Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH2:21][C@H:22]([NH3+:27])[C:23]([O:25][CH3:26])=[O:24])[CH:13]=[CH:14][C:15]=1[O:16][C:17](=[O:20])[NH:18][CH3:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:35]([O:42][C:43]([NH:45][C@@H:46]([CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[C:53]([O:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[CH:52]=1)[C:47](O)=[O:48])=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1C=CC2N(O)N=NC=2C=1>ClCCl.C(Cl)CCl>[CH3:26][O:25][C:23](=[O:24])[C@@H:22]([NH:27][C:47](=[O:48])[C@@H:46]([NH:45][C:43]([O:42][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:44])[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)=[C:53]([O:65][CH2:66][C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)[CH:52]=1)[CH2:21][C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17](=[O:20])[NH:18][CH3:19])=[C:10]([O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:11]=1
Reactant: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)O)OCc1ccccc1
Reactant: CNC(=O)Oc1ccc(C[C@H]([NH3+])C(=O)OC)cc1OCc1ccccc1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)Oc1ccc(C[C@H](NC(=O)[C@H](Cc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)NC(=O)OCc2ccccc2)C(=O)OC)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(S)-2-(3-Benzyloxy-4-methylcarbamoyloxy-phenyl)-1-methoxycarbonyl-ethyl-ammonium chloride was suspended in dichloromethane (20 ml), then triethylamine (0.18 g) was added, followed by the addition of (S)-2-benzyloxycarbonylamino-3-(3,4-bis-benzyloxy-phenyl)-propionic acid (0.85 g), [see German patent DE 2121187], and HOBt (0.25 g). The mixture was stirred at room temperature for 20 min. EDC (0.35 g) was added and stirring was continued overnight. The mixture was washed with sodium bicarbonate, dried over sodium sulfate. After removal of the solvent, the residue was purified by silica gel chromatography eluting with ethyl acetate/dichloromethane (1:2). (S)-2-[(S)-2-Benzyloxycarbonylamino-3-(3,4-bis-benzyloxy-phenyl)-propionylamino]-3-(3-benzyloxy-4-methylcarbamoyloxy-phenyl)-propionic acid methyl ester was obtained as a white solid, 1.25 g. 1H NMR (400 MHz, CDCl3) 2.63 (d, J=4.6 Hz, 3H), 2.87-3.06 (m, 4H), 3.56 (s, 3H), 4.28-4.34 (m, 1H), 4.53-4.58 (m, 1H), 4.86-5.09 (m, 8H), 6.78 (m, 2H), 6.95 (m, 2H), 7.09 (m, 2H), 7.20-7.54 (m, 22H), 8.51 (m, 1H).
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH2:17][C:18]([N:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29]3[C:33]4[C:34]([NH2:38])=[N:35][CH:36]=[CH:37][C:32]=4[O:31][CH:30]=3)=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)=[O:19].O>CN(C=O)C>[F:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH2:17][C:18]([N:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29]3[C:33]4[C:34]([NH2:38])=[N:35][CH:36]=[C:37]([I:8])[C:32]=4[O:31][CH:30]=3)=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)=[O:19]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nccc2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncc(I)c2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
A solution of NIS (147 mg, 0.653 mmol) in DMF (3 mL) was added dropwise to a solution of 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-amine (257 mg, 0.634 mmol) in DMF (3.5 mL) at −40° C., and the mixture was stirred and allowed to slowly warm to room temperature (temperature was still <−10° C. after 2 hours, and reaction had progressed to about 20% according to HPLC). After 18 hours HPLC indicated complete consumption of starting material, and only a small amount of diiodo byproduct had formed. The reaction mixture was poured into water (35 mL), stirred for about 10 minutes, and the precipitate was collected by vacuum filtration and dried by suction for several hours to give 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-iodofuro[3,2-c]pyridin-4-amine (253 mg) as a tan solid. LC/MS (ES) m/z=532 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([I:11])[C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([I:11])[C:5]([C:6]([O:8][CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cnc(Br)cc1I
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cnc(Br)cc1I
Temperature: 60 °C
Yield: 82.7 %

Procedure:
A mixture of 6-bromo-4-iodonicotinic acid (75 mg, 0.23 mmol), potassium carbonate (63 mg, 0.46 mmol), and methyl iodide (0.017 mL, 0.27 mmol) in N,N-dimethylformamide (0.5 mL) was heated at 60° C. for 30 minutes. The cooled reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (15 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as a white solid (65 mg, 83%), which was used in the next step without further purification.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:27][C:28]1[CH:29]=[C:30]([NH:34][NH2:35])[CH:31]=[CH:32][CH:33]=1>>[Cl:27][C:28]1[CH:29]=[C:30]([N:34]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:24])([F:23])[F:25])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:35]2)[CH:31]=[CH:32][CH:33]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OCC(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OCC(F)(F)F)cc2)nc1-c1ccnn1-c1cccc(Cl)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-1H-pyridazin-4-one (A-32) and 3-chloro-phenylhydrazine according to the method described for example 43. MS: M=447.1 (M+H)+
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:5]=[CH:6][C:7](OS(C2C=CC=CC=2S(N(CC)C2CCN(CC3C=CC=CC=3)C2)(=O)=O)(=O)=O)=[C:8]([CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15](=[NH:17])[NH2:16].CC1C=CC([O:70][S:71]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=2[S:80]([N:83]([CH2:96][CH3:97])[CH:84]2[CH2:88][CH2:87][N:86]([CH2:89][C:90]3[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=3)[CH2:85]2)(=[O:82])=[O:81])(=[O:73])=[O:72])=C(C=1)OCCCOC1C=CC=C2C(NC(=O)C=12)=O.C(C(=CC1C=CC(O)=CC=1)C(O)=O)#N>>[ClH:1].[ClH:1].[CH3:3][C:4]1[CH:5]=[C:6]([O:70][S:71]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=2[S:80]([N:83]([CH2:96][CH3:97])[CH:84]2[CH2:88][CH2:87][N:86]([CH2:89][C:90]3[CH:91]=[CH:92][CH:93]=[CH:94][CH:95]=3)[CH2:85]2)(=[O:81])=[O:82])(=[O:73])=[O:72])[CH:7]=[C:8]([CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15]([NH2:17])=[NH:16]
Reactant: CCN(C1CCN(Cc2ccccc2)C1)S(=O)(=O)c1ccccc1S(=O)(=O)Oc1ccc(C)cc1OCCCONC(=N)N
Reactant: CCN(C1CCN(Cc2ccccc2)C1)S(=O)(=O)c1ccccc1S(=O)(=O)Oc1ccc(C)cc1OCCCOc1cccc2c1C(=O)NC2=O
Agent: Cl
Agent: N#CC(=Cc1ccc(O)cc1)C(=O)O
Product: CCN(C1CCN(Cc2ccccc2)C1)S(=O)(=O)c1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCONC(=N)N)c1
Yield: 83 %

Procedure:
N-{3-[5-Methyl-3-[(2-(N-ethyl-N-(1-benzyl-3-pyrrolidinyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}guanidine dihydrochloride: The title compound was prepared in 83% yield from N-{3-[5-methyl-3-[(2-(N-ethyl-N-(1-benzyl-3-pyrrolidinyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phthalimide, as prepared in the preceding step, in a manner analogous to step f of Example 1. 1H-NMR (300 MHz, DMSO-d6) δ 11.15 (br s, 2H), 8.18 (d, J=7.8 Hz, 1H), 8.14 (d, J=7.8 Hz, 1H), 8.00 (t, J=7.6 Hz, 1H), 7.88 (t, J=7.7 Hz, 1H), 7.68 (br s, 4H), 7.38 (m, 5H), 6.74 (s, 1H), 6.52 (s, 1H), 6.48 (s, 1H), 4.66 (br s, 1H), 4.04 (m, 1H), 3.97 (t, J=6.3 Hz, 2H), 3.89 (t, J=6.3 Hz, 2H), 3.50 (m, 2H), 2.75-3.20 (m, 5H), 2.21 (s, 3H), 2.13 (m, 2H), 2.01 (pentet, J=6.2 Hz, 2H), 1.10 (t, J=6.9 Hz, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C30H39N5O7S2: 646.2 (M+H). Found: 646.0.
Reaction SMILES: C([Zn]CC)C.[CH:6]1([C:9]#[CH:10])[CH2:8][CH2:7]1.[Li]CCCC.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26]>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1>[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[C@@:24]([OH:29])([C:10]#[C:9][CH:6]1[CH2:8][CH2:7]1)[C:25]([F:26])([F:27])[F:28]
Reactant: C#CC1CC1
Reactant: Cc1ccc(N)c(C(=O)C(F)(F)F)c1
Agent: CC[Zn]CC
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(N)c([C@@](O)(C#CC2CC2)C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of (1R,2S)—PNE (17.6%-w/w, 21.0 g, 18.0 mmol) in a THF/toluene mixture (9:1-w/w) was charged in a vessel at room temperature. A solution of diethylzinc in toluene (29.9%-w/w, 6.10 g, 14.8 mmol) was added at 17 to 25° C. and the mixture was aged at said temperature range for 30 min. A solution of cyclopropylacetylene in toluene (69.6%-w/w, 8.55 g, 90.0 mmol) was added at 18° C. and the resulting mixture was aged at 20° C. for 60 min. A solution of BuLi in toluene (3.09 mol/kg, 17.6 g, 54.4 mmol) and a solution of 1-(2-amino-5-methylphenyl)-2,2,2-trifluoroethanone (CN46217, 36.5%-w/w, 33.4 g, 60.0 mmol) in toluene/THF (1:1-w/w) were added in parallel to the reaction mixture at 20° C. within 3 h. The addition of BuLi was started 10 min in advance of the CN46217 addition. After completed addition of CN46217 the reaction mixture was stirred for 30 min at 20° C., then heated to 30° C. over a period of 60 min and aged for 6 h at 30° C. The reaction mixture was stirred at 0° C. overnight. HPLC (Method B) indicated 72.3% conversion and 96.7% enantiomeric purity. The reaction mixture was diluted with toluene (25.8 g) and quenched by addition of aqueous citric acid (1 M, 73.9 g). After stirring for 15 min the phases were separated and the aqueous phase was discarded. The organic phase was successively washed with water (9.1 g), aqueous NaHCO3 solution (5%-w/w, 24.0 g), and water (12.0 g). The organic phase was partially concentrated (60 g residual solution), diluted with toluene (30 g), and partially concentrated again (52 g residue). The residue was diluted with toluene (65 g), cooled to 5° C. and aged over night. The crystals were filtered, washed with cold (approx. 5° C.) toluene (10 g) and dried under vacuum at 40° C. The wet product (10.8 g) obtained as off-white solid with a purity of 99.2 and 100% ep according to method B. The crude product was purified by slurring it in a mixture of toluene (10 mL) and heptane (40 mL) at room temperature for 1 h, filtered and dried at 40° C. in vacuo. The product (compound of formula II, wherein R1 is trifluoromethyl, R2 is 2-cyclopropyl-ethynyl, R8 is 5-methyl, R9 is hydrogen and R10 is hydrogen) was obtained as white solid (10.6 g, 38 mmol, 64% yield) with a purity of 99.4% and 100% ep according to method B. The assay was 97.0%-w/w according to 1H-NMR.
Reaction SMILES: [C:1]1([CH:7]([NH:10][C:11]2[N:12]=[C:13]([NH2:29])[C:14]3[N:15]=[CH:16][N:17]([C:27]=3[N:28]=2)[C@@H:18]2[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]2[OH:20])[CH2:8]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:31](=O)(O)[O-].[Na+]>>[C:1]1([C:7]([NH:10][C:11]2[N:12]=[C:13]([NH2:29])[C:14]3[N:15]=[CH:16][N:17]([C:27]=3[N:28]=2)[C@H:18]2[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]2[OH:20])([CH3:8])[CH3:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccccc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: CC(C)(Nc1nc(N)c2ncn([C@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccccc1

Procedure:
Treat the secondary amine (3) (0.46 g, 1.05 mmol) with 1M hydrochloric acid (40 ml) and heat the reaction to 45° C. for 15 minutes. Cool the reaction and pour into saturated sodium bicarbonate (300 ml). Extract the reaction with chloroform (3×150 ml). Combine the organic extracts, dry over anhydrous magnesium sulfate, filter, and concentrate under vacuum to provide the title compound (0.40 g) as the free base. Treat this with ethereal hydrogen chloride, filter, and dry the solid under high vacuum over phosphorous pentoxide. Recrystallize from 10% methanol/diethyl ether to provide, after drying under high vacuum over phosphorous pentoxide, the hydrochloride salt of the Formula I (184 mg), m.p. 155° C. dec.; [α]D20 =+9.75° (c=1.01, H2O).
Reaction SMILES: N1C=CC=CC=1.[FH:7].N[C:9]1[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=1.N([O-])=O.[Na+].[OH-].[Na+]>CCCCCC>[F:7][C:9]1[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=1
Reactant: F
Reactant: N#Cc1ccc(N)cn1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: c1ccncc1
Product: N#Cc1ccc(F)cn1
Reaction time: 0.17 h
Yield: 64 %

Procedure:
To hydrogen fluoride-pyridine (100 ml) was added 5-amino-2-cyanopyridine (24.5 g, 0.206 mol) under ice cooling. The resulting mixture was stirred for 10 minutes. To the reaction mixture was added sodium nitrite (15.6 g, 0.226 mol). The resulting mixture was stirred at room temperature for 10 minutes, and then stirred at 50° C. for 2 hours. To the reaction mixture was added a 20% aqueous solution of sodium hydroxide. The resulting mixture was extracted with diethyl ether. The organic layer thus obtained was dried over sodium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure to give the title compound (16.0 g, 0.131 mmol, 64%) as colorless needle crystals.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=3)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:39]1[CH:44]=[CH:43][CH2:42][CH2:41][CH2:40]1>O1CCCC1.C(OCC)(=O)C>[C:1]1([C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=3)[S:10][C:11]=2[C:12]2[N:16]=[CH:15][N:14]([CH:40]3[CH2:41][CH2:42][CH2:43][CH2:44][O:39]3)[N:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1cc(-c2nc(-c3ccccc3)c(-c3nnc[nH]3)s2)ccn1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Nc1cc(-c2nc(-c3ccccc3)c(-c3ncn(C4CCCCO4)n3)s2)ccn1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
To a solution of N-{4-[4-phenyl-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (65 mg, 0.18 mmol) produced in Example 1-B (vi) in tetrahydrofuran (3.0 mL) were added p-toluenesulfonic acid monohydrate (41 mg, 0.22 mmol) and 3,4-dihydro-2H-pyran (140 mg, 1.7 mmol), and the mixture was heated under reflux for 3 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (40 mL), and washed with saturated aqueous sodium bicarbonate solution (30 mL). The aqueous layer was extracted with ethyl acetate (40 mL), the combined organic layer was dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→100/0) to give the title compound (71.0 mg, 88%) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[C:22]([CH3:23])=[N:21][CH:20]=[CH:19][N:18]=1)=[O:16].[F:24][C:25]([F:38])([F:37])[O:26][C:27]1[CH:32]=[CH:31][C:30](OB(O)O)=[CH:29][CH:28]=1.C(OCC)(=O)C>O.C1(C)C=CC=CC=1>[F:24][C:25]([F:37])([F:38])[O:26][C:27]1[CH:32]=[CH:31][C:30]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([C:17]2[C:22]([CH3:23])=[N:21][CH:20]=[CH:19][N:18]=2)=[O:16])=[CH:29][CH:28]=1
Reactant: OB(O)Oc1ccc(OC(F)(F)F)cc1
Reactant: Cc1nccnc1C(=O)Nc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nccnc1C(=O)Nc1ccccc1-c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
A solution of sodium carbonate (0.31 g: 1.5 mmole) in 5 mL of water was added to a solution of N-(2-bromophenyl)-3-methylpyrazine-2-carboxamide (0.4 g: 1.4 mmole) and 4-trifluoromethoxyphenyl boric acid (0.31 g: 1.5 mmole) in 10 mL of toluene, followed by addition of tetrakis(triphenyl-Phosphine)palladium (0) (0.1 g: 0.09 mmole). After heating under reflux condition for 6 hours under argon atmosphere, the reaction mixture was cooled to room temperature, and admixed with ethyl acetate and water, followed by separation. The organic layer was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the subject compound (0.35 g).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([O:11][CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34].O.ClCCl>ClCCl>[CH3:36][O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][N:14]1[CH2:15][CH2:16][CH2:17][C@@H:13]1[CH2:12][O:11][C:10]1[CH:18]=[CH:19][C:7]([O:6][C:5]2[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)CCCBr
Reactant: Clc1ccc(Oc2ccc(OC[C@H]3CCCN3)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CCCN1CCC[C@@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
To a solution of Example 18 (step 4) (0.8 g, 2.63 mmol) in dichloromethane (7.6 mL) was added triethylamine (0.78 mL, 5.60 mmol) and methyl 4-bromobutyrate (0.35 mL, 3.04 mmol). The resulting solution was stirred at 30° C. overnight. The reaction mixture was poured into water/dichloromethane (50 mL/50 mL). The crude residue was extracted into dichloromethane. The organic portion was washed with water (50 mL), washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using hexane/EtOAc (gradient system) to give the title compound (0.60 g, 57%).
Reaction SMILES: [CH2:1]([O:3][CH:4](OCC)[CH2:5][O:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[SH:18]CCO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:7]([O:6][CH2:5][CH:4]1[S:18][CH2:2][CH2:1][O:3]1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCCS
Reactant: CCOC(COC(=O)c1ccccc1)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(OCC1OCCS1)c1ccccc1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a 5-L, three-necked, round-bottomed flask fitted with a mechanical stirrer, a Dean-Stark apparatus, and a glass stopper is added 2-(benzoyloxy)acetaldehyde diethyl acetal (0.469 mol, 111.85 g, 1.0 equiv.), 2-mercaptoethanol (0.516 mol, 40.34 g, 1.1 equiv.), para-toluenesulfonic acid monohydrate (0.047 mol, 8.92 g, 0.1 equiv.) and toluene (3.5 L). The reaction was heated to reflux and stirred while monitoring progress by TLC. When determined to be complete, the reaction was allowed to cool to ambient temperature before washing with saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated by rotary evaporation to give (+/−)-2-(benzoyloxymethyl)-1,3-oxathiolane as an oil (95.75 g, 90.9% yield). The crude product was advanced to the next reaction step without further purification.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[N:19]=[CH:18][C:17]=2[N:16]=[C:15]1SC)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[S:37]([O-:40])(O)=[O:38].[Na+].[C:42](O)(=O)C>O>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[N:19]=[CH:18][C:17]=2[N:16]=[C:15]1[S:37]([CH3:42])(=[O:40])=[O:38])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)O
Reactant: O=S([O-])O
Reactant: CSc1nc2cnn(Cc3cccc4ccccc34)c(=O)c2n1Cc1ccccc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1nc2cnn(Cc3cccc4ccccc34)c(=O)c2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
A solution of 395 mg (2.50 mmol) of potassium permanganate was added dropwise to a solution of 700 mg (1.70 mmol) of 3-benzyl-2-methylsulphanyl-5-(naphthalen-1-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one in 30 ml concentrated acetic acid with stirring at ambient temperature and stirring was continued for a further two hours. As the oxidation was not yet complete, a further 150 mg potassium permanganate, dissolved in 5 ml of water, were added and the mixture was again stirred for two hours. The reaction solution was then combined with 0.5 g sodium hydrogen sulphite, then diluted with approx. 40 ml of water and extracted three times with 20 ml of dichloromethane. The organic extracts were washed with 5% sodium hydrogen sulphite solution, then with water and dried over sodium sulphate. The crude product obtained after evaporation was purified by column chromatography (silica gel; eluant:dichloromethane with 1% ethanol).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:21]([C:22]#[N:23])=[C:20]([N:24](C)[CH3:25])[N:19](N=C)[N:18]=2)=[CH:12][CH:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[Cl:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34]>C(O)C>[Cl-:30].[C:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:21]3[C:20](=[N:24][CH:25]=[N:23][C:22]=3[NH:34][C:33]3[CH:35]=[CH:36][CH:37]=[C:31]([Cl:30])[CH:32]=3)[NH:19][N:18]=2)=[CH:12][CH:11]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: C=Nn1nc(Nc2ccc(CNC(=O)OC(C)(C)C)cc2)c(C#N)c1N(C)C
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Product: [Cl-]

Procedure:
A mixture of 94 g (245.1 mmol) of 3-[4-(N-Boc-aminomethyl)-phenylamino]-4-cyano-5-dimethylamino-methyleneamino-pyrazole, 44.2 g (269.4 mmol) of 3-chloro-aniline hydrochloride [for preparation see: Justus Liebigs Ann. Chem. 176, 45 (1875)] and 1000 ml of ethanol is heated under reflux for 60 hours and then concentrated by evaporation in vacuo. The residue is dissolved in ethyl acetate, and the organic phase is washed with ice-cold 0.5N hydrochloric acid, water and brine, dried over sodium sulfate and concentrated by evaporation in vacuo. After recrystallization of the residue from ethyl acetate/hexane and from methanolimethylene chloride, 3-[4-(N-Boc-aminomethyl)-phenylamino]-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine is obtained; m.p. 196° C.; ESI-MS: (M−H)−=464.