Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[CH:14]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:13]3[CH3:29])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[C:14]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:13]3[CH3:29])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1c2cc(OC)ccc2N(c2ccnc3cc(Cl)ccc23)C1C
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cc1c(C)n(-c2ccnc3cc(Cl)ccc23)c2ccc(OC)cc12

Procedure:
A mixture of ethyl 1-(7-chloroquinol-4-yl)-5-methoxy-2-methylindolin-3-ylacetate (7.0g.) and 2,3,5,6-tetrachloro-1,4-benzoquinone (5.6g.) in dry xylene (50ml.) was heated under reflux for 1.5 hours. The mixture was then cooled and filtered. The filtrate was washed successively with cold 2N-sodium hydroxide solution (2 × 30ml.) and water (2 × 50ml.). The organic layer was dried (MgSO4) and evaporated in vacuo to dryness, and the residue (dissolved in the minimum volume of diethyl ether) was adsorbed on a column of chromatographic silica gel (column dimensions: 15 × 3.5cm.). The column was eluted with a 1:3 v/v mixture of diethyl ether and petroleum ether (b.p. 40°-60° C.), and the eluate was evaporated in vacuo to give ethyl 1-(7-chloroquinol-4-yl)-5-methoxy-2-methylindol-3-ylacetate as a yellow oil, NMR: -OCH3, τ6.12.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=O.[CH3:16]S(C)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:3][C:4]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[CH2:16]
Reactant: CS(C)=O
Reactant: COc1ccc(F)c2c1C(=O)CC2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=C1CCc2c(F)ccc(OC)c21
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
NaH (6.8 g) suspended in dimethyl sulfoxide (40 ml) under nitrogen is heated to 80° C. for 1 h. A further 40 ml dimethyl sulfoxide and then 80 g of methyltriphenylphosphonium bromide is added in portions. After stirring for 15 min, 20 g III, partially suspended in 40 ml dimethylsulfoxide, is added and the mixture heated to 70° C. overnight. Pouring the mixture onto ice + hexane followed by extraction with hexane gives 17.6 g of crude 4-fluoro-7-methoxy-1-methyleneindan (IV) which was dissolved in 70 ml MeOH. This solution is added to a stirred solution of the trihydrate of thallium trinitrate (43.9 g) in 400 ml of MeOH and HC(OCH3)3. After stirring for 1 min, 200 ml chloroform is added at once. Washing with aqueous sodium bicarbonate, drying and concentrating gives a crude product which is purified by chromatography (silica, diethyl ether-hexane 1:1). The resulting mixture of V and its dimethylketal is hydrolyzed with 1 M HCl-diethyl ether to give 11.8 g V. 1H NMR (chloroform-d1) δ 7.02-6.64 (m, 2H); 3.79 (s, 3H); 3.51 (s, 2H); 3.10 (t, 2H); 2.56 (t, 2H).
Reaction SMILES: [O:1]=[S:2]1(=[O:13])[CH:6]=[CH:5][C:4]2[CH:7]=[CH:8][C:9]([C:11]#[N:12])=[CH:10][C:3]1=2.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>[OH-].[Pd+2].[OH-].C(O)C>[O:1]=[S:2]1(=[O:13])[CH2:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([CH2:11][NH2:12])=[CH:10][C:3]1=2
Reactant: N#Cc1ccc2c(c1)S(=O)(=O)C=C2
Agent: [Pd+2]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Agent: [OH-]
Solvent: CCO
Product: NCc1ccc2c(c1)S(=O)(=O)CC2

Procedure:
A hydrogenation par vessel was charged with 1,1-dioxo-1H-benzo[b]thiophene-6-carbonitrile (0.30 g, 1.57 mmol), ethanol (25 mL) and palladium hydroxide (66 mg). The vessel was put on a shaker under hydrogen at 40 Psi for 5 h. The reaction mixture was filtered through Celite and the filter cake was washed with methanol. The filtrate was concentrated to get the product as a white solid.
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C@H:27]1[N:35]2[C@@H:30]([CH2:31][CH2:32][CH:33](P(=O)(OCC)OCC)[C:34]2=[O:36])[CH2:29][CH2:28]1.C(O)C>O1CCCC1>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C@H:27]1[N:35]2[C@@H:30]([CH2:31][CH2:32]/[C:33](=[CH:8]\[C:7]3[CH:10]=[CH:11][C:12]([N:13]4[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]4)=[C:5]([O:4][CH3:3])[CH:6]=3)/[C:34]2=[O:36])[CH2:29][CH2:28]1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CC[C@@H](c3ccc(F)cc3F)N2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(/C=C2\CC[C@H]3CC[C@@H](c4ccc(F)cc4F)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 66.5 %

Procedure:
Lithium hydroxide (406 mg) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (550 mg) and diethyl [(3S,8aR)-3-(2,4-difluorophenyl)-5-oxooctahydroindolizin-6-yl]phosphonate (1.8 g) in tetrahydrofuran (5 mL)-ethanol (20 mL), and the reaction solution was stirred under shading at room temperature for 12 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 0.76 g of the title compound as a colorless solid. The property values of the compound are as follows.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10]([NH:12][C@H:13]1[C@H:18](OS(C)(=O)=O)[CH2:17][CH2:16][C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O.C(OCC)(=O)C>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CN1CCCC1=O>[N:1]([C@H:18]1[CH2:17][CH2:16][C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14][C@H:13]1[NH:12][C:10]([O:9][C:5]([CH3:6])([CH3:8])[CH3:7])=[O:11])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)[C@H](NC(=O)OC(C)(C)C)C1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CC[C@H](N=[N+]=[N-])[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 74 h

Procedure:
Sodium azide (357.6 mg) and benzyltriethylammonium chloride (189.1 mg) were added at room temperature to a solution (2 mL) of ethyl (1S,3R,4R)-3-[(t-butoxycarbonyl)amino]-4-methanesulfonyloxycyclohexanecarboxylate (1.01 g) in N-methyl-2-pyrrolidone, followed by stirring at 60° C. for 74 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was washed with aqueous saturated sodium bicarbonate solution and water, followed by drying over magnesium sulfate anhydrate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 655.2 mg of the title compound. Spectral data of this compound were found to be identical with those of the compound of Example 5.
Reaction SMILES: [I:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3([C:14]([OH:16])=O)[CH2:13][CH2:12]3)[N:10]=[C:6]2[C:5]([O:17][CH3:18])=[CH:4][CH:3]=1.CCN(CC)CC.CN(C(ON1N=[N:41][C:36]2[CH:37]=CC=N[C:35]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)(C)C>CN(C=O)C.O>[CH:36]([NH:41][C:14]([C:11]1([C:9]2[N:10]=[C:6]3[C:5]([O:17][CH3:18])=[CH:4][CH:3]=[C:2]([I:1])[N:7]3[N:8]=2)[CH2:12][CH2:13]1)=[O:16])([CH3:37])[CH3:35]
Reactant: COc1ccc(I)n2nc(C3(C(=O)O)CC3)nc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)N
Product: COc1ccc(I)n2nc(C3(C(=O)NC(C)C)CC3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an argon atmosphere 1-(5-Iodo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropanecarboxylic acid (compound 306) (0.05 g, 0.14 mmol) was dissolved in DMF (0.5 mL) and Et3N (0.058 mL, 0.42 mmol). HATU (0.082 g, 0.21 mmol) and isopropyl amine (0.018 mL, 0.21 mmol) were added. The solution was stirred at rt for 2 h. H2O was added and the aqueous phase was extracted with EtOAc (×3). The combined organic phases were washed with H2O and brine and dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica using DCM:EtOAc 9:1->3:1 as eluent. The title compound was obtained as a solid.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)[CH:4]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:22][N+:21]=1[O-:33]>CN(C)C=O>[N:27]1([CH2:26][C:23]2[CH:24]=[CH:25][C:20]([C:12]3[C:11]4[C:15](=[CH:16][CH:17]=[C:9]([C:5]5[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=5)[CH:10]=4)[NH:14][C:13]=3[OH:18])=[N+:21]([O-:33])[CH:22]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: O=C1Cc2cc(-c3cccnc3)ccc2N1
Reactant: [O-][n+]1cc(CN2CCOCC2)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [O-][n+]1cc(CN2CCOCC2)ccc1-c1c(O)[nH]c2ccc(-c3cccnc3)cc12
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 82.8 %

Procedure:
To a suspension of sodium hydride (0.05 g, 1.2 mmol, 60% dispersion in oil, pre-washed with hexane) in N,N-dimethylformamide (3 mL) was added a solution of 5-pyridin-3-yl-1,3-dihydro-2H-indol-2-one (0.19 g, 0.90 mmol) in N,N-dimethylformamide (4 mL). The mixture was stirred for 20 min under nitrogen atmosphere. 2-Chloro-5-(morpholin-4-ylmethyl)pyridine 1-oxide (0.14 g, 0.60 mmol), dissolved in N,N-dimethylformamide (3 mL) was added dropwise and the mixture was stirred at room temperature for 2 h and then heated at 130° C. for 1.5 h. The solvent was evaporated in vacuo and the residue was partitioned between 2 M HCl and ethyl acetate and the phases were separated. The aqueous layer was alkalized by addition of NaHCO3 (s) and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and the solvent was removed in vacuo affording 200 mg of the title compound as a yellow solid: MS (ES) m/z 403 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22](F)[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[CH2:32]([SH:34])[CH3:33]>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[C:22]([S:34][CH2:32][CH3:33])[CH:21]=3)(=[O:18])=[O:19])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(F)cc(C(F)(F)F)c1
Reactant: CCS
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(SCC)cc(C(F)(F)F)c1
Yield: 86 %

Procedure:
Starting with {(R)-4-[(3-fluoro-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester and ethanethiol using a method analogous to the one described for the 1st step of example 7-1, {(R)-4-[(3-ethylsulfanyl-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (136 mg, 86%) was obtained as a white solid. MS cald. for C21H26F3N3O4S2 505, obsd. (ESI+) [(M+H)+] 506.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:15][C:14](=[O:16])[C:13]3=[C:17]([CH3:23])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:12]3[N:11]=2)=[CH:8][C:7]([S:24](Cl)(=[O:26])=[O:25])=[C:6]([O:28][CH3:29])[CH:5]=1)[CH3:2].CN(C1C=CC=CN=1)C.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>ClCCl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:28][CH3:29])[C:7]([S:24]([N:43]2[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]2)(=[O:26])=[O:25])=[CH:8][C:9]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:23])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:12]2[N:11]=1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)c(OC)cc3OCC)nn12
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)c(OC)cc3OCC)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
20 mg (0.045mmol) of 4-ethoxy-2-methoxy-5-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo-[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride are dissolved in 0.5 ml of dichloromethane and admixed with a spatula tip of dimethylaminopyridine and 14 mg (0.136 mmol) of N-methylpiperazine, and the reaction mixture is stirred at room temperature overnight. Purification over silica gel gives 12.8 mg (55%) of 2-[2-ethoxy4-methoxy-5-(4-methylpiperazine-1-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[CH2:18]([NH2:20])[CH3:19].Cl>C1COCC1>[CH2:18]([NH:20][S:12]([C:8]1[CH:9]=[C:10]([F:11])[C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:14])=[O:13])[CH3:19]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc(F)c1F
Reactant: CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1cc(F)c(F)c(C(=O)O)c1
Yield: 82 %

Procedure:
To a 5 ml Biotage microwave reaction tube was added 2,3-difluoro-5-(chlorosulfonyl)benzoic acid (100 mg, 0.390 mmol). To this was added 2 ml of THF followed with (0.08 ml, 0.818 mmol) 10M aqueous NaOH. To the resulting stirred mixture was added ethanamine (0.195 ml, 0.390 mmol) as a 2M solution in THF. The reaction mixture was heated with stirring to 110° C. for 1.1 minutes using a Biotage Initiator 8 microwave set for high absorbance. After reaction cooled to room temperature 6M aqueous HCl (0.150 ml, 0.896 mmol) was added with stirring. The water was removed from the mixture by adding excess anhydrous Na2SO4 and subsequent filtration. The filtered salts were washed with acetonitrile and DMF (19:1, 10 ml, 2×). The combined filtrates were concentrated with rotary evaporation, yielding a DMF solution of 5-[(ethylamino)sulfonyl]-2,3-difluorobenzoic acid (82% pure by LCMS, % purity used as stoichiometry for next step), which was carried forward without purification.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].CCN(C(C)C)C(C)C.[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25]>C(#N)C>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([NH:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5])(=[O:26])=[O:25]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CC(C)(N)CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(CCO)NS(=O)(=O)c1ccccc1Br
Reaction time: 12.5 h

Procedure:
To a 20 mL vial were added a stirbar, 3-amino-3-methylbutan-1-ol (428 mg, 4.15 mmol), ACN (5 mL), and DIPEA (2.0 mL, 12 mmol). The mixture was then treated with 2-bromobenzene-1-sulfonyl chloride (994 mg, 3.89 mmol) and stirred for 12.5 hours before concentrating to dryness and subjecting the residue to FCC to give the title compound. (676 mg, 54%). MS (ESI): mass calcd. for C11H16BrNO3S 321.00, m/z found 344.0 [M+Na]+; 1H NMR (600 MHz, CDCl3) δ 8.15 (dd, J=7.9, 1.7, 1H), 7.70 (dd, J=7.8, 1.2, 1H), 7.46-7.39 (m, 1H), 7.39-7.31 (m, 1H), 6.15 (s, 1H), 3.93-3.81 (m, 2H), 1.76 (t, J=6.0, 2H), 1.20 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17]>>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[F:9]
Reactant: Fc1cc(Cl)ccc1I
Reactant: Sc1ccccc1Br
Product: Fc1cc(Cl)ccc1Sc1ccccc1Br

Procedure:
Prepared from 4-chloro-2-fluoro-1-iodo-benzene and 2-bromo-benzenethiol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19]C)=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:10]=1.Br>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:10]=1
Reactant: COc1ccc2c(-c3ccc(F)cc3F)nc(Nc3cc(C)[nH]n3)cc2c1
Agent: Br
Solvent: CC(=O)O
Product: Cc1cc(Nc2cc3cc(O)ccc3c(-c3ccc(F)cc3F)n2)n[nH]1
Temperature: 180 °C
Yield: 8.7 %

Procedure:
To a solution of [1-(2,4-difluoro-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine (11.0 g) in 10 mL acetic acid was added hydrobromic acid (1 mL, 40%). The mixture was heated at 180° C. for 30 min under microwave irradiation. After cooling, most of the solvent was removed under reduced pressure, the residue was dissolved in 100 mL of ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried with anhydrous sodium sulfate and concentrated to give an oil (0.92 g), which was used for the next reaction without further purification. (LC-MS m/e 353 MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH:11]=[O:12])[CH:5]=[C:6]2[CH:10]=[CH:9][O:8][C:7]=12.[OH:13]P([O-])(O)=O.[K+].[O-]Cl=O.[Na+].[OH-].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[N:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]2[CH:10]=[CH:9][O:8][C:7]=12
Reactant: O=P([O-])(O)O
Reactant: O=Cc1cc2ccoc2c(Cl)n1
Agent: [K+]
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cc2ccoc2c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
C6 (3.0 g, 16.5 mmol) is dissolved in 40 mL DMSO. KH2PO4 (561 mg, 4.1 mmol) in 6.5 mL H2O is added and then NaClO2 (2.6 g, 23.1 mmol) in 24 mL H2O is added, and the reaction is stirred overnight at rt. The reaction is diluted with 200 mL H2O, the pH is adjusted to 9 with 2N NaOH, and any remaining aldehyde is extracted into 3×50 mL ether. The pH of the aqueous layer is adjusted to 3 with 10% aqueous HCl and is extracted with 4×50 mL EtOAc. The combined organic layer is dried over MgSO4, filtered, and concentrated in vacuo to a white solid. The solid is washed with ether and dried to afford 7-chlorofuro[2,3-c]pyridine-5-carboxylic acid (C7) (55% yield). MS (CI) for C8H4ClNO3, m/z: 198 (M+H).
Reaction SMILES: [P:1]([Cl:4])(Cl)Cl.[CH2:5]([O:9][C:10](=[O:17])[C:11]([CH2:15][OH:16])([CH2:13][OH:14])[CH3:12])[CH2:6][CH2:7][CH3:8].O.N#N>C1(C)C=CC=CC=1>[Cl:4][P:1]1[O:14][CH2:13][C:11]([CH3:12])([C:10]([O:9][CH2:5][CH2:6][CH2:7][CH3:8])=[O:17])[CH2:15][O:16]1
Reactant: CCCCOC(=O)C(C)(CO)CO
Reactant: ClP(Cl)Cl
Agent: N#N
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)C1(C)COP(Cl)OC1
Reaction time: 1 h

Procedure:
68.70 g (0.50 mol) of phosphorus trichloride in 50 ml of toluene were added dropwise with vigorous stirring, in the course of 1 hour, to a solution of 95.15 g (0.50 mol) of 2,2-bis-hydroxymethylpropionic acid butyl ester in 250 ml of toluene at 5°-10° C. The reaction mixture was subsequently stirred for 1 hour without cooling in a water-jet vacuum, during which time a gentle flow of N2 was fed in; the solvent was then distilled off in vacuo (bath temperature=50° C./15-20 mm Hg), and the residue was purified by vacuum distillation. The product obtained was in the form of a colourless liquid; nD20 =1.4701; b.p. 113°-115° C./0.1 mm Hg.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(N(CC)CC)C.[S:15]1[CH:19]=[CH:18][C:17]2[C:20]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][O:33][C:34]4[N:38]([CH3:39])[N:37]=[C:36]([NH2:40])[CH:35]=4)[CH2:26][CH2:25]3)=[CH:21][CH:22]=[CH:23][C:16]1=2.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[S:15]1[CH:19]=[CH:18][C:17]2[C:20]([N:24]3[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][CH2:32][O:33][C:34]4[N:38]([CH3:39])[N:37]=[C:36]([NH:40][C:1](=[O:3])[CH3:2])[CH:35]=4)[CH2:28][CH2:29]3)=[CH:21][CH:22]=[CH:23][C:16]1=2
Reactant: Cn1nc(N)cc1OCCCN1CCN(c2cccc3sccc23)CC1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cc(OCCCN2CCN(c3cccc4sccc34)CC2)n(C)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
Acetic anhydride (1 ml) and triethylamine (0.09 ml, 0.65 mmol) were added to a dichloromethane solution (4 ml) of 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazol-3-yl-amine (0.20 g, 0.54 mmol) and the mixture was stirred at room temperature for 6 hours. An aqueous potassium carbonate solution was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and thereafter concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=2:1→0:1). The purified product was concentrated under reduced pressure and the residue was recrystallized from a solvent mixture of ethyl acetate-diisopropylether to obtain N-{5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazol-3-yl}acetamide (0.19 g, 89% yield) as white powder.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]#[N:4].[C:11]([CH2:19][C:20](=O)[CH3:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)C.CCCCCC>[NH2:4][C:3]1[C:19]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:20]([CH3:21])[NH:1][C:2]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#CC(N)c1ccccc1
Reactant: CC(=O)CC(=O)c1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1[nH]c(-c2ccccc2)c(N)c1C(=O)c1ccccc1

Procedure:
Starting from 2-amino-2-phenylacetonitrile and benzoylacetone, the open-chain intermediate compound is obtained, melting at 134°-135° C. (from diethyl ether/hexane). The title compound is obtained in a 60% overall yield. M.P. 285°-290° C. (from methanol/diethyl ether). The free base melts at 203°-5° C. (from methanol).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[Cl:10].[Mg].[Cl:12][CH2:13][CH:14]1[CH2:16][O:15]1.Cl>O(CC)CC>[Cl:10][C:4]1[CH:5]=[C:6]([Cl:9])[CH:7]=[CH:8][C:3]=1[CH2:2][CH2:16][CH:14]([CH2:13][Cl:12])[OH:15]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: ClCC1CO1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: OC(CCl)CCc1ccc(Cl)cc1Cl
Reaction time: 8 h

Procedure:
To a stirred and refluxing Grignard-complex, previously prepared starting from 98 parts of 1-(chloromethyl)-2,4-dichlorobenzene and 14 parts of magnesium in 70 parts of 1,1-oxybisethane, is added dropwise a solution of 46.5 parts of 2-(chloromethyl)oxirane in 350 parts of 1,1'-oxybisethane. Upon completion, stirring at reflux temperature is continued overnight. The reaction mixture is cooled in an ice-bath and decomposed by dropwise addition of 120 parts of a concentrated hydrochloric acid solution. The whole is poured onto water and the layers are separated. The organic phase is washed three times with water. The aqueous phase is extracted with 1,1'-oxybisethane. The combined organic phases are dried, filtered and evaporated. The residue is distilled, yielding 2,4-dichloro-α-(chloromethyl)benzenepropanol; bp. 130° C. at 0.04 mm. pressure.
Reaction SMILES: [N+:1]([O:4][CH2:5][C:6]([CH2:17][O:18][N+:19]([O-:21])=[O:20])([CH2:12][O:13][N+:14]([O-:16])=[O:15])[CH2:7][O:8]C(=O)C)([O-:3])=[O:2].[OH-].[Na+].C(O)C.Cl>CC(C)=O.O>[N+:1]([O:4][CH2:5][C:6]([CH2:7][OH:8])([CH2:12][O:13][N+:14]([O-:16])=[O:15])[CH2:17][O:18][N+:19]([O-:21])=[O:20])([O-:3])=[O:2]
Reactant: CC(=O)OCC(CO[N+](=O)[O-])(CO[N+](=O)[O-])CO[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(C)=O
Product: O=[N+]([O-])OCC(CO)(CO[N+](=O)[O-])CO[N+](=O)[O-]
Yield: 67.6 %

Procedure:
Pentaerythritol acetate trinitrate (2.0 grams, 0.006 mol) was dissolved in 20 ml of acetone and added to a solution of 332 mg of NaOH dissolved in 10 ml of water. To this mass was added 5 ml of ethanol to effect solution. The solution was stirred at room temperature for 30 minutes whereupon 1N HCl was added to bring the pH of the solution to approximately 7. The volatiles were removed under vacuum and the remaining liquid was extracted twice with ether. The combined ether extracts were washed with brine and concentrated. The mixture was purified by flash chromatography (1:1, ether:hexane) to isolate a product of Rf =0.5. About 1.1 gram of pentaerythritol trinitrate was isolated as a colorless oil.