Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([N:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[F:16][C:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([F:21])[C:18]([O-])=[O:19].O>O1CCCC1.CCCCC>[F:16][C:17]([F:21])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:18]([C:2]1[CH:10]=[CH:9][C:5]([N:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=1)=[O:19]
Reactant: O=C([O-])C(F)(F)c1ccccc1
Reactant: CN(C)c1ccc(Br)cc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1ccc(C(=O)C(F)(F)c2ccccc2)cc1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
A solution of 4.0 g of 4-bromo-N,N-dimethylaniline in 50 ml of dry tetrahydrofuran at -78° C. was treated with 23.5 ml of 1.7M tert-butyllithium in pentane under nitrogen over 5 minutes with rapid stirring. After 0.5 hour, the slurry was warmed to -30° C. and added to a solution of 4.0 g of α,α-difluorophenylacetate in 50 ml of dry tetrahydrofuran at -78° C. After 1 hour at -78° C., the solution was allowed to warm to room temperature and stirred overnight. The solution was poured into water and extracted with ethyl acetate. Evaporation left a solid which was purified by flash chromatography (1:1 ethyl acetate-hexane) to give a powder. Recrystallization from ethyl acetate-hexane gave 1.75 g of 2,2-difluoro-1-[4-(dimethylamino)phenyl]-2-phenylethanone, m.p. 115°-116° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[N:10](COCCOC)[N:9]=2)=[CH:4][CH:3]=1.[CH:26](=O)[CH3:27]>C(O)C.[Pd].[C]>[CH2:26]([NH:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH3:27]
Reactant: CC=O
Reactant: COCCOCn1nc(-c2ccc(F)cc2)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: CCNc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
To a solution of 1-{[3-(4-fluorophenyl)-5-nitro(1H-indazolyl)]methoxy}-2-methoxyethane (100 mg, 0.29 mmol) in ethanol (30 mL, containing a contaminant of acetaldehyde) was added a scoup of Pd/carbon. The reaction was stirred overnight at room temperature under an atmosphere of hydrogen. It was filtered over celite and the solution concentrated to an oil. The oil was taken up in methanol (20 mL) and 6N HCl (20 mL) and heated to 75° C. for 3 hours. The solution was concentrated under vacuo, added to saturated bicarbonate (100 mL), and extracted with ethyl acetate (3×30 mL). The organic layers were dried (Na2SO4), concentrated to an oil and chromatographed on silica gel, eluting with 50% ethyl acetate/hexane to give the title compound (8 mg, 11% yield). 1H NMR (CDCl3) δ 10.4 (br s, 1H), 7.91 (dd, 2H), 7.26–7.17 (m, 3H), 6.99 (s, 1H), 6.84 (dd, 1H), 3.21 (q, H), 1.31 (t, 3H); ES-MS (m/z) 256 [M+1]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[NH2:33][CH2:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:25]=[CH:26][C:27]([C:30](=[O:31])[NH:33][CH2:34][C:35]5[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=5)=[CH:28][CH:29]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: NCc1ccncc1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Product: O=C(NCc1ccncc1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 66.3 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 4-(aminomethyl)pyridine (available from Aldrich Chemical Company, Inc.; 67 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-[(pyridin-4-ylmethyl)-carbamoyl]-biphenyl-2-carboxylic acid (78 mg, 68%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.16 (br s, 1H), 9.25 (t, J=5.8 Hz, 1H), 8.60 (d, J=6.0 Hz, 2H), 8.47 (s, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.25 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.3, 2.0 Hz, 1H), 7.99 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.3 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.46-7.55 (m, 4H), 4.60 (d, J=5.8 Hz, 7H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][O-:14].[Na+].O>CO>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:14][CH3:13])[N:5]=[C:4]([CH3:12])[N:3]=1
Reactant: C[O-]
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(C)nc(Cl)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a solution of 4,6-dichloro-2-methyl-5-nitropyrimidine (6.54 g) in methanol (31.5 mL) was added sodium methoxide (28% methanol solution, 6.05 mL) in a dropwise manner under ice-cooling, and the mixture was stirred at the same temperature for 1 hour, and then stirred at room temperature for 1.5 days. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=9/1) to give the title compound (5.7 g).
Reaction SMILES: [CH:1]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:20]([CH2:23][CH2:24][C@@H:25]([NH:33][C:34]([N:36]1[CH2:45][CH2:44][C:43]2[CH:42]=[N:41][C:40]([NH:46][CH:47]([CH3:49])[CH3:48])=[N:39][C:38]=2[CH2:37]1)=[O:35])[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)=[N+]=[N-].CI.[OH-].[K+]>C1COCC1.CO>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C@H:25]([NH:33][C:34]([N:36]2[CH2:45][CH2:44][C:43]3[CH:42]=[N:41][C:40]([NH:46][CH:47]([CH3:49])[CH3:48])=[N:39][C:38]=3[CH2:37]2)=[O:35])[CH2:24][CH2:23][NH:20][CH3:1])=[CH:27][CH:28]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)Nc1ncc2c(n1)CN(C(=O)N[C@H](CCN=[N+]=[N-])c1ccc(Cl)cc1)CC2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CI
Product: CNCC[C@@H](NC(=O)N1CCc2cnc(NC(C)C)nc2C1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A suspension of PS—PPh3 (278 mg, 2.28 mmol/g, 0.634 mmol) and THF (5 mL) was was allowed to stand for 5 min then a solution 332 (136 mg, 0.317 mmol) in THF (1 mL) was added. The suspension was stirred at RT for 4 h then MeI (0.0593 mL, 0.951 mmol) was added. The mixture was stirred at RT for 17 h, filtered through a fritted funnel and the resin washed with THF (5×10 mL) and DCM (5×10 mL). The resin was transferred to a pressure tube and suspended in MeOH (8 mL) and a solution of KOH (178 mg, 3.17 mmol) in MeOH (2 mL) was added. The mixture was heated to 65° C. for 4 h, cooled to RT, filtered and the resin washed with DCM (4×3 mL) and MeOH (2×3 mL). The filtrate and washings were combined and concentrated to a white solid. The crude product was partitioned between DCM and dilute aq. NaHCO3 and the aqueous layer extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered, and concentrated. The crude product was purified on a preparative TLC plate (0.5 mm) developed with MeOH/DCM/NH4OH (9/90/1) to afford 50 mg (38%) of I-117 as a pale yellow foam: 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.72 (br s, 1H), 7.22-7.28 (m, 4H), 4.95 (m, 1H), 4.80 (d, 1H), 4.37 (m, 2H), 4.10 (m, 1H), 3.69 (m, 1H), 3.60 (m, 1H), 2.72 (m, 2H), 2.65 (t, 2H), 2.48 (s, 3H), 2.05 (m, 1H), 1.80 (m, 1H), 1.22 (d, 6H); LRMS (APCI pos) m/e=417.4 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[N:16][C:15]3[C:14]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:13][C:12]([C:24]4[CH:25]=[N:26][C:27]([NH:30]C(=O)OC(C)(C)C)=[N:28][CH:29]=4)=[N:11][C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)Cl.F[C:42](F)(F)[C:43](O)=[O:44].CO>C(Cl)(Cl)Cl>[NH2:30][C:27]1[N:28]=[CH:29][C:24]([C:12]2[N:13]=[C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:15]3[N:16]=[CH:17][C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:43](=[O:44])[CH3:42])[CH:7]=[CH:6][CH:5]=4)=[CH:9][C:10]=3[N:11]=2)=[CH:25][N:26]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(N)c4)cc3n2)cn1
Solvent: ClCCl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cccc(-c2cnc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3c2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a 250 mL round bottom flask, tert-butyl (5-(7-(3-aminophenyl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyrimidin-2-yl)carbamate (1.6 g, 0.0029 mol) and DCM (160 mL) were added and the flask cooled to 0° C. To the reaction flask, trifluoroacetic acid (16 mL, 10% volume) was added at 0° C. and the reaction mixture was stirred at room temperature for 3 hours. The volatiles were evaporated under reduced pressure and methanol was added to provide a solid. The solid was collected by filtration. The solid was suspended into water and basified with saturated sodium bicarbonate solution. The reaction mixture was extracted with chloroform (3×200 mL). The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the crude product. The crude product was subjected to flash column chromatography using 4% methanol in chloroform. The obtained solid was washed with methanol and diethyl ether, filtered and dried under vacuum to afford the title compound as off-white solid (0.900 g, 69%). 1H NMR (400 MHz, DMSO-d6): δ 10.18 (s, 1H), 9.22 (s, 2H), 9.02 (d, J=2.0 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.19 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.24 (s, 2H), 4.55 (br s, 4H), 3.87 (t, J=4.4 Hz, 4H), 2.12 (s, 3H). LC-MS (ESI): Calculated mass: 442.2; Observed mass [M+H]+: 443.1. (RT=0.18 min).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:12])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:25][Cl:26].C(N(CC)CC)C>C(O)C>[ClH:26].[ClH:26].[F:31][C:21]([F:20])([F:32])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:25][N:4]1[CH2:3][CH2:2][N:1]([CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:12])[CH2:6][CH2:5]1
Reactant: FC(F)(F)c1cc(CCl)ccc1Cl
Reactant: CCCCCCNC(=O)NCCCN1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCCCNC(=O)NCCCN1CCN(Cc2ccc(Cl)c(C(F)(F)F)c2)CC1
Product: Cl
Yield: 115.7 %

Procedure:
A mixture of 1-(3-piperazinylpropyl)-3-n-hexylurea (2.7 g; 10 mmole), 3-trifluoromethyl-4-chlorobenzyl chloride (2.29 g; 10 mmole), triethylamine (1.01 g; 10 mmole) and ethanol (30 ml) was refluxed for 3 hours. The solvent was evaporated in vacuo, and water was added to the residue. The product was extracted with ether, and the extract was dried (sodium sulfate) and concentrated. Precipitation of the oily residue with ethereal hydrochloric acid, followed by recrystallization from alcohol, provided the title compound (3.1 g; 58% yield) as colorless crystals, m.p. 216°-219° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][N:5]=[C:4]([C:7]2[CH2:8][N:9](/[N:14]=[CH:15]/[C:16]3[CH:17]=[N:18][CH:19]=[C:20]([F:22])[CH:21]=3)[C:10](=[O:13])[NH:11][N:12]=2)[CH2:3]1.[H-].[Na+].Br[CH2:27][C:28]#[N:29]>C1COCC1>[CH3:1][C:2]1([CH3:23])[O:6][N:5]=[C:4]([C:7]2[CH2:8][N:9](/[N:14]=[CH:15]/[C:16]3[CH:17]=[N:18][CH:19]=[C:20]([F:22])[CH:21]=3)[C:10](=[O:13])[N:11]([CH2:27][C:28]#[N:29])[N:12]=2)[CH2:3]1
Reactant: CC1(C)CC(C2=NNC(=O)N(/N=C/c3cncc(F)c3)C2)=NO1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CC(C2=NN(CC#N)C(=O)N(/N=C/c3cncc(F)c3)C2)=NO1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-(5,5-dimethyl-4H-isoxazol-3-yl)-4-[(E)-(5-fluoro-3-pyridyl)methyleneamino]-2,5-dihydro-1,2,4-triazin-3-one (150 mg, 0.471 mmol) in anhydrous THF (8.0 mL) was added NaH (28.2 mg, 0.707 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 10 min followed by dropwise addition of 2-bromoacetonitrile (36.2 μL, 62.2 mg, 0.518 mmol). The reaction mixture was allowed to warm to room temp. and stirring was continued for 2 h. The reaction mixture was quenched by addition of methanol followed by ice. The organic layer was evaporated in rotavap and aqueous layer extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to furnish the crude product. Purification by flash chromatography (60-70% EtOAc/hexanes) provided the desired product as a white solid. M.p. 195-197° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[O-:12][S:13]([O-:15])=[O:14].[Na+].[Na+].O>CCO>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([S:13]([OH:15])(=[O:14])=[O:12])[CH:7]=1
Reactant: O=S([O-])[O-]
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(S(=O)(=O)O)c1
Yield: 249.8 %

Procedure:
In a similar fashion using route 39 general procedure 95, 2-fluoro-4-methyl-1-nitrobenzene (2 g, 12.9 mmol) in EtOH (24 ml) and Na2SO3 (2.04 g, 16.0 mmol) in EtOH:water (40 ml: 32 ml) at 70° C. for 14 h gave the title compound (7 g) which was used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].[N+:13]([O-:16])(O)=[O:14].[C:17]1(C)C=CC(S(O)(=O)=O)=CC=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>S(=O)(=O)(O)O.C(OCC)(=O)C.C1C=CC=CC=1.CO>[CH3:17][O:11][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[C:7]([N+:13]([O-:16])=[O:14])[CH:8]=2)=[O:12]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1Cc2ccccc2N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Yield: 58 %

Procedure:
Compound 34 was prepared from indoline-2-carboxlic acid by nitration with nitric acid in sulfuric acid, methylation using methanol and p-toluenesulfonic acid, followed by reaction with dichlorodicyanobenzoquinone in ethyl acetate and benzene. Total yield: 58%. MS: 219.13 (M−H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[F:21][C:22]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[C:26]([F:38])=[CH:25][C:23]=1[NH2:24]>>[NH2:24][C:23]1[C:22]([F:21])=[CH:28][C:27]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[C:26]([F:38])[CH:25]=1
Reactant: CC1(C)OB(c2cc(F)c(N)cc2F)OC1(C)C
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3cc(F)c(N)cc3F)ccn2c1=O
Yield: 76.1 %

Procedure:
Methyl 8-(4-amino-2,5-difluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.71 mmol) and 2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (667 mg, 2.06 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (500 mg, 75%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[N:4][N:5]([CH2:7]Cl)[CH:6]=1.[F:16][C:17]([F:26])([F:25])[CH2:18][CH2:19][CH:20]([C:23]#[N:24])[C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:3]([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[N:4][N:5]([CH2:7][C:20]([CH2:19][CH2:18][C:17]([F:16])([F:25])[F:26])([C:21]#[N:22])[C:23]#[N:24])[CH:6]=1
Reactant: FC(F)(F)C(F)(F)c1nn(CCl)cc1Br
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(Br)c(C(F)(F)C(F)(F)F)n1
Yield: 74.6 %

Procedure:
6.84 g of 4-bromo-1-(chloromethyl)-3-(pentafluoroethyl)-1H-pyrazole and 3.54 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 60 ml of N,N-dimethylformamide. 6.08 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 7.15 g of [(4-bromo-3-(pentafluoroethyl)-1H-pyrazole-1-yl) methyl](3,3, 3-trifluoropropyl) malononitrile (referred as the compound of the present invention (37), hereinafter) shown by below formula.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:10]1[S:11][C:12]([S:39][CH3:40])=[C:13]([S:15]([C:18]2[CH:37]=[C:36]([Br:38])[C:21]3[N:22]([CH2:25][C:26]4[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:27]=4[F:35])[CH:23]=[N:24][C:20]=3[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])(C)(C)C.C(OC(=O)[NH:48][C:49]([C:51]1[S:52][C:53]([S:80][CH3:81])=[C:54]([S:56]([C:59]2[CH:78]=[C:77]([Br:79])[C:62]3[N:63]=[CH:64][N:65]([CH2:66][C:67]4[CH:72]=[C:71]([N+:73]([O-:75])=[O:74])[CH:70]=[CH:69][C:68]=4[F:76])[C:61]=3[CH:60]=2)(=[O:58])=[O:57])[CH:55]=1)=[NH:50])(C)(C)C.[F:83][C:84]([F:89])([F:88])[C:85]([OH:87])=[O:86]>C(Cl)Cl>[F:83][C:84]([F:89])([F:88])[C:85]([OH:87])=[O:86].[Br:79][C:77]1[C:62]2[N:63]=[CH:64][N:65]([CH2:66][C:67]3[CH:72]=[C:71]([N+:73]([O-:75])=[O:74])[CH:70]=[CH:69][C:68]=3[F:76])[C:61]=2[CH:60]=[C:59]([S:56]([C:54]2[CH:55]=[C:51]([C:49]([NH2:50])=[NH:48])[S:52][C:53]=2[S:80][CH3:81])(=[O:57])=[O:58])[CH:78]=1.[F:83][C:84]([F:89])([F:88])[C:85]([OH:87])=[O:86].[Br:38][C:36]1[C:21]2[N:22]([CH2:25][C:26]3[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:27]=3[F:35])[CH:23]=[N:24][C:20]=2[CH:19]=[C:18]([S:15]([C:13]2[CH:14]=[C:10]([C:8]([NH2:9])=[NH:7])[S:11][C:12]=2[S:39][CH3:40])(=[O:17])=[O:16])[CH:37]=1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cc(Br)c2c(c1)ncn2Cc1cc([N+](=O)[O-])ccc1F
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cc(Br)c2ncn(Cc3cc([N+](=O)[O-])ccc3F)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cc(Br)c2c(c1)ncn2Cc1cc([N+](=O)[O-])ccc1F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cc(Br)c2ncn(Cc3cc([N+](=O)[O-])ccc3F)c2c1
Temperature: 25 °C
Reaction time: 3.2 h
Yield: 47 %
Yield: 47 %

Procedure:
A solution of ({4-[7-bromo-1-(2-fluoro-5-nitro-benzyl)-1H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester and ({4-[7-bromo-3-(2-fluoro-5-nitro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester ((from above step d) 0.015 g, 0.022 mmol) in CH2Cl2 (1 mL) was cooled to 0° C. and treated with 25% trifluoroacetic acid in CH2Cl2 (1.00 mL). The mixture was allowed to warm to room temperature and was stirred 3.2 h. The solvents were removed in vacuo. Preparatory HPLC (10–80% acetonitrile in 1% TFA/water over 30 min.) afforded the products 4-[7-bromo-3-(2-fluoro-5-nitro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate (0.002 g, 47%) and 4-[7-bromo-1-(2-fluoro-5-nitro-benzyl)-1H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate (0.002 g, 47%) as white solids.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])[CH3:4].C(Cl)Cl.C(N)CN>C(O)(C(F)(F)F)=O>[OH:1][CH2:2][C@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])[CH3:4]
Reactant: C[C@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: C[C@H](CO)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-hydroxy-1-methyl-ethyl)-amide (35 mg, 0.068 mol) was dissolved in a 4:6 solution of TFA:DCM (10 mL). After stirring at room temperature overnight, the volatiles were removed under reduced pressure. The crude material was then dissolved in dichloromethane and treated with ethylenediamine (41 mg, 0.68 mmol). After stirring at room temperature overnight, the precipitate was collected by filtration to afford 15 mg (57%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-hydroxy-1-methyl-ethyl)-amide as a yellow solid. MS: (M+H)+=385; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.97 (d, J=2.64 Hz, 1H) 8.66 (d, J=8.69 Hz, 1H) 8.36 (s, 1H) 8.15 (d, J=7.93 Hz, 1H) 7.92 (s, 1H) 7.26 (d, J=8.31 Hz, 1H) 3.96-4.39 (m, 3H) 3.31-3.68 (m, 1H) 1.25 (d, J=6.80 Hz, 3H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]2[CH:12]=[C:11]([C:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH:18]=3)[NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.[N:19]1([CH2:25][CH2:26][C:27](O)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:3][C:4]1[C:5]2[CH:12]=[C:11]([C:13]3[CH2:14][CH2:15][N:16]([C:27](=[O:28])[CH2:26][CH2:25][N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:17][CH:18]=3)[NH:10][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: O=C(O)CCN1CCCCC1
Reactant: Clc1ncnc2[nH]c(C3=CCNCC3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCN1CCCCC1)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension/solution of 4-chloro-6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine bis-hydrochloride (19.1 mg, 0.0621 mmol, 1 eq), 1-piperidinepropanoic acid (24.5 mg, 0.156 mmol, 2.5 eq), 1-hydroxybenzotriazole (HOBt) (8.5 mg, 0.063 mmol, 1 eq), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (36.3 mg, 0.189 mmol, 3 eq) in anhydrous DMF (1.3 mL), DiPEA (64 μL, 0.37 mmol, 6 eq) was added and the reaction was stirred at rt, under N2, for 16 h. Solvent was concentrated in vacuo and the residue was dissolved in DCM, washed with NaHCO3 (2×) and brine (1×), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified on MDPS giving the title compound as a yellow solid. 1H NMR (400 MHz, MeOH-d4): δ=1.45-1.56 (s, br, 2H), 1.64 (sextet, J=5.6 Hz, 4H), 2.46-2.78 (m, 10H), 3.81 & 3.84 (t, J=5.6 Hz, rotamers, 2H), 4.29 & 4.33 (d, J=2.0 Hz, rotamers, 2H), 6.48 (s, br, 1H), 6.62 & 6.63 (s, rotamers, 1H), 8.50 (d, 1H). MS (ES+): m/z 373.99/376.00 (100/36) [MH+]. HPLC: tR=1.86 min (ZQ2000, polar—5 min).
Reaction SMILES: [BH4-].[Na+].C(O)C.[O:6]=[C:7]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])/[CH:8]=[CH:9]/[CH:10]1[CH2:12][C:11]1([C:17]([O:19][CH3:20])=[O:18])[C:13]([O:15][CH3:16])=[O:14].C(O)(=O)C>O>[OH:6][CH:7]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])/[CH:8]=[CH:9]/[CH:10]1[CH2:12][C:11]1([C:13]([O:15][CH3:16])=[O:14])[C:17]([O:19][CH3:20])=[O:18]
Reactant: CCCCCC(=O)/C=C/C1CC1(C(=O)OC)C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCCCCC(O)/C=C/C1CC1(C(=O)OC)C(=O)OC
Temperature: 25 °C

Procedure:
A solution of 5.5 g of sodium borohydride in 50 ml. of 95% ethanol is added to a solution of the compound of formula VI, dimethyl trans-2-(3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate (35 g), described in Example 2. After 15 min. at room temperature the mixture is cooled in ice and rendered neutral by the addition of acetic acid. Water is added and the mixture extracted with ethyl-acetate. The extract was dried (Na2SO4) and the evaporated. The residue is purified by chromatography on silica gel to afford the title compound, nmr (CDCl3) δ 0.90 (t, 3H), 2.33 (1H), 3.73 (s, 3H) 4.05 (m, 1H).