Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][N:10]3[C:15]=2[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:13][C:12]([CH:24]2[CH2:26][CH:25]2[C:27]#[N:28])=[N:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-:33])(C)C.[K+]>C(O)(C)(C)C>[C:1]1([C:7]2[CH:8]=[CH:9][N:10]3[C:15]=2[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:13][C:12]([CH:24]2[CH2:26][CH:25]2[C:27]([NH2:28])=[O:33])=[N:11]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[O-]
Reactant: N#CC1CC1c1nc(NCc2ccccn2)c2c(-c3ccccc3)ccn2n1
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)C1CC1c1nc(NCc2ccccn2)c2c(-c3ccccc3)ccn2n1
Yield: 22.5 %

Procedure:
To a solution of (±)-2-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropanecarbonitrile (550 mg, 1.50 mmol) in t-butanol (30 mL) was added KOtBu (842 mg, 7.51 mmol). The reaction mixture was heated to reflux at 90° C. for 12 h. t-Butanol was evaporated under reduced pressure and water (25 mL) was added to the reaction mixture. The aqueous layer was acidified with aqueous citric acid solution and extracted with DCM (3×50 mL). The combined organic extracts were washed with brine (25 mL), dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC (Condition B-108 as described in general methods) to obtain (±)-2-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropanecarboxamide (130 mg, 22.0%) which was resolved by chiral HPLC (Condition B-109 as described in general methods) to obtain enantiomer-1 (42 mg) and enantiomer-2 (46 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].[Li]CCCC.CN(C)CCN(C)C.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]=[O:31]>CCOCC>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[C:4]=1[CH:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=1)[OH:31]
Reactant: COc1cccc(CO)c1
Reactant: O=Cc1ccccn1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cccc(CO)c1C(O)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
To a solution of 3-methoxybenzylalcohol (50.0 g, 0.36 mol) in ether (1.1 L) at -20° C. was added n-BuLi (76.0 mL, 0.756 mol) at such a rate that the internal temperature of the reaction was maintained at less than -10° C. When the addition of n-BuLi was complete, the mixture was warmed to room temperature and stirred for 2 hours. The mixture was cooled to 0° C. and tetramethylethylene diamine (42.0 g, 0.36 mol) was added. The reaction mixture was cooled to -30° C. and 2-pyridinecarboxaldehyde (58.0 g, 0.36 mol) was added over 5 minutes. The reaction was warmed to 0° C. over a 30 minute period and was then quenched with water (500 mL). The mixture was chilled for 24 hours, and the product was collected by filtration and washed with ether. The product was recrystallized from ethanol to afford 30.0 g (34%) of α-[2-(hydroxymethyl)-6-methoxyphenyl]-2-pyridinemethanol (Formula X: R2 =6-OCH3 ; R1 =H). The mother liquor from the recrystallization step was concentrated, diluted with ether and refrigerated for 16 hours. A solid precipitated, which was collected by filtration to afford an additional 13.1 g of the desired product for a total of 43.1 g (49%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[S:6][CH:7]=1.C(C1C=CC([C:24]([NH2:26])=S)=CC=1)(C)C.ClCC(CCl)=O.[C-]#N.[Na+]>CS(C)=O.O>[CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[S:6][CH:7]=[C:3]([CH2:2][C:24]#[N:26])[N:4]=2)=[CH:9][CH:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1ccc(C(N)=S)cc1
Reactant: CC(C)c1ccc(-c2nc(CCl)cs2)cc1
Agent: O=C(CCl)CCl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)c1ccc(-c2nc(CC#N)cs2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
14.5 g (57.6 mmol) of 4-chloromethyl-2-(4-isopropyl-phenyl)-thiazole (prepared from 4-isopropyl-thiobenzamide and 1,3-dichloroacetone in analogy to the procedure described in example 4 a]) and 4.08 g (83.4 mmol) of sodium cyanide in 50 ml of dimethyl sulfoxide were stirred at 40° C. for 2 hours. Then, the reaction mixture was poured into a mixture of ice and water and was subsequently extracted with 3 portions of 75 ml of tert-butyl methyl ether. The combined organic phases were washed with water, then with brine and dried with anhydrous sodium sulfate. After evaporation of the solvent, 13.4 g (96% of theory) of [2-(4-isopropyl-phenyl)-thiazol-4-yl]-acetonitrile were obtained as brown solid.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#N)=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1CC(O)=[O:37].O>[Ni]>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([CH:14]=[O:37])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)cc1
Reactant: O=C(O)Cc1ccccn1
Agent: [Ni]
Solvent: O
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C=O)c1ccc(F)cc1
Yield: 45 %

Procedure:
(S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl) ethylamino)nicotinonitrile (Example 1, 0.4 g, 1.1 mmol) was dissolved in the mixture pyridine-acetic acid-water (1:1:1, 18 ml total volume) at room temperature, to which was added Raney nickel (0.09 g, 1.1 mmol). The reaction was purged with nitrogen, evacuated, and then placed under hydrogen filled balloon for 18 hours. The reaction mixture was flushed with nitrogen, and filtered to remove the catalyst, which was washed with MeOH (30 ml). The filtrate was then extracted with DCM (5×50 ml), washed with aq. NaHCO3, and purified by reverse phase column chromatography (5-30% ACN) to give the title compound (0.18 g, 45%). 1H NMR (400 MHz, CD3OD) δ 9.40 (s, 1H), 7.45 (d, J=10.4 Hz, 1H), 7.34-7.31 (m, 2H), 7.05-7.01 (m, 2H), 6.11 (s, 1H), 5.26 (s, 1H), 1.92-1.86 (m, 1H), 1.55 (d, J=7.0 Hz, 3H), 1.00-0.98 (m, 2H), 0.71-0.64 (m, 2H). MS: Calcd.: 383. Found: [M+H]+ 384.
Reaction SMILES: CN(C)[CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])[C:5]1=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:42][C:43]([NH2:45])=[NH:44])[CH:33]=[CH:34][C:35]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1>>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:42][C:43]2[N:45]=[CH:3][C:4]3[CH2:9][CH2:8][CH2:7][CH:6]([C:10]([N:12]4[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)=[O:11])[C:5]=3[N:44]=2)[CH:33]=[CH:34][C:35]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1
Reactant: CN(C)C=C1CCCC(C(=O)N2CCOCC2)C1=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(C(=O)N2CCOCC2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from 2-[1-dimethylamino-methylidene]-6-(morpholine-4-carbonyl)-cyclohexanone (16 mg, 0.06 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (17 mg, 0.045 mmol) using in analogous manner the procedure described in example 45b). Obtained as a yellow solid (5 mg, 25%). MS ISP (m/e): 449.4 (100) [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH:7]([CH3:17])[CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[F:24][C:25]([F:31])([F:30])[S:26](O)(=[O:28])=[O:27]>ClCCl.N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:18])[CH:7]([CH3:17])[CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][S:26]([C:25]([F:31])([F:30])[F:24])(=[O:28])=[O:27])=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CC(CSc1ccc(O)cc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(CSc1ccc(OS(=O)(=O)C(F)(F)F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon and at −78° C., to a solution of the compound prepared in Example 1(2) (1.50 g) in dichioromethane (10 ml), pyridine (1.1 3 ml) and anhydrous trifluoromethanesulfonic acid (1.13 ml) were added dropwise. The mixture solution was stirred for 2 hours at room temperature. A saturated aqueous solution of sodium bicarbonate (20 ml) was added to the reaction mixture and it was vigorously stirred for 1 hour at room temperature. The reaction mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (hexane:ethyl acetate=19: 1) to give the title compound (2.05 g) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:55]1[C@@H:59]2[CH2:60][CH2:61][CH2:62][CH2:63][C@H:58]2[N:57]=[C:56]1[C:64]1[CH:69]=[CH:68][C:67]([CH2:70][CH2:71][NH2:72])=[CH:66][CH:65]=1>CN(C=O)C>[NH:57]1[C@@H:58]2[CH2:63][CH2:62][CH2:61][CH2:60][C@H:59]2[N:55]=[C:56]1[C:64]1[CH:65]=[CH:66][C:67]([CH2:70][CH2:71][NH:72][C:21]([C:18]2[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]3[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:24])(=[O:11])=[O:12])[CH3:14])[O:20][CH:19]=2)=[O:23])=[CH:68][CH:69]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: NCCc1ccc(C2=N[C@@H]3CCCC[C@H]3N2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCCc3ccc(C4=N[C@@H]5CCCC[C@H]5N4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AG using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (56 mg, 0.16 mmol), EDCI (36 mg, 0.19 mmol), HOAt (26 mg, 0.19 mmol), DIPEA (0.084 mL, 0.48 mmol) and 2-{4-[(3aR,7aR)-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl]phenyl}ethanamine (82 mg, 0.14 mmol) in DMF (1 mL). The crude product was purified using Ambersep resin, then using prep method C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([OH:21])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C)C=O>[CH3:18][O:17][C:15]([C:14]1[CH:19]=[CH:20][C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:12][C:13]=1[O:21][CH:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:16]
Reactant: CCOC(=O)CCC(Cl)c1ccccc1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(Oc1cc(OCc2ccccc2)ccc1C(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
A stirred suspension of sodium hydride (340 mg) in dry dimethylformamide (100 mL) is treated portionwise with methyl 4-benzyloxy-2-hydroxybenzoate (2 g). After stirring at ambient temperature for 30 minutes, it is treated with ethyl (RS)-4-chloro-4-phenylbutanoate (1.9 g) in one portion and stirred for 16 hours at ambient temperature, and then for two hours at 80° C. The reaction mixture is then concentrated in vacuo and the residue is partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer is dried over magnesium sulphate, filtered and concentrated in vacuo. Flash chromatography of the resulting oil, eluting with 5-10% ethyl acetate/cyclohexane, affords ethyl (RS)-4-(2-methoxycarbonyl-5-benzyloxyphenoxy)-4-phenylbutanoate (2 g), in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].N1C=CC=CC=1.[CH2:19]([O:21][C:22]([CH2:24][S:25](Cl)(=[O:27])=[O:26])=[O:23])[CH3:20]>C1(C)C=CC=CC=1>[CH2:19]([O:21][C:22]([CH2:24][S:25]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[O:27])=[O:26])=[O:23])[CH3:20]
Reactant: CCOC(=O)CS(=O)(=O)Cl
Reactant: COC(=O)Cc1ccccc1N
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CS(=O)(=O)Nc1ccccc1CC(=O)OC
Temperature: 25 °C

Procedure:
To a solution of 82.7 g of methyl 2-aminophenylacetate (see Example l) in 1.2 l of toluene is added 42 ml of pyridine and the mixture is stirred at room temperature. To this mixture is added a solution of 93.2 g of ethoxycarbonylmethylsulfonyl chloride in 150 ml of toluene in a dropwise manner over a period of 30 minutes, maintaining the temperature of the reaction below 10° by means of an ice-water bath. After stirring at 0° for an additional 1 hour, the mixture is poured into 50 ml of ice-water, the organic layer is separated and washed with 150 ml of cold dilute hydrochloric acid followed by 150 ml of brine. The toluene extract is dried over anhydrous magnesium sulfate, filtered and the solvent evaporated under reduced pressure to yield methyl 2-(ethoxycarbonylmethylsulfonylamino)-phenylacetate as an oil which is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH:10](=O)/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([F:9])=[C:4]2[C:6]([CH:10]=[CH:11][C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:5]2)=[CH:7][CH:8]=1
Reactant: O=C/C=C/c1ccccc1
Reactant: Nc1cccc(Cl)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Fc1c(Cl)ccc2ccc(-c3ccccc3)nc12

Procedure:
To a stirred solution of 3-chloro-2-fluoroaniline (2.9 g, 20 mmol) and trans-cinnamaldehyde (2.64 g, 20 mmol) in toluene (25 ml) was added 6N HCl (100 ml). The resulting suspension was heated at reflux for 40 hours. After cooling, the reaction mixture was poured into 5N NaOH solution (200 ml) and extracted with EtOAc (3×100 ml). The combined organics were washed with brine (2×100 ml), dried (MgSO4), filtered and concentrated. The crude product was dissolved in MeOH and loaded onto an SCX-2 cartridge (50g/150 ml), and the product eluted with MeOH, giving the title compound as a yellow solid. Additionally, the title compound could be prepared as follows: 4-Bromo-7-chloro-8-fluoro-2-phenyl-quinoline (6.0 g, 0.018 mole) and THF (240 mL) were combined in a 3 neck 1 L round bottom flask with a magnetic stir bar under an atmosphere of nitrogen. The reaction was stirred and cooled with a THF/liquid nitrogen bath to −100° C. 2.5 M of n-butyllithium in Hexane (7.34 mL) was then added dropwise over 3 minutes so as not to exceed −90° C. The solution turned light green, and darkened over a few minutes. Acetic acid (1.22 mL, 0.0214 mole) was added 3 minutes after the n-butyllithium addition was done. The cooling bath was removed, and the reaction was allowed to stir for 20 minutes. To work up, saturated sodium bicarbonate solution (100 mL) was added, and the mixture was transferred to a 1 L separatory funnel with 250 mL of ethyl acetate. The layers were separated, and the organic layer was washed with 2×60 mL of brine. The organic solution was suction filtered through a short pad of silica gel, rinsing with ethyl acetate. The filtrate was concentrated in vacuo, and the residue was placed under high vacuum overnight to afford the crude product. The crude product was pre-adsorbed on 55 mL of Silica gel from methylene chloride. 100 mL of Toluene was added, and the slurry was concentrated on the rotovap to afford a finely divided powder. This was applied to a silica column and chromatographed (4:3 hexanes/methylene chloride) affording the title compound as a white solid. The solid was re-chromatographed with, and then placed in the vacuum oven at 45° C. overnight to afford the very pure product as a white solid; 1H NMR (CDCl3, 400 MHz) δ 8.24-8.21 (3H, m), 7.96 (1H, d, J=8.6Hz), 7.58-7.48 (5H, m); MS (ES+): m/z 258.13 [MH+]; HPLC: tR=3.64 min (MicromassZQ, non-polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)(=[O:14])=[O:13])[CH:9]=2)[NH:4][N:3]=1.[C:23](Cl)(=[O:25])[CH3:24]>N1C=CC=CC=1>[F:21][C:19]1[CH:20]=[C:15]([S:12]([NH:11][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[NH:1][C:23](=[O:25])[CH3:24])(=[O:14])=[O:13])[CH:16]=[C:17]([F:22])[CH:18]=1
Reactant: Nc1n[nH]c2ccc(NS(=O)(=O)c3cc(F)cc(F)c3)cc12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1n[nH]c2ccc(NS(=O)(=O)c3cc(F)cc(F)c3)cc12

Procedure:
N-[5-(3,5-Difluorobenzenesulfonylamino)-1H-indazol-3-yl]acetamide can be obtained as described in Example 28 from 0.1 g of N-(3-amino-1H-indazol-5-yl)-3,5-difluorobenzenesulfonamide, 9 ml of pyridine and 0.024 ml of acetyl chloride. 338 mg of N-[5-(3,5-difluorobenzenesulfonylamino)-1H-indazol-3-yl)-acetamide are thus obtained in the form of a cream solid melting at 268° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].[H-].[Na+].[CH3:17]I.O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:5]([N:7]([CH:8]1[CH2:9][CH2:10]1)[CH3:17])=[O:6]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)N(C)C2CC2)cc1Br
Temperature: 25 °C

Procedure:
A stirred, cooled (ice bath) solution of 3-bromo-N-cyclopropyl-4-methyl-benzamide (Intermediate 95, 6 g, 23.25 mmol) in anhydrous tetrahydrofuran (100 mL) under argon was treated with small portions of sodium hydride (1.6 g, 40 mmol, 60% dispersion in mineral oil). The reaction mixture was allowed to warm to ambient temperature and after 1 h, methyl iodide (3.11 mL, 50 mmol) was added and the reaction mixture was refluxed for 5 h. It was cooled to ambient temperature, poured into cold water and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a dirty brown solid that was used as such for the next step (6.3 g, 100%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][C:27]=1[CH3:38].[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][N:35]([C:47](=[O:48])[CH2:46][N:43]3[C:44]([CH3:45])=[C:40]([Cl:39])[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42]3)[CH2:34][CH2:33]2)=[CH:28][C:27]=1[CH3:38]
Reactant: Cc1cc(N2CCNCC2)ccc1Br
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1cc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)ccc1Br

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Bromo-3-methylphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.38 (d, 1H), 7.01 (s, 1H), 6.78 (d, 1H), 5.38 (s, 2H), 3.60 (m, 4H), 3.26 (m, 2H), 3.16 (m, 2H), 2.28 (s, 3H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=479.0, found=478.9.
Reaction SMILES: [ClH:1].[C:2]([NH:12][C@H:13]([C:21]([OH:23])=O)[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([CH3:36])=[CH:30][C:31](=[O:35])[O:32]2)=[CH:27][CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1.CO>CN(C)C=O>[ClH:1].[C:2]([NH:12][C@H:13]([C:21]([NH:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([CH3:36])=[CH:30][C:31](=[O:35])[O:32]2)=[CH:27][CH:26]=1)=[O:23])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:3]
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCc3ccccc3)ccc12
Temperature: 25 °C
Yield: 28.9 %

Procedure:
Nα -carbobenzoxy-L-arginine hydrochloric acid salt (69.0 g, 0.2 M) and 7-amino-4-methylcoumarin (17.5 g, 0.1 M) were dissolved in dimethylformamide (DMF) (300 ml). Dicyclohexylcarbodiimide (DCCD) (21 g, 0.1 M) was added to the mixture with stirring at room temperature. This mixture was stirred overnight at room temperature, and the produced dicyclohexyl urea was removed by filtration. The obtained filtrate was concentrated under reduced pressure and to the thus obtained residue methyl alcohol (50 ml) and ethyl acetate (500 ml) were added. The precipitated material was separated by filtration to give crude crystals (19 g). These crystals were dissolved in a mixture of heated DMF (30 ml) and heated methyl alcohol (100 ml) and insoluble material was removed by filtration. To the filtrate ethyl acetate (400 ml) was added and the thereby precipitated white crystals were separated by filtration and dried to give 7-(Nα -carbobenzoxy-L-arginyl)amino-4-methylcoumarin hydrochloric acid salt (14.5 g, yield: 29%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:14][O:13]1.[CH3:15][CH:16]1[CH2:21][NH:20][CH2:19][CH2:18][NH:17]1>CS(C)=O.O>[CH3:15][CH:16]1[CH2:21][N:20]([CH2:14][CH:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:11])[O:8][CH2:9][C:10]=3[C:2]=2[CH3:1])[OH:13])[CH2:19][CH2:18][N:17]1[CH2:14][CH:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[OH:13]
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Reactant: CC1CNCCN1
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(C(O)CN2CCN(CC(O)c3ccc4c(c3C)COC4=O)C(C)C2)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
A mixture of 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (700 mg, 3.684 mmol) and 2-methylpiperazine (184 mg, 1.842 mmol) in 2 mL DMSO was heated under microwave condition (150° C.) for 1 hr. After cooling to rt., the mixture was diluted with water (50 mL), extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and dried over Na2SO4, then concentrated. The residue was purified by prep-HPLC to obtain two peaks (peak 1 and peak 2). Each peak was further separated by SFC chiral chromatography to obtain three chiral isomers for each (of 8 isomers six were obtained, though two may be mixtures of 2 isomers).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([OH:7])=O.[F:8][C:9]1[C:37]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:36][C:12]2[N:13]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)[C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:15][C:11]=2[CH:10]=1>ClCCl>[F:8][C:9]1[C:37]([N:38]2[CH2:39][CH2:40][N:41]([C:5](=[O:7])[CH2:4][CH2:3][O:2][CH3:1])[CH2:42][CH2:43]2)=[CH:36][C:12]2[N:13]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:34])([F:35])[F:33])=[CH:27][CH:26]=3)[C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:15][C:11]=2[CH:10]=1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(OC(F)(F)F)cc3)c2cc1N1CCNCC1
Reactant: COCCC(=O)O
Solvent: ClCCl
Product: COCCC(=O)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)CC1

Procedure:
0.020 ml 3-methoxy-propionic acid (0.2 mmol) and 40 mg 1′1-carbonyldiimidazole (0.24 mmol) were refluxed in 4 ml dichloromethane under nitrogen for 40 minutes. 100 mg of 5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole (0.2 mmol) were added and the resulting mixture refluxed for additional 4.5 h. The reaction mixture was then diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 129 mg yellow solid. This residue was purified by column chromatography (40 g silicagel, dichloromethane/methanol 24:1) leading to 44 mg off-white solid (37%). MS (ISP) 587.2 (M+H)+.