J=5.2 Hz, 1H), 7.68-7.71 (m, 1H), 7.45-7.63 (m, 3H), 7.36-7.45 (m, 1H), 7.21-7.35 (m, 2H), 7.05-7.20 (m, 1H), 3.38-3.78 (m, 5H), 3.32 (s, 3H), 2.56-3.18 (m, 4H), 1.38-2.43 (m, 8H). MS (ESI): 710 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.C[O:14][C:15](=O)[CH2:16][CH2:17][CH2:18][NH2:19].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:19]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCCN
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCCN1C1CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 50.6 %

Procedure:
Dissolve 1,4-dioxaspiro{4.5}decan-8-one (100 g, 640.3 mmol), methyl-4-aminobutyrate hydrochloride (98.5 g, 640.3 mmol), triethylamine (90 mL, 640.3 mmol) and dichloromethane (2 L) and stir at room temperature. Add Sodium triacetoxyborohydride (135.7 g, 640.3 mmol) stir 17 h at room temperature. Quench with water (1 L), separate, wash the aqueous layer with dichloromethane (3×500 mL), combine the organic phases and dry over anhydrous sodium sulfate, filter and concentrate. Purify the material on a 1.5 kg silica column, 6 inches in diameter, and eluted with 8:2 hexanes/ethyl acetate to 95:5 ethyl acetate/methanol to give 73 g of the title compound as a waxy brown solid. 1H NMR (CDCl3) δ 3.99-4.10 (m, 1H), 3.93 (s, 4H), 3.32-3.36 (m, 2H), 2.36-2.40 (m, 2H), 1.94-2.03 (m, 2H), 1.65-1.83 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:18][CH:19]([NH2:21])[CH3:20]>>[Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([NH:21][CH:19]([CH3:20])[CH3:18])=[O:17])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C(O)C1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: CC(C)N
Product: CC(C)NC(=O)C1CCc2c(sc3ncnc(Cl)c23)C1

Procedure:
13.18 g (49.05 mmol) (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 31b) were transformed in analogy to example 3 using propan-2-amine to give after working up and purification 11.39 g (71%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:8]([CH3:13])=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2].[Se](=O)=[O:15].C(OCC)(=O)C>O1CCOCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:8]([CH:13]=[O:15])=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: O=[Se]=O
Reactant: CCOCCOc1cccnc1C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOCCOc1cccnc1C=O
Temperature: 75 °C
Yield: 38.6 %

Procedure:
A mixture of 3-(2-ethoxyethoxy)-2-methylpyridine (0.506 g, 2.79 mmol) and selenium dioxide (0.31 g, 2.79 mmol) in 1,4-dioxane (10 mL) was heated at 75° C. overnight. After cooling to r.t., the mixture was filtered and the solids were washed with ethyl acetate. The solvent was removed in vacuo. The reaction was not complete and the solid was dissolved in 1,4 dioxane (15 mL) and selenium dioxide (0.31 g, 2.79 mmol) was added. The mixture was heated at 110° C. overnight. Ethyl acetate (10 mL) was added and the mixture was filtered. The black solid was washed with ethyl acetate and the filtrate was evaporated in vacuo. The crude product was purified by flash column chromatography (heptane/ethyl acetate gradient; 0 to 100% ethyl acetate), obtaining 0.21 g (39%) of the title compound.
Reaction SMILES: [NH2:1][C:2](=[O:24])[C@@H:3]([N:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[OH:22])[C:14]1=[O:23])[CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].Cl.Cl[CH2:27][C:28]1[CH:40]=[CH:39][C:31]([CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O.C(OCC)(=O)C>[NH2:1][C:2](=[O:24])[C@@H:3]([N:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[O:22][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:39][CH:40]=2)[C:14]1=[O:23])[CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:7]
Reactant: ClCc1ccc(CN2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)CC[C@@H](C(N)=O)N1Cc2c(O)cccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@@H](C(N)=O)N1Cc2c(OCc3ccc(CN4CCOCC4)cc3)cccc2C1=O
Temperature: 45 °C
Reaction time: 18 h
Yield: 85.9 %

Procedure:
(S)-tert-Butyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (160 g), 4-(4-(chloromethyl)benzyl)morpholine hydrochloride (138 g, 0.87×) and potassium carbonate (165 g, 1.04×) were added to DMF (960 mL, 6×) in a 5 liter jacketed vessel. The mixture was heated to 40 to 50° C. and agitated for 12 to 24 hours. The mixture was cooled to 25 to 35° C., then ethyl acetate (1600 mL, 10×) and water (1600 mL, 10×) were added. The mixture was agitated at 25 to 35° C., settled, and split. Additional ethyl acetate (800 mL, 5×) and water (800 mL, 5×) were added. The mixture was agitated at 25 to 35° C., settled, and split. The combined organic phase was washed four times with water (400 mL, 2.5×). The organic phase was distilled under vacuum below 50° C. to 6× volume. Additional ethyl acetate (2880 mL, 18×) was continuously added, and the distillation was continued to maintain about 6× volume. The temperature was adjusted to 40 to 45° C., then seeds (0.8 g, 0.005×) were added. The mixture was held for about 30 minutes to build seed bed, then heptane (960 mL, 6×) was added over about 1.5 hours. The mixture was cooled to 15 to 25° C. over about 1 to 1.5 hours, agitated at 15 to 25° C. for at least one hour, and held for 16 hours. The solid was filtered, washed with heptane:ethyl acetate (5× total, 2.5× heptane, 2.5× ethyl acetate), and dried under reduced pressure with nitrogen sweep at 35 to 45° C. until LOD≦1%, to give (S)-tert-butyl 5-amino-4-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate as a white solid (215.3 g, 86% yield); MS m/z: 524.3 (M+1); 1H NMR (DMSO-d6, 300 MHz) δ 7.57 (br s, 1H), 7.48-7.43 (m, 3H), 7.34 (d, J=8.1 Hz, 2H), 7.29 (d, J=7.5 Hz, 2H), 7.19 (br s, 1H), 5.21 (s, 2H), 4.71 (dd, J=10.2, 4.2 Hz, 1H), 4.54 (d, J=17.4 Hz, 1H), 4.40 (d, J=17.7 Hz, 1H), 3.56 (dd, J=4.5, 4.5 Hz, 4H), 3.45 (s, 2H), 2.34 (dd, J=4.5, 4.5 Hz, 4H), 2.15-1.99 (m, 4H), 1.32 (s, 9H) ppm; 13C NMR (DMSO-d6, 75 MHz) δ 171.8, 171.3, 167.8, 153.4, 137.7, 135.3, 133.3, 130.2, 129.5, 129.0, 127.6, 115.1, 114.6, 79.7, 69.4, 66.2, 62.1, 53.5, 53.1, 44.8, 31.8, 27.6, 24.8 ppm.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]1[C:16]2[CH:11]([CH2:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][C:8]1=[O:17].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][CH2:2][C:3]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:7]([CH3:6])[C:8](=[O:17])[CH2:9][CH2:10]2)=[O:4]
Reactant: CN1C(=O)CCC2CC=CC=C21
Reactant: O=C(Cl)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CN1C(=O)CCc2cc(C(=O)CBr)ccc21
Temperature: 25 °C

Procedure:
Bromoacetyl chloride (28.3 g) is added dropwise to a suspension of N-methyl-tetrahydroquinolin-2-one (14.7 g) and AlCl3 (26.7 g) in methylene chloride (400 ml), and the reaction mixture is refluxed for 5 hours. The reaction mixture is cooled to RT, stirred with an ice/water mixture for 30 minutes, diluted with methylene chloride (200 ml) and separated. The aqueous layer is extracted with methylene chloride, and the combined organic extracts are washed with H2O, dried, filtered and concentrated in vacuo, yielding a crude solid which is recrystallized from isopropanol affording the desired product as a solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([CH3:28])[CH3:27]>>[CH:26]([N:29]1[CH2:34][CH2:33][N:32]([CH2:2][C:3]([NH:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([NH:14][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22][CH3:23])[O:12][CH2:13][C:8]=3[CH:7]=2)=[O:4])[CH2:31][CH2:30]1)([CH3:28])[CH3:27]
Reactant: CC(C)N1CCNCC1
Reactant: COc1ccccc1CNC1=Nc2ccc(NC(=O)CCl)cc2CO1
Product: COc1ccccc1CNC1=Nc2ccc(NC(=O)CN3CCN(C(C)C)CC3)cc2CO1
Yield: 257.5 %

Procedure:
Prepared from 2-chloro-N-[2-(2-methoxy-benzylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 26 step A) (50 mg, 0.129 mmol, HPLC 0.889 min 81%) and N-isopropylpiperazine (1 ml, 8 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (150 mg, 72%, HPLC 0.492 min 87%), MS (ISP) m/e=452.3 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[S:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1>C(=S)=S>[Cl:1][C:2]1[C:3]([C:4]([C:16]2[S:15][CH:19]=[CH:18][CH:17]=2)=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: c1ccsc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(c1cccs1)c1cccnc1Cl
Temperature: 25 °C

Procedure:
10 g of 2-chloronicotinic acid chloride was added to a mixture of 7.2 g of aluminum chloride and 100 ml of carbon disulfide under ice-cooling, followed by adding 8.8 ml of thiophene was slowly added dropwise thereinto. After stirring at room temperature for two nights, the reaction solution was slowly poured into ice water. The mixture was extracted with ethyl acetate, and the organic phase was successively washed with aqueous saturated sodium bicarbonate and brine. After removing the solvent, the residue was subjected to silica gel column chromatography and eluted with hexane/ethyl acetate (3:1) and then with hexane/ethyl acetate (2:1), to give 1.64 g of the target compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8](Cl)=[C:7]([C:10]#[N:11])[S:6](=[O:13])(=[O:12])[N:5]=1)[CH3:2].C[Si](C)(C)[NH:16][Si](C)(C)C>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([NH2:16])=[C:7]([C:10]#[N:11])[S:6](=[O:13])(=[O:12])[N:5]=1)[CH3:2]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CCOC1=NS(=O)(=O)C(C#N)=C1Cl
Solvent: CCO
Product: CCOC1=NS(=O)(=O)C(C#N)=C1N

Procedure:
The product from Step A was reacted with hexamethyldisilazane followed by ethanol according to the procedure of Example 5. After recrystallization of the crude product from ethanol, there was obtained pure title compound, mp 228°-229°.
Reaction SMILES: [P:1]([Cl:4])(Cl)Cl.[CH2:5]([OH:11])[C:6]([CH3:10])([CH3:9])[CH2:7][OH:8].Cl>C(Cl)(Cl)Cl>[Cl:4][P:1]1[O:11][CH2:5][C:6]([CH3:10])([CH3:9])[CH2:7][O:8]1
Reactant: CC(C)(CO)CO
Reactant: ClP(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC1(C)COP(Cl)OC1
Yield: 95.3 %

Procedure:
To phosphorus trichloride (775.4 g, 5.5 M, 10% molar excess) was added dropwise with stirring over two hours a solution of neopentylene glycol (520.8 g, 5.0 M) in chloroform (1200 ml). After the slight endotherm and evolution of HCl had subsided, the clear colorless solution was freed of most of the chloroform and excess PCl3 by distillation at atmospheric pressure to a pot temperature of 100° C. Distillation of the residue through a short vacuum-jacketed Vigreaux column yielded 803.6 g (95.3% yield) of 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane (III), bp 65° C./10 mm nD25 1.4738, % Cl found 20.71 (21.03 calculated).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(N(C(C)C)CC)(C)C>C(O)(C)C>[NH2:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[C:3]([N:23]2[CH2:22][CH2:21][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:25][CH2:24]2)[C:2]([Br:1])=[CH:7][N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (9 ml) was added 1-BOC-piperazine (0.102 g, 0.55 mmol) followed by diisopropylethylamine (0.10 ml, 0.57 mmol). The reaction mixture was heated at 45° C. for 20 h, then allowed to cool to room temperature, and diluted with isopropanol (3 ml). The precipitate was collected by filtration and washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.112 g, 56%). 1H-NMR (500 MHz, DMSO-d6) 1.42 (s, 9H, C(CH3)3), 2.99 (br s, 4H, piperazine N(CH2)2), 3.45 (br s, 4H, piperazine N(CH2)2), 7.02 (s, 2H, NH2), 8.20 (s, 1H, 6-H); LC (Method B)-MS (ESI, m/z): Rt=5.00 min—402, 404 [(M+H)+, Br isotopic pattern].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=1.[C:17](OCC)(=[O:19])[CH3:18]>[Zn]>[C:17]([O:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:14][CH:13]=1)(=[O:19])[CH3:18]
Reactant: CCOC(C)=O
Reactant: OCc1ccc(COC2CCCCO2)cc1
Agent: [Zn]
Product: CC(=O)OCc1ccc(COC2CCCCO2)cc1
Yield: 84 %

Procedure:
Under a nitrogen atmosphere, a mixture of (4-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)methanol (6 mmol), a zinc cluster Zn4O (OCOCF3)6 (0.075 mmol), and ethyl acetate (1.7 ml) was refluxed for 18 hours. As a result, 4-((tetrahydro-2H-pyran-2-yloxy)methyl)benzyl acetate was obtained in a yield of 84%.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]([C:5]1[C:20]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)=[CH:19][C:8]([C:9]([O:11]CC2C=CC=CC=2)=[O:10])=[C:7]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=1)=[O:4].[OH-].[Li+].O.Cl>O1CCCC1>[CH3:1][N:2]([CH3:35])[C:3]([C:5]1[C:20]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)=[CH:19][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc(OCc2ccccc2)c(C(=O)OCc2ccccc2)cc1-c1cnn(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(OCc2ccccc2)c(C(=O)O)cc1-c1cnn(C)c1
Reaction time: 18 h

Procedure:
To a solution of phenylmethyl 4-[(dimethylamino)carbonyl]-5-(1-methyl-1H-pyrazol-4-yl)-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 40; 195 mg, 0.42 mmol) in tetrahydrofuran (4 ml) was added lithium hydroxide (34 mg, 1.42 mmol) and water (1 ml). The mixture was for 18 hours then 2M hydrochloric acid (0.73 ml, 1.45 mmol) was added. The solvent removed in vacuo to give the title compound as a gum. 154 mg.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].C(OC([N:14](C(OC(C)(C)C)=O)[C:15]1[C:16]([C:27]2[N:28](C(OC(C)(C)C)=O)[C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:17][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:19][N:20]=1)=O)(C)(C)C.C(N(CC)CC)C.Cl.O1CCOCC1>C(Cl)Cl>[CH2:1]([S:3]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[N:17]=[C:16]([C:27]3[NH:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:15]([NH2:14])=[N:20][CH:19]=2)[CH2:26][CH2:25]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(N2CCNCC2)nc1-c1cc2ccccc2n1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3cc4ccccc4[nH]3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.5 %

Procedure:
Ethanesulfonyl chloride (43.25 mg, 31.87 μL, 0.3364 mmol) was added to a solution of tert-butyl 2-[3-(bis(tert-butoxycarbonyl)amino)-6-piperazin-1-yl-pyrazin-2-yl]indole-1-carboxylate (100 mg, 0.1682 mmol) and triethylamine (18.72 mg, 25.79 μL, 0.1850 mmol) in DCM (2 mL) at 0° C. and the reaction mixture allowed to stir at ambient temperature for 30 minutes. The reaction was then treated with HCl in dioxane (210.2 μL of 4 M, 0.8410 mmol) and allowed to stir at ambient temperature overnight. The mixture was concentrated in vacuo and the resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a yellow solid (5.5 mg, 8% Yield). 1H NMR (DMSO) d 1.25 (3H, t), 3.12 (2H, q), 3.30 masked signal, 3.59 (4H, m), 5.66 (2H, br s), 7.00-7.04 (1H, m), 7.14-7.18 (2H, m), 7.51 (1H, m), 7.58 (1H, m), 7.81 (1H, s), 11.25 (1H, br s) ppm; MS (ES+) 386.87
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14](Cl)[C:5]2=[N:4][CH:3]=1)=[CH:11][C:10]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:9][CH:8]=3.[NH2:21][CH2:22][CH2:23][CH2:24][OH:25]>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([NH:21][CH2:22][CH2:23][CH2:24][OH:25])[C:5]2=[N:4][CH:3]=1)=[CH:11][C:10]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:9][CH:8]=3
Reactant: FC(F)(F)Oc1ccc2c(c1)nc(Cl)c1ncc(Br)n12
Reactant: NCCCO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: OCCCNc1nc2cc(OC(F)(F)F)ccc2n2c(Br)cnc12
Yield: 87.6 %

Procedure:
To a stirred solution of 1-bromo-4-chloro-7-trifluoromethoxy-imidazo[1,2-a]quinoxaline (6.5 g, 17.7 mmol, 1 eq) in dioxane (87 mL) is added 3-aminopropan-1-ol (3.4 mL; 44.3 mmol; 2.5 eq). The resulting solution is then heated at reflux for 16 hours until completion of the reaction. The mixture is diluted with ethyl acetate (100 mL) and washed with a 1M aqueous solution of sodium hydroxide (50 mL). The organic layer is separated, dried over sodium sulphate and concentrated in vacuo to afford a beige solid. This powder is washed with diethyl ether to afford after filtration the title compound (6.3 g; 15.5 mmol; 87%) with a 99% HPLC purity.
Reaction SMILES: O1CCCC1.N.[C:7](#[N:16])[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[H][H]>[Co].O>[C:8]1([CH2:7][NH2:16])[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(C#N)cc1
Agent: [Co]
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(CN)cc1
Temperature: 120 °C

Procedure:
A stirred autoclave was charged with 400 ml. tetrahydrofuran (THF), 100 ml. ammonia, 50 g. terephthalonitrile (TPN) and 6.0 g. cobalt supported catalyst and various amounts of water. The autoclave was heated to 120° C. Hydrogen was introduced rapidly until the selected pressure was reached. The absorption of hydrogen started immediately and additional hydrogen was added to keep the pressure at the selected level. The course of the reaction was monitored by measuring the volume of hydrogen consumed and by periodic withdrawal of a small sample of the reaction mixture for analysis. When the analysis indicated that all of the terephthalonitrile had reacted, the agitation was stopped and the reactor was cooled rapidly and vented. The reaction mixture was filtered to recover the catalyst and then was flash evaporated to remove solvent. The residual oil was flash distilled at about 100° C. and 0.5 mm Hg. to give practically pure p-xylylene diamine. A small amount of high boiling residue remained in the distillation pot. Results of experiments conducted with various amounts of water and at 1500 and 2500 psig are listed in Table I.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][N:8]=1.[CH:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH:17]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][N:8]=2)=[O:25])=[CH:27][CH:28]=1)([CH3:19])[CH3:18]
Reactant: CC(C)c1ccc(C(=O)O)cc1
Reactant: CCN(CC)CCSc1nnc(N)s1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCSc1nnc(NC(=O)c2ccc(C(C)C)cc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
Sodium hydride (0.6 g) and 2-amino-5-diethylaminoethylthio-1,3,4-thiadiazole (2.3 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Isopropylbenzoic acid (1.6 g) and carbonyldiimidazole (1.8 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 3.5 g of the aimed compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][C:21]([N+:30]([O-:32])=[O:31])=[C:20](Cl)[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[NH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46].Cl>CCO.O>[C:1]([O:5][C:6]([NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]([NH:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:21]([N+:30]([O-:32])=[O:31])=[CH:22][C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)=[O:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCN
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(Cl)c([N+](=O)[O-])cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCNc1nc(-c2ccc(C3(NC(=O)OC(C)(C)C)CCC3)cc2)c(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl(1-(4-(6-chloro-5-nitro-3-phenylpyridin-2-yl)phenyl)cyclobutyl)carbamate (1.03 g, 2.14 mmol) in EtOH (8 ml) was added triethylamine (1.49 ml, 10.72 mmol) and ethyl 3-aminopropanoate.HCl (1.65 g, 10.72 mmol) under nitrogen. The resulting mixture was stirred for 1.5 hours at 80° C. under microwave irradiation. Water was added and the mixture was extracted with AcOEt (3×15 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 30% EtOAc in cyclohexane) to give the title compound (1.2 g, quantitative). 1H NMR (500 MHz, CDCl3): 8.50 (1H, s), 8.38 (1H, s), 7.32 (2H, d), 7.23-7.18 (5H, m), 7.09-7.07 (2H, m), 5.00 (1H, br s), 4.12 (2H, q), 3.98 (2H, q), 2.71-2.68 (2H, t), 2.52-2.20 (4H, m), 2.00-1.95 (1H, m), 1.79-1.65 (1H, m), 1.40-1.10 (9H, br), 1.20 (3H, t).