Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:16]2[C:11](=[C:12]([OH:31])[C@:13]3([OH:30])[C:21](=[O:22])[C:20]([C:23]([NH2:25])=[O:24])=[C:19]([OH:26])[C@@H:18]([N:27]([CH3:29])[CH3:28])[C@@H:14]3[C@H:15]2[OH:17])[C:9](=[O:10])[C:8]2[C:7]([OH:32])=[CH:6][CH:5]=[CH:4][C:3]1=2.C1(C)C=CC(S([O-])(=O)=[O:40])=CC=1.[ClH:44]>CC(C)=O>[CH3:8][CH2:9][OH:10].[CH3:1][C@@H:2]1[C@@H:16]2[C:11](=[C:12]([OH:31])[C@:13]3([OH:30])[C:21](=[O:22])[C:20]([C:23]([NH2:25])=[O:24])=[C:19]([OH:26])[C@@H:18]([N:27]([CH3:28])[CH3:29])[C@@H:14]3[C@H:15]2[OH:17])[C:9](=[O:10])[C:8]2[C:7]([OH:32])=[CH:6][CH:5]=[CH:4][C:3]1=2.[OH2:40].[ClH:44]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: C[C@H]1c2cccc(O)c2C(=O)C2=C(O)[C@]3(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3[C@@H](O)[C@@H]21
Agent: Cl
Solvent: CC(C)=O
Product: CCO
Product: O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Doxycycline p-toluenesulphonate (35.0 g) prepared as above was dissolved in a mixture of acetone (105 ml) and concentrated hydrochloric acid (16.45 ml). The solution was then filtered, and the recovered solid dried. Ethanol (35 ml) was added to the clear filtrate, and the mixture was stirred at room temperature for 2 hours 30 minutes. The crystals thus formed were filtered, washed with ethanol (41.5 ml) and then with acetone (20.75 ml), dried at 35° C. and gave 23.3 g of doxycycline hyclate. This product was indistinguishable from that obtained according to Example 4, complying in all aspects with the respective monographs in the British Pharmacopoeia 1980 and the U.S. Pharmacopoeia XX. The mother liquors were diluted with an equal volume of water and 5-sulphosalicylic acid (5.25 g) was added. After stirring overnight and recovery in the usual manner, the product, doxycycline sulphosalicylate, weighed 5.96 g.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[NH:9][CH:8]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[C:6]=2[CH2:5][CH2:4][CH2:3]1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25](O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([N:9]2[C:10]3[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=3[C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8]2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)c1c[nH]c2c1CCCC2=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cn(C2CCN(C(=O)OC(C)(C)C)CC2)c2c1CCCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a mixture of methyl 7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylate (100 mg 0.52 mmol), tert-butyl-4-hydroxypiperidine-1-carboxylate (105 mg, 0.52 mmol), and triphenylphosphine (136 mg, 0.52 mmol), in anhydrous THF (5 mL) at room temperature, was added di tert-butyl-diazadicarboxylate (DTAD) (120 mg, 0.52 mmol). The mixture was stirred at room temperature for 8 h. HPLC/MS suggested 40% conversion and 60% SM remained. Reagents were added, triphenylphosphine (136 mg, 0.52 mmol) and DTAD (120 mg, 0.52 mmol), the mixture was stirred for 4 hours. HPLC/MS showed 80% conversion and 20% SM remained. Reagents were re-added TPP (136 mg, 0.52 mmol) and DTAD (120 mg, 0.526 mmol) and the solution was stirred for additional 4 hours. The volatiles were removed in vacuo, the crude solid was purified by flash chromatography on silica gel (hexane/EtOAc 7/3) to afford 140 mg (70% yield) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:25][CH:24]=3)=[CH:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([O:5]C(C)(C)C)=[O:4].[C:37]([C:41]1[S:45][C:44]([C:46](O)=[O:47])=[CH:43][CH:42]=1)([CH3:40])([CH3:39])[CH3:38].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:37]([C:41]1[S:45][C:44]([C:46]([NH:1][C@@H:2]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]4[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:27][CH:28]=4)=[CH:19][N:18]=3)=[CH:15][CH:16]=2)[C:3]([OH:5])=[O:4])=[O:47])=[CH:43][CH:42]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)c1ccc(C(=O)O)s1
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](N)C(=O)OC(C)(C)C)cc3)nc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)s4)C(=O)O)cc3)nc2)cc1
Reaction time: 1 h
Yield: 75 %

Procedure:
A stirring solution of (S)-tert-butyl 2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoate INT-9 (5.50 g, 11.23 mmol) and 5-(tert-butyl)thiophene-2-carboxylic acid (2.13 g, 11.57 mmol) in DMF (50 mL) and DIEA (6.22 ml, 33.70 mmol) was treated portion wise with HATU (4.48 g, 11.79 mmol). After stirring for 1 h, the mixture was treated with water (200 mL) and iso-hexanes (20 mL) and stirred for 10 min. The product was collected by filtration, washed with iso-hexanes (2×30 mL), water (2×50 mL) then MeOH (20 mL) and iso-hexanes (30 mL). The ester was taken up in DCM (50 mL) and treated with TFA (10 mL). After 1 h, additional TFA (15 mL) was added. After a further 5 h, the mixture was treated with toluene (20 mL) and concentrated. The residue was washed with acetonitrile (25 mL) then taken up in DMSO (20 mL) then treated with water (100 mL) and stirred for 1 h. The product was collected by filtration, washed with water (4×50 mL) then acetonitrile (3×30 mL), and dried in a vacuum oven to give 5.30 g (75%) of (S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoic acid, Compound 192 as an off-white solid. LCMS-ESI (m/z) calculated for C35H41N3O4S: 599.3; no m/z observed, tR=11.10 min (Method 10). The chiral purity was 98% e.e. (Chiral Method). 1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 9.17 (s, 2H), 8.68 (d, J=8.3 Hz, 1H), 8.47-8.17 (m, 2H), 7.96-7.71 (m, 2H), 7.64 (d, J=3.8 Hz, 1H), 7.55-7.29 (m, 2H), 7.26-7.02 (m, 2H), 6.93 (d, J=3.8 Hz, 1H), 4.79-4.48 (m, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.27 (dd, J=13.9, 4.5 Hz, 1H), 3.12 (dd, J=13.9, 10.6 Hz, 1H), 1.90-1.58 (m, 2H), 1.58-1.01 (m, 17H), 1.01-0.69 (m, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:36])[CH2:21][NH:22][C:23]([CH3:35])([CH3:34])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[CH:27][CH:26]=2)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1>CO.[Pd]>[CH2:32]([O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:23]([NH:22][CH2:21][CH:20]([C:11]2[C:12]3[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=3[CH:19]=[C:9]([OH:8])[CH:10]=2)[OH:36])([CH3:35])[CH3:34])=[CH:26][CH:27]=1)[CH3:33]
Reactant: CCOc1ccc(CC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OCC(=O)N3)cc1
Agent: [Pd]
Solvent: CO
Product: CCOc1ccc(CC(C)(C)NCC(O)c2cc(O)cc3c2OCC(=O)N3)cc1

Procedure:
1.5 g (2.8 mmol) of 6-benzyloxy-8-{2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}4H-benzo[1,4]oxazin-3-one in 80 mL methanol are hydrogenated with 250 mg palladium on charcoal (10%) as catalyst at ambient temperature and normal pressure. The catalyst is suction filtered and the filtrate is evaporated down. The residue is dissolved in 5 mL ethanol by heating, seeded, and diluted with ethyl acetate. The solid precipitated is filtered off and washed. White solid. Yield 1.0 g (83%, hydrochloride); melting point: 232° C.–235° C.; mass spectrometry: [M+H]+=401.
Reaction SMILES: [N:1]1[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[CH3:15]I.[H-].[Na+].[CH2:19]([C:21]([CH3:23])=[O:22])[CH3:20]>>[CH3:15][O:22][C:21]([C:2]1[CH:3]=[CH:4][C:5]2[C:14](=[C:13]3[C:8](=[CH:7][CH:6]=2)[CH:9]=[CH:10][CH:11]=[N:12]3)[N:1]=1)([CH3:23])[CH2:19][CH3:20]
Reactant: CCC(C)=O
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CCC(C)(OC)c1ccc2ccc3cccnc3c2n1

Procedure:
An embodiment of the above described 2-step process is shown in the following reaction scheme wherein R is hydrogen and 2-[(1-hydroxy-1-methylpropyl)]-1,10-phenanthroline is prepared by coupling methyl ethyl ketone with 1,10-phenanthroline, and the coupling product alkylated with methyl iodide and sodium hydride to form 2-[(1-methoxy-1-methylpropyl)]-1,10-phenanthroline. The latter is reduced with the lanthanideII reducing agent, samarium diiodide, to provide 2-(1-methylpropyl)-1,10-phenanthroline.
Reaction SMILES: [H-].[Na+].C([O:5][C:6](=[O:24])[CH2:7][CH2:8][C:9]1([CH3:23])[CH:14](CCC)[CH2:13][C:12]2[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:11]=2[O:10]1)C.Br[CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[C:32]([OH:39])[C:31]=1[CH2:40][CH2:41][CH3:42].[I-].[Na+].[CH3:45][CH2:46][CH2:47]CCC>CN(C)C=O>[C:36]([C:33]1[CH:34]=[CH:35][C:30]([O:29][CH2:28][CH2:27][CH2:26][O:22][C:20]2[CH:19]=[CH:18][C:12]3[CH2:13][CH2:14][C:9]([CH3:23])([CH2:8][CH2:7][C:6]([OH:5])=[O:24])[O:10][C:11]=3[C:21]=2[CH2:45][CH2:46][CH3:47])=[C:31]([CH2:40][CH2:41][CH3:42])[C:32]=1[OH:39])(=[O:38])[CH3:37]
Reactant: CCCC1Cc2ccc(O)cc2OC1(C)CCC(=O)OCC
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Reactant: CCCCCC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc3c(c2CCC)OC(C)(CCC(=O)O)CC3)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 69.1 %

Procedure:
To a stirred slurry of 108 mg of 50% sodium hydride-mineral oil dispersion (prewashed with hexane) in 1 ml of anhydrous N,N-dimethylformamide was added a solution of 268 mg of racemic-3,4-dihydro-7-hydroxy-2-methyl-3-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester in 3 ml of dry N,N-dimethylformamide at room temperature, over a 1 minute period. After being stirred for 30 minutes at room temperature, the mixture was treated dropwise with a solution of 313 mg of 4'-(3-bromopropoxy)-2'-hydroxy-3'-n-propylacetophenone in 3 ml of dry N,N-dimethylformamide. Sodium iodide (0.3 g) was added and the mixture was stirred at room temperature for 2.5 hours before being quenched with 1 ml of water. After 30 minutes, 0.3 g of lithium hydroxide monohydrate and 1 ml of water were added and stirring was continued for 3 hours. The mixture was acidified to pH 1 with 1N hydrochloric acid and worked-up with ether in the usual manner. The orange oily product (0.7 g) was chromatographed on 50 g of silica gel. Elution with 4:1 toluene-ethyl acetate gave 310 mg (69.1%) of racemic-7-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid as a viscous yellow oil after drying at 60° C. under high vacuum.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25](Cl)=[O:26])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:28]([NH2:31])([CH3:30])[CH3:29].N1C=CC=CC=1>ClCCl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25]([NH:31][CH:28]([CH3:30])[CH3:29])=[O:26])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)N
Reactant: CCCCc1cc(C(=O)Cl)nn1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1cc(C(=O)NC(C)C)nn1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 5-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]pyrazole-3-carbonyl chloride (550 mg) in dichloromethane (5 ml) were added isopropylamine (0.2 ml) and pyridine (0.2 ml), and the mixture was stirred at room temperature for 0.5 hours. The mixture was then evaporated to dryness under reduced pressure, and the residue was shaken with a mixture of 0.1 N hydrochloric acid (50 ml), dichloromethane (15 ml), and ether (60 ml). The mixture was allowed to separate into layers. The organic layer was washed with an aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate, followed by evaporation of the solvent to give a light yellow syrup (550 mg, 98%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[C:22]([NH2:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>ClCCl>[CH2:9]([O:16][C:17]1[C:22]([NH2:23])=[C:21]([F:24])[C:20]([F:25])=[C:19]([Br:1])[CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1c(OCc2ccccc2)ccc(F)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: Nc1c(OCc2ccccc2)cc(Br)c(F)c1F

Procedure:
A round bottom flask containing N-bromosuccinimide (0.52 mg, 2.93 mmol), and dichloromethane (5 mL) is stirred in an ice bath. A solution of the 6-benzyloxy-2,3-difluoro-phenylamine (0.69 mg, 2.93 mmol) in 10 mL of dichloromethane is added quickly in one portion. The resulting mixture is stirred for 20 min then water is added and the resulting mixture is extracted twice with DCM. The organic portion is dried over MgSO4, filtered and concentrated to afford the title compound, which is used directly in the next step without purification.
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:23]([Cl:38])=[CH:22][N:21]=1>>[Cl:38][C:23]1[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[N:25][C:20]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][CH:2]([F:1])[F:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:21][CH:22]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(F)F)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)CCN(CC(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in a analogous manner to Example 61e. Product was isolated as a white solid (0.029 g, 27%). MP: 103-127° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.99 (s, 1H), 7.95 (s, 1H), 7.31 (s, 1H), 6.65 (s, 1H), 6.07-5.74 (m, 1H), 5.34 (d, 1H, J=8.1 Hz), 5.22 (d, 1H, J=7.1 Hz), 4.01-3.90 (m, 1H), 3.87 (s, 3H), 3.29-3.19 (m, 1H), 2.98-2.74 (m, 14H), 2.29-2.16 (m, 2H), 1.89-1.74 (m, 2H), 1.41-1.34 (m, 3H). MS: 559 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21]Br)[CH3:18]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:21][CH:20]([O:23][CH2:24][CH3:25])[O:19][CH2:17][CH3:18])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CCOC(CBr)OCC
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(Cl)cc1C=O)OCC
Yield: 46.8 %

Procedure:
To a stirred suspension of 5-chloro-2-hydroxybenzaldehyde (5.0 g, 32.1 mmol) and K2CO3 (4.87 g, 35.3 mmol) in DMF (20 mL), bromoacetaldehyde diethyl acetal (5.43 mL, 35.3 mmol) was added dropwise. The mixture was refluxed for 4 h. After cooling, the precipitate was filtered off and the solvent was evaporated in vacuo. The crude residue was adsorbed on silica gel and purified by flash chromatography. The product was eluted with hexane/EtOAc (4:1) to give 33 (4.10 g, 38%) as an oil. 1H NMR (500 MHz, CDCl3): δ: 10.42 (1H, s, CHO), 7.76 (1H, d, J=2.8 Hz, ArH), 7.46 (1H, dd, J=6.15 & 2.75 Hz, ArH), 6.96 (1H, d, J=8.90 Hz, ArH), 4.87 (1H, t, J=5.25 Hz, CH), 4.10 (2H, d, J=5.25 Hz, CH2), 3.80-3.77 (2H, m, CH2CH3), 3.67-3.62 (2H, m, CH2CH3), 1.24 (6H, t, J=7.05 Hz, 2×CH3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:15])[C:10]=1[S:11]([NH2:14])(=[O:13])=[O:12])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22]([N:26]=[C:27]=[O:28])[CH2:23][CH2:24][CH3:25]>CC(C)=O>[CH2:22]([NH:26][C:27]([NH:14][S:11]([C:10]1[N:9]([CH3:15])[N:8]=[CH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])(=[O:13])=[O:12])=[O:28])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCN=C=O
Reactant: CCOC(=O)c1cnn(C)c1S(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1c(C(=O)OCC)cnn1C
Yield: 71.6 %

Procedure:
To a mixture of 5.0 g of4-ethoxycarbonyl-1-methylpyrazole-5-sulfonamide(Reference example 25), 4.45 g of dry potassium carbonate and 50 ml of acetone was added 2.13 g of n-butyl isocyanate at room temperature, and the mixture was stirred under reflux for 3 hours. After the reaction, acetone was evaporated under reduced pressure, and ice-water was added to the residue, followed by filtration of the insolubles. The filtrate was made acidic with hydrochloric acid and the crystals precipitated were filtered, washed with water and dried to give 5.1 g of N-(n-butylcarbamoyl)-4-ethoxycarbonyl-1-methylpyrazole-5-sulfonamide melting at 117°-119° C. Then, this product was added into 120 ml of dry toluene, and 9.1 g of phosgene was passed into the mixture under reflux, followed further by refluxing for 1.5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain crude sulfonyl isocyanate.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:43]1([CH3:53])[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1>N1C=CC=CC=1>[CH2:25]([O:24][CH2:23][CH:21]([CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[O:22][S:49]([C:46]1[CH:47]=[CH:48][C:43]([CH3:53])=[CH:44][CH:45]=1)(=[O:51])=[O:50])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCC/C=C\CCCCCCCCOCC(O)COCCCCCCCC/C=C\CCCCCCCC
Solvent: c1ccncc1
Product: CCCCCCCC/C=C\CCCCCCCCOCC(COCCCCCCCC/C=C\CCCCCCCC)OS(=O)(=O)c1ccc(C)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 80.3 %

Procedure:
In 5 ml of pyridine was dissolved 150 mg (0.25 mmol) of 1,3-O-dioleylglycerol followed by addition of 77 mg (0.40 mmol) of p-toluenesulfonyl chloride and the mixture was heated at 60° C. and stirred for 2 days. After completion of the reaction, the solvent was distilled off and the residue was diluted with water and extracted with ether. The extract was dried and concentrated to provide 150 mg (80%) of 1,3-O-dioleyl-2-O-(p-toluenesulfonyl)glycerol as yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[NH:20][N:19]=[C:18]([C:21]5[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=5)[CH:17]=4)[NH:13][C:12]=3[CH:28]=2)[CH2:4][CH2:3]1.[N:29]([C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=1)=[C:30]=[O:31].C(N(CC)CC)C>CS(C)=O.CC#N>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[NH:15][C:14]([C:16]4[CH:17]=[C:18]([C:21]5[CH:27]=[CH:26][C:24]([NH:25][C:30]([NH:29][C:32]6[CH:37]=[CH:36][C:35]([O:38][C:39]([F:40])([F:41])[F:42])=[CH:34][CH:33]=6)=[O:31])=[CH:23][CH:22]=5)[NH:19][N:20]=4)=[N:13][C:12]=3[CH:28]=2)[CH2:4][CH2:3]1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CN1CCN(c2ccc3nc(-c4cc(-c5ccc(N)cc5)n[nH]4)[nH]c3c2)CC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CC#N
Product: CN1CCN(c2ccc3[nH]c(-c4cc(-c5ccc(NC(=O)Nc6ccc(OC(F)(F)F)cc6)cc5)[nH]n4)nc3c2)CC1
Yield: 50.2 %

Procedure:
To a solution of 4-{5-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-3-yl}aniline (45 mg, 0.12 mmol) in DMSO (2 mL) were added 1-isocyanato-4-trifluoromethoxybenzene (36.6 mg, 0.18 mmol), triethylamine (36.4 mg, 0.36 mmol) in CH3CN (1 mL) at room temperature. The reaction mixture was monitored by LC-MS until reaction was complete (1 h). The resulting mixture was concentrated in vacuo and separated by preparative HPLC (0.1% TFA/CH3CN, 0.05% TFA/water). The corresponding fractions were concentrated and dried. The resulting solid was dissolved in MeOH (1 mL) and was added 4N HCl (0.5 mL). The solution was concentrated and repeated three times to afford product (24%, 34.7 mg) as light yellow solid as the hydrochloride salt: 1H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 9.68 (d, 2H), 7.79-7.57 (7H, m), 7.38-7.29 (m, 3H), 7.17 (s, 1H), 3.90 (m, 2H), 3.46 (m, 2H), 3.21 (m, 4H), 2.85 (m, 3H) MS (EI) for C29H27F3N8O2: 577.3 (MH+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]3)[CH:6]=[CH:7][N:8]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].Cl>ClCCl>[CH3:1][N:2]([CH2:3][C:4]1[N:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]3)[CH:6]=[CH:7][N:8]=1)[S:33]([CH3:32])(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: CNCc1nccn1-c1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1nccn1-c1ccc2c(c1)CCN2C(=O)OC(C)(C)C)S(C)(=O)=O
Reaction time: 2 h
Yield: 100.8 %

Procedure:
To tert-butyl 5-{2-[(methylamino)methyl]-1H-imidazol-1-yl}-1-indolinecarboxylate (0.20 g, 0.61 mmol; from Part H of Example 37) was added dichloromethane (6 mL) and triethylamine (0.25 mL, 0.67 mmol). Methanesulfonyl chloride (0.052, 0.67 mmol) was added in one portion, and the resulting yellow solution was stirred for 2 h. The reaction was then poured into aqueous 1N hydrogen chloride (10 mL). The layers were separated, and the organic layer was washed with saturated aqueous sodium bicarbonate (10 mL) and saturated aqueous sodium chloride (10 mL), dried over sodium sulfate, and concentrated to give tert-butyl 5-(2-{[methyl(methylsulfonyl)amino]methyl}-1H-imidazol-1-yl)-1-indolinecarboxylate (250 mg, 100%) as a brown oil). LC/MS (ESI+): 407.3 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1([CH2:36][OH:37])[CH2:35][O:34][CH2:33]1>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:31][C:32]2([CH2:36][OH:37])[CH2:35][O:34][CH2:33]2)[C:5]=1[O:21][CH3:22]
Reactant: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1O
Reactant: OCC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1OCC1(CO)COC1
Temperature: 80 °C
Yield: 38.1 %

Procedure:
To a stirring solution of 4-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (103.5 mg, 0.75 mmol) and (3-bromomethyl-oxetan-3-yl)-methanol (135.7 mg, 0.75 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) to afford title compound as a solid (40 mg, 38%).