Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:15])=[O:14])=[CH:11][CH:10]=1.[OH-].[Na+]>O.O1CCCC1.CO>[ClH:15].[Br:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:2]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)=[O:14])=[CH:11][CH:10]=1
Reactant: C1CNCCN1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(c1ccc(Br)cc1)N1CCNCC1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
With ice cooling, 100 mL (1.2 mol) of concentrated hydrochloric acid was added in portions to a solution of 100.0 g (1.16 mol) of piperazine in water (200 mL)-methanol (300 ml) and the mixture was stirred for 30 minutes. To the resulting solution was added dropwise a solution of 127.4 g (0.58 mol) of 4-bromobenzoyl chloride in tetrahydrofuran (300 mL) over about 40 minutes, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. To the residue was added water (2 L) and the mixture was stirred for 2 hours at 70° C. At this temperature, insoluble materials were filtered off and the residue was washed with hot water (20 mL). The filtrate and the washing were combined. After cooling to about 20° C., 74.4 g (1.86 mol) of sodium hydroxide was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Isopropanol (400 mL) was added to the residue and the mixture was concentrated under reduced pressure. Isopropanol (1 L) was added again to the residue. The mixture was stirred at 50° C. to obtain a homogenous solution. Over about 20 minutes, 50 mL (0.60 mol) of concentrated hydrochloric acid was added dropwise to the resulting solution. After stirring for 10 minutes at 50° C., the mixture was cooled to room temperature, and stirred in an ice bath. The precipitates were collected by filtration and washed with isopropanol, whereby 140.1 g of 1-(4-bromobenzoyl)piperazine hydrochloride was obtained as colorless fine needles (yield: 79%).
Reaction SMILES: S(Cl)(Cl)=O.CC1C=CC=CC=1CCC(O)=O.CC1C=CC=CC=1CCC(Cl)=O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][C:40]=1[O:41][CH3:42])[N:37]=[CH:36][CH:35]=[C:34]2[O:43][C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][C:45]=1[F:51].[CH3:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[CH2:59][CH2:60][C:61]([N:63]=[C:64]=[S:65])=[O:62]>C1(C)C=CC=CC=1.C(O)C>[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][C:40]=1[O:41][CH3:42])[N:37]=[CH:36][CH:35]=[C:34]2[O:43][C:44]1[CH:50]=[CH:49][C:47]([NH:48][C:64]([NH:63][C:61](=[O:62])[CH2:60][CH2:59][C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[CH3:52])=[S:65])=[CH:46][C:45]=1[F:51]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: Cc1ccccc1CCC(=O)N=C=S
Agent: Cc1ccccc1CCC(=O)Cl
Agent: Cc1ccccc1CCC(=O)O
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CCc4ccccc4C)cc3F)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 3-(2-methylphenyl)propanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 3-(2-methylphenyl)propanoyl isothiocyanate was prepared using the resultant 3-(2-methylphenyl)propanoyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-(2-methylphenyl)propanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (45 mg, yield 54%).
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10]1[CH:15]=[C:14]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:17])[CH:13]=[C:12]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:30])[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2].[C:42]([O:48][CH2:49]Cl)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44].[I-].[Na+]>CC(C)=O>[CH3:44][C:43]([CH3:46])([CH3:45])[C:42](=[O:47])[O:48][CH2:49][O:2][C:1](=[O:3])[CH2:4][N:5]([C:10]1[CH:15]=[C:14]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:17])[CH:13]=[C:12]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:30])[CH:11]=1)[CH2:6][C:7]([O:9][CH2:49][O:48][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])=[O:8]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCCCCCCCCCNC(=O)c1cc(C(=O)NCCCCCCCCCC)cc(N(CC(=O)O)CC(=O)O)c1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCCCCCCNC(=O)c1cc(C(=O)NCCCCCCCCCC)cc(N(CC(=O)OCOC(=O)C(C)(C)C)CC(=O)OCOC(=O)C(C)(C)C)c1
Yield: 66.5 %

Procedure:
A mixture of 0.1023 g (0.174 mmol) of N-(carboxymethyl)-N-[3,5-bis[(decylamino)carbonyl]phenyl]glycine, 0.12 ml (0.84 mmol) of chloromethyl pivalate, 0.07 ml (0.49 mmol) of triethylamineand 0.04 1 g of sodium iodide in 3 ml of anhydrous acetone was stirred at reflux under argon for 17 hours. The solvent was removed, NaHCO3 solution was added to the residue and the product was extracted with ethylacetate. The dried extract was concentrated to an oil and purified by chromatography on 20 g of silica gel using 50% ethyl acetate-hexane to give 0.093 g (66% yield) of N-[3,5-bis[(decylamino)carbonyl]phenyl]-N-[2-[(2,2-dimethyl-1-oxopropoxy)methoxy]-2-oxoethyl]glycine (2,2-dimethyl-1-oxopropoxy)methyl ester as a waxy solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](=[O:26])[CH:18]([CH3:25])[C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:11][C:10]=1[O:27][CH3:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:31]I.O>C1COCC1.C(Cl)Cl>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](=[O:26])[C:18]([CH3:31])([CH3:25])[C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])=[CH:11][C:10]=1[O:27][CH3:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1cc(/C=C/C(=O)C(C)C(=O)C(C)(C)C)ccc1O[Si](C)(C)C(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(/C=C/C(=O)C(C)(C)C(=O)C(C)(C)C)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 47.8 %

Procedure:
To a stirring solution of (E)-1-(4-tert-butyldimethylsilyloxy-3-methoxyphenyl)-4,6,6-trimethylhept-1-ene-3,5-dione (540 mg, 1.33 mmol) in THF (10 ml) under N2 was added sodium hydride (64 mg (of 60%), 1.60 mmol) and stirred for a further 45 min at room temperature. A solution of methyl iodide (0.1 ml, 1.60 mmol) in THF (1 ml) was added and the mixture heated at reflux for 5 h. Water (25 ml) was added to the cooled mixture followed by DCM (25 ml). The organic layer was separated, washed with water (25 ml), dried (MgSO4(anh)), filtered and concentrated. The residue was purified by column chromatography on silica using dichloromethane as eluent to give (E)-1-(4-tert-butyldimethylsilyloxy-3-methoxyphenyl)-4,4,6,6-tetramethylhept-1-ene-3,5-dione (266 mg, 48%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 0.17 (6H, s, Si(CH3)2), 0.99 (9H, s, SiC(CH3)3), 1.18 (9H, s, C(CH3)3), 1.41 (6H, s, 2×C(CH3)), 3.83 (3H, s, OCH3), 6.54 (1H, d, J=15.6 Hz, vinyl CH), 6.84 (1H, d, J=8.0 Hz, ArH), 6.98 (1H, d, J=2.0 Hz, ArH), 7.06 (1H, dd, J=8.0, 2.0 Hz, ArH), 7.66 (1H, d, J=15.6 Hz, vinyl CH) ppm.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13]1([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH:13]1([N:17]2[CH2:22][CH2:21][N:20]([C:2]3[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=3)[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: C1CC(N2CCNCC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCN(C3CCC3)CC2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
Ethyl 4-fluorobenzoate (0.753 g, 4.48 mmol) was added to a solution of 1-cyclobutylpiperazine (0.571 g, 4.07 mmol) and potassium carbonate (0.563 g, 4.07 mmol) in DMSO (8 mL) under nitrogen. The resulting solution was stirred at 100° C. for 18 h and evaporated to dryness. The residue was triturated with diethyl ether, filtered, and evaporated and the crude product was purified by silica column chromatography, eluting with a gradient of 0 to 2.5% 2.5N MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 4-(4-cyclobutylpiperazin-1-yl)benzoate (0.387 g, 32.9%) as a white solid.
Reaction SMILES: O.[OH:2]N1C2C=CC=CC=2N=N1.CN(C)[CH2:14][CH2:15][CH2:16][N:17]=[C:18]=NCC.C(N(C(C)C)CC)(C)C.C[O:33][C:34]1C=C[CH:37]=[CH:36][C:35]=1[C@H](C)C(O)=O.[Cl-].[Na+]>ClCCl.O>[CH2:16]1[CH:15]2[CH:14]([CH:34]([OH:33])[CH:35]([OH:2])[CH2:36][CH2:37]2)[CH2:18][NH:17]1
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1ccccc1[C@H](C)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: OC1CCC2CNCC2C1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
30 mg of 1-hydroxybenzotriazole hydrate, 0.66 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 0.6 cm3 of diisopropylethylamine are added to a solution of 1.1 g of (3AS,4S,5S,7AS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindole-4,5-diol and 0.58 g of (S)-2-(2-methoxyphenyl)propanoic acid in 30 cm3 of dichloromethane, cooled to 0° C. The mixture is stirred at room temperature for 3 hours and 30 minutes and 100 cm3 of water and 50 cm3 of an aqueous saturated solution of sodium chloride are added. The organic phase is decanted, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The yellow residue obtained is chromatographed on a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm) by eluting under a nitrogen pressure of 50 kPa with a mixture of cyclohexane and ethyl acetate (60/40 by volume) and collecting fractions of 25 cm3. Fractions 6 to 14 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.9 g of (3AS,4S,5S,7AS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[S)- 2-(2methoxyphenyl)propionyl]perhydroisoindole-4,5-diol which melts at 256° C. is obtained.
Reaction SMILES: C1(C(=[N:14][CH:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:16]#[N:17])C2C=CC=CC=2)C=CC=CC=1.[ClH:26].O>C1COCC1>[ClH:26].[NH2:14][CH:15]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[C:16]#[N:17]
Reactant: N#CC(Cc1ccc(F)cc1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: N#CC(N)Cc1ccc(F)cc1
Reaction time: 3 h
Yield: 93 %

Procedure:
To a solution of 2-(diphenylmethyleneamino)-3-(4-fluorophenyl)propanenitrile (1.65 g, 5.02 mmol, 1.0 equiv) in THF (20.1 mL) was added HCl (5.53 mL of a 1 M aqueous solution, 5.53 mmol, 1.1 equiv). After stirring 3 h, the reaction was poured into water and washed with ether (×3). The aqueous layer was neutralized by the addition of 10 M NaOH and extracted with CH2Cl2 (×3). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo to provide the title compound (0.77 g, 93% yield) as a colorless oil. For convenience, the amine could be converted into the hydrochloride salt by dissolution in ether, treating with 2 M HCl in ether, and filtering the resulting white solid: 1H NMR (400 MHz, CDCl3) δ ppm 7.24-7.29 (m, 2H), 7.01-7.08 (m, 2H), 3.85-3.96 (m, 1H), 2.92-3.07 (m, 2H), 1.60 (d, J=7.55 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([O:8][CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:7]=1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Reactant: BrCC1CCCC1
Product: Fc1cc2nc(-c3ccc(Cl)cc3OCC3CCCC3)n(CC3CCCCC3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 19, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) and bromomethyl-cyclopentane (CAS Reg. No. 3814-30-0). Colorless powder (41%). MS (Turbo Spray): m/z=459.2 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[NH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([C:35]([OH:38])([CH3:37])[CH3:36])[CH2:30]1>>[CH3:28][N:4]1[C:3]([CH2:2][N:29]2[CH2:34][CH2:33][CH2:32][CH:31]([C:35]([OH:38])([CH3:37])[CH3:36])[CH2:30]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CC(C)(O)C1CCCNC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCCC(C(C)(C)O)C3)n(C)c2n1

Procedure:
Following General Procedure E of amine alkylation, 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 2-(piperidin-3-yl)propan-2-ol were reacted to give 265. M+H+=505.3
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH2:34]([S:36](Cl)(=[O:38])=[O:37])[CH3:35]>C(Cl)Cl>[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:36]([CH2:34][CH3:35])(=[O:38])=[O:37])[CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCS(=O)(=O)Cl
Reactant: CCCCc1cc(OC2CCN(CCCCN)CC2)c2ncccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1cc(OC2CCN(CCCCNS(=O)(=O)CC)CC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)amine (for example, as prepared for Intermediate 37) (248 mg, 0.7 mmol) was dissolved in DCM (5 ml), and treated with triethylamine (156 μl, 1.12 mmol), and ethanesulfonyl chloride (commercially available, for example, from Aldrich) (80 μl, 0.84 mmol). The mixture was stirred at room temperature for 2 h, then left to stand at room temperature overnight. The mixture was washed with saturated aqueous sodium hydrogen carbonate, passed through a hydrophobic frit and the organic solution was concentrated in vacuo. The residue was applied to a silica cartridge (20 g), eluting with DCM-ethanol-aqueous 0.88 s.g. ammonia (100:8:1). The relevant fractions were concentrated in vacuo to give the title compound (as the free base) as a yellow gum (167 mg). LCMS RT=2.66 min, ES+ve m/z 448 (M+H)+; 1H NMR δ (CD3OD) 8.72 (1H, dd, J=4, 1.5 Hz), 8.21 (1H, dd, J=8, 1.5 Hz), 7.48 (1H, dd, J=8, 4 Hz), 7.26 (1H, s), 7.10 (1H, s), 4.74-4.64 (1H, m), 3.10-2.92 (6H, m), 2.78 (2H, t, J=7.5 Hz), 2.50-2.38 (4H, m), 2.20-2.10 (2H, m), 2.08-1.95 (2H, m), 1.76-1.53 (6H, m), 1.47-1.36 (2H, m), 1.30 (3H, t, J=7 Hz), 0.97 (3H, t, J=7 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[OH:20])=[O:9])([CH3:6])[CH3:5].[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]O)=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:27][C:26]1[CH:29]=[CH:30][C:23]([Br:22])=[CH:24][CH:25]=1)=[O:9])([CH3:6])[CH3:5]
Reactant: OCc1ccc(Br)cc1
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCc1ccc(Br)cc1

Procedure:
To a solution of 80 mg of 2-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester, 52 mg 4-bromobenzyl alcohol and 73 mg triphenyl phosphine in 3 ml of dry THF 56 mg of diisopropylazodicarboxylate were added. After 2 h at room temperature 36 mg of triphenylphosphine and 25 mg of diisopropylazodicarboxylate were added, and after 16 h again 36 mg of triphenylphosphine and 25 mg of diisopropylazodicarboxylate were added. After additional 24 h the reaction was concentrated in vacuo and after chromatography on silica (ethyl acetate/heptane) 96 mg of 2-{[1-(4-bromo-benzyloxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester were obtained.
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20](=O)[CH2:21][C:22]1([CH3:25])[CH2:24][CH2:23]1)(=O)OC.O.[NH2:28][NH2:29]>>[CH3:1][C@:2]12[C:8]([CH3:10])([CH3:9])[C@H:5]([C:4]3[CH:19]=[C:20]([CH2:21][C:22]4([CH3:25])[CH2:24][CH2:23]4)[N:28]=[N:29][C:3]=31)[CH2:6][CH2:7]2
Reactant: COP(=O)(CC(=O)CC1(C)CC1)OC
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Reactant: NN
Solvent: O
Product: CC1(Cc2cc3c(nn2)[C@@]2(C)CC[C@@H]3C2(C)C)CC1

Procedure:
Light-yellow solid MS (ESI): 257.1 (MH+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione (commercially available), [3-(1-methyl-cyclopropyl)-2-oxo-propyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
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:54]=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][C:46](=[O:53])[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[F:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[S:62](Cl)(=[O:64])=[O:63]>>[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:54]=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][C:46]([N:47]1[CH2:52][CH2:51][N:50]([S:62]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2[F:55])(=[O:64])=[O:63])[CH2:49][CH2:48]1)=[O:53]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCN(S(=O)(=O)c2ccccc2F)CC1
Yield: 50 %

Procedure:
The desired compound was prepared according to the procedure of Example D20, step A, using 6-chloro-12-(2-oxo-2-piperazin-1-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 2-fluorobenzenesulphonyl chloride as the starting materials in 50% yield. LCMS for C29H28ClFN7O4S (M+H)+: m/z=624.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16](Cl)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:29]2[CH:38]=[CH:37][C:36]3[C:35]([CH3:40])([CH3:39])[CH2:34][CH2:33][C:32]([CH3:42])([CH3:41])[C:31]=3[CH:30]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:38]3[CH:29]=[CH:30][C:31]4[C:32]([CH3:42])([CH3:41])[CH2:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36]=4[CH:37]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc(Cl)c2)CC1
Reactant: CC1(C)CCC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccnc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)CC1

Procedure:
202 mg (0.68 mmol) of 4-(2-chloropyridin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, 256 mg (0.81 mmol) of 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane and 187 mg (1.36 mmol) of potassium carbonate are dissolved in 6 ml of acetonitrile and 650 μl of water. The reaction mixture is degassed a number of times, 78 mg (0.07 mmol) of tetrakis(triphenylphosphine)palladium are added under nitrogen atmosphere, the mixture is irradiated in the microwave at 120° C. for 90 min, subsequently diluted with water and extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4 and evaporated. The crude product is purified by column chromatography on RP silica gel.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[CH:5]=[N:6][C:7]=1[N:8]1[CH:12]=[N:11][N:10]=[N:9]1.C1(SC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[N:6][C:7]=1[N:8]1[CH:12]=[N:11][N:10]=[N:9]1
Reactant: CC(C)(C)OC(=O)Cc1cnc(-n2cnnn2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CSc1ccccc1
Product: O=C(O)Cc1cnc(-n2cnnn2)c(F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To tert-butyl 2-(5-fluoro-6-(1H-tetrazol-1-yl)pyridin-3-yl)acetate (70 mg, 0.25 mmol) in DCM (0.50 mL) was added thioanisole (163 μl, 1.38 mmol) and TFA (241 μl, 3.13 mmol) at 0° C. The reaction mixture was stirred at rt for 5 h. The reaction mixture was concentrated to give the crude product, which was used in the next step without further purification: LC/MS: [(M+1-28)]+=196.5.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[C:14]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=4)=[CH:21][C:20]=3[F:33])=[O:17])=[CH:13][C:12]([C:34]([CH3:37])([CH3:36])[CH3:35])=[N:11]2)[CH:5]=1.COC(=O)C1C=CC(N2C(NC(NC3C=CC(OC4C=CN=C(C)C=4)=CC=3F)=O)=CC(C(C)(C)C)=N2)=CC=1.[OH-].[K+]>CO.O>[C:34]([C:12]1[CH:13]=[C:14]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=3)=[CH:21][C:20]=2[F:33])=[O:17])[N:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:38])=[O:2])[N:11]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: COC(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(C)c3)cc2F)c1
Agent: COC(=O)c1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(C)c3)cc2F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(C(=O)O)c3)c(F)c2)ccn1
Temperature: 40 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 3-(3-tert-butyl-5-{3-[2-fluoro-4-(2-methyl-pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzoic acid methyl ester (2.0 g, 4.12 mmol; prepared in a similar manner as described for 4-(3-tert-butyl-5-{3-[2-fluoro-4-(2-methyl-pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzoic acid methyl ester) in methanol, was added potassium hydroxide (692 mg, 12.4 mmol) in water. The mixture was stirred at 40° C. overnight, then cooled to room temperature. Methanol was evaporated at reduced pressure, and the aqueous residue neutralized to pH 7 by addition of 2N HCl. The white solid that formed was collected by filtration and dried in vacuo to give the title compound (1.9 g, 98%). 1H-NMR (DMSO-d6) δ 8.95 (s, 1H), 8.92 (s, 1H), 8.30 (d, J=5.7 Hz, 1H), 8.11-8.03 (m, 2H), 7.94 (d, 10.2 Hz, 1H), 7.79 (d, J=9.9 Hz, 1H), 7.65 (t, J=7.5 Hz, 1H), 7.18 (J=14.1 Hz, 1H), 6.95 (d, J=12.9 Hz, 1H), 6.75 (m, 2H), 6.39 (s, 1H), 2.39 (s, 3H), 1.89 (s, 9H); MS LC-MS [M+H]+=504.2, RT=2.47 min.