Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][O:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[O:10]1[CH2:11][CH2:12][CH2:13][CH:8]([C:7]2[C:2]([O:30][C:27]3[CH:26]=[CH:25][C:24]([NH:23][C:15]4[S:14][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=5[N:16]=4)=[CH:29][CH:28]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9]1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: Fc1ncccc1C1CCCOC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: c1cnc(Oc2ccc(Nc3nc4ccccc4s3)cc2)c(C2CCCOC2)c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
2-Fluoro-3-(tetrahydro-2H-pyran-3-yl)pyridine (0.10 g, 0.55 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (0.33 g, 1.38 mmol), and cesium carbonate (0.54 g, 1.66 mmol) were mixed in NMP (2 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at 120° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic layers were washed with 1 M aqueous sodium hydroxide, sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give N-(4-(3-(tetrahydro-2H-pyran-3-yl)pyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine. MS (ESI, pos. ion) m/z: 404.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7](OC1C=CC=CC=1)=[O:8].Br.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH2:28])=[CH:21][CH:20]=1.C(N(CC)CC)C>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH:28][C:7]([N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])=[O:8])=[CH:21][CH:20]=1
Reactant: O=C1CCCN1C(=O)Oc1ccccc1
Reactant: COc1ccc(OCCN)cc1
Agent: Br
Solvent: CCN(CC)CC
Product: COc1ccc(OCCNC(=O)N2CCCC2=O)cc1
Temperature: 110 °C
Yield: 118.5 %

Procedure:
A mixture of 1.16 g (5.64 mmol) of 2-oxo-1-phenoxycarbonylpyrrolidine (II) were added 2.0 g (8.06 mmol) of 2-(4-methoxyphenyloxy)ethylamine hydrobromide and 1.63 g (16.1 mmol) of triethylamine was heated at 110° C. for 3 hr. After evaporation of the solvent, the residue was refined by silica gel column chromatography, whereby 1.86 g of the objective compound (Ia-42) was obtained as crystals from the eluate with toluene/ethyl acetate (5/1-3/1 v/v). Yield:83.0%
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:26])[CH2:15][CH:16]([CH2:22][CH2:23][O:24][CH3:25])[C:17]([O:19]CC)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:28]1[S:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.[OH-].[Na+].Cl>C(O)CCC.CO>[S:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14](=[O:26])[CH2:15][CH:16]([CH2:22][CH2:23][O:24][CH3:25])[C:17]([OH:19])=[O:18])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CCOC)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: Clc1nc2ccccc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: CO
Product: COCCC(CC(=O)c1ccc(-c2ccc(Nc3nc4ccccc4s3)cc2)cc1)C(=O)O
Temperature: 90 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To a solution of ethyl 4-(4′-amino-1,1′-biphenyl-4-yl)-2-(2-methoxyethyl)-4-oxobutanoate (75 mg, 0.21 mmol) in butanol (4 mL), 2-chloro-benzothiazole (43 mg, 0.25 mmol) was added and the reaction mixture was heated at 90° C. overnight. The solvent was removed by rotary evaporation, the residue was redissolved in DMF (1 mL), a solution of 1 N aqueous NaOH (0.63 mL, 0.63 mmol) was added, and the mixture was stirred at rt overnight. A solution of 1 N aqueous HCl (0.3 mL, 0.3 mmol) and methanol (5 mL) were added to the reaction mixture, and the crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford 4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2-(2-methoxyethyl)-4-oxobutanoic acid as a white solid (30 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, 2 H), 7.95 (d, 2 H), 7.70 (m, 5 H), 7.60 (d, 1 H), 7.30 (t, 1 H), 7.15 (t, 2 H), 3.35 (m, 2 H), 3.25 (s, 3 H), 3.20 (m, 2 H), 2.90 (m, 1 H), 1.95-1.75 (m, 2 H); LC-MS ret. time 3.29 min (method 2), m/z 461.15 (MH+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:14][C:15]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl.CN(C=O)C>[CH2:7]([O:14][C:15]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:16]=1[CH:17]=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccc(C(=O)O)c(OCc2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C=O)c(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
Oxalyl chloride (3.6 ml) was added to a solution of 2-benzyloxy-4-methylbenzoic acid (9.02 g) in dichloromethane (20 ml), one drop of DMF was added and the mixture was stirred for 2 hours then evaporated to dryness. The residue was dissolved in diglyme (70 ml) and cooled to -78° C. under argon. Lithium-tri-t-butoxyaluminohydride (78 ml of 0.5M solution in diglyme) was added at such a rate that the temperature did not exceed -60° C. The mixture was stirred below this temperature for 2 hours and was then poured carefully onto ice and acidified with concentrated HCl. The mixture was extracted with diethylether (3×150 ml) and the gum obtained on work up was subjected to chromatography on silica eluted with dichloromethane to give 2-benzyloxy-4-methylbenzaldehyde (3.73 g).
Reaction SMILES: Br[CH2:2][CH2:3][O:4]C1CCCCO1.[ClH:11].[C:12]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[O:24][C@H:25]2[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27][CH2:26]2)[CH:17]=[N:16][CH:15]=1)#[N:13]>>[ClH:11].[C:12]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[O:24][C@H:25]2[CH2:30][CH2:29][C@H:28]([NH:31][CH2:2][CH2:3][OH:4])[CH2:27][CH2:26]2)[CH:17]=[N:16][CH:15]=1)#[N:13]
Reactant: N#Cc1cncc2cccc(O[C@H]3CC[C@H](N)CC3)c12
Reactant: BrCCOC1CCCCO1
Agent: Cl
Product: N#Cc1cncc2cccc(O[C@H]3CC[C@H](NCCO)CC3)c12

Procedure:
According to the method of Example 144, an alkylation reaction with 2-(2-bromoethoxy)tetrahydro-2H-pyran and a deprotection reaction were performed by using the compound of Example 134 to obtain the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1([CH3:19])[C:12]2[S:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:9][C:8]=2[CH2:7][CH2:6][O:5]1.[CH3:20][NH2:21]>O1CCCC1>[CH3:20][NH:21][CH2:2][CH2:3][C:4]1([CH3:19])[C:12]2[S:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:9][C:8]=2[CH2:7][CH2:6][O:5]1
Reactant: CN
Reactant: CC1(CCBr)OCCc2nc(-c3ccccc3)sc21
Solvent: C1CCOC1
Product: CNCCC1(C)OCCc2nc(-c3ccccc3)sc21
Reaction time: 8 h

Procedure:
To a solution of 4-(2-bromoethyl)-6,7-dihydro-4-methyl-2-phenyl-4H-pyrano[ 4,3-d]thiazole (3.14 g, 9.28 mmoles, described above) in dry tetrahydrofuran (50 ml), methylamine gas is slowly added during one hr. After standing overnight additional methylamine gas is introduced and the solution is allowed to stand for 24 hr. After evaporation under reduced pressure the residue is taken up in aqueous sodium bicarbonate solution and extracted with chloroform. The organic extract is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is dissolved in acetone-ether and the crystalline precipitate is removed by filtration. The filtrate is evaporated under reduced pressure to give the title compound, nmr (CDCl3) δ 1.57 (s, 3H), 2.07 (t, J= 5Hz), 2.44 (s, 3H), 2.60 (m, 2H), 2.94 (t, J= 5.5 Hz), 4.10 (t, J= 5.5 Hz), 7.5-8.0 (m, 5H), identical to the amine described in Example 31.
Reaction SMILES: [C:1]1([NH2:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:15]1[C:32]2[C:23](=[CH:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=3[CH:31]=2)[CH:22]=[C:21]2[C:16]=1[C:17]1[CH:48]=[CH:47][C:46]3[C:33](=[CH:34][C:35]4[C:44]([CH:45]=3)=[CH:43][C:42]3[C:37](=[CH:38][C:39](Br)=[CH:40][CH:41]=3)[CH:36]=4)[C:18]=1[CH:19]=[CH:20]2>O.[Cu]>[C:1]1([NH:7][C:15]2[C:32]3[C:23](=[CH:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=4[CH:31]=3)[CH:22]=[C:21]3[C:16]=2[C:17]2[CH:48]=[CH:47][C:46]4[C:33](=[CH:34][C:35]5[C:44]([CH:45]=4)=[CH:43][C:42]4[C:37](=[CH:38][C:39]([NH:7][C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)=[CH:40][CH:41]=4)[CH:36]=5)[C:18]=2[CH:19]=[CH:20]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccc2cc3cc4ccc5c(ccc6cc7cc8ccccc8cc7c(Br)c65)c4cc3cc2c1
Reactant: Nc1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: c1ccc(Nc2ccc3cc4cc5ccc6c(ccc7cc8cc9ccccc9cc8c(Nc8ccccc8)c76)c5cc4cc3c2)cc1

Procedure:
Naphthacenonaphthacene is dissolved in carbon tetrachloride. While the resultant mixture is cooled, 1 mol equivalent of bromine is added thereto. The mixture is reacted for 4 hours and brominated. Thereafter, the mixture is purified in accordance with a usual method, and 6,13-dibromonaphthacenonaphthacene is obtained. Phenylamine, potassium carbonate, and copper powder are added to the 6,13-dibromonaphthacenonaphthacene obtained in this way, and the mixture is reacted for 30 hours at 200° C. After the reaction solution is diluted with water, the reactant is eluted with chloroform. Thereafter, the resultant substance is purified in accordance with a usual method, and the 6,13-bis(phenylamino)naphthacenonaphthacene represented by the following formula is synthesized. (Note that, in the formula, “Ph” represents a phenyl group.)
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[K+].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[O:20])=[C:15](F)[CH:14]=1>O1CCCC1.O>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH:27]([O:28][CH2:29][CH3:30])[O:31][CH2:32][CH3:33])=[O:20])=[C:17]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])[CH:18]=1
Reactant: CC(C)=NO
Reactant: CCOC(OCC)c1ccccc1C(=O)c1ccc(Br)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccccc1C(=O)c1ccc(Br)cc1ON=C(C)C
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
To a mechanically stirred solution of acetone oxime (20.33 g) in tetrahydrofuran (500 mL) under nitrogen was added a solution of 1M potassium tert-butoxide in tetrahydrofuran (325 mL) while cooling in an ice water bath. The thick white suspension was stirred at 20° C. for 20 min then a solution of (4-bromo-2-fluorophenyl)(2-(diethoxymethyl)phenyl)methanone (Compound 2a) (118 g) in tetrahydrofuran (400 mL) was added over 20 min and the resulting pale orange suspension stirred at room temperature for 1 h then refluxed for 2 h. The reaction mixture was diluted with water (680 mL) and extracted into ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and evaporated to give the title compound (116 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[C:14]3=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=[C:13]3[CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[CH2:33][C:34](=O)[C:35]([O:37][CH2:38][CH3:39])=[O:36]>C(#N)C>[CH2:38]([O:37][C:35]([C:34]1[N:1]=[C:2]2[CH:7]=[C:6]([NH:8][C:9]([C:11]3[N:23]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[C:14]4=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=[C:13]4[CH:12]=3)=[O:10])[CH:5]=[CH:4][N:3]2[CH:33]=1)=[O:36])[CH3:39]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1cc(NC(=O)c2cc3cc(C(F)(F)F)cnc3n2Cc2cccc(F)c2)ccn1
Solvent: CC#N
Product: CCOC(=O)c1cn2ccc(NC(=O)c3cc4cc(C(F)(F)F)cnc4n3Cc3cccc(F)c3)cc2n1
Yield: 53.8 %

Procedure:
The compound is prepared according to a process similar to that described in step 15.3, by reacting 0.197 g (0.46 mmol) of N-[2-aminopyrid-4-yl]-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, prepared according to the protocol described in step 15.2, with 0.179 g (0.92 mmol) of ethyl 3-bromo-2-oxopropionate in 5 mL of acetonitrile. 130 mg of the expected product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:17]1[CH:18]=[N:19][C:20]([O:23]C)=[CH:21][CH:22]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].Cl.CCOC(C)=O.O>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:17]1[CH:22]=[CH:21][C:20](=[O:23])[NH:19][CH:18]=1)([OH:16])[C:12]([F:14])([F:15])[F:13]
Reactant: COc1ccc(C(C)C(O)(c2ccc(OC)nc2)C(F)(F)F)c(Cl)c1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(C(C)C(O)(c2ccc(=O)[nH]c2)C(F)(F)F)c(Cl)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
To a solution of 3-(2-chloro-4-methoxy-phenyl)-1,1,1-trifluoro-2-(6-methoxy-pyridin-3-yl)-butan-2-ol (212 mg) in dioxane (8.5 ml) was added concentrated HCl (0.934 ml). The mixture was stirred at 100° C. for 1 h. After cooling to room temperature, EtOAc and water were added and the mixture was extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated to dryness to give the title compound (207 mg) as a colorless solid. MS (m/e, ISP neg. ion)=360.0 [M−H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][C:10]2[S:14][C:13]([NH2:15])=[N:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.[C:16]1([CH:22]([CH2:26][CH3:27])[C:23](O)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:1][O:2][C:3]1[C:8]([CH2:9][C:10]2[S:14][C:13]([NH:15][C:23](=[O:24])[CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:26][CH3:27])=[N:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CCC(C(=O)O)c1ccccc1
Reactant: COc1ncccc1Cc1cnc(N)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC(C(=O)Nc1ncc(Cc2cccnc2OC)s1)c1ccccc1
Reaction time: 16 h

Procedure:
5-(2-Methoxy-pyridin-3-ylmethyl)-thiazol-2-ylamine (44 mg, 0.20 mmol) and 2-phenyl-butyric acid (33 mg, 0.20 mmol) were dissolved in acetonitrile (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (15 mg, 0.041 mmol, 21%). ESI-MS m/z calc. 367.1, found 368.1 (M+1)+ Retention time 3.24 minutes.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH:10]=[CH:9][N:8]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:3][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH:10]=[CH:9][N:8]=1
Reactant: COCCCOc1ccnc(CO)c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COCCCOc1ccnc(CCl)c1
Reaction time: 1 h
Yield: 83.2 %

Procedure:
A solution of 2.60 g (0.022 mol) of thionyl chloride in 10 ml of chloroform was dropwise added to a solution of 3.64 g (0.018 mol) of 2-hydroxymethyl-4-methoxypropoxypyridine in 60 ml of chloroform under cooling with ice. The obtained mixture was stirred for one hour, neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with chloroform. The chloroform layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure to obtain 3.23 g of the title compound as a crude product.
Reaction SMILES: C([O:3][C:4](=[O:16])[C@@H:5]([CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)[NH:6]C(=O)C)C.[ClH:17]>>[ClH:17].[ClH:17].[S:14]1[CH:15]=[C:11]([CH2:10][C@@H:5]([C:4]([OH:16])=[O:3])[NH2:6])[N:12]=[CH:13]1
Reactant: CCOC(=O)[C@@H](Cc1cscn1)NC(C)=O
Agent: Cl
Product: N[C@@H](Cc1cscn1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 2 L round bottom flask equipped with a magnetic stirrer was charged with N-acetyl-3-(4-thialzoyl)-L-alanine from Example 3L (92.6 g, 0.43 mol) and 6M HCl (1 L). The resultant solution was heated to reflux. After 3 h the mixture was allowed to cool to room temperature. The solution was then concentrated under reduced pressure, evaporated from toluene (3×200 mL), and dried under vacuum overnight to give 120 g of a slightly wet solid. This material was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]([C:5]1[N:6]=[C:7]([CH3:16])[O:8][C:9]=1[C:10](=O)[C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])[CH3:3].[OH-].[NH4+:18]>>[CH3:1][C:2]([C:5]1[C:9]([OH:8])=[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:18]=[C:7]([CH3:16])[N:6]=1)([CH3:4])[CH3:3]
Reactant: [NH4+]
Reactant: Cc1nc(C(C)(C)C)c(C(=O)C(C)(C)C)o1
Agent: [OH-]
Product: Cc1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Yield: 75 %

Procedure:
A mixture of 1-[4-(1,1-dimethylethyl)-2-methyl-5-oxazolyl]-2,2-dimethyl-1-propanone (8.5 g, 38 mmol) and concentrated ammonium hydroxide (100 mL) is heated at 180° C. for 36 hours in a steel bomb. The reaction mixture is cooled and the excess ammonia is evaporated on the rotovap. The pH of the resulting mixture is adjusted to pH 6 with concentrated HCl with ice bath cooling. The product is extracted into ether (3×250 mL) and the organic layer is dried (MgSO4) and evaporated. The residue is purified by flash chromatography (silica, 7% EtOAc/hexane) to give pure 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-methylpyrimidine (6.35g, 75%) as a partial hydrate; mp 62°-65° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:28]1C=CN=C1)=O.[OH-].[NH4+].[Cl-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([NH2:28])=[O:23])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1nc(OCc2c(-c3ccc(F)cc3)noc2CO)cc1C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(OCc2c(-c3ccc(F)cc3)noc2CO)cc1C(N)=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (200 mg, 0.58 mmol) in DMF (16.7 mL) was added 1,1′-carbonyldiimidazole (116 mg, 0.69 mmol). The resulting reaction mixture was stirred for 1 h at 60° C. and then treated with an ammonium hydroxide solution (887 μL, 5.8 mmol) and stirred overnight at room temperature. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and saturated sodium hydrogen carbonate solution and then dried over sodium sulfate, filtered and evaporated. Concentration and purification by chromatography (silica, dichloromethane:methanol=98:2 to 9:1) afforded the title compound (170 mg, 85%) as a white solid. MS: m/e=345.0 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([SH:18])[N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]=2[CH:25]=1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)(O)[O-].[K+].C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3>CN(C)C=O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:15]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:14]=2[CH:25]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)CCCCCOc1ccc2nc(S)n(-c3ccccc3)c2c1
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCOc1ccc2nc(SCc3ccccc3)n(-c3ccccc3)c2c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
490 mg of 6-[(2-mercapto-1-phenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid methyl ester was dissolved in 7 ml of N,N-dimethylformamide, mixed with 0.19 ml of benzyl bromide, 278 mg of potassium bicarbonate and 49 mg of dicyclohexano-18-crown-6, and the mixture was stirred for 15 hours at 20° C. It was filtered, and the filtrate was concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 548 mg was obtained.
Reaction SMILES: O1CCCC1.[C:6]([O:10][C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[H-].[Na+]>O.CS(C)=O>[C:6]([O:10][C:11]([NH:13][C@H:14]1[CH2:15][CH2:16][C@H:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:19]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OCc2ccccc2)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To 6 mL of a tetrahydrofuran solution containing 1.0 g of trans-4-(tert-butoxycarbonylamino)cyclohexanol and 873 mg of benzylbromide was gradually added 204 mg of 60% sodium hydride, 0.5 mL of dimethyl sulfoxide was then further added thereto, and the mixture was stirred at 70° C. for 2 hours. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was applied to silica gel column chromatography (solvent: hexane-ethyl acetate (4:1)), and the obtained powdery crystals were suspended in an ethyl acetate-hexane mixed solvent, and collected by filtration to obtain trans-1-tert-butoxycarbonylamino-4-(benzyloxy)cyclohexane.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH:18][CH3:19])(=[O:17])=[O:16])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH2:21]1[N:30]2[C@H:24]([CH2:25][O:26][CH2:27][C:28]3[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:29]=32)[CH2:23][CH2:22]1>>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH:18][CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:35][C:33]2[CH:32]=[CH:31][C:29]3[N:30]4[C@H:24]([CH2:25][O:26][CH2:27][C:28]=3[CH:34]=2)[CH2:23][CH2:22][CH2:21]4)=[N:3][CH:4]=1
Reactant: Nc1ccc2c(c1)COC[C@@H]1CCCN21
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)COC[C@@H]2CCCN32)ncc1Cl

Procedure:
Following an analogous procedure to that described in Example 5, the reaction of 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide and (S)-(2,3,3a,4-Tetrahydro-1H,6H-5-oxa-10b-aza-benzo[e]azulen-8-yl)amine gave 2-{5-Chloro-2-[(S)-(2,3,3a,4-tetrahydro-1H,6H-5-oxa-10b-aza-benzo[e]azulen-8-yl)amino]-pyrimidin-4-ylamino}-N-methyl-benzenesulfonamide, upon purification by flash chromatography (Dichloromethane: MeOH 98:2) followed by trituration with Et2O, as solid (32%)2-{5-Chloro-2-[(S)-(2,3,3a,4-tetrahydro-1H,6H-5-oxa-10b-aza-benzo[e]azulen-8-yl)amino]-pyrimidin-4-ylamino}-N-methyl-benzenesulfonamide; 1H NMR (400 MHz, DMSO-d6) δ9.30 (s, 2H), 8.56 (m, 1H), 8.22 (s, 1H), 7.79 (m, 2H), 7.63 (m, 1H), 7.44 (s, 1H), 7.34 (m, 1H), 7.28 (m, 1H), 6.81 (d, J=8.71 Hz, 1H0, 4.53 (d, J=13.04 Hz, 1H), 4.27 (d, J=13.01 Hz, 1H), 3.88 (d, J=9.54 Hz, 1H), 3.31-3.19 (2m along with water peak, 2H), 2.88 (m, 1H), 2.43 (d, J=4.73 Hz, 3H), 2.07 (m, 1H), 1.84 (m, 1H), 1.47 (m, 1H); MS (m/e) 501, 502 (M+H); mp 187-188° C.
Reaction SMILES: C(C(C)=O)=C.[CH:6](=[CH:13][C:14](=[O:16])[CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([CH2:13][C:14](=[O:16])[CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)C=Cc1ccccc1
Agent: C=CC(C)=O
Product: CC(=O)CCc1ccccc1
Reaction time: 7 h
Yield: 38 %

Procedure:
The reaction and analysis were carried out in the same manner as described in Example 12 except that 1.4 g of vinylmethyl ketone was used instead of methyl acrylate and the reaction time and temperature were adjusted to 7 hours and 220° C., respectively. It was confirmed that 0.433 g of benzalacetone and 0.167 g of benzylacetone were formed. The yields of benzalacetone and benzylacetone were 2970% and 1130%, respectively, based on the Rh atom. Identification of the products was performed by comparison with the standard substances with respect to the retention time in GC.