Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]([C:11]2([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[O:17])[CH2:14][CH:13](O)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1.[C:30]1(=[O:53])[N:34]([CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][C:49](O)=[O:50])[C:33](=[O:52])[CH:32]=[CH:31]1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][O:18][C:16]([C:11]2([C:9]([O:8][CH2:7][C:6]3[CH:28]=[CH:29][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:10])[CH2:12][CH:13]([C:49](=[O:50])[CH2:48][CH2:47][O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][N:34]3[C:30](=[O:53])[CH:31]=[CH:32][C:33]3=[O:52])[CH2:14]2)=[O:17])=[CH:21][CH:22]=1
Reactant: O=C(O)CCOCCOCCOCCOCCN1C(=O)C=CC1=O
Reactant: COc1ccc(COC(=O)C2(C(=O)OCc3ccc(OC)cc3)CC(O)C2)cc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)C2(C(=O)OCc3ccc(OC)cc3)CC(C(=O)CCOCCOCCOCCOCCN3C(=O)C=CC3=O)C2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of PMB-CB-OH (1.154 g, 2.881 mmol), 15-maleinimido-4,7,10,13-tetroxapentadecanoic acid (1.49 g, 4.32 mmol) and triethylamine (1.20 ml, 8.64 mmol) in 20 ml anhydrous dichloromethane is admixed with 2-chloro-1-methylpyridinium iodide (1.10 g, 4.32 mmol) and stirred for three hours at room temperature. It is diluted with 80 ml dichloromethane, washed each time twice with 50 ml 1 n hydrochloric acid, 50 ml water and once with 50 ml sodium chloride solution (saturated) and dried over magnesium sulfate. Subsequently the solvent is removed in a vacuum and the residue is purified by column chromatography (silica gel, ethyl acetate). 1.93 g PMB-CB-4-Mal (92% of theory) is obtained as a colourless oil.
Reaction SMILES: Cl.C([O:4][C:5]1[CH2:11][CH2:10][CH2:9][NH:8][C:7](=[O:12])[CH:6]=1)C>CC(C)=O>[NH:8]1[CH2:9][CH2:10][CH2:11][C:5](=[O:4])[CH2:6][C:7]1=[O:12]
Reactant: CCOC1=CC(=O)NCCC1
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCCNC(=O)C1
Reaction time: 12 h
Yield: 99.8 %

Procedure:
A solution of 10% aqueous HCl (17 mL) was added to an acetone solution (70 mL) of the 4-ethoxy-6,7-dihydro-1H-azepin-2(5H)-one (2.5 g, 16 mmol) from Example 1 at 25° C. The reaction mixture was stirred for 12 hours. The acetone was removed in vacuo, and the resulting mixture was extracted with CH2Cl2 (10×15 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afforded the crude product as a yellow solid. Purification by flash column chromatography (silica, 10% MeOH/EtOAc) afforded azepane-2,4-dione (2.03 g, 100%) as a white solid: 1H NMR (400 MHz, CDCl3) d 7.55 (s, NH), 3.47 (s, 2H), 3.40 (m,), 2.59 (t, J=6.8 Hz, 2H), 1.96 (m, 2H); 13C NMR (100 MHz, CDCl3) d 202.5, 169.5, 51.9, 43.2, 40.8, 27.6; IR (KBr) nmax 3213, 3105, 2942, 1702, 1671, 1482, 1412, 1348 cm−1; HRMS (ESI) m/z calcd for C6H9NO2Na: 150.0525. found: 150.0507.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9][CH3:10])=[O:8]>[Pd].C(OC)(=O)C>[NH:1]1[CH2:6][CH2:5][NH:4][CH:3]=[C:2]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cnccn1
Agent: [Pd]
Solvent: COC(C)=O
Product: COC(=O)C1=CNCCN1
Reaction time: 9 h

Procedure:
100 ml of methyl acetate, 7.8 g of methyl pyrazinecarboxylate (prepared according to Example 1) and 1.5 g of palladium on activated charcoal (10% Pd) were placed in a 500 ml autoclave. The autoclave was flushed twice with nitrogen and twice with hydrogen, the gas being introduced under a pressure of up to 8 bar and allowed to expand again. Hydrogenation was then carried out for 9 hours at 20° C. and a hydrogen pressure of 10 bar, with stirring. The autoclave was then flushed with nitrogen, the reaction mixture was filtered on a suction filter (0.45 μm pore width) and the catalyst was washed with methyl acetate. Crude methyl 1,4,5,6-tetrahydropyrazine-2-carboxylate was obtained by concentration. Other data concerning the title compound was:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7]([C:10](OCC)=[O:11])[N:8]=[CH:9][N:4]2[CH:3]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>ClCCl>[Br:1][C:2]1[S:6][C:5]2=[C:7]([CH2:10][OH:11])[N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: CCOC(=O)c1ncn2cc(Br)sc12
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OCc1ncn2cc(Br)sc12
Reaction time: 0.17 h
Yield: 98.6 %

Procedure:
A solution of ethyl 2-bromoimidazo[5,1-b] thiazole-7-carboxylate (101 mg, 0.37 mmol) in dichloromethane (5 ml) was cooled to −50° C. A toluene solution of diisobutylaluminium hydride (1.01 M solution; 1.1 ml, 1.1 mmol) was then added dropwise to the cooled solution, and the mixture was stirred at the same temperature for 10 min. After the completion of the reaction, a saturated aqueous potassium sodium tartrate solution was added thereto, and the mixture was stirred at room temperature for one hr and was extracted with ethyl acetate (7 ml×3). The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give 2-bromo-7-hydroxymethylimidazo[5,1-b]thiazole (85 mg, 99%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl.Cl[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:7]=1
Reactant: Oc1ccc(Cl)nn1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccc(Cl)nn1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6-Chloro-pyridazin-3-ol (5.34 g, 40.8 mmol), 4-(2-chloro-ethyl)-morpholine hydrochloride (7.61 g, 40.8 mmol) and potassium carbonate (11.3 g, 81.7 mmol) were added to 20 mL of acetonitrile, 10 mL of N,N-dimethylformamide and 0.5 mL of water. The reaction mixture was heated using an oil bath at 116° C. After 4 hours, LC/MS showed the disappearance of 6-chloro-pyridazin-3-ol and the formation of the alkylated product. After cooling to room temperature, 100 mL of water was added to the mixture. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4, concentrated, and subjected to flash column chromatography (ethyl acetate/hexane/triethyl amine; 1:6:0.05) on silica gel to give 6-chloro-2-(2-morpholin-4-yl-ethyl)-2H-pyridazin-3-one after removal of solvents in vacuo. To the residue was added 20 mL of 4 M aqueous HCl and 20 mL of methanol were added (pH ˜2). The mixture was concentrated to get a solid residue, which could be further purified through re-crystallisation in hot ethanol. Finally, 4.2 g (37%) of the product as a mono hydrochloride salt was obtained as colourless solid material.
Reaction SMILES: C(Cl)Cl.[F:4][C:5]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:6]=1[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH2:17][OH:18])[C:11]=2[N:10]=[C:9]1[C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[F:26]>N1C=CC=CC=1.N1C=CC=CC=1.C(Cl)Cl>[F:4][C:5]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:6]=1[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH:17]=[O:18])[C:11]=2[N:10]=[C:9]1[C:19]1[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=1[F:25]
Reactant: OCc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=Cc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Reaction time: 6 h
Yield: 78 %

Procedure:
To CrO3 (1.26 g) dissolved in pyridine (1.0 mL) and CH2Cl2 (9.0 mL) was added 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-hydroxylmethylbenzimidazole (Example 112) (0.49 g, 1.27 mmol) dissolved in pyridine:CH2Cl2 (1:1) (2 mL). After stirring for 6 h, the reaction was filtered. The filtrate was diluted with CH2Cl2, and washed with NaHCO3 (sat. soln) and NaCl (sat. aq). The combined washings were dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash chromatography eluting with 1% methanol/CH2Cl2. Recrystallization from diethylether:hexane (3:1) yielded white crystals of 1-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-benzimidazole-4-carbaldehyde (0.38 g, 0.99 mmol, 78% yield). M.p. 151-153° C. 1H-NMR (300 MHz, CD2Cl2): δ 10.82 (d, J=0.6 Hz, 1H, CHO), 7.83 (dd, J=7.5, 1.1 Hz, 1H, H7), 7.78 (dd, J=8.1, 1.1 Hz, H5), 7.58 (m, 1H, H4′), 7.44 (ddd, J=8.1, 7.5, 0.6 Hz, 1H, H6), 7.27 (m, 1H, H4″), 7.11 (m, 2H, H3′,5′), 6.84 (m, 2H, H3″,5″), 5.42 (s, 2H, CH2PhF2).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N(CC)C(C)C)(C)C.[C:14]([NH:18][C:19]([C:21]1[S:54][C:24]2[N:25]=[C:26]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:27]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36]([O:38]C4C=CC([N+]([O-])=O)=CC=4)=O)[CH:30]=3)[C:23]=2[C:22]=1[NH2:55])=[O:20])([CH3:17])([CH3:16])[CH3:15]>ClCCl>[C:14]([NH:18][C:19]([C:21]1[S:54][C:24]2[N:25]=[C:26]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:27]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36]([N:3]([CH3:4])[CH3:2])=[O:38])[CH:30]=3)[C:23]=2[C:22]=1[NH2:55])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CNC
Reactant: CC(C)(C)NC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc(NC(=O)Oc4ccc([N+](=O)[O-])cc4)c3)c2c1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)Nc1cccc(-c2nc(-c3ccccc3)nc3sc(C(=O)NC(C)(C)C)c(N)c23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethyl amine hydrochloride (150 mg) was added to a solution of N,N-diisopropylethylamine (DIPEA, 0.50 ml) and tert-butyl 5-amino-2-phenyl-4-(3-(p-nitro-phenoxycarbonylamino)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 31(h), 250 mg) in dichloromethane (5 ml) and the reaction mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was diluted with CH2Cl2 and washed with H2O. The organic layer was concentrated under reduced pressure. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: H2O/CH3CN=80/20 to 0/100 (v/v) in 45 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[Cl-].[Li+].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(O)C>[CH2:9]([O:8][C:6]([NH:5][CH:4]([CH2:3][OH:2])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:7])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(NC(CO)Cc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.2 %

Procedure:
To a solution of the objective compound of step (8) (109 g, 0.345 mol) in THF (500 mL) were added mortar-pulverized lithium chloride (29.2 g, 0.689 mol) and sodium tetrahydroborate (26.1 g, 0.690 mol). To the resulting suspension was added ethanol (1000 mL) with dropwise over 40 minutes, and the mixture was stirred at room temperature for 14 hours. To the reaction mixture was added 10% citric acid aqueous solution (700 mL), and the mixture was stirred at room temperature for 30 minutes. The organic solvent was distilled off under reduced pressure. The residue was added to water (700 mL) and extracted with dichloromethane. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give white crystals. The crystals were recrystallized from ethyl acetate-hexane (1:2.7, 370 mL) to give 87.8 g (89%) of N-benzyloxycarbonyl-DL-phenylalaninol as white crystals.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:69])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[N:63]([CH:66]([CH3:68])[CH3:67])[N:64]=[CH:65][C:52]3=[CH:51][CH:50]=4)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:78]>CO.O>[ClH:78].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:69])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[N:63]([CH:66]([CH3:67])[CH3:68])[N:64]=[CH:65][C:52]3=[CH:51][CH:50]=4)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)n1ncc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: CC(C)n1ncc2ccc3c(=O)c(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)oc3c21
Yield: 81 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(1-isopropyl-6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (3 mL), water (7 mL) and 1 M HCl (0.2 mL) and chromatographed on a 5 g C18 cartridge {gradient 30 to 70% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound (26.5 mg, 81%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.55 (br s, 3H), 8.33 (s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.53-7.39 (m, 7H), 7.32 (d, J=8.2 Hz, 2H), 5.46 (septet, J=6.6 Hz, 1H), 2.62-2.49 (m, 4H), 2.23-2.13 (m, 1H), 1.86-1.74 (m, 1H), 1.59 (d, J=6.6 Hz, 6H). LCMS (Method E): RT=3.81 min, [M+H]+=450.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([Br:11])[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[OH:21])=[O:4].[CH3:22][C:23]([CH3:28])([CH3:27])[C:24](Cl)=[O:25].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([Br:11])[C:8]2[N:12]=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:14][C:7]=2[C:6]=1[O:21][C:24](=[O:25])[C:23]([CH3:28])([CH3:27])[CH3:22])=[O:4]
Reactant: COC(=O)c1nc(Br)c2nc(-c3ccccc3)oc2c1O
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1nc(Br)c2nc(-c3ccccc3)oc2c1OC(=O)C(C)(C)C
Yield: 41.2 %

Procedure:
A solution of 4-bromo-7-hydroxy-2-phenyl-oxazolo[4,5-c]pyridine-6-carboxylic acid methyl ester (0.1 g, 0.286 mmol; example 3a), trimethylacetyl chloride (42.3 μL, 0.344 mmol), triethylamine (79.7 μL, 0.572 mmol), and 4-(dimethylamino)pyridine (3.5 mg, 0.03 mmol) in methylene chloride (2.5 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, brine, saturated ammonium chloride solution, and brine. The organic fraction was dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-70% ethyl acetate in hexanes to give 51 mg of the title compound as a white solid. MS: (+) m/z 432.8, 434.8 (M+1, 79Br/81Br).
Reaction SMILES: [Cl-].[CH2:2]([N+:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH3:24][C:25]([N-:27][S:28]([C:31]1[CH:32]=[CH:33][C:34]([NH2:37])=[CH:35][CH:36]=1)(=[O:30])=[O:29])=[O:26].[Na+].C(Cl)(Cl)Cl.CS(C)=O>O>[CH2:2]([N+:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH3:24][C:25]([NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])=[O:26]
Reactant: CC(=O)[N-]S(=O)(=O)c1ccc(N)cc1
Agent: CCCCCCCCCCCCCCCC[n+]1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)NS(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C
Yield: 99.22 %

Procedure:
Hexadecylpyridinium chloride (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. Sodium sulfacetamide (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. The two solutions were combined and the reaction mixture was heated and stirred for 30 minutes. The reaction mixture cooled to room temperature and then 60 mL of chloroform was added. The reaction mixture was stirred for an additional 30 minutes. The two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any inorganic salt. The presence of chloride anions was monitored by silver nitrate test. A rotary evaporator removed the chloroform and an orange wax was obtained in 99.22% yield. 1H and 13C NMR (DMSO) were obtained. Melting point (hot plate apparatus)=30-40° C. Thermal data determined by thermalgravimetric analysis (TGA): Tonset5%=211° C. and Tonset=219° C.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH:26][CH3:27])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:25]4[O:24][CH2:23][CH2:22][O:21][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:35][C:36]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([N:26]([CH3:27])[C:42]([C:36]2([CH3:35])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:43])[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[C:25]4[O:24][CH2:23][CH2:22][O:21][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN[C@H](CC1CCCCC1)CN1CCN(c2cccc3c2OCCO3)CC1
Reactant: CC1(C(=O)Cl)CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)C1(C)CCCCC1)[C@H](CC1CCCCC1)CN1CCN(c2cccc3c2OCCO3)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of 0.7 g (1.87 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-ethyl}-methyl-amine and 0.5 mL (3.7 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.3 g (1.87 mmol) of 1-methyl-cyclohexanecarboxylic acid chloride in dichloromethane. The reaction mixture was allowed to stir under nitrogen overnight at ambient temperature and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H2O and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (ethyl acetate/hexanes) and converted to the hydrochloride salt of the title compound with ethereal HCl to yield 0.85 g (91%) of the title compound as a white solid; mp=219-220° C.; MS (+) ESI m/z=498 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[C:18]([O:19]C)=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:2].[I-].[Mg+2].[I-].Cl>O1CCCC1.CCOCC>[CH:1]([C:3]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:2]
Reactant: CCOC(=O)CCCCOc1cccc(OC)c1C=O
Agent: Cl
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CCCCOc1cccc(O)c1C=O

Procedure:
To a stirred solution of ethyl 5-(2-formyl-3-methoxyphenoxy)pentanoate (Example 4) (4.38 g, 0.0156 M) in dry tetrahydrofuran (45 ml) was added dropwise a solution of magnesium iodide (6.533 g, 0.0235 M) in dry ether (95 ml). The mixture was then stirred under reflux (5 hr). The cooled mixture was poured into 10% hydrochloric acid (65 ml). The organic layer was separated and the aqueous phase extracted with ethyl acetate. The combined organic solutions were washed with water, dried (sodium sulphate) and evaporated. The oily residue was chromatographed on silica gel eluting with chloroform to give ethyl 5-(2-formyl-3-hydroxyphenoxy)pentanoate, m.p. 32°-33° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[CH:2]1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)Cl>[Br:19][C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: N#Cc1ccc2cc[nH]c2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: N#Cc1ccc2c(Br)c[nH]c2c1
Yield: 100.5 %

Procedure:
To a solution of 1H-indole-6-carbonitrile (1.6 g, 11.25 mmol) in DCM (60 mL) was added NBS (2.0 g, 11.25 mmol) in portions over a period of 5 minutes. The resultant mixture was stirred for 1 h. The reaction mixture was quenched with saturated sodium thiosulfate solution (25 mL) and further diluted with DCM (60 mL). The organic layer was washed with water (2×25 mL) followed by brine solution and dried over anhydrous sodium sulfate, filtered and concentrated to afford 2.50 g (99%) of the title compound, 1H NMR (300 MHz, CDCl3): δ 7.43 (d, J=7.4 Hz, 1 H), 7.45 (s, 1 H), 7.67 (d, J=6.9 Hz, 1 H), 7.79 (s, 1 H), 8.67 (br. s., 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH2:29]([C:31]1[C:36]([NH:37][S:38]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)(=[O:40])=[O:39])=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1)[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH2:1][C:2]1[C:3]([C:34]2[CH:35]=[C:36]([NH:37][S:38]([C:41]3[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=3)(=[O:40])=[O:39])[C:31]([CH2:29][CH3:30])=[N:32][CH:33]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: CCc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(OC)cc1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1ncc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1NS(=O)(=O)c1ccc(OC)cc1
Yield: 54.6 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (180 mg, 0.41 mmol) was treated with N-(2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-methoxybenzenesulfonamide (250 mg, 0.60 mmol), 2M cesium carbonate (410 μl, 0.82 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (30 mg, 0.04 mmol) according to the method described in Example 3 to give 146 mg (55% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]2[N:29]=[CH:28][CH:27]=[N:26]2)[C:3]=1[C:4]([N:6]1[C@H:13]2[C@H:8]([CH2:9][CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12]2)[CH2:7]1)=[O:5].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C@H:13]12[N:6]([C:4]([C:3]3[C:21]([N:25]4[N:26]=[CH:27][CH:28]=[N:29]4)=[CH:22][CH:23]=[CH:24][C:2]=3[F:1])=[O:5])[CH2:7][C@H:8]1[CH2:9][CH2:10][NH:11][CH2:12]2
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN(C(=O)c3c(F)cccc3-n3nccn3)[C@@H]2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1c(F)cccc1-n1nccn1)N1C[C@H]2CCNC[C@H]21

Procedure:
To (1S,6R)-tert-butyl 8-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate (400 mg, 1.0 mmol) in CH2Cl2 (5 mL) was added TFA (5 mL). After the reaction was judged complete, the volatiles were removed under reduced pressure. The resulting residue was neutralized using 5% Na2CO3(aq) followed by extraction with CH2Cl2 (3×). The combined organics were dried (Na2SO4) and concentrated to give the title compound as an oil that was used without further purification.