Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[NH:15][CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+].C1(C)C=CC=CC=1.Cl[C:87]1[C:88]2[CH:95]([CH2:96][CH3:97])[CH2:94][CH2:93][C:89]=2[N:90]=[CH:91][N:92]=1>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[N:15]([C:87]3[C:88]4[CH:95]([CH2:96][CH3:97])[CH2:94][CH2:93][C:89]=4[N:90]=[CH:91][N:92]=3)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC1CCc2ncnc(Cl)c21
Reactant: CC(C)(C)OC(=O)NCc1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CCC1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CNC(=O)OC(C)(C)C)cccc43)c21
Temperature: 95 °C
Yield: 69.9 %

Procedure:
A 3-neck round bottom flask was charged with tert-butyl (1′-benzylspiro[indoline-3,4′-piperidine]-4-yl)methylcarbamate (446 mg, 1.09 mmol; see Example 27, Step 3), Pd(OAc)2 (24.6 mg, 0.109 mmol), Xantphos (95 mg, 0.164 mmol) and Cs2CO3 (536 mg, 1.64 mmol) and purged with N2. Toluene (6 mL, 0.547 mmol; sparged with N2 for 30 minutes) and 4-chloro-5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (200 mg, 1.09 mmol) were injected into the reaction, and the reaction was heated to 95° C. for 24 hours. LCMS showed most of the starting material had been consumed. The reaction was cooled, mixed with EtOAc and filtered through glass filter paper. The filtrate was concentrated to a residue and purified by silica gel chromatography (gradient: 5-50% (80 DCM: 19 MeOH: 1 NH4OH)/DCM). Purification provided tert-butyl (1′-benzyl-1-(5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methylcarbamate (422 mg, 0.762 mmol, 70% yield). 1H NMR (CDCl3, 400 MHz) δ 8.62 (s, 1H), 7.29-7.35 (m, 5H), 7.25 (m, 1H), 7.16 (t, 1H), 6.91 (d, 1H), 4.54 (br.s, 1H), 4.20-4.30 (m, 3H), 3.97 (m, 2H), 3.53 (s, 2H), 3.27 (m, 1H), 2.85-2.97 (m, 4H), 2.51 (m, 1H), 2.26 (m, 1H), 2.11 (d, 2H), 2.04 (t, 1H), 1.85 (m, 1H), 1.75 (d, 1H), 1.59 (d, 1H), 1.46 (s, 9H), 1.18 (m, 1H), 0.77 (t, 3H). MS (APCI+) [M+H]: 554.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:29][CH2:28]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH2:35][CH2:34][CH2:33][N:30]5[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCN2CCN(C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1CCN(CCCOc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1
Yield: 48.9 %

Procedure:
A mixture of 0.037 g (0.1 mmole) of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d), 0.062 g (0.2 mmole) of toluene-4-sulfonic acid 3-(4-methyl-piperazin-1-yl)-propyl ester, 1 mL of dimethylformamide and 0.160 g (0.5 mmole) of cesium carbonate was heated at 100 degrees for 20 minutes. The mixture was cooled, the solid was removed by filtration and the filtrate purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 40:60-100:0) to give 0.025 g of 4-(3-chloro-phenyl)-2-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzoimidazol-1-yl}-thiazole-5-carboxylic acid amide (I.33) as a white powder. MH+/Z=511
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:20]1[N:21]=[C:22]([NH:25][C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:23][CH:24]=1)\[C:4]([O:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].Cl[CH2:46][C:47]#[N:48]>>[C:47]([CH2:46][O:1]/[N:2]=[C:3](/[C:20]1[N:21]=[C:22]([NH:25][C:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[S:23][CH:24]=1)\[C:4]([O:6][CH:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:5])#[N:48]
Reactant: O=C(OC(c1ccccc1)c1ccccc1)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N#CCCl
Product: N#CCO/N=C(\C(=O)OC(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 77 %

Procedure:
Diphenylmethyl (Z)-2-hydroxyimino-2-(2-tritylaminothiazol-4-yl)acetate (1.5 g) was alkylated with chloroacetonitrile (0.38 g) as described in Example 5a to give the title compound as a white solid (1.23 g); νmax (CH2Cl2) 3400, 1740, 1535 and 1490 cm-1 ; δH (CDCl3) 4.82 (2H, s), 6.45 (1H, s), 6.98 (1H, broad s), 7.17 (1H, s) and 7.26-7.52 (25H, m). [Mass spectrum: +ve ion (3NOBA) MH+ (635) and (3NOBA/Na+) MNa+ (657)]
Reaction SMILES: COC(=O)CC1C=CC([C:11]([F:14])([F:13])[F:12])=CC=1Cl.C1(COC2C=C(C(O)=O)C=CN=2)C=CC=CC=1.[CH2:34]([O:41][C:42]1[CH:47]=[C:46]([C:48](=[O:59])[CH:49]([C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][C:52]=2[Cl:58])[CH3:50])[CH:45]=[CH:44][N:43]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>N1C=CC=CC=1>[CH2:34]([O:41][C:42]1[CH:47]=[C:46]([C:48]([OH:59])([CH:49]([C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][C:52]=2[Cl:58])[CH3:50])[C:11]([F:14])([F:13])[F:12])[CH:45]=[CH:44][N:43]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)Cc1ccc(C(F)(F)F)cc1Cl
Reactant: CC(C(=O)c1ccnc(OCc2ccccc2)c1)c1ccc(Cl)cc1Cl
Agent: O=C(O)c1ccnc(OCc2ccccc2)c1
Solvent: c1ccncc1
Product: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccnc(OCc2ccccc2)c1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to the reaction sequence outlined in Example 1, steps 2 to 5, from 2-chloro-4-(trifluoromethyl)-benzeneacetic acid methyl ester and 2-(phenylmethoxy)-4-pyridinecarboxylic acid with the following modification: In the methylation step (Example 1, step 4), an inseparable mixture of the desired intermediate 1-(2-benzyloxy-pyridin-4-yl)-2-(2,4-dichloro-phenyl)-propan-1-one with the dimethylated compound 2-benzyloxy-4-[(E or Z)-2-(2,4-dichloro-phenyl)-1-methoxy-propenyl]-pyridine was obtained. This mixture was treated as follows:
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[ClH:10].[CH:11](O)([CH3:13])[CH3:12].N[C@H](C(O)=O)CCC(=O)O.N[C@H](C(O)=O)CCCNC(=N)N>>[ClH:10].[CH:11]([O:8][C:7](=[O:9])[C@H:2]([C@H:3]([CH2:5][CH3:6])[CH3:4])[NH2:1])([CH3:13])[CH3:12]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: CC(C)O
Agent: Cl
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Agent: N[C@@H](CCC(=O)O)C(=O)O
Product: CC[C@H](C)[C@H](N)C(=O)OC(C)C

Procedure:
Isoleucine isopropyl ester-hydrochloride is prepared in a known manner from isoleucine and HCl/isopropanol. 2.1 g of this compound are reacted analogously to Example 5 (C) with 14.4 g of Adoc-Arg(Adoc)2 -Arg(Adoc)2 -Glu(OBut)-OH.2H2O and the product is worked up. Yield 6.2 g. Aminoacid analysis: Glu 1.00, Ile 0.95 and Arg 2.06.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:36])[CH2:7][C@@H:8]([OH:35])[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[OH:34])[N:18]=2)[CH2:13][CH2:12]1)=[O:10].Cl>C1COCC1.O>[OH:35][C@@H:8]([C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[OH:34])[N:18]=2)[CH2:15][CH2:16]1)=[O:10])[CH2:7][C:6]([OH:36])=[O:5]
Reactant: COC(=O)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)CC1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(N3CCN(C(=O)[C@H](O)CC(=O)O)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
LiOH.H2O (19.8 mg, 0.47 mmol) was added to a solution of (R)-3-hydroxy-4-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-oxo-butyric acid methyl ester (71 mg, 0.16 mmol) in 2 mL THF:H2O (1:1) and stirred at room temperature for 3 h. The reaction mixture was acidified with 1 M HCl and then extracted with EtOAc. After drying the organic layer over Na2SO4, it was concentrated and then purified via silica gel chromatography using 0-15% MeOH/CH2Cl2 to provide (R)-3-hydroxy-4-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-oxo-butyric acid (52 mg, 75%). LC/MS: m/z 437.3 (M+H)+ at 2.04 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [F-:1].[K+].ClCl.[Cl:5][C:6]1[C:14]([Cl:15])=[C:13]([Cl:16])[C:12]([Cl:17])=[CH:11][C:7]=1[C:8](Cl)=[O:9].F>>[Cl:5][C:6]1[C:14]([Cl:15])=[C:13]([Cl:16])[C:12]([Cl:17])=[CH:11][C:7]=1[C:8]([F:1])=[O:9]
Reactant: [F-]
Reactant: O=C(Cl)c1cc(Cl)c(Cl)c(Cl)c1Cl
Agent: ClCl
Agent: F
Agent: [K+]
Product: O=C(F)c1cc(Cl)c(Cl)c(Cl)c1Cl

Procedure:
The quantity of potassium fluoride to be used depends on the number of chlorine atoms which are to be exchanged. At least one mole of KF is used, but in general 1.1-1.5 mole, for 1 chlorine atom. A maximum of 2 moles of KF is used for 1 chlorine; beyond this, the quantity of KF has virtually no effect on the degree of fluorination, and the process becomes uneconomic. However, it is possible to save part of the costly KF when the 2,3,4,5-tetrachlorobenzoyl chloride is previously fluorinated with hydrofluoric acid, and the 2,3,4,5-tetrachlorobenzoyl fluoride, which results in virtually quantitative yield from this reaction, is used for the Cl/F exchange reaction with KF. Because of the greater activation by the more electronegative fluorocarbonyl group, its greater thermal stability, and the reduced load of KCl in the reaction mixture, this two-stage fluorination leads to an overall improvement in the balance of the nuclear fluorination.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[CH2:8][C:9]([OH:11])=[O:10].[C:13]1(C)C=CC(S(O)(=O)=O)=C[CH:14]=1>C(O)C>[CH2:13]([O:10][C:9](=[O:11])[CH2:8][CH:3]1[CH2:4][CH:5]=[C:6]([CH3:7])[C:2]1([CH3:12])[CH3:1])[CH3:14]
Reactant: CC1=CCC(CC(=O)O)C1(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)CC1CC=C(C)C1(C)C
Temperature: 78 °C
Yield: 3289.9 %

Procedure:
A solution of α-campholenic acid (100 g) and p-toluene-sulfonic acid (2 g) in ethanol (3 liters) was kept at reflux (78° C.) for 3 hours. The alcohol was then removed, the residue taken up in CH2Cl2 (1.5 liters) and the solution extracted with ice cold 5% aqueous sodium hydroxide (2×500 ml) and water (500 ml). Concentration of the CH2Cl2 solution gave a crude product (81 g) which was distilled through a 9" glass packed column to give 75 g of a colorless liquid; bp 90° C. @ 4,8 mm Hg; analysis: 97% (CW 20M fused silica column, 120° C.) ethyl α-campholenate.
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][CH:5]=1.ClC(Cl)(Cl)C1C=CC(C(Cl)(Cl)Cl)=CC=1.CCl>[Mo](=O)(=O)=O>[C:8]([OH:10])(=[O:9])[C:7]1[CH:12]=[CH:13][C:4]([C:3]([OH:14])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: O=[Mo](=O)=O
Agent: CCl
Agent: ClC(Cl)(Cl)c1ccc(C(Cl)(Cl)Cl)cc1
Product: O=C(O)c1ccc(C(=O)O)cc1
Yield: 234.6 %

Procedure:
A two-liter round flask, equipped with thermometer, magnetic stirrer, Vigreux column (40 cm), fractionating column, air cooler and receiver, was filled with 777 g (4 moles) of dimethylterephthalate, 1252 g (4 moles) of 1,4-bis-(trichloromethyl)-benzene and 4 g of molybdenum trioxide. The flask contents were maintained for 3 hours at 170° to 175° C. The escaping methyl chloride was captured in a cooling trap following the receiver. In the vacuum distillation that followed, 1559 g of terephthalic acid was obtained in a purity of 99.8% (GC). This corresponds to a yield of 95.8%.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:46])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:34][C@H:33]([CH2:35][O:36]C(=O)C4C=CC=CC=4)[C@@H:23]([O:24]C(=O)C4C=CC=CC=4)[C@@:13]3([CH3:45])[O:14]C(=O)C3C=CC=CC=3)[C:6]=2[N:7]=1.N>CO>[NH2:1][C:2]1[NH:3][C:4](=[O:46])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:34][C@H:33]([CH2:35][OH:36])[C@@H:23]([OH:24])[C@@:13]3([CH3:45])[OH:14])[C:6]=2[N:7]=1
Reactant: C[C@@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Agent: N
Solvent: CO
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.5 %

Procedure:
A mixture of nucleoside triester 119 (209 mg, 0.325 mmol) and MeOH (10 mL) saturated with NH3 (g) at −30° C. was stirred in a sealed tube for 48 h. The mixture was warmed to rt, depressurized, concentrated then submitted to HPLC purification (MeCN—H2O), affording 36 mg (34%) of the title compound as a white solid after lyophilization: 1H (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 6.92 (br s, 2H), 5.95 (s, 1H), 5.18-5.28 (br m, 1H), 4.75 (br s, 1H), 4.53 (dd, J=11.3, 5.46, 1H), 3.95 (br s, 1H), 3.73-3.78 (m, 1H), 3.29 (br s, 2H), 1.04 (s, 3H); [M+H]+ m/z 331.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[C:5]([C:18]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[CH:20][CH:19]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:8][CH:7]=1>C(O)C.C(OCC)(=O)C.C(N(CC)CC)C>[Cl:1][CH2:2][CH2:3]/[C:4](/[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[C:5](\[C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)/[C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:10][CH:11]=1
Reactant: CN(C)CCOc1ccc(C(=C(CCCl)c2ccccc2)c2ccc(OCc3ccccc3)cc2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)CCOc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccc(O)cc2)cc1

Procedure:
8.4 g of 4-chloro-1-(4-benzyloxyphenyl)-1-[4-[2-(N,N-dimethylamino )-ethoxy]phenyl]-2-phenyl-1-butene is hydrogenated in 340 ml of ethanol-ethyl acetate (1: 1) containing 11 drops of triethylamine using 5%Pd--C as a catalyst. The catalyst is filtered off and the solvent is evaporated. The residue is treated with ethanol and the product is filtered. The yield is 4.9 g (71%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=12.[ClH:23].O1CCOCC1>O1CCOCC1>[ClH:23].[ClH:23].[ClH:23].[NH2:1][C:2]1[C:11]2[CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccccc3c(N)c2C1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1c2c(nc3ccccc13)CCNC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10-Amino-2-t-butoxycarbonyl-1,2,3,4-tetrahydro-benzo[b][1,6]-naphthyridine (0.538 g, 1.80 mmol) was suspended in dioxane (3 ml), followed by adding thereto 4N-hydrogen chloride/dioxane (9 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain the desired compound (0.585 g, quant.).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Br:8])=[CH:5][C:6]=1I.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:13][CH:12]=1)#[CH:10]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:1][C:2]1[S:3][C:4]([Br:8])=[CH:5][C:6]=1[C:10]#[C:9][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:13][CH:12]=1
Reactant: Brc1cc(I)c(Br)s1
Reactant: C#Cc1ccc(CCCCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCCCc1ccc(C#Cc2cc(Br)sc2Br)cc1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a solution of 2,5-dibromo-3-iodothiophene (3.52 grams, 9.57 mmol) and 1-ethynyl-4-pentylbenzene (1.65 grams, 9.57 mmol) in triethylamine (50 milliliters) were added dichlorobis(triphenylphosphine)palladium (II) (0.28 gram, 0.4 mmol) and copper(I) iodide (38 milligrams, 0.2 mmol) at 0° C. under argon. The resulting reaction mixture was stirred at 0° C. for 6 hours and at room temperature for 20 hours under argon. After evaporation of the solvent, the product obtained was purified by column chromatography on a silica gel using hexane as eluent. 2,5-Dibromo-3-(4-pentylphenyl)ethynylthiophene was obtained as a colorless liquid was. Yield: 3 grams (73 percent).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5]O.CS(Cl)(=O)=O.[CH2:17]([N:19](CC)CC)C.[Li+].[Br-].Cl.[C-]#N.[Na+]>ClCCl.CS(C)=O.O.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5][C:17]#[N:19]
Reactant: CCN(CC)CC
Reactant: COc1cc(Cl)cc(CO)c1
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1cc(Cl)cc(CC#N)c1
Temperature: -40 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a solution of 38b (13.3 g, 77 mmol, 1.0 equiv.) in 200 mL of dichloromethane cooled at −40° C. was added methanesulfonyl chloride (7.45 mL, 96 mmol, 1.25 equiv.), followed by dropwise addition of triethylamine (12.9 mL, 92 mmol, 1.2 equiv.). The mixture was stirred at −40° C. for 1 h. LiBr (20.0 g, 231 mmol, 3.0 equiv.) was added, followed by 400 mL of THF. The mixture was warmed to 0° C. After stirring at 0° C. for another 2 h, the mixture was poured into 200 mL of 1 M aqueous HCl. The mixture was evaporated in vacuo to remove organic solvents. The residue was extracted with 400 mL of ether. The ether layer was washed with 150 mL of saturated NaHCO3, 150 mL of brine, dried over Na2SO4, and evaporated in vacuo to give a light tan oil, which was dissolved in 100 mL of DMSO. NaCN (4.15 g, 85 mmol, 1.1 equiv.) was added to the solution. The mixture was stirred vigorously for 14 h. The mixture was poured into 300 mL of water. The aqueous mixture was extracted with 200 mL of ether. The ether extracts were washed with 100 mL of saturated NaHCO3, 100 mL of brine, dried over Na2SO4, and evaporated in vacuo to give 9.8 g of a brown oil. 1H-NMR (DMSO-d6): δ 7.00 (m, 2H), 6.90 (m, 1H), 4.02 (s, 2H), 3.78 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](I)=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.[Cl-].[Na+].O.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>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:24]3[CH:23]=[N:22][N:21]([CH3:20])[CH:25]=3)=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(Br)cc21
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cn1cc(-c2nn(COCC[Si](C)(C)C)c3cc(Br)ccc23)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of Example 1B (0.500 g, 1.103 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.275 g, 1.324 mmol) in toluene (8 ml) and ethanol (8 ml) under argon was treated with an aqueous solution of sodium carbonate (0.292 g, 2.76 mmol) in water (2 ml). Added Pd(PPh3)4(0.217 g, 0.188 mmol) and the resulting heterogeneous mixture was refluxed at 80° C. for 2 hours, then stirred at room temperature for 18 hours. The reaction mixture was diluted with brine and extracted twice with ethyl acetate. The combined organics were dried with MgSO4, concentrated and the residue purified via silica gel chromatography eluting with 0.5% methanol in CH2Cl2 to afford the title compound.
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:9]([C:11]2[S:30][C:14]3[N:15]=[C:16]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)[N:17]([CH3:18])[C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[ClH:1].[C:2]1([N:8]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:9]([C:11]2[S:30][C:14]3[N:15]=[C:16]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=4)[N:17]([CH3:18])[C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1cc2c(nc(CNc3ccc(C(=N)N)cc3)n2C)s1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2sc(C(=O)N(CCC(=O)O)c3ccccc3)cc21
Yield: 85 %

Procedure:
Prepared analogously to Example 2 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]-thieno[2.3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 85% of theory, C24H24N6O3S (476.56) Rf value: 0.36 (Reversed Phase silica gel RP-8; methanol+5% saline solution) ##EQU117##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:32]([F:35])([F:34])[F:33])[O:13][N:12]=[C:11]([C:14]3[CH:31]=[CH:30][C:17]([CH2:18][N:19]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.NN>CO.C(OC)(C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:32]([F:34])([F:33])[F:35])[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([CH2:18][NH2:19])=[CH:30][CH:31]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Agent: NN
Solvent: COC(C)(C)C
Solvent: CO
Product: NCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Yield: 41.1 %

Procedure:
A solution of 2-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}-1H-isoindole-1,3(2H)-dione (0.65 g) and aqueous hydrazine solution (0.07 g) in methanol (5 mL) was refluxed for one hour. After the reaction solution was diluted with t-butylmethylether, the solution was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel chromatography to yield 1-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]phenyl}methanamine (0.2 g).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[CH3:9][O:10][C:11]1[N:12]=[N+:13]([O-:21])[C:14]([CH3:20])=[CH:15][C:16]=1[N+]([O-])=O.O>C(Cl)Cl>[CH3:9][O:10][C:11]1[N:12]=[N+:13]([O-:21])[C:14]([CH3:20])=[CH:15][C:16]=1[O:4][CH2:3][C:2]([F:6])([F:5])[F:1]
Reactant: OCC(F)(F)F
Reactant: COc1n[n+]([O-])c(C)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1n[n+]([O-])c(C)cc1OCC(F)(F)F
Temperature: 55 °C
Reaction time: 1 h

Procedure:
2,2,2-Trifluoroethanol (3 ml) was initially charged at RT and admixed with sodium hydride (403 mg) in portions while cooling with ice. Thereafter, the reaction mixture was heated to 55° C. for 2 h and then 3-methoxy-6-methyl-4-nitropyridazine 1-oxide solution (500 mg, dissolved in 3 ml of 2,2,2-trifluoroethanol) was added dropwise. After stirring at RT for 1 h, the mixture was heated to 55° C. for 2.5 h. After standing at RT overnight, the mixture was admixed with water and DCM. After removing the DCM phase, the aqueous phase was extracted three times with DCM and the combined DCM phases were dried over sodium sulfate, filtered and concentrated. 571 mg of the title compound were obtained.