Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([S:13][CH2:14][CH3:15])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=O)[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([CH3:49])[C:27]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)([CH3:28])[NH:26]C(C3C=CC(C(C)(C)C)=CC=3OCC)=[N:24]2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([CH3:49])[C:27]([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)([CH3:28])[NH:26][C:6]([C:5]3[CH:9]=[CH:10][C:11]([S:13][CH2:14][CH3:15])=[CH:12][C:4]=3[O:3][CH2:1][CH3:2])=[N:24]2)=[CH:19][CH:18]=1
Reactant: CCOc1cc(SCC)ccc1C(=O)Cl
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Product: CCOc1cc(SCC)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1

Procedure:
rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-ethylsulfanyl-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was prepared from 2-ethoxy-4-ethylsulfanyl-benzoyl chloride (prepared from ethyl 2-ethoxy-4-fluoro-benzoate and sodium ethanethiolate) and meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) in an analogous manner as described in example 2 (method 1).
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.[C:6]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:10][C:9]([CH:12]=O)=[CH:8][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:12][C:9]1[CH:10]=[CH:11][C:6]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tetrabromomethane (21.8 g, 166 mmol) was added to a cooled solution of biphenyl-4-carbaldehyde (10.0 g, 54.9 mmol) and triphenylphosphine (35.5 g, 131.8 mmol) in dry methylene chloride (100 mL). Reaction mixture was stirred for 3 h at ambient temperature and saturated solution of sodium hydrogen carbonate (50 mL) was added. The organic layer was washed with water (50 mL), dried with anhydrous magnesium sulfate and subsequently evaporated in vacuo. The crude product was twice re-crystallized from methanol giving 1,1-dibromo-2-(4-biphenylyl)ethene as a white solid.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[N:5]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2>C(Cl)Cl.CO.[NH4+].[Cl-].CCOC(C)=O>[Cl:3][C:4]1[N:5]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:17])[C:6]2[C:11]([C:12]=1[CH2:13][OH:14])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=Cc1c(Cl)n(S(=O)(=O)c2ccccc2)c2ccccc12
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=S(=O)(c1ccccc1)n1c(Cl)c(CO)c2ccccc21
Yield: 99.6 %

Procedure:
NaBH4 (7.81 mg, 0.206 mmol) was added to a solution of 2-chloro-1-(phenylsulfonyl)-1H-indole-3-carbaldehyde (33 mg, 0.103 mmol) in DCM/MeOH 1:1 (10 mL). After 16 h the mixture was diluted with sat. NH4Cl and EtOAc, the organic layer separated and washed with H2O, dried over MgSO4, filtered and the filtrate concentrated to give the title compound (33 mg, 99%) which was used without purification.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Cl:13][CH2:14][CH2:15][OH:16]>C(#N)C>[CH3:8][S:9]([CH2:8][S:9]([O:16][CH2:15][CH2:14][Cl:13])(=[O:11])=[O:10])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CS(=O)(=O)OCCCl
Reaction time: 1 h

Procedure:
A solution of 133 g (1.32 mol.) of triethylamine in 400 ml of anhydrous acetonitrile was cooled to -30° to -40° C., and a solution of 100 g (0.88 mol.) of methanesulfonyl chloride in anhydrous acetonitrile (67 ml) was added dropwise at a rate that prevented the temperature from rising above -30° C. The mixture was stirred at -30° to -40° C. for 1 hour, and a solution of 35.4 g of 2-chloroethanol in anhydrous acetonitrile (30 ml) was added. The resulting mixture was stirred for 2 hours at -30° to -40° C. and then was filtered to separate triethylamine hydrochloride. The latter material was washed with ethyl acetate, the washings were combined with the filtrate, and the organic solution was concentrated in vacuo to an oil. A solution of the residual oil in ethyl acetate (1200 ml) was washed quickly with two portions (2×200 ml) of dilute sodium chloride solution and then with two portions (2×200 ml) of saturated sodium chloride solution, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residual solid (70 g) was dissolved in methylene chloride (450 ml), the solution was filtered and diluted slowly with cyclohexane (450 ml). The mixture, protected from atmospheric moisture, was allowed to stand at room temperature for about an hour and was then stored at low temperatures (about 5° C.) overnight. The precipitate was collected by filtration, washed with cyclohexane, and dried in vacuo over phosphorus pentoxide: yield, 58.7 g (56%); m.p. 60°-62° C.; IR (cm-1, medium and strong bands) 3040, 3025, 2990 s, 2930, 2935 sh, 1465, 1430, 1415, 1390, 1370 s, 1320 s, 1240, 1200, 1185 s, 1175 s, 1165 s, 1125, 1070, 990 s, 955 s, 915 s, 870 s, 790 s, 765, 755, 665, 605 sh, 600, 525 s, 505, 465 s, 420; 1H NMR (300.6 MHz, CDCl3, Me4Si as internal reference), δ3.26 (s, CH3), 3.80 (t, CH2Cl), 4.65 (t, OCH2), 4.67 (s, SCH2S). Anal. Calcd. for C4H9ClO5S2C, 20.30; H, 3.83. Found: C, 20.26; H, 4.00.
Reaction SMILES: [N+](C1C=CC(O[C:9]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]3)=[O:10])=CC=1)([O-])=O.[OH:28][CH2:29][CH2:30][NH:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C)C=O>[OH:28][CH2:29][CH2:30][N:31]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:9]([CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]2)=[O:10]
Reactant: O=C(CCCOc1ccc2[nH]c(=O)ccc2c1)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCCNC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(CCCOc1ccc2[nH]c(=O)ccc2c1)N(CCO)C1CCCCC1
Reaction time: 12 h

Procedure:
3.8 Grams of 6-[3-(p-nitrophenoxycarbonyl)propoxy]carbostyril was dissolved in 40 ml of dimethylformamide, then 1.6 ml of N-(2-hydroxyethyl)cyclohexylamine was added thereto and the reaction mixture was stirred at 60°-70° C. for 12 hours. After the reaction was completed, the solvent was removed by distillation and the residue thus obtained was purified by a silica-gel column chromatography [Silica-gel used was "Wako C-200" and the solvent used was a mixture of chloroform:methanol=20:1 (vol/vol)]. The crude crystals thus obtained was recrystallized from chloroform-petroleum ether to obtain 1.3 g of 6-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}carbostyril as in the form of colorless needle-like crystals. Melting point: 165°-166° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:54]([C:57]1[CH:61]=[CH:60][S:59][CH:58]=1)=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:55]([NH:54][C:57]2[CH:61]=[CH:60][S:59][CH:58]=2)=[O:56])[CH2:51][CH2:52]1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: O=C=Nc1ccsc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccsc1)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 30 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 3-isocyanatothiophene as the starting materials in 30% yield. LCMS for C29H31ClN7O2S (M+H)+: m/z=576.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]([OH:19])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:29][O:30][CH2:31]Cl.Cl>ClCCl>[CH2:1]([O:3][C:4]([NH:6][C:7]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]([O:19][CH2:29][O:30][CH3:31])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])[CH3:2]
Reactant: CCOC(=O)Nc1c(F)ccc(O)c1C(=O)OCC
Reactant: COCCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)Nc1c(F)ccc(OCOC)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
26.6 g of the resulting ethyl 2-(N-ethoxycarbonylamino)-3-fluoro-6-hydroxybenzoate was dissolved in 300 ml of dichloromethane under argon atmosphere, 20.5 ml of diisopropylethylamine and 9.0 ml of chloromethyl methyl ether were added under ice-cooling and the mixture was stirred at room temperature for 1.5 hours. Additional 20.5 ml of diisopropylethylamine and 9.0 ml of chloromethyl methyl ether were added and the mixture was stirred for 1.6 hours. Additional 5.1 ml of diisopropylethylamine and 2.2 ml of chloromethyl methyl ether were added and the mixture was stirred for 1 hour. An aqueous dilute solution of hydrochloric acid was added to the reaction solution, the mixture was extracted with dichloromethane, the organic layer was washed with water and an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give ethyl 2-(N-ethoxycarbonylamino)-3-fluoro-6-methoxymethoxybenzoate.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([CH:9]=[O:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[OH:11]OS([O-])=O.[K+]>CO.O.C(Cl)Cl>[CH3:1][S:2]([C:3]1[C:4]([CH:9]=[O:10])=[N:5][CH:6]=[CH:7][CH:8]=1)=[O:11]
Reactant: CSc1cccnc1C=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CS(=O)c1cccnc1C=O
Reaction time: 5 h
Yield: 22.6 %

Procedure:
To a cold (0° C.), stirred solution of 3-methylsulfanyl-pyridine-2-carbaldehyde (prepared as described for AMD9574) (280 mg, 1.83 mmol) in a mixture of MeOH (20 mL) and water (2 mL) was added solid oxone (2.25 g, 3.66 mmol) and the resulting heterogeneous mixture was stirred for 5 h. At this point, the reaction mixture was diluted with CH2Cl2 (50 mL), and then filtered through celite, washed with CH2Cl2 (3×20 mL) and concentrated and dried in vacuo. Flash chromatography (silica gel, 4:1 hexanes-EtOAc) of the residue thus obtained afforded 70 mg (23%) of 3-methanesulfinyl-pyridine-2-carbaldehyde. 1H NMR (CDCl3) □ 2.86 (s, 3H), 7.81 (dd, 1H, J=8, 5 Hz), 8.66-8.69 (m, 1H), 8.90 (d, 1H, J=3 Hz), 10.12 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:9]([CH:10]2[CH2:12][O:11]2)=[CH:8][CH:7]=[C:6]([F:13])[C:3]=1[C:4]#[N:5].[OH:14][CH2:15][C@@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1>C(O)C>[C:4]([C:3]1[C:2]([F:1])=[C:9]([CH:10]([OH:11])[CH2:12][N:21]2[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:17][C@@H:16]2[CH2:15][OH:14])[CH:8]=[CH:7][C:6]=1[F:13])#[N:5]
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Reactant: N#Cc1c(F)ccc(C2CO2)c1F
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CC(O)c2ccc(F)c(C#N)c2F)[C@@H](CO)C1

Procedure:
2,6-difluoro-3-(oxiran-2-yl)benzonitrile (3.70 g, 20.4 mmol) and (R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (6.63 g, 30.6 mmol) were dissolved in ethanol (36.0 mL) then placed in 3-20 mL sealed tubes and microwaved at 140° C. for 1 h. The solvents were evaporated and the combined residue was purified by chromatography through a 120 g ISCO Redi-sep column with 50% to 100% ethyl acetate/hexane solvent system to yield the title compound LC-MS (IE, m/z): 398 [M+1]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]1[C:15]2=[C:16]3[C:11](=[CH:12][CH:13]=[CH:14]2)[CH2:10][CH2:9][C:8](=[O:17])[N:7]3[CH2:6]1.[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>ClCCCl>[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([C:13]1[CH:12]=[C:11]2[C:16]3=[C:15]([CH2:5][CH2:6][N:7]3[C:8](=[O:17])[CH2:9][CH2:10]2)[CH:14]=1)=[O:24]
Reactant: O=C1CCc2cccc3c2N1CC3
Reactant: O=C(Cl)CCCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(CCCCCl)c1cc2c3c(c1)CCN3C(=O)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Aluminum chloride (55 g, 410 mmol) was added by portions to a solution of 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (30.0 g) and 5-chlorovaleryl chloride (26.8 ml) in 1,2-dichloroethane (70 ml) under ice-cooling. After stirring at room temperature for 30 minutes, the reaction mixture was poured into ice (500 g), extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol-diethyl ether to give a pale yellow solid (36.5 g). Further recrystallization from ethanol-diethyl ether afforded the title compound as colorless crystals (32.4 g) having a melting point of 110-111° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH2:11]([S:14](Cl)(=[O:16])=[O:15])[CH2:12][CH3:13]>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([F:10])=[C:4]([NH:5][S:14]([CH2:11][CH2:12][CH3:13])(=[O:16])=[O:15])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1cc(Cl)cc(Br)c1F
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1cc(Cl)cc(Br)c1F
Yield: 102.3 %

Procedure:
To a solution of 3-bromo-5-chloro-2-fluoroaniline (SM-5, step 3, 0.52 g, 2.3 mmol) in pyridine (2.5 mL) cooled in an ice water bath was added propane-1-sulfonyl chloride (0.3 mL, 2.8 mmol). After 4 hours the solution was concentrated and partitioned between EtOAc (75 mL) and aqueous 0.1 M HCl solution (30 mL). The layers were separated and the organic phase was then washed with brine, dried (Na2SO4) and concentrated to give 778 mg of N-(3-bromo-5-chloro-2-fluorophenyl)propane-1-sulfonamide as a yellow solid which was carried forward without further purification: LCMS (m/z) not observed, tR=0.95 minute.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3I)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.O.[CH3:23][N:24](C)C=O>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([C:23]#[N:24])=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: Ic1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Temperature: 160 °C
Yield: 79 %

Procedure:
A mixture of (R)-indan-1-yl-(5-iodo-quinolin-2-yl)-amine (example 1, step A) (1.44 g, 3.73 mmol), zinc cyanide (482 mg, 4.1 mmol) and tetrakis-(triphenylphosphine)-palladium (431 mg, 0.37 mmol) in dimethylformamide (20 ml) was heated at 160° C. for 15 min in a microwave reactor. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (diethyl ether/hexane) to yield 2-((R)-indan-1-ylamino)-quinoline-5-carbonitrile as light yellow solid (840 mg, 79%). M.p. 150° C.; MS: m/e=286.2 (M+H+).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=[O:5])C.CO.C1COCC1.CO.[CH3:37][N:38]([CH3:48])[CH2:39][C:40]1[N:41]=[C:42]([N+:45]([O-])=O)[NH:43][CH:44]=1>[Ni].C(Cl)Cl.CO>[CH3:37][N:38]([CH2:39][C:40]1[N:41]=[C:42]([NH:45][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=3[Cl:27])=[CH:14][CH:15]=2)=[O:5])[NH:43][CH:44]=1)[CH3:48]
Reactant: CN(C)Cc1c[nH]c([N+](=O)[O-])n1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3nc(CN(C)C)c[nH]3)c3nccnc23)c1F

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2, and dimethyl-(2-nitro-1H-imidazol-4-ylmethyl)-amine (Step 22.1) instead of 2-nitroimidazole in Step 14.3. The title compound: ESI-MS: 485.1 [M+H]+; tR=3.24 min (System 1); TLC: Rf=0.20 (DCM/MeOH/NH3aq, 91.5:7.5:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])=[N:10][N:11]([C:13]3[CH:18]=[CH:17][C:16](=[O:19])[NH:15][N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.NC1C=C(C2C(C3C=CC=CC=3)=NN(C3C=CC(=O)NN=3)C=2)C=CN=1>>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])=[N:10][N:11]([C:13]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(-c2cn(-c3ccc(=O)[nH]n3)nc2-c2ccccc2F)ccn1
Agent: Nc1cc(-c2cn(-c3ccc(=O)[nH]n3)nc2-c2ccccc2)ccn1
Product: Nc1cc(-c2cn(C3=NNC(=O)CC3)nc2-c2ccccc2F)ccn1
Yield: 38.3 %

Procedure:
The reaction was carried out in the same manner as in Example 49 except for using 1.40 g (4.02 mmol) of 4-(2-aminopyridin-4-yl)-3-(2-fluorophenyl)-1-(1,6-dihydro-6-oxopyridazin-3-yl)-1H-pyrazole obtained in Example 26-5) in place of 4-(2-aminopyridin-4-yl)-1-(1,6-dihydro-6-oxopyridazin-3-yl)-3-phenyl-1H-pyrazole to obtain 540 mg of the title compound as a white powder. (Yield: 38%)
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[C:6]1([P:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[C:19]1([P:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:2][C:3](=[O:5])[CH3:4])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)CCl
Solvent: ClC(Cl)Cl
Product: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 23.3 %

Procedure:
A solution of 1-chloropropan-2-one (50 g, 540.4 mmol) in chloroform (150 mL) was added dropwise to a solution of triphenylphosphine (141.72 g, 540.4 mmol) in chloroform (150 mL) under nitrogen. The mixture was stirred at 70° C. for 12 hr, and the resulting phosphonium salt was filtered. The precipitate was washed with ethyl acetate and dried under vacuum. The dried phosphonium salt was suspended in a mixture of water (250 mL) and methanol (250 mL), and the mixture was stirred for 1 hr. Aqueous sodium hydroxide (2.00 M) was added to the mixture until a pH between 7 and 8 was reached. The mixture was then stirred vigorously for 1 hr. The phosphorane precipitate was filtered and washed with water. After drying in vacuum, the phosphorane was recrystallized from ethyl acetate and dried under vacuum to afford 1-(triphenylphosphoranylidene)propan-2-one (40.00 g, 23.3%) as a white solid.
Reaction SMILES: [C:1]([N:5]1[CH:13]=[C:12]2[C:7]([C:8]([N:17]3[CH:21]=[CH:20][CH:19]=[N:18]3)=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C>[C:1]([N:5]1[CH:13]=[C:12]2[C:7]([C:8]([N:17]3[CH:21]=[CH:20][CH:19]=[N:18]3)=[CH:9][C:10]([NH2:14])=[CH:11]2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1cc2cc([N+](=O)[O-])cc(-n3cccn3)c2n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)n1cc2cc(N)cc(-n3cccn3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10% Palladium on carbon (300 mg) was added to a solution of 2-(tert-butyl)-5-nitro-7-(1H-pyrazol-1-yl)-2H-indazole obtained in the above-described Step 2 (255 mg) in ethyl acetate (5 mL), and the reaction solution was stirred under hydrogen atmosphere at room temperature overnight. The insolubles were filtrated, and the solvent was evaporated under vacuum. Thereafter, the resultant residue was purified by column chromatography on basic silica gel (developing solvent:hexane/ethyl acetate) to obtain 2-(tert-butyl)-7-(1H-pyrazol-1-yl)-2H-indazol-5-amine as brown amorphous.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[C:9]([C:11]2[CH:32]=[CH:31][C:14]3[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)[CH3:20])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[C:2]1([N:8]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:9]([C:11]2[CH:32]=[CH:31][C:14]3[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=4)[CH3:20])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(Cc1nc2cc(C(=O)N(CCC(=O)O)c3ccccc3)ccc2n1C)c1ccc(C(=N)N)cc1
Yield: 80 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 80% of theory, C27H28N6O3 (484.6) ##EQU54##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.C([O-])(O)=O.[Na+]>COC(C)(C)C>[CH3:7][C:4]([CH3:8])([CH2:5][O:6][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][O:22]1)[C:3]([O:2][CH3:1])=[O:9]
Reactant: C1=COCCC1
Reactant: COC(=O)C(C)(C)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: COC(=O)C(C)(C)COC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of hydroxypivalic acid methyl ester (50.0 g, 378 mmol) and p-toluenesulfonic acid monohydrate (1.439 g, 7.57 mmol) in 250 mL of methyl-tert-butylether was added dihydropyran (48.1 mL, 568 mmol) slowly with cooling. The mixture was stirred at room temperature overnight, 50 mL of saturated NaHCO3 added and the mixture shaken and separated. The organic layer dried over MgSO4 and concentrated. Purification of the residue by flash chromatography using 330 g column, 0%-5% ethyl acetate in hexane gave methyl 2,2-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)propanoate as a clear oil: 1H NMR (400 MHz, CDCl3) δ 4.5 (s, 1H), 3.8-3.6 (m, 2H), 3.6 (m, 3H), 3.4 (s, 1H), 3.25 (m, 1H), 1.7 (m, 1H), 1.6-1.18 (m, 5H), 1.05 (m, 6H).