Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][CH2:16][C:15]([C:21]([OH:23])=O)=[CH:14]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:48]1[C:49]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)=[CH:50][N:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=12>CN(C=O)C>[N:48]1[C:49]([C:57]2[CH:58]=[C:59]([NH:63][C:21]([C:15]3[CH2:16][O:17][C:18]4[C:13]([CH:14]=3)=[CH:12][C:11]([Cl:10])=[CH:20][CH:19]=4)=[O:23])[CH:60]=[CH:61][CH:62]=2)=[CH:50][N:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: O=C(O)C1=Cc2cc(Cl)ccc2OC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)C1=Cc2cc(Cl)ccc2OC1
Temperature: 25 °C
Yield: 69.1 %

Procedure:
DIEA (45.5 μL, 0.26 mmol) was added to 6-chloro-2H-chromene-3-carboxylic acid (50.0 mg, 0.24 mmol) and HATU (99.3 mg, 0.26 mmol) in 2 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (49.7 mg, 0.24 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 66.6 mg of product in 69% yield: LCMS (ESI) m/z 401 (MH+).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:10])[CH2:6][CH:7]([CH3:9])[CH3:8].C[Si]([C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH3:21])(C)C>C(Cl)(Cl)(Cl)Cl>[CH3:8][CH:7]([CH2:6][C:5](=[O:10])[C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:9]
Reactant: CC(C)CC(=O)Cl
Reactant: CCCCC#C[Si](C)(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCC#CC(=O)CC(C)C
Temperature: 2 °C
Reaction time: 24 h
Yield: 100.2 %

Procedure:
21.6 g of AlCl3 (0.162 moles) in 65 mL of CCl4 are cooled to 2° C. and 19.7 mL of isovaleroyl chloride (0.162 moles) in 30 mL of CCl4 are added dropwise. 25 g of trimethylsilylhexyne (0.162 moles) in 30 mL of CCl4 are then added dropwise. The mixture is stirred for 1 h at 2° C. and for 24 h at ambient temperature. It is poured into 200 mL of 1:3 37% HCl/ice, stirred for 1 h, the phases are separated and the aqueous phase is extracted with CH2Cl2. The combined organic phases are washed to neutrality, dried with Na2SO4 and evaporated. 27 g of product are obtained, which are used in the subsequent step without further purification. Formula: C11H18O (m.w. 166.27). Quantitative yield. IR (film) 2956; 2209; 1670 cm−1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:11]3[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.O1CCOCC1.C(N(CC)CC)C.[C:42](Cl)(Cl)=[O:43].[CH2:46]([CH2:48][NH2:49])[OH:47]>C1(C)C=CC=CC=1>[OH:47][CH2:46][CH2:48][NH:49][C:42]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:11]3[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:14][C:12]=3[N:13]=2)=[CH:6][CH:7]=1)=[O:43]
Reactant: O=C(Cl)Cl
Reactant: NCCO
Reactant: CCC(=O)N1CCc2c(nc(-c3ccc(N)cc3)nc2N2CCOC[C@@H]2C)C1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCC(=O)N1CCc2c(nc(-c3ccc(NC(=O)NCCO)cc3)nc2N2CCOC[C@@H]2C)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
(S)-1-(2-(4-aminophenyl)-4-(3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)propan-1-one (0.100 g, 0.000262 mol) in dry 1,4-Dioxane (2.00 mL, 0.0256 mol) was added Triethylamine (0.0402 mL, 0.000288 mol) followed by 20% Phosgene in toluene (1:4, Phosgene:Toluene, 0.150 mL). The reaction mixture was heated at 50° C. for 1 hour. The reaction mixture was cooled to room temperature and then added Ethanolamine (0.0950 mL, 0.00157 mol). The reaction mixture was stirred overnight. The reaction mixture was concentrated and purified by HPLC. 1H NMR (500 MHz, DMSO) δ 8.80 (s, 1H), 8.18 (d, J=8.7, 2H), 7.48 (d, J=8.6, 2H), 6.29 (s, 1H), 4.75-4.55 (m, 2H), 4.47 (d, J=18.2, 1H), 4.11 (s, 1H), 3.87 (d, J=12.4, 1H), 3.70 (d, J=11.5, 2H), 3.61 (d, J=11.7, 3H), 3.44 (d, J=16.7, 3H), 3.17 (dd, J=11.3, 5.7, 2H), 2.73 (s, 1H), 2.62 (s, 1H), 2.45 (dd, J=14.7, 7.6, 2H), 1.26 (d, J=6.2, 3H), 1.04 (dd, J=15.4, 7.6, 3H). LC/MS-m/z+469.3 (M+H)+
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:13]3[C:14]([O:18][CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:3][CH2:2]1.[CH:25]([C:27]1([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1)=O.C(C1(C(OC)=O)CCC1)=O>>[O:22]1[CH2:23][CH2:24][CH:19]([O:18][C:14]2[C:13]3[C:9]([O:8][CH2:7][CH:4]4[CH2:3][CH2:2][N:1]([CH2:25][C:27]5([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]5)[CH2:6][CH2:5]4)=[N:10][O:11][C:12]=3[CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21]1
Reactant: COC(=O)C1(C=O)CCCC1
Reactant: c1cc(OC2CCOCC2)c2c(OCC3CCNCC3)noc2c1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(OC5CCOCC5)c34)CC2)CCCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using 3-(piperidin-4-ylmethoxy)-4-(tetrahydro-2H-pyran-4-yloxy)-1,2-benzisoxazole (EXAMPLE 27, Step 1) and methyl 1-formylcyclopentanecarboxylate (Synthesis, 1997, 32) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH:10]1[CH2:16][CH:15]2[N:17]([CH3:18])[CH:12]([CH2:13][CH2:14]2)[CH2:11]1)=O.[ClH:19].C([O-])(=[O:22])C.[NH4+:24]>C(O)C.O>[ClH:19].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](/[CH:10]1[CH2:11][CH:12]2[N:17]([CH3:18])[CH:15]([CH2:14][CH2:13]2)[CH2:16]1)=[N:24]\[OH:22]
Reactant: [NH4+]
Reactant: CN1C2CCC1CC(C(=O)c1ccccc1F)C2
Reactant: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN1C2CCC1CC(/C(=N/O)c1ccccc1F)C2

Procedure:
A mixture of (2-fluorophenyl)(8-methyl-8-azabicyclo[3.2.1 ]octan-3-yl)methanone (29.5 g), hydroxylmine hydrochloride (16.5 g) and ammonium acetate (27.5 g) were heated in 80 ml of refluxing ethanol-water (3:1 mixture) for 19 hours. The mixture was and the precipitated product was collected (25.2g).
Reaction SMILES: C1C2C(COC([N:18]3[C@H:27]([C:28](O)=[O:29])[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[CH2:31]([C:35]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH2:40][NH:41][CH2:42][CH2:43][C:38]=2[C:37](=[O:44])[O:36]1)[CH:32]([CH3:34])[CH3:33].CCN(C(C)C)C(C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH2:31]([C:35]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH2:40][N:41]([C:28]([C@@H:27]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][NH:18]3)=[O:29])[CH2:42][CH2:43][C:38]=2[C:37](=[O:44])[O:36]1)[CH:32]([CH3:34])[CH3:33]
Reactant: O=C(O)[C@@H]1Cc2ccccc2CN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CNCC2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)[C@@H]1Cc3ccccc3CN1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.2 %

Procedure:
To a solution of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (147 mg, 0.369 mmol), 3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (50 mg, 0.184 mmol), and N,N′-diisopropylethylamine (112 mg, 0.870 mmol) in THF (5 mL) was added BOP reagent (144 mg, 0.326 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness, re-dissolved in 20% piperidine in DMF (5 mL), and stirred at room temperature for 1 hour. The crude reaction mixture was concentrated and purified by column chromatography (12 g, SiO2, 0 to 100% ethyl acetate in hexanes) to provide 3-isobutyl-3-phenyl-5-((S)-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (54 mg, 68%) as a mixture of diastereoisomers in form of white solid: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.81-1.01 (m, 6H), 1.59-1.74 (m, 1H), 1.75-1.88 (m, 1H), 2.26-2.52 (m, 3H), 2.71-2.85 (m, 1H), 2.87-3.10 (m, 1H), 3.37-3.72 (m, 2H), 3.76-3.99 (m, 2H), 4.00-4.15 (m, 3H), 4.62-4.86 (m, 1H), 7.01-7.22 (m, 4H), 7.28-7.45 (m, 5H); MS m/z 431 (M+H)+, 429 (M−H)−.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH:14]([C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=[CH:9]1)=O)(C)(C)C.C(N(CC)CC)C.[C:36]1([C:42](Cl)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>FC(F)(F)C(O)=O.ClCCl>[C:36]1([C:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH:14]([C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=[CH:9]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)C(Cc1cn(C(=O)OC(C)(C)C)cn1)c1ccc2c(c1)OCO2
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.6 %

Procedure:
A solution of ethyl 3-(1-tert-butoxycarbonylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionate (633 mg) in trifluoroacetic acid (5 ml) was stirred at ambient temperature for 10 minutes. Trifluoroacetic acid was removed by evaporation and the residue was diluted with ethyl acetate followed by washing successively with saturated sodium bicarbonate aqueous solution and brine. Drying, filtering and removal of the solvents afforded a crude intermediate compound. To a solution of the above compound and triethylamine (214 mg) in dichloromethane (10 ml) was added portionwise triphenylmethyl chloride (545 mg) and the mixture was stirred at ambient temperature for 20 minutes. The resulting solution was washed successively with saturated ammonium chloride aqueous solution and saturated sodium bicarbonate aqueous solution. Drying, filtering and removal of the solvents afforded ethyl 3-[1-(triphenylmethyl)imidazol-4-yl]-2-(3,4-methylenedioxyphenyl)propionate (740 mg) as a slightly yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][OH:15])[C:8](=O)[CH2:7][CH2:6]2.CC1C=CC(N=[CH:25][C:26]2[C:27]([NH2:35])=[CH:28][C:29]3[O:33][CH2:32][O:31][C:30]=3[CH:34]=2)=CC=1>>[OH:15][CH2:14][CH2:13][O:12][C:11]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[CH2:6][C:7]3[C:8]([C:9]=2[CH:10]=1)=[N:35][C:27]1[CH:28]=[C:29]2[O:33][CH2:32][O:31][C:30]2=[CH:34][C:26]=1[CH:25]=3
Reactant: COc1cc2c(cc1OCCO)C(=O)CC2
Reactant: Cc1ccc(N=Cc2cc3c(cc2N)OCO3)cc1
Product: COc1cc2c(cc1OCCO)-c1nc3cc4c(cc3cc1C2)OCO4
Yield: 68 %

Procedure:
Using the procedure of Example 1, 5-methoxy-6-(2-hydroxyethoxy)indan-1-one (222 mg, 1 mmol) is reacted with 6[[(4-methylphenyl)imino]methyl]-1,3-benzodioxol-5-amine (255 mg, 1 mmol) to yields 7-(2-hydroxyethoxy)-8-methoxy-10H-1,3-dioxolo[4,5-g]indeno[1,2-b]quinoline (239 mg, 68% of theory).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C@:12]3([CH2:17][CH2:16][NH:15][C@@H:14]([CH3:18])[CH2:13]3)[N:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[C:10](=[O:26])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]1([CH3:41])[CH:37]=[CH:36][C:35]2[C:30](=[C:31]([C:38](O)=[O:39])[CH:32]=[CH:33][CH:34]=2)[NH:29]1.C(N(C(C)C)CC)(C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:1]1([NH:7][C:8]2[C@:12]3([CH2:17][CH2:16][N:15]([C:38]([C:31]4[CH:32]=[CH:33][CH:34]=[C:35]5[C:30]=4[NH:29][C:28]([CH3:41])([CH3:27])[CH:37]=[CH:36]5)=[O:39])[C@@H:14]([CH3:18])[CH2:13]3)[N:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[C:10](=[O:26])[N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)C=Cc2cccc(C(=O)O)c2N1
Reactant: C[C@H]1C[C@]2(CCN1)C(NC1CCCCC1)=NC(=O)N2c1cccc(F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1C[C@]2(CCN1C(=O)c1cccc3c1NC(C)(C)C=C3)C(NC1CCCCC1)=NC(=O)N2c1cccc(F)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 11-9 (0.309 g, 0.861 mmol) in DMF (10 mL) was added: 2,2-dimethyl-1,2-dihydroquinoline-8-carboxylic acid (0.175 g, 0.861 mmol), diisopropyethylamine (0.334 g, 2.58 mmol) and BOP reagent (0.381 g, 0.861 mmol). After stirring at 50° C. overnight the reaction mixture was diluted with water and extracted using chloroform (three times). The combined organic layer were dried over MgSO4 and concentrated under vacuum. Purification by silica gel chromatography (4% methanol/chloroform/1% triethylamine) afforded the desired product.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C([Li])CCC.[B:26](OC)([O:29]C)[O:27]C.Cl>CCCCCC.O1CCCC1>[C:4]1([N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:19]=[CH:18][C:17]([B:26]([OH:29])[OH:27])=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: -80 °C
Yield: 59.9 %

Procedure:
10 g (30 mmol) of 4-bromotriphenylamine was put into a 500 mL three-neck flask. The air in the flask was replaced with nitrogen. To the mixture were added 20 mL of tetrahydrofuran (THF), and then the mixture was stirred at −80° C. Into this solution, 20 mL (32 mmol) of n-butyllithium (a 1.6 mol/L hexane solution) was dropped by a syringe. After the dropping, this solution was stirred at the same temperature for 1 hour. After the stirring, 40 mL (60 mmol) of trimethyl borate was added to the solution, and the solution was stirred for 1 hour while the temperature of the solution was being increased to room temperature. To the solution was added 200 mL (1.0 mol/L) of hydrochloric acid, and then the solution was stirred for about 15 hours. The organic layer was washed with a saturated sodium hydrogen carbonate solution and then a saturated saline solution. Then, the organic layer was dried with magnesium sulfate. This mixture was subjected to gravity filtration. The obtained filtrate was condensed to give a white solid. The obtained solid was recrystallized with chloroform/hexane to give 5.2 g of a white powdered solid, which was the object of the synthesis, at a yield of 58%. A synthesis scheme of Step 2 is shown in (c-2) given below.
Reaction SMILES: [CH2:1]([C:5](=[CH2:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:2]([CH3:4])[CH3:3].C[C:13]([CH3:16])([O-])C.[K+].C[SH:19]>C(OCC)(=O)C>[CH2:13]([S:19][CH2:11][CH:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:16]
Reactant: C=C(CC(C)C)C(=O)OCC
Reactant: CC(C)(C)[O-]
Reactant: CS
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CSCC)CC(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
650 mg of ethyl 2-isobutyl-2-propenoate was dissolved in 3 ml of methylmercaptan, and 50 mg of potassium tert-butoxide was added thereto. The mixture was stirred at room temperature for two hours. The reaction solution was diluted with 60 ml of ethyl acetate, washed with water and then with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 660 mg of ethyl 2-ethylthiomethyl-4-methylpentanoate as colorless oily substance.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:10](=O)[CH:11]=O.C(O)(=O)C.C(O)C>O>[I:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:11][CH:10]=[N:9]2
Reactant: Nc1ccc(I)cc1N
Reactant: O=CC=O
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Ic1ccc2nccnc2c1
Temperature: 25 °C
Yield: 64 %

Procedure:
A solution of 4-iodo-benzene-1,2-diamine (0.46 g, 1.96 mmol), ethanedial [40% in water] (2.25 mL), acetic acid (1 mL) and ethanol (20 mL) were heated to 100° C. for several hours and then cooled to room temperature. Water was added and the crude product was extracted with ethyl acetate. The product was purified via silica gel column chromatography with hexane:ethyl acetate (1:1) to give 0.323 g (64%) of 6-iodo-quinoxaline.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12]Br)[CH:3]=1.[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[Br-:1].[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][P+:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COC(=O)c1ccc(Br)cc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
The product of step (i) (26.45 g) and triphenylphosphine (11.7 g) in acetonitrile (100 ml) was heated under reflux for 1.5 hours. The solvent was evaporated and the residue triturated with diethyl ether. The precipitate was collected. Yield 22.8 g. Used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH2:13].Cl[C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[Cl:1][C:2]1[C:3]([N:13]=[C:15]=[O:17])=[C:4]([Cl:12])[C:5]([O:10][CH3:11])=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1cc(OC)c(Cl)c(N)c1Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: COc1cc(OC)c(Cl)c(N=C=O)c1Cl
Temperature: 130 °C
Yield: 162 %

Procedure:
A mixture of 2,6-dichloro-3,5-dimethoxy-phenylamine (500 g, 2.25 mmol), triphosgene (335 mg, 1.12 mmol) and TEA (342 g, 3.38 mmol) in dioxane (15 mL) was heated to 130° C. for 2 hours under microwave. The reaction was concentrated and the residue was purified by flash chromatography on silica eluting with DCM to obtain the title compound (450 mg, yield: 80%). 1H-NMR (400 MHz, CDCl3) δ 3.92 (s, 6H), 6.42 (s, 1H).
Reaction SMILES: [NH2:1][C:2]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1)=[S:3].Cl[CH:16]([CH3:20])[C:17](=O)[CH3:18]>CC(O)C>[CH3:20][C:16]1[N:1]=[C:2]([N:4]2[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]2)[S:3][C:17]=1[CH3:18]
Reactant: CC(=O)C(C)Cl
Reactant: CCOC(=O)C1CCN(C(N)=S)CC1
Solvent: CC(C)O
Product: CCOC(=O)C1CCN(c2nc(C)c(C)s2)CC1
Yield: 94.5 %

Procedure:
A mixture of ethyl 1-(aminocarbonothioyl)piperidine-4-carboxylate (5.85 g), 3-chloro-2-butanone (5.75 g) and 2-propanol (100 mL) was heated under reflux for 15 hrs, and concentrated. Ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried ver anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:4, v/v) to give ethyl 1-(4,5-dimethyl-1,3-thiazol-2-yl)piperidine-4-carboxylate as a colorless oil (6.86 g, yield 95%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[C:10]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:3][CH:2]=1.C(Cl)Cl.C(N(CC)CC)C.[N:31]([C:34]1[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:44]([F:47])([F:46])[F:45])[CH:35]=1)=[C:32]=[O:33]>CCOC(C)=O>[F:41][C:40]([F:42])([F:43])[C:38]1[CH:39]=[C:34]([NH:31][C:32]([N:18]2[CH2:19][CH2:20][N:15]([C:10]3[C:9]([O:8][CH2:7][C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[N:14][CH:13]=[CH:12][N:11]=3)[CH2:16][CH2:17]2)=[O:33])[CH:35]=[C:36]([C:44]([F:47])([F:45])[F:46])[CH:37]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: c1cc(COc2nccnc2N2CCNCC2)ccn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nccnc2OCc2ccncc2)CC1
Reaction time: 3 h
Yield: 31.3 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 3′-(pyridin-4-ylmethoxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.3 g, 0.97 mmol, 1.0 eq.), dry CH2Cl2 (3 mL), triethyl amine (TEA) (0.54 g, 0.4 mL, 5.1 mmol, 5 eq) and was then cooled in an ice bath. 1-Isocyanato-3,5-bis-trifluoromethyl-benzene (0.29 g, 0.2 ml, 1.2 mmol, 1.2 eq.) was then added drop wise to the reaction mixture. Total reaction time was 3 hours at which point the reaction was diluted with 3× the volume EtOAc. This solution was then washed 3× with NaHCO3 and 2× with brine. The organic layer was dried with Na2SO4, concentrated, and the solid was columned with a Biotage system using a gradient. The initial eluent was 1:1 ethyl acetate/hexane followed by an eluent 3:1 ethyl acetate/hexane. The solvent was then removed and dried under high vacuum to yield the title compound (0.16 g, 32% yield) as a solid. 1H NMR (CDCl3) 8.63 (d, 2H), 7.90 (s, 2H), 7.81 (d, 1H), 7.62 (d, 1H), 7.54 (s, 1H), 7.34 (d, 2H), 7.26 (s, 2H), 6.78 (s, 1H), 5.48 (s, 2H), 3.67 (m, 8H) ppm.
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.C([Li])(C)(C)C.[Cl:18][C:19]1[CH:30]=[CH:29][C:22]([C:23](N(OC)C)=[O:24])=[CH:21][C:20]=1[S:31](=[O:34])(=[O:33])[NH2:32]>O1CCCC1>[Cl:18][C:19]1[CH:30]=[CH:29][C:22]([C:23]([C:4]2[CH:12]=[C:11]3[C:7]([CH:8]=[CH:9][NH:10]3)=[CH:6][CH:5]=2)=[O:24])=[CH:21][C:20]=1[S:31]([NH2:32])(=[O:34])=[O:33]
Reactant: CON(C)C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(C(=O)c2ccc3cc[nH]c3c2)ccc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dispersion of potassium hydride in oil (33.15 mmol) is washed with hexanes under argon then tetrahydrofuran (310 mL) is added at 0° C. and the resulting suspension is treated by dropwise addition of 6.77 g of 6-bromoindole in tetrahydrofuran (61 mL). The reaction mixture is stirred at 0° C. for 15 min to give a yellow solution. A solution of 44.2 mL of tert-butyllithium (1.5 M in pentane) is added slowly at −78° C. while maintaining the temperature below −75° C. to produce a yellow suspension. After 15 min a solution of 3.08 g of 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide in tetrahydrofuran (61 mL) is added and the temperature is allowed to increase slowly to 0° C. The reaction mixture is quenched by addition of 62 mL of saturated aqueous ammonium chloride and extracted with ethyl ether. The organics were washed with water, dried over magnesium sulfate and concentrated to 9.65 g of a brown oil which is chromatographed on silica gel (1:1 hexanes/ethyl acetate) to give 2-chloro-5-(1H-indole-6-carbonyl)-benzenesulfonamide as a yellow foam. MS (m/z): 333 (M−1); Rf 0.37 (1:1 hexanes/ethyl acetate).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]>C(O)C.O>[OH:3][NH:2][C:17](=[NH:18])[C:16]1[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:20][CH:19]=1
Reactant: NO
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1ccc([N+](=O)[O-])cc1
Temperature: 85 °C
Yield: 97.4 %

Procedure:
Hydroxylamine hydrochloride (1.9 g, 27.2 mmol) then sodium carbonate (2.2 g, 20.4 mmol) were added to a stirred solution of 4-nitro-benzonitrile (1 g, 6.8 mmol) in ethanol (20 mL) and water (8 mL). The resulting mixture was refluxed at 85° C. under an atmosphere of nitrogen for 2 hours. The volatiles were then evaporated and the residue was extracted with ethyl acetate. The organics were washed with brine solution, dried over Na2SO4 and evaporated to afford 1.2 g (98%) of N-hydroxy-4-nitro-benzamidine. 1H NMR: (DMSO-d6): δ 10.2 (s, 1H), 8.24 (d, 2H), 7.97 (d, 2H), 6.03 (s, 2H).