Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[CH3:12][NH2:13].C1COCC1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH3:12][NH:13][C:2]1[C:3]([NH2:4])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CNc1ccc([N+](=O)[O-])cc1N
Temperature: 120 °C

Procedure:
In a 350 mL pressure flask, 2-fluoro-5-nitroaniline (10 g, 0.064 mol), methylamine as a 2M solution in THF (65 mL, 0.13 mol) and potassium carbonate (18 g, 0.13 mol) in 1-Methyl-2-pyrrolidinone (80 mL) were combined. The flask was sealed and heated to 120 degrees C. overnight. The reaction was monitored by TLC. When reaction was judged to be complete based upon consumption of 2-fluoro-5-nitroaniline, it was cooled to room temperature and poured into 2-3 times the total reaction volume of water. When a precipitate was formed, it was filtered and dried. The product was carried on without purification. 1H NMR (300 MHz, d6DMSO) δ 7.54 (dd, J=8.79, 2.64 Hz, 1H), 7.39 (d, J≦2.64 Hz, 1H), 6.41 (d, J=8.79 Hz, 1H), 6.11 (d, J=4.39 Hz, 1H), 5.07 (s, 2H), 2.83 (d, 1H), 4.83 Hz, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:8][N:7]=1)=O)C.[BH4-].[Na+].O>C(O)C>[OH:3][CH2:4][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:8][N:7]=1
Reactant: CCOC(=O)c1nnc(-c2ccccn2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1nnc(-c2ccccn2)s1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(5-ethoxycarbonyl-1,3,4-thiadiazol-2-yl)-pyridine (8 gm) in ethanol (80 ml), was added sodium borohydride (2.51 gm) in lots at 30° C. It was stirred at 30° C. over a period of 2 h. The solvent was evaporated under vacuum to provide a crude mass. To the crude mass, water (100 ml) was added and it was extracted with dichloromethane (200 ml×2). Combined organic layers was washed with water and concentrated under vacuum to provide title compound in 6.1 gm quantity (92%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(C(C)C)CC)(C)C.[OH:35][C:36]([CH2:38][CH:39]1[NH:44][CH2:43][CH2:42][NH:41][C:40]1=[O:45])=[O:37].ClCl>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:44]1[CH2:43][CH2:42][NH:41][C:40](=[O:45])[CH:39]1[CH2:38][C:36]([OH:35])=[O:37])=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(O)CC1NCCNC1=O
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCNC(=O)C2CC(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 32 %

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, PFTU, diisopropylethylamine, and 3-(hydroxycarbonylmethyl)piperazin-2-one in dimethylformamide. Yield: 32%; C23H21Cl2N5O5 (518.355); mass spectrum: (M+H)+=518/520/522 (chlorine isotope).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]2[O:16][CH2:17][O:18][C:13]2=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH:19](I)([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>>[CH:19]([NH:1][C:2]1[CH:15]=[C:14]2[O:16][CH2:17][O:18][C:13]2=[CH:12][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])([CH3:21])[CH3:20]
Reactant: Nc1cc2c(cc1C(=O)c1ccccc1)OCO2
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)Nc1cc2c(cc1C(=O)c1ccccc1)OCO2
Temperature: 25 °C

Procedure:
To a flask equipped with a stirrer and condenser are charged 80 g. of 2-amino-4,5-methylenedioxybenzophenone, 600 ml. of isopropyliodide and 80 g. anhydrous potassium carbonate. The mixture is stirred and refluxed for ca. 48 hours, cooled to room temperature, filtered and concentrated in vacuo on a rotary evaporator. The residue is dissolved in 1:1 chloroform-hexane and chromatographed through a silica gel (500 g.) column with the same solvent system. There is obtained 2-isopropylamino-4,5-methylenedioxybenzophenone, which, when recrystallized from ethanol, has a melting point of 77-78°C.
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:9])[CH2:7][OH:8].Br[CH2:11][CH:12]=[C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]>O>[CH3:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])=[CH:12][CH2:11][O:8][CH2:7][CH2:6][OH:9]
Reactant: Cc1ccccc1C(=CCBr)c1ccccc1C
Reactant: OCCO
Agent: [Li]CCCC
Solvent: O
Product: Cc1ccccc1C(=CCOCCO)c1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
A solution of n-butyllithium in hexanes (14 ml, 2.5 M) was added drop-wise under a nitrogen atmosphere to ethylene glycol (28 ml) at 0° C. When addition was complete the mixture was stirred 0.5 h at room temperature. 3-Bromo-1,1-bis(2-methyl-phenyl)-1-propene (10.5 g, 35 mmol, prepared in a similar way to the method described in Example 26) was added and the reaction mixture was stirred at room temperature for 12 h and at 70° C. for 24 h. Water (100 ml) was added and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic extracts was dried (MgSO4) and the solvent evaporated in vacuo. Flash chromatography of the residue on silica gel (250 g) using a mixture of n-heptane and ethyl acetate (10:1) as eluent provided 3.0 g (30%) of 2-(3, 3-bis(2-methylphenyl)-2-propen-1-yloxy) ethanol.
Reaction SMILES: [OH:1][CH:2]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:31][C:32]([F:41])([F:40])[C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1>>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([CH:2]([O:1][C:36]2[CH:37]=[CH:38][C:33]([C:32]([F:41])([F:40])[F:31])=[CH:34][CH:35]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[CH:28][CH:27]=1
Reactant: COc1ccc(C(O)CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1
Reactant: Oc1ccc(C(F)(F)F)cc1
Product: COc1ccc(C(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-hydroxy-3-(4-methoxyphenyl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-trifluoromethyphenol: ESMS m/e: 555.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:23])([F:22])[F:21])[C:17]([C:24]([O:26]CC)=[O:25])=[CH:16][C:15]=2[CH:29]=1>>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][C:12]1[C:11]([Cl:10])=[CH:29][C:15]2[CH:16]=[C:17]([C:24]([OH:26])=[O:25])[CH:18]([C:20]([F:22])([F:23])[F:21])[O:19][C:14]=2[CH:13]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Oc1ccc(Cl)cc1Br
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(Cl)cc3Br)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 2-bromo-4-chlorophenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 223.6–225.6° C. 1H NMR (acetone-d6/300 MHz) 7.89 (s, 1H), 7.83 (d, 1H, J=2.6 Hz), 7.73 (s,1H), 7.52 (dd, 1H, J=8.7 Hz, 2.4 Hz), 7.25 (d, 1H, J=8.9 Hz), 6.55 (s, 1H), 5.83 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −79.4 (d, J=7.2 Hz). FABLRMS m/z 481 (M−H). ESHRMS m/z,480.8856 (M−H, Calc'd 480.8857). Anal. Calc'd for C17H8BrCl2F3O4: C, 42.18; H, 1.67; Br, 16.51; Cl, 14.65. Found: C, 42.15; H, 1.54; Br, 16.56; Cl, 14.39.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[CH3:14])=[N:5][S:4][N:3]=1.C1C(=O)N([Br:22])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:14][C:8]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[C:6]1[C:2]([Cl:1])=[N:3][S:4][N:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)ccc1-c1nsnc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2nsnc2Cl)c(CBr)c1

Procedure:
A mixture of 3-chloro-4-(4-chloro-2-methylphenyl)-1,2,5-thiadiazole (0.211 g, 0.86 mmol), NBS (0.153 g, 0.86 mmol) and benzoyl peroxide (10.4 mg, 0.04 mmol) in carbon tetrachloride (5.0 mL) were refluxed for 1 h. More benzoyl peroxide (10.4 mg, 0.04 mmol) was added and the solution was refluxed for a further 16 h. The resulting suspension was filtered, rinsing with ether. The filtrate was washed with 10% aqueous sodium sulfite, saturated aqueous sodium bicarbonate solution and brine. The ether layer was separated, dried (Na2SO4) and reduced in vacuo. The residue was purified by flash chromatography on silica (eluting with EtOAc/hexanes gradient, 1–3% EtOAc). 3-[2-(Bromomethyl)-4-chlorophenyl]-4-chloro-1,2,5-thiadiazole was isolated as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 4.51 (s, 2H), 7.43 (s, 2H), 7.55 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[C:19]2=[C:20]3[N:15]([CH:16]([CH3:21])[CH2:17][CH2:18]2)[CH:14]=[C:13]([C:22](=[O:24])[CH3:23])[C:12](=[O:25])[C:11]3=[CH:10][C:9]=1[F:26]>CN(C)P(=O)(N(C)C)N(C)C>[N:1]1([C:8]2[C:19]3=[C:20]4[N:15]([CH:16]([CH3:21])[CH2:17][CH2:18]3)[CH:14]=[C:13]([C:22](=[O:24])[CH3:23])[C:12](=[O:25])[C:11]4=[CH:10][C:9]=2[F:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1cn2c3c(c(Cl)c(F)cc3c1=O)CCC2C
Reactant: C1CCNCC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(=O)c1cn2c3c(c(N4CCCCC4)c(F)cc3c1=O)CCC2C
Yield: 48.6 %

Procedure:
Anhydrous piperidine (8 g) was added to 5.3 g of 8-chloro-9-fluoro-5-methyl-2-acetyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine. 70 ml of hexamethylphosphoric triamide was added thereto and the mixture was allowed to react at 140° C. on an oil bath for 6 hours. After completion of the reaction any excess solvent and piperidine were removed by distillation under reduced pressure and 100 ml of ethyl acetate was added to the residue to precipitate light yellow crystals. The crystals thus obtained were separated by filtration and 300 ml of water was added thereto followed by adjusting the resulting solution to a pH of 2 with 1N hydrochloric acid. The solution was heated and filtered. The filtrate was concentrated to 50 ml and rendered alkaline with a 10% aqueous sodium hydroxide solution to obtain 3.0 g of 8-(1-piperidyl)-9-fluoro-5-methyl-2-acetyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:8](C)=[N:7][C:6](=S)[N:5]=1.[CH2:11](O)C>[Ni]>[CH3:11][C:4]1([N:5]=[CH:6][N:7]=[CH:8]1)[CH2:3][CH2:2][NH2:1]
Reactant: CC1=NC(=S)N=C1CCN
Reactant: CCO
Agent: [Ni]
Product: CC1(CCN)C=NC=N1

Procedure:
Reaction of 4-(2-aminoethyl)-5-methylimidazole-2-thione with Raney nickel in ethanol yielded 4-methylhistamine.
Reaction SMILES: C1([I:7](OC(=O)C(F)(F)F)OC(=O)C(F)(F)F)C=CC=CC=1.[CH3:22][N:23]1[C:27]2[N:28]=[N:29][CH:30]=[C:31]([OH:32])[C:26]=2[C:25]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:24]1.II.N1C=CC=CC=1>C(Cl)Cl>[I:7][C:30]1[N:29]=[N:28][C:27]2[N:23]([CH3:22])[N:24]=[C:25]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:26]=2[C:31]=1[OH:32]
Reactant: Cn1nc(-c2ccccc2)c2c(O)cnnc21
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: II
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1nc(-c2ccccc2)c2c(O)c(I)nnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 105.7 %

Procedure:
Phenyl[bis(2,2,2-trifluoroacetoxy)]-λ3-iodane (190 mg, 0.43 mmol) was added to a suspension of 1-methyl-3-phenyl-pyrazolo[3,4-c]pyridazin-4-ol (166 mg, 0.73 mmol) in CH2Cl2 (3.7 mL), followed by the addition of iodine (111 mg, 0.43 mmol) and pyridine (71 μL). The reaction mixture was stirred at room temperature for 16 h, then filtered. The collected solid was washed with CH2Cl2 and dried, to yield the title compound (160 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[N:10]=1.Br[C:32]1[CH:33]=[C:34](OC)[CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].BrCCCCCC>C(OCCO)C>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:34][CH2:33][CH2:32][CH2:37][CH2:36][CH3:35])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[N:10]=1
Reactant: COc1cccc(Br)c1
Reactant: COc1cccc(-c2nc(-c3cccc(OC)c3)nc(-c3ccc(O)cc3O)n2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCCO
Solvent: CCCCCCBr
Product: CCCCCCOc1ccc(-c2nc(-c3cccc(OC)c3)nc(-c3cccc(OC)c3)n2)c(O)c1
Reaction time: 1 h

Procedure:
10 g (0.025 mol) of 2-(2,4-dihydroxyphenyl)-4,6-bis(3-methoxyphenyl)-1,3,5-triazine (prepared by the method of Example 8 starting from 3-bromoanisole), 3.8 g of potassium carbonate and 30 mg of potassium iodide are heated in 25 ml of 2-ethoxyethanol at 110 C. for one hour, followed by dropwise addition of 6.7 g (0.041 mol) of 1-bromohexane and stirring at 110 C. for a further 32 hours. After cooling, the mixture is filtered, the solid material is washed neutral with water and then washed with methanol and dried. The crude product is purified by column chromatography (250 g SiO2 35-70 μm; eluent toluene/petroleum ether 1:1). This gives the compound of formula ##STR24##
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]Cl.[I:13][C:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[N:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[I:13][C:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[N:16][N:17]([CH2:5][C:4]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[CH:3]=2)[CH:18]=1
Reactant: FC(F)(F)c1n[nH]cc1I
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Cn2cc(I)c(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Yield: 64.4 %

Procedure:
3-Methyl-4-nitrobenzyl chloride (0.77 g), 4-iodo-3-trifluoromethyl-1H-pyrazole (0.99 g) and potassium carbonate (0.63 g) were stirred in DMF (10 ml) at 60° C. for 1 hour. After cooling, the reaction solution was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 4-iodo-1-(3-methyl-4-nitrobenzyl)-3-trifluoromethyl-1H-pyrazole (1.0 g).
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:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][C:21]4[N:22]([C:24](Br)=[CH:25][N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:35](B1OB(C=C)OB(C=C)O1)=[CH2:36].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[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:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][C:21]4[N:22]([C:24]([CH:35]=[CH2:36])=[CH:25][N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nn4c(Br)cnc4cc3-c3ccccc3)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C=Cc1cnc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn12
Reaction time: 0.5 h

Procedure:
133 mg (0.256 mmol) {1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, intermediate example Int-2-1, 61.6 mg (0.256 mmol) 2,4,6-trivinyl-cyclotriboroxane, 29.6 mg (0.026 mmol) tetrakis triphenylphosphine palladium(0) and 35.4 mg (0.256 mmol) potassium carbonate in 2 mL dimethoxyethane and 0.7 mL water were heated in a microwave vial (heating block) at 110° C. for 16 hours. The reaction mixture was poured on water/saturated ammonium chloride/dichloromethane and vigorously stirred for 30 minutes. The organic phase was separated, washed with brine, dried, and the solvent was removed. The crude product (168 mg>100%) was used in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8]1([CH:15]=C[C:12](O)=[CH:11][CH:10]=1)O.C=C/C=C/C.C=C/C=C\C>C1(C)C=CC=CC=1>[CH3:12][CH:11]1[CH2:10][CH:8]=[CH:15][CH:2]2[C:1]([O:6][C:4](=[O:5])[CH:3]12)=[O:7]
Reactant: Oc1ccc(O)cc1
Reactant: O=C1C=CC(=O)O1
Agent: C=C/C=C/C
Agent: C=C/C=C\C
Solvent: Cc1ccccc1
Product: CC1CC=CC2C(=O)OC(=O)C12
Temperature: 60 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
Maleic anhydride (68.6 parts) and 70 parts of toluene were introduced into a pressure autoclave, and melted at 55° C. Then, 0.162 part of hydroquinone was added, and 130.9 parts (corresponding to 1.1 moles of trans-1,3-pentadiene per mole of maleic anhydride) of crude trans-1,3-pentadiene composed of 40 % of trans-1,3-pentadiene, 20 % of cis-1,3-pentadiene and 40 % of pentanes was continuously added over 6 hours at 50° C. The temperature was then raised to 60° C., and the reaction was carried out for 3 hours. After the reaction, the reaction mixture was distilled at 90° C. under atmospheric pressure to remove volatile components to give 3-methyltetrahydrophthalic anhydride (melting point 61° C.) in a yield of 99 % as a Diels-Alder reaction product.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[C:44]([O:48][C:49](=[O:88])[CH:50]([CH2:73][C:74]1[CH:75]=[N:76][C:77]([NH:80][C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])=[CH:78][CH:79]=1)[CH:51]([S:63][CH2:64][C:65]1[CH:70]=[CH:69][C:68]([O:71][CH3:72])=[CH:67][CH:66]=1)[CH2:52][CH2:53][C:54]1[CH:55]=[C:56]([CH:60]=[CH:61][CH:62]=1)[C:57]([OH:59])=O)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C>[C:84]([O:83][C:81]([NH:80][C:77]1[N:76]=[CH:75][C:74]([CH2:73][CH:50]([CH:51]([S:63][CH2:64][C:65]2[CH:66]=[CH:67][C:68]([O:71][CH3:72])=[CH:69][CH:70]=2)[CH2:52][CH2:53][C:54]2[CH:62]=[CH:61][CH:60]=[C:56]([C:57]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:59])[CH:55]=2)[C:49]([O:48][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:88])=[CH:79][CH:78]=1)=[O:82])([CH3:85])([CH3:86])[CH3:87]
Reactant: CNCCc1ccccc1
Reactant: COc1ccc(CSC(CCc2cccc(C(=O)O)c2)C(Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(=O)OC(C)(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CSC(CCc2cccc(C(=O)N(C)CCc3ccccc3)c2)C(Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(=O)OC(C)(C)C)cc1
Reaction time: 2 h
Yield: 81.4 %

Procedure:
N-methylphenethylamine (20 μL, 0.14 mmoL), HATU (55 mg, 0.15 mmoL) and iPr2EtN (46 μL, 0.26 mmoL) was added to a solution of 3-{5-tert-butoxy-4-({6-[(tert-butoxycarbonyl) amino]pyridin-3-yl}methyl)-3-[(4-methoxybenzyl)thio]-5-oxopentyl}benzoic acid (84 mg, 0.132 mmol) in DMF (2 mL) under argon at 0° C. The reaction mixture was stirred for 2 h and was then quenched with ice. Diethylether and water was added and the aqueous phase was extracted diethyl ether. The combined organic phase was dried and concentrated. Flash chromatography (heptan/EtOAc, 3:1) gave tert-butyl 2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)-3-[(4-methoxybenzyl)thio]-5-(3-{[methyl(2-phenylethyl)amino]carbonyl}phenyl)pentanoate (81 mg, 81.4%).
Reaction SMILES: [CH:1]1([C:4](=[O:16])[CH:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([O:8]C)=O)[CH2:3][CH2:2]1.[CH2:17]=[N:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1(C)C(C)=CC=CC=1>[CH:1]1([C:4]2[O:16][CH2:17][N:18]([C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6](=[O:8])[C:5]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:2][CH2:3]1
Reactant: C=NC(C)(C)C(=O)OCC
Reactant: COC(=O)C(C(=O)C1CC1)c1ccccc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)C(C)(C)N1COC(C2CC2)=C(c2ccccc2)C1=O

Procedure:
A mixture of methyl 3-cyclopropyl-3-oxo-2-phenylpropanoate (6.54 g) and ethyl 2-(N-methyleneamino)-2-methylpropanoate was heated under reflux in xylene in the presence of 5A molecular sieve (33 g) for 7 hours. The mixture was evaporated and purified by chromatography on silica gel, eluting with hexane/ethyl acetate (7:3) to give ethyl 2-(6-cyclopropyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (7.56 g), as an oil, NMR (CDCl3)δ 0.7-0.78(m,2H), 0.95-1.01(m,2H), 1.22(t,3H), 1.54(s,6H), 1.52-1.61(m,1H), 4.14(q,2H), 5.17(s,2H), 7.21-7.42(m,5H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:22][C@H:21]([CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[N:8]2[C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N+:12]([O-])=[CH:11][C:10]=3[N:20]=[C:7]2[CH2:6]1)(=[O:4])=[O:3].[NH4+:34].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[NH2:34][C:11]1[C:10]2[N:20]=[C:7]3[CH2:6][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:22][C@H:21]([CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[N:8]3[C:9]=2[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)NCCC[C@H]1CN(S(C)(=O)=O)Cc2nc3c[n+]([O-])c4ccccc4c3n21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC[C@H]1CN(S(C)(=O)=O)Cc2nc3c(N)nc4ccccc4c3n21
Reaction time: 3 h

Procedure:
tert-Butyl 3-[(11S)-9-(methylsulfonyl)-5-oxido-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-11-yl]propylcarbamate (6.37 g, 13.4 mmol) was dissolved in 120 mL of CH2Cl2 and treated with 12 mL of concentrated NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (2.81 g, 14.7 mmol) was carefully added. Rapid stirring was continued for 3 hours. The reaction mixture was treated with 100 mL of CH2Cl2 and 25 mL of H2O. The layers were separated and the organic portion was washed successively with 2% Na2CO3 solution (3×50 mL), H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 33% CMA/CHCl3) gave tert-butyl 3-[(11S)-6-amino-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-11-yl]propylcarbamate (5.41 g) as light-orange foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]([CH2:21][OH:22])[CH2:15]3)=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][N:14]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]([CH2:21][OH:22])[CH2:15]3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(N1CCCCC(CO)C1)C1(c2ccc(Cl)cc2)CCC1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OCC1CCCCN(CC2(c3ccc(Cl)cc3)CCC2)C1
Yield: 36.2 %

Procedure:
To a stirring 0° C. solution of [1-(4-Chloro-phenyl)-cyclobutyl]-(3-hydroxymethyl-azepan-1-yl)-methanone (0.075 g, 0.26 mmol) under N2 in toluene (2.6 mL, 0.1M) was added sodium bis(2-methoxyethoxy)aluminum hydride (65+ weight % in toluene) (0.28 mL, 0.91 mmol) dropwise with stirring. When the reaction was complete by HPLC, the reaction was quenched with H2O. 10% NaOH and ethyl acetate were added, and the organic was removed, dried with Na2SO4, and concentrated. The crude reaction mixture was purified by silica gel chromatography (90:8:2 Hexanes:methylene chloride:2N NH3 in ethyl alcohol). A 39% yield (0.0290 g) of pure material was obtained as well as other impure fractions. 1H NMR (CDCl3, 300 MHz) 7.28–7.25 (2H, m), 7.15–7.09 (2H, m), 3.44 (1H, dd, J=10.5, 4.5 Hz), 3.27 (1H, dd, J=10.3, 5.5 Hz), 2.89 (1H, d, J=13.9 Hz), 2.83 (1H, d, J=13.9 Hz), 2.72–2.60 (1H, m), 2.50–1.10 (16H, m) ppm. 13C NMR (CDCl3, 75 MHz) 146.5, 131.22, 128.10, 127.93, 70.95, 67.49, 61.85, 59.10, 47.62, 40.59, 32.12, 31.90, 29.92, 25.41, 16.20 ppm. LRMS: 308.24.