Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]#[N:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:12])[CH:6]=2.C1C(=O)N([Cl:22])C(=O)C1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:13]#[N:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:12])[C:6]=2[Cl:22]
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1cc(Br)cc2ccc(O)cc12
Solvent: C1CCOC1
Product: N#Cc1cc(Br)cc2ccc(O)c(Cl)c12

Procedure:
The title compound was prepared by reacting 3-bromo-7-hydroxy-1-naphthonitrile (0.32 g, 1.28 mmol) with NCS (0.24 g, 1.8 mmol) in THF (25 mL) at 45° C. for 3 hr according to method C to yield 0.30 g (83%) of a yellow solid. An analytical sample was prepared by preparative reverse phase HPLC to yield the title compound as a white solid: mp 148-150° C.; 1H NMR (DMSO-d6): δ 7.47 (1H, d, J=8.98 Hz), 7.95 (1H, d, J=9.02 Hz), 8.32 (1H, d, J=2.08 Hz), 8.55 (1H, d, J=2.08 Hz), 11.33 (1H, s); MS (ESI) m/z280/282/284 (M−H)−
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:9][CH:8]2[CH:6]([O:7]2)[CH2:5][N:4]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])[CH2:3]1.[N-:20]=[N+:21]=[N-:22].[Na+].[NH4+].[Cl-]>CO.O>[N:20]([CH:8]1[CH2:9][C:2]([CH3:19])([CH3:1])[CH2:3][N:4]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])[CH2:5][CH:6]1[OH:7])=[N+:21]=[N-:22]
Reactant: CC1(C)CC2OC2CN(S(=O)(=O)c2ccccn2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)CC(N=[N+]=[N-])C(O)CN(S(=O)(=O)c2ccccn2)C1
Yield: 28.6 %

Procedure:
5,5-Dimethyl-3-(pyridine-2-sulfonyl)-8-oxa-3-aza-bicyclo[5.1.0]octane from Example 92e (1.2 g, 4.3 mmol) was dissolved in the mixture of 7 ml MeOH and 1 ml H2O. NaN3 (0.83 g, 13 mmol) and NH4Cl (0.7 g, 13 mmol) were added to the solution. The resulting mixture was refluxed overnight. After the removal of MeOH, the residue was diluted in EtOAc and washed with 10% NaHCO3 and brine. Purified on column chromatography gave 0.4 g 4-azido-6,6-dimethyl-1-(pyridine-2-sulfonyl)-azepan-3-ol (yield 29%); MS (M+H+): 326.2; 1H-NMR (400 MHz, CDCl3): •8.68-8.67(m, 1H), 8.05-7.90(m, 2H), 7.53-7.50(m, 1H), 3.75-3.60(m, 3H), 3.49-3.30(m, 3H), 1.73-1.66(m, 1H), 1.56-1.52(d, 1H), 1.07(s, 3H), 0.99(s, 3H)
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[H][H]>CCOC(C)=O.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]#[N:10])=[CH:11][CH:12]=1
Reactant: N#Cc1ccc(C#CCO)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CCCO)cc1
Reaction time: 4 h

Procedure:
To a solution of 4-(3-hydroxyprop-1-ynyl)benzonitrile (2.0 g, 12.7 mmol) in EtOAc (25 mL), Pd/C (500 mg, 0.47 mmol) was added. A hydrogen balloon was placed over the reaction, and the reaction stirred for approximately four hours. An additional 200 mg (0.19 mmol) of Pd/C was added and the balloon was placed back over the reaction. Upon completion, the reaction mixture was filtered through a pad of celite and concentrated to give 4-(3-hydroxypropyl)benzonitrile which was used without further purifications.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH3:35]>CN(C)C=O>[CH2:1]([O:8][CH2:9][C:10]1[N:11]([CH2:34][CH3:35])[C:12]([S:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCBr
Reactant: CC(C)c1nc(COCc2ccccc2)[nH]c1Sc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(COCc2ccccc2)nc(C(C)C)c1Sc1cc(F)cc(F)c1
Yield: 4.3 %

Procedure:
In dimethylformamide (10 ml) was dissolved 432 mg (1.2 mmol) of 2-benzyloxymethyl-5-(3,5-difluorophenylthio)-4-isopropyl-1H-imidazole (16f), followed by addition of 192 mg (1.4 mmol) of potassium carbonate and 153 mg (1.4 mmol) of bromoethane at room temperature with stirring, the mixture was stirred at the same temperature for 3 days. The reaction mixture was extracted with ether, and the ether layer was washed with water, dried over magnesium sulfate, and filtered. The ether layer was concentrated under reduced pressure, and the residual oil was purified by silica gel column chromatography (methanol:methylene chloride=3:97). From the first fraction, 20 mg (yield 4.3%) of positional isomer (17z') of the target compound was obtained. From the subsequent fraction, 300 mg of 2-benzyloxymethyl-5-(3,5-difluorophenylthio)-1-ethyl-4-isopropyl-1H-imidazole (17z), which was useful compound for the next reaction, was obtained (yield 65%). Oil.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:7]=1)(=O)[CH3:2].P(Cl)(Cl)(Cl)=[O:23].C(=O)(O)[O-].[Na+]>>[F:19][C:18]([F:21])([F:20])[C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:8]([NH:9][CH:10]=[CH:11][C:6]2[N:7]=[C:1]([CH3:2])[NH:4][N:5]=2)=[O:23])[CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)NNc1ccnc(-c2cccc(C(F)(F)F)c2)n1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc(C=CNC(=O)c2cccc(C(F)(F)F)c2)n[nH]1

Procedure:
A mixture of 1-acetyl-2-[2-(3-trifluoromethylphenyl)pyrimidin-4-yl]hydrazine and 15 ml. of phosphorus oxychloride is heated at the reflux temperature for about 20 hours. The cooled reaction mixture is poured over ice, the aqueous mixture neutralized with saturated sodium bicarbonate solution and the product collected. It is then taken up in ether, the ether dried and then evaporated to a solid residue. This residue is triturated with hexane and the precipitate collected. Recrystallization from chloroform/methanol then gives the product of the example, m.p. 153°-154° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:33]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:20]([CH3:32])[N:21]=[CH:22][C:23]=4[C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:35][CH2:36][F:37].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:37][CH2:36][CH2:35][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:33]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:20]([CH3:32])[N:21]=[CH:22][C:23]=4[C:24]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[O:25])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3cccc(O)c3)nc2c1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3cccc(OCCF)c3)nc2c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 23.3 %

Procedure:
To a solution of 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(3-hydroxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (Example 80) (350 mg, 0.782 mmol) in DMF (5 ml) was added 1-bromo-2-fluoroethane (250 mg, 1.96 mmol) and K2CO3 (108 mg, 0.782 mmol). The reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was diluted with EtOAc (30 ml) and washed with water (2×10 ml) and brine (15 ml). The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated off in vacuum. The crude material thus obtained was purified by column chromatography over silica gel (5% MeOH/DCM) to afford 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid {2-[3-(2-fluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-amide as off-white solid (90 mg, 23%). LC-MS: m/z=494.2 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[H-].[Li+].I[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26]I)=[CH:19][CH:18]=1>CN(C)C=O>[C:5]([CH:4]([C:3](=[O:9])[CH2:2][CH3:1])[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH:4]([C:3](=[O:9])[CH2:2][CH3:1])[C:5](=[O:8])[CH2:6][CH3:7])=[CH:19][CH:18]=1)(=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)CC(=O)CC
Reactant: ICCCOc1ccc(OCCCI)cc1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCC(=O)C(CCCOc1ccc(OCCCC(C(=O)CC)C(=O)CC)cc1)C(=O)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.9 %

Procedure:
A solution of 16.1 g (0.126 m) of 3,5-heptanedione in 50 ml of dimethylformamide was added during 15 minutes to a stirred suspension of 1.2 g of lithium hydride in 100 ml of dimethylformamide. The mixture was stirred one hour at room temperature and then a solution of 27.6 g (0.0619 m) of 1,4-bis(3-iodopropyloxy)benzene in 100 ml of dimethylformaide was added. The reaction mixture was heated at 60°-70° C. for about 16 hours and then concentrated in vacuo. The residue was distilled to remove volatiles (150° C., 0.05 mm) and chromatographed on 400 g of silica with chloroform:acetonitrile 95:5. The product was distilled at 250° C. (0.02 mm) and crystallized from ether to give 4.4 g of 1,4-bis(4,4-dipropionylbutyloxy)benzene, m.p. 57°-58° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:29])[N:14]([CH3:28])[N:15]=[C:16]([CH2:26]Br)[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2].[C-:30]#[N:31].[Na+]>CS(C)=O.O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:29])[N:14]([CH3:28])[N:15]=[C:16]([CH2:26][C:30]#[N:31])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2]
Reactant: [C-]#N
Reactant: CCc1cc(C)cc(CC)c1-c1c(OCc2ccccc2)c(CBr)nn(C)c1=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1cc(C)cc(CC)c1-c1c(OCc2ccccc2)c(CC#N)nn(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
To a solution of 4-(2,6-diethyl-4-methylphenyl)-6-bromomethyl-5-benzyloxy-2-methyl-3(2H)-pyridazinone (675 mg, 1.48 mmol) in DMSO (4 ml) was added sodium cyanide (80 mg, 1.63 mmol), and stirred at room temperature for 30 minutes. The reaction solution was diluted with water, and extracted with ethyl acetate 2 times. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 405 mg of Compound (I-30) (yield: 66%) as solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[C:17]([OH:18])[C:10]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[C:25]([O:31][C@@H:32]1[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@H:36]([O:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])[C@@H:35]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[O:34][C@@H:33]1Br)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27].C(#N)C>O>[C:1]1([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[C:17]([O:18][C@@H:33]4[O:34][C@H:35]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:36]([O:45][C:46](=[O:51])[C:47]([CH3:48])([CH3:49])[CH3:50])[C@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])[C@H:32]4[O:31][C:25](=[O:30])[C:26]([CH3:29])([CH3:27])[CH3:28])[C:10]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1n[nH]c2nccc(CCc3ccccc3)c12
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccccc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 12.1 %

Procedure:
A mixture of 4-(2-phenylethyl)-1H-pyrazolo[3,4-b]-pyridin-3-ol (0.59 g), potassium carbonate (0.68 g), 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (1.71 g) and acetonitrile (10 mL) was stirred at 50° C. overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water twice and brine, and dried over an hydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1-1/1) to give the title compound (0.22 g).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[Br:13]>S(=O)(=O)(O)O>[Br:13][C:7]1[C:6]([F:5])=[C:11]([N+:1]([O-:4])=[O:2])[CH:10]=[CH:9][C:8]=1[F:12]
Reactant: O=[N+]([O-])O
Reactant: Fc1cccc(F)c1Br
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(F)c(Br)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A mixture of 10 ml concentrated HNO3 and 10 ml concentrated H2SO4 was added dropwise with cooling to a stirred solution of 30 g 2,6-difluorobromobenzene in 50 ml of concentrated sulfuric acid. The rate of addition was controlled such that the temperature of the mixture did not rise above 55° C. After the addition was complete the reaction mixture was allowed to stir at room temperature for 2 hours. It was then poured onto ice and the resulting solid was collected by filtration, washed with water and dried, yielding a pale yellow solid, m.p. 50°-51.5° C., 84% yield (31.2 g).
Reaction SMILES: C([Li])CCC.[Cl-].[Cl:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C@H:35]2[CH2:41][C@H:40]3[N:42]([CH3:43])[C@H:37]([CH2:38][CH2:39]3)[C@H:36]2[CH:44]=O)=[CH:31][CH:30]=1.O>CCOCC>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C@H:35]2[CH2:41][C@H:40]3[N:42]([CH3:43])[C@H:37]([CH2:38][CH2:39]3)[C@H:36]2/[CH:44]=[CH:8]/[Cl:7])=[CH:31][CH:30]=1
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN1[C@H]2CC[C@@H]1[C@@H](C=O)[C@@H](c1ccc(Cl)cc1)C2
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CN1[C@H]2CC[C@@H]1[C@@H](/C=C/Cl)[C@@H](c1ccc(Cl)cc1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.5 %

Procedure:
A solution of butyllithium (0.32 mL, 2.5M in hexane, 0.68 mmol) was added to a stirred solution of chloromethyltriphenylphosphonium chloride (237 mg, 0.68 mmol) in dry EtzO (5 mL) at room temperature under N2 atmosphere. The resulting orange mixture was stirred for 30 min at that temperature, and then crude 3β-(4-chlorophenyl)-2β-formyltropane (60 mg, 0.23 mmol) in dry ether (4 mL) was added dropwise. The mixture was stirred at room temperature for 2 hr, cooled at 0° C., mixed with water (2 mL), and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude product was purified by flash column chromatography on silica gel saturated with NH3 eluting with hexane:ethyl acetate=1:1. Removal of the solvent gave 2d (14 mg, 20%); [α]D22 =-124° (c=0.52, CHCl3); IR (thin film) 3061, 2930, 2798, 1618, 1492, 941, 925 cm-1 ; 1H NMR (CDCl3, 300 MHz) δ 7.23 (d, 2H, J=8.5 Hz), 7 (d, 2H, J=8.5 Hz), 6.14 (dd, 1H, J=13.4, 10 Hz), 5.47 (d, 1H, J=13.4 Hz), 3.27 (s, 1H), 3.03 (m, 2H), 2.28 (m, 1H), 2.22 (s, 3H), 2.18-1.64 (m, 6H); 13C NMR (CDCl3, 75.46 MHz) 141.14, 133.88, 131.75, 129.34, 128.17, 117.55, 67.29, 61.99, 49.64, 41.96, 36.61, 34.50, 26.44, 24.98; mass spectrum, m/z 297 (M+, 37Cl), 195 (M+, 35Cl), 260, 218, 141, 97, 82.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[C:31]2[CH:32]=[CH:33][C:34]([C:36](O)=[O:37])=[CH:35][C:30]=2[O:29][CH2:28][CH2:27]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:36]([C:34]5[CH:33]=[CH:32][C:31]6[O:26][CH2:27][CH2:28][O:29][C:30]=6[CH:35]=5)=[O:37])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)c1ccc2c(c1)OCCO2

Procedure:
The title compound, white solid (28 mg, 69.5%), MS (ISP) m/z=493.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and 2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].O1CCOCC1.CC(C)([O-])C.[K+].Cl[C:23]1[N:24]=[N+:25]([O-:30])[C:26]([Cl:29])=[CH:27][CH:28]=1>CS(C)=O>[Cl:29][C:26]1[N+:25]([O-:30])=[N:24][C:23]([O:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:28][CH:27]=1
Reactant: Cc1cccc(C)c1O
Reactant: [O-][n+]1nc(Cl)ccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: Cc1cccc(C)c1Oc1ccc(Cl)[n+]([O-])n1
Reaction time: 0.17 h
Yield: 63.2 %

Procedure:
268 mg (2.20 mmol) of 2,6-dimethylphenol, 1,4-dioxane (3 mL) and dimethylsulfoxide (3 mL) were mixed, 270 mg (2.41 mmol) of potassium tert-butoxide was added to the mixture in an ice bath, and the resulting mixture was stirred for 10 minutes. To the mixture was added 370 mg (2.24 mmol) of 3,6-dichloropyridazine 1-oxide, and the resulting mixture was stirred at room temperature for 10 hours and allowed to stand for 2 days. The reaction mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, gradient) to obtain 350 mg (1.39 mmol, Yield: 63.1%) of 6-chloro-3-(2,6-dimethylphenoxy)pyridazine 1-oxide.
Reaction SMILES: C([NH:4][C:5]1([CH:22]([CH3:24])[CH3:23])[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)(=O)C.[ClH:25].C>C(O)C.C(OC(C)C)(C)C>[ClH:25].[NH2:4][C:5]1([CH:22]([CH3:24])[CH3:23])[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2
Reactant: CC(=O)NC1(C(C)C)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: Cl
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: CC(C)C1(N)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: 20 °C
Reaction time: 1 h

Procedure:
1.18 g of 10-acetamido-10-isopropyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are dissolved in 25 ml of boiling 2N hydrochloric acid and the solution is stirred for 1 hours at boiling, cooled and concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 60° C. The product obtained is dissolved in 20 ml of ethanol and, after addition of decolorizing charcoal, the solution is filtered. The filter is washed with 20 ml of ethanol and the filtrate and washing are then combined, 200 ml of acetone are added and the solution is stored for 45 minutes at a temperature in the region of 5° C. The insoluble product formed is isolated by filtration, washed with 10 ml of acetone and dried under reduced pressure (1 mmHg; 0.13 kPa) at 60° C. The product obtained (0.6 g) is stirred in suspension in 20 ml of boiling isopropyl ether for 15 minutes and, after cooling to a temperature in the region of 20° C., the insoluble product is isolated by filtration, washed twice with 20 ml in total of isopropyl ether and dried under reduced pressure (1 mmHg; 0.13 kPa) at 60° C. 0.46 g of 10-amino-10-isopropyl-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one hydrochloride is thus obtained, decomposing without melting above 250° C. (Analysis, % calculated C: 58.97, H: 5.34, Cl: 13.60, N: 17.19, O: 4.91, % found C: 59.0, H: 5.4, Cl: 13.6, N: 16.8, O: 4.9).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:9]([NH:11][C@@H:12]2[C@@H:19]3[C@@H:15]([CH2:16][NH:17][CH2:18]3)[CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([N:34]([CH3:43])[C@@H:35]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]([NH:11][C@@H:12]2[C@@H:19]3[C@@H:15]([CH2:16][N:17]([C:36](=[O:37])[C@@H:35]([N:34]([CH3:43])[C:32](=[O:33])[O:31][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:18]3)[CH2:14][CH2:13]2)=[O:10])=[CH:25][CH:24]=1
Reactant: O=C(N[C@H]1CC[C@@H]2CNC[C@@H]21)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@@H](C(=O)N1C[C@H]2CC[C@H](NC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)[C@H]2C1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,2-Bis(4-fluorophenyl)-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide (30 mg, 0.084 mmol) and (S)-2-(tert-butoxycarbonyl(methyl)amino)-4-methylpentanoic acid (22.71 mg, 0.093 mmol) were dissolved in dichloromethane (0.5 mL) and then treated with 1-hydroxybenzotriazole hydrate (14.18 mg, 0.093 mmol). After 10 minutes, N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.016 mL, 0.093 mmol) was added, and the reaction mixture was stirred at ambient temperature overnight followed by quenching with water. The material in the organic layer was purified with a 4 g silica gel cartridge eluting with 1-10% methanol (2 N ammonia)/dichloromethane to give tert-butyl(S)-1-((3aR,4S,6aS)-4-(2,2-bis(4-fluorophenyl)acetamido)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-methyl-1-oxopentan-2-yl(methyl)carbamate: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.25 (s, 1H), 7.46 (td, J=8.5, 5.5, 4H), 7.08-6.96 (m, 4H), 5.08 (s, 2H), 4.29-4.18 (m, 1H), 3.80 (s, 2H), 3.69 (s, 1H), 3.43 (dd, J=11.7, 3.5, 1H), 2.93 (s, 3H), 2.63 (s, 2H), 2.10 (td, J=12.9, 6.9, 1H), 1.91-1.69 (m, 3H), 1.63 (dt, J=13.2, 6.5, 2H), 1.51 (s, 9H), 1.40-1.26 (m, 1H), 0.97 (d, J=6.5, 3H), 0.92 (d, J=6.6, 3H); MS (ESI+) m/z 584 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=1)=[O:15])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[S:44]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45]1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][CH2:9][CH:10]([NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:45]2[S:44][CH:48]=[CH:47][CH:46]=2)[CH:22]=1)=[O:15])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(COCc1ccccc1)NC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1-c1cccc(Br)c1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCC(COCc1ccccc1)NC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1-c1cccc(-c2cccs2)c1
Temperature: 110 °C

Procedure:
To a solution of 281A (27 mg, 50 umol) in 1 mL dioxane was added 2M solution of K3PO4 (100 uL), Pd(PPh3)4 (3 mg, 2 umol) and the contents were degassed and purged with nitrogen. To this solution was added 3-thiophene boronic acid (7 mg, 55 umol) and the resulting mixture was heated in a sealed 1 dram vial at 110° C. for 48 h. Contents were cooled to room temperature and passed through a waters HLB u elution plate to get rid of insoluble material and the filtrate was further purified via prep HPLC (Xterra 10×50 mm, S5 column, MeOH— Water gradient) to give the title compound. HPLC retention time (2.04 min). Observed mass 576.13.