Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:27][CH2:26][C@:4]2([N:8]=[C:7]([C:9]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:25])([F:24])[F:23])[CH:16]=4)[CH:12]=[CH:11][N:10]=3)[CH2:6][CH2:5]2)[C:3]1=[O:28].Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.O>[CH3:1][N:2]1[CH2:27][CH2:26][C@:4]2([NH:8][C@@H:7]([C:9]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:24])([F:25])[F:23])[CH:16]=4)[CH:12]=[CH:11][N:10]=3)[CH2:6][CH2:5]2)[C:3]1=[O:28]
Reactant: CN1CC[C@@]2(CCC(c3cc(-c4cccc(OC(F)(F)F)c4)ccn3)=N2)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN1CC[C@@]2(CC[C@H](c3cc(-c4cccc(OC(F)(F)F)c4)ccn3)N2)C1=O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 99.3 %

Procedure:
A solution of (5S)-7-methyl-2-[4-[3-(trifluoromethoxy)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 12) (5.77 g, 14.82 mmol) in DCM (75 mL) was cooled to −78° C. under nitrogen and a solution of borane tert-butylamine complex (1.43 g, 16.44 mmol) in DCM (15 ml) was added dropwise maintaining the internal temperature below −70° C. over 10 mins. The mixture was stirred at −78° C. for 90 mins and then the cooling bath was removed and 5M hydrochloric acid (30 mL, 150 mmol) was added via the dropping funnel over 1-2 mins. The mixture was brought to 25-30° C. with a water bath and the mixture stirred vigourously for 30 mins. More DCM (200 ml) was added and the mixture was then slowly poured into a beaker containing sodium carbonate (17.28 g, 163.01 mmol) in water (150 ml) and the mixture was stirred for 10 mins. The layers were separated and the aqueous layer (pH 9) was re-extracted with DCM (2×150 ml). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give a yellow gum, a 15:1 mixture of (2R,5S) and (2S,5S) isomers. This mixture was separated by chromatography using a Biotage SNAP 340 g cartridge eluting with 5% of 0.5M methanolic ammonia in ethyl acetate (isocratic) to obtain the major isomer (2R,5S)-7-methyl-2-[4-[3-(trifluoromethoxy)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]nonan-6-one (5.76 g), increasing to 10% of 0.5M methanolic ammonia to elute the minor (2S,5S)-7-methyl-2-[4-[3-(trifluoromethoxy)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]nonan-6-one isomer (111 mg) which was contaminated by traces of the (2R,5S) isomer. The (2R,5S) isomer was identical spectroscopically to that prepared in Example 1. This was then converted to the salt form: Sulphuric acid (0.75 mL, 13.48 mmol) was added to a solution of (2R,5S)-7-methyl-2-[4-[3-(trifluoromethoxy)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]nonan-6-one (5.27 g, 13.48 mmol) in DCM (70 mL) at 20° C. and the reaction stirred for 5 mins. The solvent was evaporated and the residue was triturated with diethyl ether and dried. This solid (approx. 6 g) was dissolved in acetone (30 ml) and then added dropwise to diethyl ether (600 ml) with rapid stirring.
Reaction SMILES: [C:1](#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.II.[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br.[OH2:20]>CCOCC>[C:2]1([C:1]([CH2:11][C:12]2[CH:19]=[CH:18][CH:17]=[C:14]([CH3:15])[CH:13]=2)=[O:20])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1
Reactant: O
Reactant: Cc1cccc(CBr)c1
Agent: II
Solvent: CCOCC
Product: Cc1cccc(CC(=O)c2ccccc2)c1

Procedure:
A solution of benzonitrile (58.5 g) in anhydrous ether (150 ml) is added dropwise with stirring to Grignard reagent which is prepared from magneisum turnings (14.6 g), a small amount of iodine and m-methylbenzylbromide (100 g) in anhydrous ether (800 ml) at moisture-free atmosphere. The mixture is refluxed for 6 hours. The reaction mixture is decomposed by adding water thereto, and the ether layer is separated and distilled to remove the solvent. The residue is mixed with 10% hydrochloric acid and the mixture is refluxed for 1.5 hours. After cooling, the mixture is extracted with ether. The ether layer is dried over anhydrus sodium sulfate and the solvent is distilled off to give crude m-methylbenzyl phenyl ketone (82 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)[N:5]=[C:4]([NH2:17])[N:3]=1.[C-:18]#[N:19].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.CCOC(C)=O>[NH2:17][C:4]1[N:5]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=[C:2]([C:18]#[N:19])[N:3]=1
Reactant: Nc1nc(Cl)nc(N2CCc3ccccc32)n1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1nc(N)nc(N2CCc3ccccc32)n1
Reaction time: 2 h
Yield: 26.2 %

Procedure:
4-Chloro-6-(2,3-dihydro-indol-1-yl)-[1,3,5]triazin-2-ylamine (Intermediate 40, 680 mg, 2.48 mmol), potassium cyanide (323 mg, 4.96 mmol) and 18-crown-6 (328 mg, 1.24 mmol) were charged to a round-bottomed flask then taken up in DMF (12 mL). The resulting mixture was lowered into a heating block preheated to 110 C and stirred under nitrogen for 2 h and then at room temperature for 56 h. The reaction was then diluted with EtOAc (60 ml) and extracted with 5% aq. sodium carbonate solution (2×10 ml), brine (10 ml) and dried further over anhydrous magnesium sulfate. After evaporation of the solvent the crude residue was purified by FCC over silica gel eluting with heptane:EtOAc 1:0 to 8:2 to 1:1 to 0:1 and the column flushed with THF to give the title compound (155 mg, 26%). Method B HPLC-MS: MH+ requires m/z=239. Found: m/z=239, Rt=1.36 min (75%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:23][C:24]=1[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[CH3:25][C:24]1[O:23][C:22]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:21][C:20]=1[CH2:19][O:1][C:2]1[CH:3]=[C:4]([O:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CC(=O)Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Oc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of acetic acid 3-hydroxyphenyl ester (5.0 g, 32.86 mmol) and potassium carbonate (6.8 g, 49.3 mmol) in DMF (40 mL) is added 4-chloromethyl-5-methyl-2-phenyl-oxazole (6.8 g, 32.86 mmol) at RT. The reaction mixture is stirred for 3 h at RT followed by 24 h at 70° C. The reaction mixture is cooled to RT, diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated at reduced pressure. The crude product is purified on a Biotage 40M column using 20% ethyl acetate in hexane to yield acetic acid-3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl ester as a clear oil.
Reaction SMILES: ClC1C=CN=C2C=C(C3N(C)C=CN=3)[S:10][C:3]=12.CN1C=CN=C1C1SC2C(=NC=CC=2[O:32]C2C=CC(NC(NC(=O)CC3C=CC=CC=3)=S)=CC=2)C=1.Cl.Cl.[F:54][C:55]1[CH:56]=[C:57]([NH:77]C(NC(=O)CC2C=CC=CC=2F)=S)[CH:58]=[CH:59][C:60]=1[O:61][C:62]1[CH:67]=[CH:66][N:65]=[C:64]2[CH:68]=[C:69](C3N(C)C=CN=3)[S:70][C:63]=12>>[CH3:3][S:10]([C:69]1[S:70][C:63]2[C:64](=[N:65][CH:66]=[CH:67][C:62]=2[O:61][C:60]2[CH:59]=[CH:58][C:57]([NH2:77])=[CH:56][C:55]=2[F:54])[CH:68]=1)=[O:32]
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4F)cc3F)c2s1
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3)c2s1
Agent: Cl
Product: CS(=O)c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Yield: 31 %

Procedure:
Starting from the compound 214 (scheme 46) and following the procedures described above for the synthesis of compound 228 (example 202) and 303a (example 232), title compound 234 was obtained in 31% yield as an off-white solid. 1H NMR (d-DMSO) δ (ppm): 12.34 (s, 1H), 11.81 (s, 1H), 8.68 (m, 1H), 8.24 (s, 1H), 7.79 (m, 3H), 7.62 (s, 1H), 7.40-7.13 (m, 6H), 6.86(d, 1H), 4.02 (s, 3H), 3.93 (s, 2H). MS (m/z): 518.1 (M+H) (found).
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]1.[Cl:20][C:21]1[C:26](Cl)=[N:25][CH:24]=[CH:23][N:22]=1.O>CN(C=O)C>[Cl:20][C:21]1[C:26]([O:19][C@H:16]2[CH2:15][CH2:14][C@H:13]([NH:12][C:4]3[S:3][C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[N:5]=3)[CH2:18][CH2:17]2)=[N:25][CH:24]=[CH:23][N:22]=1
Reactant: O[C@H]1CC[C@H](Nc2nc3ccccc3s2)CC1
Reactant: Clc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nccnc1O[C@H]1CC[C@H](Nc2nc3ccccc3s2)CC1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
Sodium hydride (60% dispersion, 0.41 g, 10.2 mmol) was added to a solution of trans-4-(benzo[d]thiazol-2-ylamino)cyclohexanol (as prepared according to Scheme 5) (1.10 g, 4.43 mmol) in DMF (20 mL) under argon. The mixture was stirred for 45 min and then 2,3-dichloropyrazine (0.66 g, 4.43 mmol) was added via syringe. This mixture was heated to 60° C. for 16 h, cooled to room temperature, then water was added slowly. The resulting suspension was filtered and the collected solid was purified by silica gel chromatography to give N-(trans-4-(3-chloropyrazin-2-yloxy)cyclohexyl)benzo[d]thiazol-2-amine (0.92 g, 2.54 mmol, 57% yield) as a white solid.
Reaction SMILES: [CH:1]1([N:4]([CH:32]2[CH2:34][CH2:33]2)[C:5]([C:7]2[N:29]([CH2:30][CH3:31])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:24]=[C:23]([C:25](O)=[O:26])[N:22]([CH3:28])[N:21]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:35][N:36](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:37].F[P-](F)(F)(F)(F)F.CNC.C1COCC1>CN(C=O)C.O>[CH:32]1([N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]([C:7]2[N:29]([CH2:30][CH3:31])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:24]=[C:23]([C:25](=[O:26])[N:36]([CH3:37])[CH3:35])[N:22]([CH3:28])[N:21]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:33][CH2:34]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3cc(C(=O)O)n(C)n3)nc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3cc(C(=O)N(C)C)n(C)n3)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
A mixture of 3-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-1-methyl-1H-pyrazole-5-carboxylic acid (39.8 mg, 0.086 mmol), HATU (49.0 mg, 0.129 mmol) and dimethylamine, 2M in THF (0.086 mL, 0.172 mmol) in DMF (2 mL) was stirred at room temperature for 2 h. Water was added and the reaction mixture was extracted with ethyl acetate 3 times. The combined organic layers were washed twice with 10% lithium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude was purified by preparative HPLC to give N,N-dicyclopropyl-4-(5-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (23 mg, 54.1% yield) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:11][C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.O=[C:18]([CH2:25][CH3:26])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:25]([C:18]1[NH:11][C:12]2=[N:13][NH:14][CH:15]=[C:16]2[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[O:2][CH3:1])[C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:26]
Reactant: COc1ccccc1C=O
Reactant: CCOC(=O)CC(=O)CC
Reactant: Nc1cc[nH]n1
Product: CCOC(=O)C1=C(CC)Nc2n[nH]cc2C1c1ccccc1OC

Procedure:
The title compound was prepared from 2-methoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketopentanoate in the same manner as in Example 1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[CH:18]1([N:24]=[C:25]=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(Cl)[Cl:28]>>[ClH:28].[ClH:28].[CH2:11]([N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:25]([NH:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:26])[CH2:10][CH2:9]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCCl
Reactant: NCCCN1CCN(Cc2ccccc2)CC1
Reactant: O=C=NC1CCCCC1
Product: Cl
Product: O=C(NCCCN1CCN(Cc2ccccc2)CC1)NC1CCCCC1
Yield: 65 %

Procedure:
A solution of 1-(3-aminopropyl)-4-benzylpiperazine (2 g; 12.9 mmole) and cyclohexyl isocyanate (1.6 g; 12.9 mmole) in methylene chloride (50 ml) was stirred overnight at room temperature. The reaction mixture was concentrated, and the crude product was precipitated as the dihydrochloride from ether in the manner described in Example 6. Recrystallization from ethanol provided the title compound as colorless crystals (3.62 g; 65% yield), m.p. 202°-213° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:3]=1.[Cl:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:20][CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:3]=1
Reactant: Cc1cc(C)nc(N2C(=O)c3ccccc3C2=O)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(CCl)cc(N2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Yield: 17.2 %

Procedure:
A mixture of (29) (2.52 g, 10 mmol)), N-chlorosuccinimide (1.6 g, 12 mmol), and benzoyl peroxide (1.21 g, 5 mmol) in carbon tetrachloride (50 ml) was refluxed for 2 hr. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, dichloromethane:EA (95:5)) to afford 493 mg (17%) of a yellow solid; 1H NMR (200 MHz, CDCl3) δ 2.63 (3H, s), 4.48 (2H, s), 7.27 (1H, s), 7.28 (1H, s), 7.76-7.98 (4H, m); m/z (EI) 286 (M+).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:11][CH:12]([CH3:44])[C@H:13]([NH:21][CH2:22][C@H:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)[O:34][C:35]=2[CH3:36])[CH2:24]1)[C:14]([O:16]C(C)(C)C)=[O:15]>ClCCl.O>[C:1]([N:21]([CH2:22][C@H:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][CH:42]=3)[O:34][C:35]=2[CH3:36])[CH2:24]1)[C@@H:13]([CH:12]([CH3:44])[CH3:11])[C:14]([OH:16])=[O:15])(=[O:3])[CH3:2]
Reactant: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](CN[C@H](C(=O)OC(C)(C)C)C(C)C)C3)c(C)o2)cc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(C[C@H]1CCC[C@@H](OCc2nc(-c3ccc(C)cc3)oc2C)C1)[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
12 μl of acetyl chloride and 22 μl of pyridine are added to 40 mg of tert-butyl (S)-3-methyl-2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}butyrate in 0.5 ml of dichloromethane, and the mixture is stirred at room temperature for 18 h. The solution is then diluted with water and dichloromethane, the aqueous phase is removed and extracted with dichloromethane and the combined phases are dried over MgSO4 and concentrated. The residue is taken up in 0.5 ml of trifluoroacetic acid and allowed to stand at room temperature overnight. The solvent is distilled off completely and the residue is purified by HPLC, which gives 17 mg of (S)-2-{acetyl-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}-3-methylbutyric acid. C26H36N2O5 (456.59); LCMS (ESI): 457.36 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:4]=1.[CH:16]1([CH2:20][NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([N:33]3[CH2:38][CH2:37]NCC3)=[O:32])=[CH:27][C:26]=2[F:39])=[O:23])[CH2:19][CH2:18]C1.C(=O)([O-])[O-].[K+].[K+].[C:46](#[N:48])[CH3:47]>>[C:12]([NH:11][C:9](=[O:10])[C:5]1[CH:4]=[C:3]([CH2:2][N:48]2[CH2:37][CH2:38][N:33]([C:31](=[O:32])[C:28]3[CH:29]=[CH:30][C:25]([NH:24][C:22]([NH:21][CH:20]4[CH2:18][CH2:19][CH2:16]4)=[O:23])=[C:26]([F:39])[CH:27]=3)[CH2:47][CH2:46]2)[CH:8]=[CH:7][N:6]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(NCC1CCC1)Nc1ccc(C(=O)N2CCNCC2)cc1F
Reactant: CC(C)(C)NC(=O)c1cc(CBr)ccn1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)NC(=O)c1cc(CN2CCN(C(=O)c3ccc(NC(=O)NC4CCC4)c(F)c3)CC2)ccn1

Procedure:
4-(Bromomethyl)-N-tert-butylpicolinamide (70 mg, 0258 mmol), 1-(cyclobutyl-methyl)-3-(2-fluoro-4-(piperazine-1-carbonyl)phenyl)urea (83 mg, 0.258 mmol) and potassium carbonate (106 mg, 0.744 mmol) were combined and heated to reflux in acetonitrile for 1 hour. The reaction mixture was concentrated at reduced pressure and the resulting residue purified by reverse phase acidic preparative HPLC to afford the title compound (41 mg). MS (ESI) m/z 511.6 [M+H]+
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=1.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.[OH-].[Na+]>O.C1COCC1>[CH:14]1([O:13][C:10]2[CH:11]=[CH:12][C:7]([B:20]([OH:25])[OH:21])=[CH:8][CH:9]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Brc1ccc(OC2CCCCC2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OB(O)c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 73.9 %

Procedure:
n-Butyllithium (1.6 M in hexane) (136 mL) was dropwised to a mixture of 1-bromo-4-(cyclohexyloxy)benzene (46.3 g) and THF (dry) (500 mL) at −78° C. and the mixture was stirred at the same temperature under nitrogen for 40 min. Triisopropyl borate (51.2 g) was dropwised to the mixture at −78° C. for 15 min and the mixture was stirred at the same temperature for 5 min. Then the mixture was warmed up to room temperature and stirred for additional 30 min. The mixture was poured into 1N NaOH aq. (250 mL) and water (750 mL) and the mixture was further stirred for 30 min. The organic layer was separated and the aqueous phase was washed with Et2O (300 mL×2) and acidified by 6N HCl aq. The mixture was extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated in vacuo to give 4-(cyclohexyloxy)phenylboronic acid (29.5 g) as a white powder. Tetrakis(triphenylphosphine)palladium(0) (0.656 g) was added to a suspension of 3-bromopyridin-2-amine (9.83 g), 4-(cyclohexyloxy)phenylboronic acid (15.0 g) and sodium carbonate (12.0 g) in DME (325 mL) and water (65.0 mL) and the mixture was stirred at 100° C. under nitrogen for 3 hr and at 90° C. for 12 hr. Volatiles were removed in vacuo with silica-gel. The silica-supported mixture was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (14.1 g) as a white powder.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[H-].[Na+].Cl[C:18]1[O:19][C:20]2[C:21](=[C:23]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=[CH:25][CH:26]=2)[N:22]=1>C1COCC1>[C:11]([O:10][C:8]([N:3]1[CH2:4][CH2:5][N:6]([C:18]2[O:19][C:20]3[C:21](=[C:23]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=[CH:25][CH:26]=3)[N:22]=2)[CH2:7][CH:2]1[CH3:1])=[O:9])([CH3:13])([CH3:12])[CH3:14]
Reactant: CC1CNCCN1C(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc2oc(N3CCN(C(=O)OC(C)(C)C)C(C)C3)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.5 %

Procedure:
To a solution of tert-butyl 2-methylpiperazine-1-carboxylate (340 mg, 1.70 mmol) in THF (5 mL) was added sodium hydride (60%, 82 mg, 2.04 mmol). The reaction mixture was stirred at room temperature for 5 min, then methyl 2-chlorobenzoxazole-4-carboxylate (300 mg, 1.41 mmol) in THF (5 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 19 h. The mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography (silica gel, 20% EtOAc in hexane) to afford methyl 2-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)benzoxazole-4-carboxylate (336 mg, 63%) as yellow solid. MS consistent.
Reaction SMILES: ClC1C=NC=CC=1[C:4]([NH:6][C:7]1[CH:12]=[C:11](C(F)(F)F)[C:10](Cl)=[CH:9][C:8]=1[OH:18])=O.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[O:18]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[CH:4]1
Reactant: O=C(Nc1cc(C(F)(F)F)c(Cl)cc1O)c1ccncc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: c1ccc2ocnc2c1
Reaction time: 2 h

Procedure:
To a mixture of 0.46 g of 3-chloro-N-[4-chloro-2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, 5 ml of tetrahydrofuran and 0.38 g of triphenylphosphine, 0.63 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature, and the reaction mixture was stirred for two hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.39 g of 6-chloro-2-(3-chloropyridin-4-yl)-5-trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 81”).
Reaction SMILES: C(C1C=CC(CC[OH:9])=CC=1)#N.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.[C:30]1([P:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:43]1([P:36](=[O:9])([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: N#Cc1ccc(CCO)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
Ethyl 2-ethoxy-3-(4-hydroxyphenyl) propanoate, described in example 3(b)(6.62 g; 27.78 mmole) and p-cyanophenethyl alcohol (2.73 g; 18.52 mmole) were mixed in dichloromethane (85 ml). ADDP (7.01 g; 27.78 mmole) was added followed by addition of triphenylphosphine (5.83 g; 22.23 mmole). The reaction was interrupted after 2 hours. Triphenylphosphine oxide formed in the reaction was filtered off and the filtrate was evaporated. The residue was purified bychromatography on silica gel using first dichloromethane and then petroleum ether:diethyl ether as eluants giving a mixture of product and starting material which was dissolved in ethyl acetate and washed with sodium hydroxide (1 N). The organic phase was washed with water, dried (sodium sulfate), filtered and the solvent was evaporated to give 4.23 g (yield 62%) of the desired product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Si:5]([CH3:35])([CH3:34])[CH2:6][CH2:7][C:8]1[C:20]2[CH2:19][N:18]3[C:13](=[CH:14][C:15]4[C@:25]([CH2:27][CH3:28])([OH:26])[C:24](=[O:29])[O:23][CH2:22][C:16]=4[C:17]3=[O:21])[C:12]=2[N:11]=[C:10]2[CH:30]=[CH:31][CH:32]=[CH:33][C:9]=12.[C:36]1([S:42]([OH:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Na]>CN(C)C=O>[C:36]1([S:42]([CH2:2][CH2:3][CH2:4][Si:5]([CH3:35])([CH3:34])[CH2:6][CH2:7][C:8]2[C:20]3[CH2:19][N:18]4[C:13](=[CH:14][C:15]5[C@:25]([CH2:27][CH3:28])([OH:26])[C:24](=[O:29])[O:23][CH2:22][C:16]=5[C:17]4=[O:21])[C:12]=3[N:11]=[C:10]3[CH:30]=[CH:31][CH:32]=[CH:33][C:9]=23)(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCBr
Reactant: O=S(O)c1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCS(=O)(=O)c1ccccc1

Procedure:
A slurry of Compound 11 (25 mg) and benzenesulfinic acid, sodium salt (15 mg) in N,N-dimethylformamide (0.5 mL) was heated at 70° C. for 5 hours under argon. The N,N-dimethylformamide was removed from the reaction mixture under vacuum and the residue was directly eluted on a silica gel using 2% ethanol in dichloromethane to obtain the required product in quantitative yield (28 mg).