Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:9]=[C:10]([OH:21])[CH:11]=[C:12]([C:14](=[O:20])[NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].F[C:29]1[C:34]([F:35])=[C:33]([F:36])[CH:32]=[CH:31][C:30]=1[N+:37]([O-:39])=[O:38]>C1COCC1>[C:1]([NH:5][C:6](=[O:7])[C:8]1[CH:9]=[C:10]([O:21][C:29]2[C:30]([N+:37]([O-:39])=[O:38])=[CH:31][CH:32]=[C:33]([F:36])[C:34]=2[F:35])[CH:11]=[C:12]([C:14]([NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:20])[CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: CC(C)(C)NC(=O)c1cc(O)cc(C(=O)NC(C)(C)C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1cc(Oc2c([N+](=O)[O-])ccc(F)c2F)cc(C(=O)NC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
A 22 L round-bottom flask was charged with 3,5-bis-tert-butylcarbamoyl-phenol (20, 360 g, 1.23 mol) and THF (12.5 L). The resulting slurry was cooled to 0° C. and potassium tert-butoxide (1.35 L, 1.0 M in THF, 1.35 mol) was added dropwise over approximately 30 min. After the addition was complete, the reaction mixture was cooled to between −30 and −35° C. and 2,3,4-trifluoronitrobenzene (239, 1.35 mol) was added dropwise over approximately 5 min. The reaction mixture was stirred at approximately −30° C. for 1 h whereupon the cooling bath was removed. The reaction mixture was then stirred for 20 h with warming to ambient temperature. A mixture of water (2.0 L) and brine (1.0 L) was added, and the reaction mixture was stirred vigorously in a 20 L extractor ball. Following removal of the aqueous phase, the organic layer was washed with additional brine (1.5 L), and the resulting THF solution was transferred to a 22 L round bottom flask for distillation. The extractor ball was rinsed with THF (500 mL). After approximately 10 L of THF had been removed by distillation, addition of isopropyl alcohol (11 L) was initiated and the distillation was continued until approximately 23 L of distillate had been collected. When the residual volume was 5 L and the pot temperature was 82° C., water (2.0 L) was added dropwise. Heating was then discontinued, and the reaction mixture was stirred overnight with cooling to room temperature. The resulting solid was filtered through a 3 L course-flit sintered glass filter funnel. The filter cake was washed with IPA/H2O (1:1, 2×600 mL) and dried in a vacuum oven (70° C., 25 Torr) to afford N,N′-di-tert-butyl-5-(2,3-difluoro-6-nitro-phenoxy)-isophthalamide (21; 488 g, 88% theory).
Reaction SMILES: [C:1]1([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][NH:13][C:8]=1[CH:7]=[CH:6]2.CN(C)C=O.[H-].[Na+].[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)(=O)C>[C:24]1([CH2:23][N:13]2[C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[C:1]([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=4)[C:9]=3[CH:11]=[CH:12]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ClCc1ccccc1
Reactant: Nc1nc(N)c2c(ccc3[nH]ccc32)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Nc1nc(N)c2c(ccc3c2ccn3Cc2ccccc2)n1
Reaction time: 1.5 h

Procedure:
A suspension of 13.95 g. 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 600 ml. dry dimethylformamide is stirred under nitrogen as 3.70 g. ca. 50% sodium hydride-mineral oil dispersion is added carefully. After stirring for 1.5 hours, a solution of 9.30 g. benzyl chloride (8.5 ml.) in 20 ml. dry dimethylformamide is added during ca. 10 min. Stirring is continued for 5 hours and then 120 ml. gl. acetic acid is added to the reaction mixture. After removal of solvent (in vacuo), the residue is stirred thoroughly with excess aqueous potassium carbonate solution and filtered. The solids are collected, washed with water, and dried. The crude product is dissolved in 1.4 l. boiling methanol, treated with charcoal, and filtered through Celite. The filtrate is concentrated to ca. 125 ml. and chilled. The crystalline solid is collected, washed with acetone, and again recrystallized from methanol to afford 11.76 g. title compound, m.p. 228°, NMR (dDMSO): δ 5.53 (singlet, N-CH2C6H5), 7.12 (doublet, J-3Hz, 9H), 7.23 (doublet, 8Hz, 5 or 6H), 7.63 (doublet, J=3Hz, 8H), 7.77 (doublet, J=9Hz, 5 or 6H) p.p.m.; λmax95%EtOH 235 (ε 26,900), 260 (ε 28,620), 317 (ε 9,640), 345 sh (ε 7,520) nm; λmin95%EtOH 243 (ε 26,020), 281 (ε 2,430) nm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[C:14]2[C@@H:13]3[CH2:15][C@@H:12]3[CH2:11][C:10]=2[C:9]([C:16]([OH:18])=O)=[N:8]1.[NH2:19][CH:20]([CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[CH2:21][OH:22]>>[OH:22][CH2:21][CH:20]([NH:19][C:16]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:15][C@H:13]3[C:14]=2[N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[N:8]=1)=[O:18])[CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: NC(CO)C1CCOCC1
Reactant: O=C(O)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21
Product: O=C(NC(CO)C1CCOCC1)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G using Intermediate 2 and 2-amino-2-(tetrahydro-2H-pyran-4-yl)ethanol. LCMS m/z=370.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.46-0.50 (m, 1H), 1.26 (td, J=7.8 and 4.6 Hz, 1H), 1.42-1.54 (m, 2H), 1.72 (d, J=12.6 Hz, 2H), 1.98-2.09 (m, 1H), 2.27-2.34 (m, 1H), 2.51 (bs, 1H), 2.73-2.79 (m, 1H), 2.94 (d, J=16.8 Hz, 1H), 3.01 (dd, J=16.4 and 6.1 Hz, 1H), 3.36-3.45 (m, 2H), 3.82-3.89 (m, 3H), 4.01 (dd, J=11.2 and 4.0 Hz, 2H), 7.11 (d, J=7.6 Hz, 1H), 8.42 (dd, J=2.5 and 1.5 Hz, 1H), 8.51 (d, J=2.4 Hz, 1H), 9.26 (d, J=1.4 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:16]3[N:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[NH:13][C:12]3[CH:22]=[CH:23][CH:24]=[N:25][C:11]2=3)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:28]I.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:16]3[N:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[N:13]([CH3:28])[C:12]3[CH:22]=[CH:23][CH:24]=[N:25][C:11]2=3)=[CH:5][CH:4]=1
Reactant: CI
Reactant: COc1ccc(CN2c3ncccc3NC(=O)c3cccnc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2c3ncccc3C(=O)N(C)c3cccnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
10.0 g (0.030 mol) of 5,11-dihydro-11-[(4-methoxyphenyl)methyl]-6H-dipyrido-[3,2-b:2',3'-e][1,4]diazepin-6-one was added to a flask containing 2.16 g of a 50% dispersion of sodium hydride in mineral oil and 100 ml of dimethylformamide. The resulting mixture was stirred at room temperature for 30 min. and then heated to 50° C. for 30 min. After cooling, 8.51 g (0.060 mol) of methyl iodide in 10 ml of dimethylformamide was added dropwise and the mixture was allowed to stir at room temperature overnight. Excess sodium hydride was decomposed by the careful addition of ice. Water was then added, and the product was extracted with ether, dried (anhydrous sodium sulfate), and concentrated to give 10.3 g (99% of theory) of 5,11-dihydro-11-[(4-methoxy-phenyl)-methyl]-5-methyl-6H-dipyrido-[3,2-b:2',3'-e][1,4]diazepin-6-one as a light yellow oil suitable for use in the next reaction.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:6](=[O:14])[C:7]([C:10]([O:12]C)=[O:11])=[N:8][CH:9]=1.Cl>CCO>[CH3:3][C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:16]=2)[C:6](=[O:14])[C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1
Reactant: COC(=O)c1ncc(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cnc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
NaOH (1M, 6 ml) was added to methyl 5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (0.60 g, 1.92 mmol) dissolved in EtOH (12 ml) and the mixture was stirred for 15 minutes. The aqueous phase was neutralized by addition of HCl (1M, 7 ml) to pH 6 to 7 and extracted with ethyl acetate (3×15 ml). The organic phase was dried (MgSO4), filtered and evaporated. No further purification was performed.
Reaction SMILES: [Br-:1].[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N+:7]([CH2:10][CH2:11][NH:12][C:13]([C:15]1[C:20]([NH2:21])=[N:19][C:18]([NH2:22])=[C:17]([Cl:23])[N:16]=1)=[O:14])([CH3:9])[CH3:8].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.CN1CCOCC1>CN(C=O)C>[Br-:1].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][N+:7]([CH2:10][CH2:11][NH:12][C:13]([C:15]2[C:20]([NH2:21])=[N:19][C:18]([NH2:22])=[C:17]([Cl:23])[N:16]=2)=[O:14])([CH3:9])[CH3:8])(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: C[N+](C)(CCCCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[N+](C)(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCNC(=O)c1nc(Cl)c(N)nc1N

Procedure:
A solution of (4-amino-butyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate N) (0.25 g, 0.60 mmol), 4-chlorobenzenesulfonyl chloride (0.125 g, 0.59 mmol) and N-methylmorpholine (0.3 mL, 2.73 mmol) in DMF (5 mL) is shaken at RT for 16 h. The reaction mixture is concentrated in vacuo, and the residue is purified by chromatography (basic alumina, 0-15% methanol in DCM) to obtain the title compound. M+ 504.
Reaction SMILES: [C:1]([NH:4][OH:5])(=[O:3])[CH3:2].[CH3:6][N:7]=[C:8]=[O:9]>C(N(CC)CC)C.C(Cl)Cl>[CH3:6][NH:7][C:8]([N:4]([O:5][C:8]([NH:7][CH3:6])=[O:9])[C:1](=[O:3])[CH3:2])=[O:9]
Reactant: CC(=O)NO
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)ON(C(C)=O)C(=O)NC
Reaction time: 1 h

Procedure:
A mixture of acetohydroxamic acid (7.5 grams), methyl isocyanate (12.0 grams), 80 milliliters (ml) of methylene chloride, and about three drops of triethylamine were stirred together for about one hour in order to obtain solution. The solution was allowed to stand at room temperature overnight after which the solvent was removed under vacuum, leaving a residue. The residue was recrystallized from methylene chloride leaving the desired N-((methylamino)carbonyl)-N-(((methylamino)carbonyl)oxy)acetamide as white crystals having a melting point (m.p.) of 121°-123.5° C.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([O:9][C:10]3([C:23]4[C:18](=[CH:19][C:20]([OH:25])=[C:21]([Cl:24])[CH:22]=4)[O:17][C:16]4[C:11]3=[CH:12][C:13]([Cl:27])=[C:14]([OH:26])[CH:15]=4)[C:4]2=[CH:3][CH:2]=1)=[O:8].C(O)(=O)C>C1COCC1.[Zn]>[Cl:24][C:21]1[C:20]([OH:25])=[CH:19][C:18]2[O:17][C:16]3[C:11](=[CH:12][C:13]([Cl:27])=[C:14]([OH:26])[CH:15]=3)[CH:10]([C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=3[C:7]([OH:9])=[O:8])[C:23]=2[CH:22]=1
Reactant: O=C1OC2(c3cc(Cl)c(O)cc3Oc3cc(O)c(Cl)cc32)c2ccccc21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1C1c2cc(Cl)c(O)cc2Oc2cc(O)c(Cl)cc21
Reaction time: 8 h

Procedure:
2′,7′-Dichlorofluorescein (2.0 g, 5.0 mmol) was dissolved in 80 mL of THF, containing 2 mL of acetic acid. Zn (powder, 8.0 g, 122 mmol) was added portionwise (0.5 g with ˜15 min intervals) to the solution of 2′,7′-Dichlorofluorescein. After all amount of Zn was added the reaction mixture was stirred overnight. All solids have been filtered off, washed with THF and evaporated. The residue was re-dissolved in ethyl acetate (120 mL) and washed with water (2×30 mL), brine (30 mL), dried over sodium sulfate and evaporated. The crude product (˜2.0 g, oil) was used for the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:62])[C@H:5]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:61])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]/[CH:51]=[CH:52]\[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[NH:6][C:7](=[O:31])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])C.[OH-].[Na+].Cl>>[C:7]([NH:6][C@H:5]([C:4]([OH:62])=[O:3])[CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:61])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]/[CH:51]=[CH:52]\[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])(=[O:31])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)NCCCC[C@H](NC(=O)CCCCCCCCCCCCC/C=C\CCCCCCCC)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)NCCCC[C@H](NC(=O)CCCCCCCCCCCCC/C=C\CCCCCCCC)C(=O)O
Reaction time: 8 h

Procedure:
Nα,Nε-di-(z-15-tetracosenoyl)-L-lysine ethyl ester (2 mmol, 1.74 g, prepared according to Example 2) was heated to gentle reflux with 3% methanolic sodium hydroxide solution (25 mL) for 2 hours and left at room temperature overnight. The soapy material was acidified to pH 2 with 1 N cold hydrochloric acid and the white solid was collected and recrystallised from acetone-water (1:1) giving the free acid title compound as a white powder.
Reaction SMILES: [C:1]([C:3]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([N:13]=CN(C)C)[N:5]([C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][C:19]=2[Cl:29])[N:4]=1)#[N:2].[H-].[Na+].ClC(Cl)(Cl)S(O[CH2:38][C:39]([F:42])([F:41])[F:40])(=O)=O.ClCCl>CN1CCCC1=O>[NH2:13][C:6]1[N:5]([C:18]2[C:19]([Cl:29])=[CH:20][C:21]([C:25]([F:26])([F:27])[F:28])=[CH:22][C:23]=2[Cl:24])[N:4]=[C:3]([C:1]#[N:2])[C:7]=1[N:8]([CH2:38][C:39]([F:42])([F:41])[F:40])[S:9]([CH3:12])(=[O:10])=[O:11]
Reactant: CN(C)C=Nc1c(NS(C)(=O)=O)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)N(CC(F)(F)F)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.3 %

Procedure:
To a solution of N-(3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-{[(dimethylamino)methylene]amino}-1H-pyrazol-4-yl)methanesulfonamide (250 mg, 0.53 mmol) in 1-methyl-2-pyrrolidinone (anhydrous, 5 ml) was added sodium hydride (60% in oil, 16.6 mg, 0.69 mmol) and 2,2,2-trifluoroethyl trichloromethanesulphonate (195 mg, 0.69 mmol). The reaction mixture was then stirred at room temperature for 3 h. To the reaction mixture was added dichloromethane (20 ml) and the resulting mixture was extracted with water (20 ml). The organic phase was washed with water (2×20 ml) and brine (2×20 ml), dried (Na2SO4) and concentrated in vacuo. To the residue was added methanol (5 ml) and hydrochloric acid (4M, 3 ml) and the mixture was heated at reflux for 60 h. The reaction mixture was concentrated in vacuo and to the residue was added ethyl acetate (20 ml) and water (20 ml). The organic phase was separated, washed with water (2×20 ml) and brine (2×20 ml), dried (Na2SO4) and concentrated in vacuo. The crude product was dissolved in acetonitrile/dimethyl sulphoxide/water (1:4:1, 6 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm×30 mm Phenomonex LUNA C18(2) 10 μm column) using an acetonitrile:water gradient [52.5:47.5 to 95:5]. The appropriate fractions were concentrated in vacuo to give the titled compound (135 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[C:4]([F:31])[CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:9][C:10](=[O:11])[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[C:4]([F:31])[CH:3]=1
Reactant: CCOC(=O)c1cccc(C(CC(=O)c2ccc(OC)nc2)c2ccc(Cl)cc2F)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc(C(CC(=O)c2ccc(=O)[nH]c2)c2ccc(Cl)cc2F)c1

Procedure:
In analogy to example 162, step 2, ethyl 3-(1-(4-chloro-2-fluorophenyl)-3-(6-methoxy-pyridin-3-yl)-3-oxopropyl)benzoate was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as an colourless solid, MS (ESI+): m/z=426.0 [M+H]+.
Reaction SMILES: [Li]C(C)(C)C.I[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]([CH3:15])[CH3:14].[CH2:16]=[O:17].[NH4+].[Cl-]>C1COCC1>[CH:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:16][OH:17])([CH3:15])[CH3:14]
Reactant: CC(C)c1ccccc1I
Reactant: C=O
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)c1ccccc1CO
Reaction time: 0.17 h

Procedure:
Add 1.7M tert-BuLi (26 ml, 44 mmol) dropwise, at −78° C. under inert atmosphere, to a solution of 1-Iodo-2-iso-propylbenzene (5 g, 20.3 mmol) in 70 ml of dry THF and stir. After 10 min, add Paraformaldehyde (2 g, 66.7 mmol) in a single portion. Stir the reaction at this temperature for 15 min and then at room temperature for 2 h. Add a saturated aqueous solution of NH4Cl and extract with CH2Cl2 three times. Dry the combined organic extracts over Na2SO4, filter and concentrate under reduced pressure to give a residue. Purify the residue by column chromatography on silica gel eluting with CH2Cl2 to afford pure (2-Isopropyl-phenyl)-methanol as pale purple oil. Add aqueous concentrated HBr (15 ml) to a solution of (2-Isopropyl-phenyl)-methanol (1,93 g, 12.85 mmol) in CH2Cl2(15 ml) and stir at room temperature. After 2 h. separate phases and wash the organic one with H2O; dry over Na2SO4 and evaporate at vacuum to obtain a residue. Purify the residue by column chromatography on silica gel eluting with CH2Cl2 to obtain 1-Bromomethyl-2-isopropyl-benzene as very pale pink light oil. 1H-NMR (CDCl3, 200 MHz): δ 7.33-7.25 (m, 3H), 7.19-7.11 (m, 1H), 4.58 (s, 1H), 3.31 (sep, J=6.8 Hz, 1H), 1.30 (d, J=6.8 Hz, 6H).
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:8]=1[C:9]([O:11]C)=O)=[C:2]=[S:3].[CH3:19][C:20]1[N:24]([CH2:25][CH2:26][CH2:27][NH2:28])[CH:23]=[N:22][CH:21]=1>>[CH3:19][C:20]1[N:24]([CH2:25][CH2:26][CH2:27][N:28]2[C:9](=[O:11])[C:8]3[CH:7]=[C:6]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[S:5][C:4]=3[NH:1][C:2]2=[S:3])[CH:23]=[N:22][CH:21]=1
Reactant: Cc1cncn1CCCN
Reactant: COC(=O)c1cc(-c2ccccc2)sc1N=C=S
Product: Cc1cncn1CCCn1c(=S)[nH]c2sc(-c3ccccc3)cc2c1=O

Procedure:
The compound was synthesized starting from methyl 2-isothiocyanato-5-phenylthiophene-3-carboxylate (0.10 g, 0.36 mmol) and 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5) (0.051 g, 0.36 mmol) as described above.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:26]([NH:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34])(=[O:28])[CH3:27]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:33]([C:32]4[CH:31]=[C:30]([NH:29][C:26](=[O:28])[CH3:27])[CH:38]=[CH:37][CH:36]=4)=[O:34])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: CC(=O)Nc1cccc(C(=O)Cl)c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc(NC(C)=O)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 3-(acetylamino)benzoyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]=[N:17][N:18]([C:20]([CH2:26][OH:27])([CH2:24][OH:25])[C:21](O)=[O:22])[CH:19]=2)[C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:4]=2[CH:3]=1.C(O)C.O.C(=O)([O-])O.[Na+]>O1CCCC1>[F:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]=[N:17][N:18]([C:20]([CH2:21][OH:22])([CH2:24][OH:25])[CH2:26][OH:27])[CH:19]=2)[C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:4]=2[CH:3]=1
Reactant: O=C(O)C(CO)(CO)n1cc(-c2cc(F)cc3c2-c2ccccc2C3(O)C(F)(F)F)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: OCC(CO)(CO)n1cc(-c2cc(F)cc3c2-c2ccccc2C3(O)C(F)(F)F)cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
To a solution of an optically active form (28.3 g) of 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-hydroxy-2-hydroxymethyl-propionic acid in tetrahydrofuran (40 ml) were successively added dropwise at room temperature a 0.93M solution (225 ml) of borane-tetrahydrofuran complex in tetrahydrofuran and a 1.09M solution (32 ml) of borane-tetrahydrofuran complex in tetrahydrofuran, and the mixture was stirred for 3 hr. To the reaction mixture, ethanol (57 ml) was added dropwise at room temperature and the mixture was stirred at 80° C. for 1 hr. To this mixture were added water (150 ml) and saturated aqueous sodium hydrogen carbonate (100 ml), and the mixture was extracted twice with ethyl acetate (100 ml, 50 ml). The combined organic layer was successively washed twice with water (100 ml) and once with saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. A solution of the obtained residue in ethanol (50 ml) was cooled to 0° C., sodium borohydride (2.3 g) was added thereto, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 1N hydrochloric acid (100 ml), and the mixture was extracted with ethyl acetate (100 ml). The separated aqueous layer was extracted again with ethyl acetate (50 ml). The combined organic layer was successively washed with water (100 ml), saturated aqueous sodium hydrogen carbonate (100 ml) and saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1 to 9/1) to give the title compound (21.6 g).
Reaction SMILES: [C:1]([N:4]1[C:12]2[CH:11]=[C:10]([Cl:13])[CH:9]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[C:7]=2[CH:6]=[N:5]1)(=O)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:25]1[CH2:29]CC[CH2:26]1>C(#N)C>[Cl:13][C:10]1[CH:9]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[C:7]2[CH:6]=[N:5][N:4]([CH:1]3[CH2:29][CH2:25][CH2:26][CH2:2]3)[C:12]=2[CH:11]=1
Reactant: COC(=O)c1cc(Cl)cc2c1cnn2C(C)=O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1cc(Cl)cc2c1cnn2C1CCCC1
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 30 %

Procedure:
To a stirred solution of methyl 1-acetyl-6-chloro-1H-indazole-4-carboxylate (1 equiv.) in acetonitrile (3 mL per 1 mmol), cesium carbonate (1.5 equiv.) was added followed by bromocyclopentane (2 equiv.). The reaction mixture was stirred at 90° C. for 3-4 h. On completion of reaction, acetonitrile was removed under reduced pressure and water was added. Extraction was carried out using ethyl acetate and the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. The solvent was then removed under reduced pressure and residue was purified by silica gel column chromatography to obtain methyl 6-chloro-1-cyclopentyl-1H-indazole-4-carboxylate (yield 30-35%). The structure was confirmed as the desired regioisomer by NOE.