Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:12](=O)[NH:11][C:10]([CH:14]2[CH2:16][CH2:15]2)=[N:9][C:8]=1[C:17]([OH:19])=[O:18]>>[Cl:6][C:7]1[C:8]([C:17]([OH:19])=[O:18])=[N:9][C:10]([CH:14]2[CH2:16][CH2:15]2)=[N:11][C:12]=1[Cl:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1nc(C2CC2)[nH]c(=O)c1Cl
Product: O=C(O)c1nc(C2CC2)nc(Cl)c1Cl
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Phosphorus oxychloride (200 mL, 328 g, 2.14 mol) and 5-chloro-2-cyclopropyl-1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acid (i.e. the product of Step B1 or B2) (96.8 g, 451 mmol) were combined and heated at 90° C. for 5 h. The reaction mixture was cooled to 50-60° C. and concentrated at reduced pressure to half volume. After cooling to 30° C. the reaction mixture was added over 60 minutes to a mixture of t-butanol (200 mL) and water (300 mL), with the temperature maintained at 8-10° C. The mixture was seeded, water (300 mL) was added gradually at 10-15° C. and the mixture was stirred for 1 h. After cooling to 5° C. the precipitated product was isolated by filtration and washed with water (3×50 mL). The solid was dried in a vacuum oven to afford the title compound (93 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH:26]([O:29][CH2:30][CH2:31][CH2:32][NH2:33])([CH3:28])[CH3:27]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:33][CH2:32][CH2:31][CH2:30][O:29][CH:26]([CH3:28])[CH3:27])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CC(C)OCCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: CC(C)OCCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-isopropoxypropylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.73 (1H, br s), 10.71 (1H, br s), 10.23 (1H, br s), 8.17 (1H, br s), 7.28-7.24 (3H, m), 7.15-7.10 (2H, t, J=8.4 Hz), 4.00 (2H, s), 3.52-3.46 (1H, m), 3.39 (2H, t, J=6 Hz), 3.30-3.21 (2H, m), 1.68-1.62 (2H, m), 1.06 (6H, d, J=6.1 Hz); HRMS calcd for C22H24FN3O4+H+: 414.1829. Found 414.1810.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=3Br)[C:21]#[N:22])=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:27])[CH:5]=1)(=[O:3])[CH3:2].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=3[N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:21]#[N:22])=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:27])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C#N)ccc3Br)CC2)c(F)c1
Reactant: C1COCCN1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C#N)ccc3N3CCOCC3)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described for example 1 from 3-[4-(4-Acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-bromo-benzonitrile (example L) and morpholine (71%, white solid), MS (m/e): 437.2 (M+H, 100%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([Cl:26])=[CH:5][C:6]([N+:23]([O-])=O)=[C:7]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:8]=1.O.NN>C(O)C.[Ni]>[NH2:23][C:6]1[CH:5]=[C:4]([Cl:26])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[NH:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]1
Reactant: COc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1Cl
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)cc1Cl
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
1,1-Dimethylethyl 4-[(5-methoxy-4-chloro-2-nitrophenyl)amino]-piperidinecarboxylate (D47) (400 mg) was dissolved in ethanol (10 ml) and Raney nickel (50% aqueous suspension, 1.0 ml) was added at room temperature; the mixture was heated to 40° C. and hydrazine monohydrate (0.5 ml) was added over 30 min. After 30 min more, the reaction mixture was cooled to room temperature, filtered through Celite evaporated and chromatographed on silica gel eluting with ethyl acetate-hexane mixtures to yield the title compound, 300 mg.
Reaction SMILES: CS(O[CH2:6][C@H:7]([CH3:15])[CH2:8][CH2:9]OS(C)(=O)=O)(=O)=O.[NH2:16][C@@H:17]([CH3:20])[CH2:18][OH:19]>C(Cl)Cl.C([O-])([O-])=O.[K+].[K+].O>[CH3:15][C@@H:7]1[CH2:8][CH2:9][N:16]([C@@H:17]([CH3:20])[CH2:18][OH:19])[CH2:6]1
Reactant: C[C@H](N)CO
Reactant: C[C@H](CCOS(C)(=O)=O)COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1CCN([C@@H](C)CO)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.8 %

Procedure:
(R)-2-Methylbutane-1,4-diyl dimethanesulfonate (37.5 g, 0.144 mol) was added to neat (S)-2-aminopropan-1-ol (54.8 g, 0.730 mol). The mixture was stirred in a room temperature water bath to minimize the exotherm. After 24 h, the reaction was diluted with DCM (150 mL), sat'd K2CO3 solution (150 mL), and just enough water (60 mL) to dissolve the resulting ppt. The organic layer was separated, and the aqueous layer was extracted with DCM (150 mL). The organic layers were combined, dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography (10:7; ethyl acetate:hexanes→10:7:2:1; ethyl acetate:hexanes:methanol:triethylamine) to give (S)-2-((R)-3-methylpyrrolidin-1-yl)propan-1-ol (17.9 g) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 4.33 (t, 1H), 3.48 (m, 1H), 3.18 (m, 1H), 2.79 (dd, 1H), 2.58 (m, 1H), 2.48 (m, 1H), 2.26 (m, 1H), 2.08 (m, 1H), 2.01 (dd, 1H), 1.88 (m, 1H), 1.20 (m, 1H), 0.98 (d, 3H), 0.96 (d, 3H); LCMS: 144.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH:7](O)[CH3:8])=[CH:4][CH:3]=1.[H-].[Na+].S(OC)([O:17][CH3:18])(=O)=O>C1COCC1>[CH3:18][O:17][CH2:8][CH2:7][O:6][C:5]1[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: COS(=O)(=O)OC
Reactant: CC(O)Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1ccc(Br)cc1
Temperature: 0 °C
Yield: 103.5 %

Procedure:
To an ice-cooled solution of 4-bromophenoxyethanol (5 g, 23.0 mmol) in THF (30 ml) was added a suspension of sodium hydride (1.10 g, 46.1 mmol) in THF (30 ml), with stirring. After 20 minutes dimethyl sulfate (4.37 ml, 46.1 mmol) was added dropwise. The reaction mixture was stirred for 4 hours at room temperature then quenched slowly with saturated aq. ammonium chloride (50 ml). The mixture was extracted with ethyl acetate (100 ml) and the organic extract was washed successively with 1M hydrochloric acid (50 ml) and brine (50 ml), dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure to leave 4-(2-methoxy-ethoxy)-bromobenzene (5.5 g, ca. quant.) as a pale brown oil. 1H-NMR; δ (CDCl3), 7.36 (2H, d, J=9.1 Hz), 6.80 (2H, d, J=9.1 Hz), 4.09 (2H, t, J=4.7 Hz), 3.74 (2H, t, J=4.7 Hz) and 3.45 (3H, s).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH:20]1[CH2:22][O:21]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[O:32])=[C:26]([F:39])[CH:25]=1)#[N:7]>O1CCCC1>[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH:20]([OH:21])[CH2:22][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[O:32])=[C:26]([F:39])[CH:25]=1)#[N:7]
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)ccnc2cc1OCC1CO1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)ccnc2cc1OCC(O)CN1CCCC1
Temperature: 50 °C

Procedure:
After adding tetrahydrofuran (1 ml) and pyrrolidine (0.1 ml) to N-[4-(6-cyano-7-oxiranylmethoxy-quinolin-4-yloxy)-2-fluorophenyl]-N′-(thiazol-2-yl)urea (120 mg), the mixture was heated at 50° C. for 40 minutes. The reaction solution was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to obtain the title compound (70 mg) as light yellow crystals.
Reaction SMILES: N[C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1.N([O-])=O.[Na+].[BrH:14]>O.CCCCCO>[Br:14][C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1
Reactant: Nc1ncc([N+](=O)[O-])s1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCCCCO
Solvent: O
Product: O=[N+]([O-])c1cnc(Br)s1
Temperature: -10 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To 72.5 g of 2-amino-5-nitrothiazole in 300 mL of 48% hydrobromic acid and 200 mL of water stirred and cooled to about -10° C. was slowly added, in portions, 51.8 g of sodium nitrite dissolved in 80 mL of water from one addition funnel and 250 mL of n-amyl alcohol from a second addition funnel. The addition of both solutions required about 3 hours. The cooling bath was removed and the mixture allowed to warm to about 15° C. overnight and then stirred at room temperature for 2 hours. The solid was collected by vacuum filtration and steam distilled to give 67 g of crude product. The crude product was recrystallized from hot ethanol to give 61 g (60% yield) of the 2-bromo-5-nitrothiazole as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[C:8]([SH:11])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH2:21]Cl)[CH:16]=1>O.CO>[F:1][C:2]1[C:10]2[N:9]=[C:8]([S:11][CH2:21][C:17]3[CH:16]=[C:15]([O:14][CH3:13])[CH:20]=[CH:19][N:18]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc2[nH]c(S)nc12
Reactant: COc1ccnc(CCl)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccnc(CSc2nc3c(F)cccc3[nH]2)c1

Procedure:
To a solution of 4-fluoro-2-mercapto-1H-benzimidazole (1.15 g, 0.0068 mol) in methanol (60 ml) NaOH (0.54 g, 0.014 mol) dissolved in water (3 ml) and 4-methoxy-2-chloromethylpyridine hydrochloride 1.32 g, 0.0068 mol) dissolved in methanol (20 ml) were added in the given order. The mixture was refluxed for one hour whereupon the solution was evaporated. The residue was partitioned between methylene chloride and water. After separation the organic solution was dried over MgSO4 and evaporated giving an oil which was purified on silica gel (50 g) using 1% methanol in methylene chloride as eluent. In this way the title compound was obtained (1.35 g, 69%). NMR data for the product is given below.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:7][CH2:8][C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:26]([O:28]CC)=[CH2:27])CCC.Cl.C(OCC)(=O)C>C1COCC1.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>[CH3:12][C:9]1([CH3:13])[C:10]2[CH:11]=[C:2]([C:26](=[O:28])[CH3:27])[CH:3]=[CH:4][C:5]=2[C:6]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:7][CH2:8]1
Reactant: Cc1ccc(C2=CCC(C)(C)c3cc(Br)ccc32)cc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)C(C)(C)CC=C2c1ccc(C)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 94.9 %

Procedure:
A solution of 7-bromo-1,1-dimethyl-4-p-tolyl-1,2-dihydro-naphthalene (Compound 4, 295 mg, 0.90 mmol) in 5 ml of THF was first degassed by bubbling with argon for 30 min. Tributyl(1-ethoxyvinyl)tin (650 mg, 1.80 mmol) and PdCl2(PPh3)2 (63 mg, 0.09 mmol) were added. After stirring at 80° C. for 18 h, the mixture was cooled to room temperature and 3 mL of 10% HCl was added. The mixture was then stirred for another 30 min before extraction with ethyl acetate (3×10 mL). The combined organic layer was washed with brine (1×10 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chromatography (80:20 hexane/ethyl acetate) afforded the title compound (248 mg, 95% yield) as a colorless oil:
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[S:10][C:11]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)(=O)C>[C:1]1([CH2:7][CH2:8][C:9]2[S:10][C:11]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(=Cc1nc2cnc3ccccc3c2s1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: c1ccc(CCc2nc3cnc4ccccc4c3s2)cc1
Yield: 75.3 %

Procedure:
A small amount of catalyst (5% palladium on activated carbon) was added to a suspension of 2-(2-phenyl-1-ethenyl)thiazolo[4,5-c]quinoline (1.16 g, Example 21 Part B) in acetic acid (200 mL). The mixture was reduced on a Parr apparatus under a 50 psi (3.5 Kg/cm2) hydrogen atmosphere for 1 day. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under vacuum. The residue was dissolved in dichloromethane, washed with sodium bicarbonate then with water, dried over magnesium sulfate and then concentrated under vacuum to provide 0.88 g of 2-(2-phenyl-1-ethyl)thiazolo[4,5-c]quinoline as an oily solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: COc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccccc1-c1cc(Cl)ncn1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
A solution of 4,6-dichloropyrimidine (2.0 g, 13 mmol), 2-methoxyphenylboronic acid (2.0 g, 13 mmol), and sodium carbonate (4.4 g, 42 mmol, dissolved in minimal amount of water) was degassed with argon. To the degassed solution Pd(Ph3)4 was added and the resultant reaction mixture was refluxed for 18 hours. The reaction mixture was cooled to room temperature and diluted with dichloromethane. The organics were washed with water and the aqueous layer was extracted with additional dichloromethane. The combined organics were washed with brine and dried over sodium sulfate. Following filtration, the organics were dried in vacuo and the residue was purified by Si gel chromatography (1:10 ethyl acetate:hexanes) to yield 2.4 g (80%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][C:7]=3[CH:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.[SiH](CC)(CC)[CH2:35]C.B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:35][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][C:7]=3[CH:8]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:16][CH:17]=3)[O:9]2)=[CH:4][CH:3]=1
Reactant: CC[SiH](CC)CC
Reactant: CC(=O)c1ccc2c(c1)C(c1ccc(OCCN3CCCCC3)cc1)Oc1cc(O)ccc1-2
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc2c(c1)OC(c1ccc(OCCN3CCCCC3)cc1)c1cc(C(C)=O)ccc1-2
Temperature: -78 °C

Procedure:
The compound from Step G (1.66 g, 3.2 mmol) was dissolved in CH2Cl2 (90 mL) and cooled to −78° C. Et3SiH (3.1 ml, 19.2 mmol) and BF3-Et2O (2.6 ml, 19.2 mmol) were added slowly under Ar. The mixture was stirred at −78° C., then at room temperature overnight. Saturated NaHCO3 (100 ml) was added and the mixture extracted three times with ethyl acetate (150 ml). The combined organic layer was washed with brine (100 ml) and dried over MgSO4. The solvent was removed and the crude product was chromatographed on silica gel with 7% CH3OH/CH2Cl2 to yield a fraction containing a mixture of the title compound along with side products and a fraction containing 0.52 g (32%) of the title compound. 1H-NMR (400 MHz, CDCl3) δH 1.42 (2H, m, NCH2CH2CH2), 1.59 (4H, m, NCH2CH2CH2), 2.50 (7H, m, NCH2CH2CH2 and COCH3), 2.76 (2H, m, NCH2CH2O), 3.77 (3H, s, OCH3), 4.08 (2H, m, NCH2CH2O), 6.14 (1H, s, Ph2CHO), 6.50 (1H, s, ArH), 6.61 (1H, d, ArH), 6.86 (2H, d, ArH), 7.22 (2H, d, ArH), 7.45 (1H, s, ArH), 7.66 (1H, d, ArH), 7.72 (1H, d, ArH), 7.93 (1H, d, ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:23]#[N:24])[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: N#Cc1ccccc1B(O)O
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccccc1-c1cccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 46.9 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-cyanobiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 2-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.033 g (46%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-cyanobiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12]O.P(Br)(Br)[Br:15].O>C(OCC)C>[Br:15][CH2:12][C:3]1[C:4]([C:8]([F:11])([F:10])[F:9])=[N:5][N:6]([CH3:7])[C:2]=1[F:1]
Reactant: Cn1nc(C(F)(F)F)c(CO)c1F
Reactant: BrP(Br)Br
Solvent: O
Solvent: CCOCC
Product: Cn1nc(C(F)(F)F)c(CBr)c1F
Temperature: -30 °C
Reaction time: 12 h
Yield: 67.3 %

Procedure:
A solution of 35.4 g (178.7 mmoles) of 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-methanol dissolved in 500 ml of diethyl ether was cooled to −30° C. Thereto was added 54.0 g (199.5 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 31.4 g (yield: 80.8%) of 4-bromomethyl-5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[CH:11]=[C:10]([C:20]([O:22]C(C)(C)C)=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([OH:19])[C:15]([F:17])([F:18])[F:16])[CH:11]=[C:10]([C:20]([OH:22])=[O:21])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(C(O)C(F)(F)F)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(O)C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a DCM (22 mL) solution tert-butyl 4′-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)biphenyl-3-carboxylate (1.6 g, 4.4 mmol) from step A was added trifluoroacetic acid (22 mL). The mixture was stirred at rt for 3 h and concentrated to dryness. The crude title compound was used in step C without further purification.
Reaction SMILES: [S:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].N[C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[CH:21]2>>[NH:23]1[C:24]2[C:20](=[CH:19][CH:18]=[CH:17][C:16]=2[NH:2][S:1]([C:5]2[CH:6]=[CH:7][C:8]([SH:11]=[O:13])=[CH:9][CH:10]=2)(=[O:3])=[O:4])[CH:21]=[CH:22]1
Reactant: Nc1cccc2cc[nH]c12
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: O=[SH]c1ccc(S(=O)(=O)Nc2cccc3cc[nH]c23)cc1
Yield: 69.4 %

Procedure:
767 mg (3.0 mmol) of 4-sulfamoylbenzenesulfonyl chloride was reacted with 264 mg (2.0 mmol) of 7-amino-1H-indole and treated, to give 445 mg of N-(1H-indole-7-yl)-4-sulfanoylbenzenesulfonamide. The resulting compound was chlorinated using N-chlorosuccinimide in dichloromethane, to give 349 mg of the title compound.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH2:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>C(O)(C)C>[F:12][C:11]([F:14])([F:13])[C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][CH2:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[NH2:20])=[N:3][C:4]=2[CH:10]=1
Reactant: Nc1ccccc1CCl
Reactant: FC(F)(F)c1ccc2nc(S)[nH]c2c1
Agent: Cl
Solvent: CC(C)O
Product: Nc1ccccc1CSc1nc2cc(C(F)(F)F)ccc2[nH]1
Yield: 37.1 %

Procedure:
The title compound was prepared by the method of Example 1 using 4.36 g of 2-mercapto-5-(trifluoromethyl)benzimidazole instead of 2-mercaptobenzimidazole and 3.56 g of 2-(chloromethyl)aniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline in isopropyl alcohol. The basic extraction used 5% sodium hydroxide instead of sodium carbonate. Washing the solid residue from the dichloromethane extract with additional dichloromethane gave 2.40 g of the title compound: m.p. ca. 155° C. Anal. Calc'd. for C15H12N3F3S: C, 55.72; H, 3.74; N, 13.00; S, 9.92; F, 17.63. Found: C, 55.55; H, 3.68; N, 13.10; S, 10.12; F, 17.38.
Reaction SMILES: [F:1][CH:2]([F:25])[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]1[CH2:20][CH2:19][N:18]([CH:21]=[O:22])[CH2:17][CH2:16]1)[C:10](=[O:23])[NH:9][C:8]2=[O:24].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:9]2[C:8](=[O:24])[C:7]3[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH2:3][CH:2]([F:1])[F:25])[CH:6]=3)[N:11]([CH:15]3[CH2:20][CH2:19][N:18]([CH:21]=[O:22])[CH2:17][CH2:16]3)[C:10]2=[O:23])=[CH:29][CH:30]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=CN1CCC(n2c(=O)[nH]c(=O)c3cc(OCC(F)F)ccc32)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=CN1CCC(n2c(=O)n(Cc3ccc(Cl)cc3)c(=O)c3cc(OCC(F)F)ccc32)CC1
Reaction time: 1 h
Yield: 57.2 %

Procedure:
A mixture of 0.15 g of 4-[6-(2,2-difluoroethoxy)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]piperidine-1-carbaldehyde obtained in stage 3.7, 0.096 g of 1-(bromomethyl)-4-chlorobenzene and 0.3 g of Cs2CO3 in 3 ml of DMF is stirred at AT for 1 h 00. AcOEt is added and washing is carried out with water and then with a saturated NaCl solution. The organic phase is dried over MgSO4, filtered and evaporated under reduced pressure. The residue is chromatographed on silica gel, elution being carried out with AcOEt, to give 0.116 g of the expected product.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[O:15][C:14]([C:16](=[N:18][OH:19])[NH2:17])=[CH:13][CH:12]=1)([O-])=O.[H][H]>[Pd].CO>[ClH:1].[ClH:1].[NH2:2][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[O:15][C:14]([C:16](=[N:18][OH:19])[NH2:17])=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: NC(=NO)c1ccc(-c2ccccc2[N+](=O)[O-])o1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC(=NO)c1ccc(-c2ccccc2N)o1
Yield: 148.9 %

Procedure:
A mixture of the compound of Example XV (14.2 g 0.05 mole), 5% Pd/C (50% H2O) (1 teaspoon), and anhydrous methanol (300 ml) was shaken in a Parr apparatus until the theoretical amount of hydrogen was absorbed. The catalyst was removed by filtration and washed with anydrous methanol. Gaseous HCl was introduced into the filtrate with cooling in ice. The solid was collected by filtration and washed with anhydrous ether to give 10.8 g (75%) of product. An analytical sample, m.p. 238°-239°, was obtained by drying in an Abderhalden.