Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH2:27]O)[CH:24]=[N:25][CH:26]=2)=[CH:17][CH:16]=1.[CH2:31]([N:33](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>O.CS(C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH2:27][C:31]#[N:33])[CH:24]=[N:25][CH:26]=2)=[CH:29][CH:30]=1
Reactant: CCN(CC)CC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2cncc(CO)c2)cc1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2cncc(CC#N)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 44.2 %

Procedure:
To a mixture of [5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]methanol (1.68 g), triethylamine (0.85 g) and ethyl acetate (100 mL) was dropwise added methanesulfonyl chloride (0.96 g) at room temperature, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was washed successively with water, saturated aqueous sodium hydrogencarbonate, 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give pale-yellow crystals. To a mixture of the crystals and dimethyl sulfoxide (20 mL) was added an aqueous solution (2 mL) of sodium cyanide (0.41 g) at room temperature and the mixture was stirred at room temperature for 2 days. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (0.76 g, 44%) of 2-[5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 137-138° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:9][C:10]1[S:11][C:12]2[CH2:13][N:14]([C:19](=[O:27])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[CH2:15][CH2:16][C:17]=2[N:18]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([N:14]1[CH2:15][CH2:16][C:17]2[N:18]=[C:10]([CH2:9][O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[S:11][C:12]=2[CH2:13]1)=[O:27]
Reactant: O=C(c1ccccc1F)N1CCc2nc(CCl)sc2C1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(c1ccccc1F)N1CCc2nc(COc3ccccc3)sc2C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
Phenol (0.12 g, 1.24 mmol) was added to a stirred solution of 2-(chloromethyl)-5-(2-fluorobenzoyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine (0.19 g, 0.62 mmol) and K2CO3 (0.25 g, 1.86 mmol) in ACN (5 mL). The reaction mixture was stirred at 80° C. for 16 hours, filtered and the solvent evaporated in vacuo. The crude product was purified by HPLC on a C18 XBridge 30×100 mm, 5 μm column (gradient elution: 0.1% TFA in ACN/0.1% TFA in H2O). The desired fractions were collected and extracted with a saturated solution of NaHCO3 and the aqueous layer extracted with AcOEt. The combined organic layers were dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield 5-(2-fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-thiazolo[5,4-c]pyridine (95 mg, 42% yield) as a solid. C20H17FN2O2S. 1H NMR (DMSO-d6, T=80° C.) δ ppm 2.81 (br. s., 2 H), 3.79 (br. s., 2 H), 4.76 (br. s., 2 H), 5.32 (s, 2 H), 6.85-7.09 (m, 3 H), 7.10-7.28 (m, 4 H), 7.30-7.39 (m, 1 H), 7.40-7.55 (m, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH3:9])[C:3]=1[C:10]1[CH2:14][CH2:13][O:12][N:11]=1.S(=O)(=O)(O)O.[Br:20]Br>>[Br:20][C:7]1[C:2]([CH3:1])=[C:3]([C:10]2[CH2:14][CH2:13][O:12][N:11]=2)[C:4]([S:8][CH3:9])=[CH:5][CH:6]=1
Reactant: CSc1cccc(C)c1C1=NOCC1
Reactant: BrBr
Agent: O=S(=O)(O)O
Product: CSc1ccc(Br)c(C)c1C1=NOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 10 g (48 mmol) of 3-(2-methyl-6-methylthiophenyl)-4,5-dihydroisoxazole are added a little at a time to 120 ml of conc., sulfuric acid, and the mixture is stirred for about 30 minutes. 3.7 g (23 mmol) of bromine are then added dropwise, and the mixture is stirred at 0° C. for 2.5 hours. The mixture is then allowed to warm to room temperature over a period of about 45 minutes. A homogeneous solution is formed. For work-up, the reaction mixture is poured onto ice-water and extracted three times with methylene chloride. The organic phase is washed with sodium bicarbonate solution, dried with magnesium sulfate and concentrated. This gives 11.4 g of crude product which is used for the next step without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[H][H]>CO.O1CCCC1.[C].[Pd]>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(N2CCC(O)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(N2CCC(O)CC2)cc1

Procedure:
The 4-hydroxy-N-(4-nitrophenyl)piperidine (11.1 g, 50 mmol) obtained in Example 1(1) was dissolved in methanol (100 ml) and tetrahydrofuran (50 ml), and 10% palladium-carbon (8.0 g) was added thereto, followed by stirring at room temperature in an atmosphere of hydrogen gas for 7 hours. After the insoluble material was filtered with Celite, the filtrate was concentrated under reduced pressure, diethyl ether was added to the obtained residue, and the precipitate was collected by filtration, thereby obtaining 4-hydroxy-N-(4-aminophenyl)piperidine (9.25 g, 94%) as a reddish-purple solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([C:23](O)=[O:24])=[C:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[S:11][C:5]=2[N:4]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:3]1=[O:30].[NH2:31][CH2:32][CH2:33][OH:34].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl>ClCCl>[CH3:12][CH2:10][CH2:9][CH:6]([CH3:7])[CH3:5].[OH:34][CH2:33][CH2:32][NH:31][C:23]([C:9]1[C:6]2[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:30])[N:4]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:5]=2[S:11][C:10]=1[CH2:12][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][CH:22]=1)=[O:24]
Reactant: NCCO
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)O)c(Cc3cccc4ccccc34)sc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)NCCO)c(Cc3cccc4ccccc34)sc21
Product: CCCC(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid (50 mg) and 2-aminoethanol (14 μl ) in dichloromethane (2 ml) was added 1-hydroxybenzotriazole hydrate (48 mg) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (45 mg). The reaction mixture was stirred at room temperature for 18 hours then hydrochloric acid (1M, 20 ml) was added and the mixture was extracted with ether (30 ml). The organic extracts were washed with water, then with 1M sodium hydroxide solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was recrystallised from ethyl acetate: isohexane to give the title compound (28 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[C:32]([Cl:33])=[CH:31][N:30]=[C:29]([C:34]#[N:35])[N:28]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O>[Cl:33][C:32]1[C:27]([NH:26][C:2]2[N:7]=[C:6]([N:8]([CH:18]3[CH2:19][CH2:20]3)[CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:5]3=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]3[N:3]=2)=[N:28][C:29]([C:34]#[N:35])=[N:30][CH:31]=1
Reactant: N#Cc1ncc(Cl)c(N)n1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nc(Nc3nc(C#N)ncc3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 70 °C
Yield: 15.1 %

Procedure:
2-Bromo-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 9) (168 mg, 0.421 mmol), 4-amino-5-chloropyrimidine-2-carbonitrile (65 mg, 0.421 mmol) Pd2(dba)3 (77 mg, 0.084 mmol), xantphos (48.7 mg, 0.084 mmol) and cesium carbonate (274 mg, 0.841 mmol) were suspended in dioxane (4206 μl) at rt. The reaction was degassed using the vacuum/purge method (4 times) to put the reaction under N2. The reaction was heated to 70° C. for 4 h before cooling to room temperature, diluting with EtOAc, filtered through celite and concentrated. The crude product was purified by column chromatography (40 g SiO2, 0 to 100% EtOAc-hexane gradient elution) to afford 30 mg of 2-((5-Chloro-2-cyanopyrimidin-4-yl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
Reaction SMILES: C([O:3][C:4]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5])C.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:42](O)[C:41]3[CH2:40][CH2:39][CH2:38][CH2:37][C:36]=3[C:35]2=[O:44])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([N:34]2[C:35](=[O:44])[C:36]3[CH2:37][CH2:38][CH2:39][CH2:40][C:41]=3[CH:42]2[CH2:6][C:4]([OH:5])=[O:3])=[CH:32][CH:33]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(N2C(=O)C3=C(CCCC3)C2O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(N2C(=O)C3=C(CCCC3)C2CC(=O)O)cc1
Yield: 948 %

Procedure:
Ethoxycarbonylmethylenetriphenylphosphorane (3.0 g) was added to a solution of 2-(4-methoxyphenyl-3-hydroxy-4,5,6,7-tetrahydroisoindolin-1-one (2.59 g) in toluene (30 ml) and the solution was refluxed gently for 48 hours. After cooling, the solvent was distilled off and the residue was dissolved in 30 ml of methanol. Potassium carbonate (3 g) and water (10 ml) were added and the mixture was refluxed for an hour. After cooling, the methanol was distilled off, 100 ml of water and 100 ml of dichloromethane were added and the mixture was stirred well. The aqueous layer was separated and acidified with 5% hydrochloric acid to give crystals, which was washed with water, dried and recrystallized from methanol-ether (1:3) to give 24.6 g of 2-(4-methoxyphenyl)-3-oxo-4,5,6,7-tetrahydroisoindoline-1-acetic acid.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][N:5]=1.Cl[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]3)[N:20]2[CH3:23])=[C:16]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:15]=1>CN(C=O)C>[I:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]4)[N:20]3[CH3:23])=[C:16]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)[N:15]=2)[N:5]=1
Reactant: Ic1n[nH]c2ccccc12
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3nc(I)c4ccccc43)nc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.5 eq) was added to 3-iodoindazole (0.5 g) in DMF (5 mL) and the reaction was stirred for 30 minutes at 0° C. 2-(1-((2-Chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol was subsequently added to the reaction mixture and heated in a Biotage microwave for 10 minutes at 180° C. The reaction was purified by flash column chromatography to afford 2-(1-((2-(3-iodo-1H-indazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.4 g) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=4[F:35])=[O:23])=[C:17]([F:36])[CH:16]=3)[CH:9]=[C:10]([C:11](=[O:14])[CH2:12]Br)[N:6]2[N:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[N:46]1([CH2:52][CH2:53][CH2:54][OH:55])[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>CS(C)=O>[NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=4[F:35])=[O:23])=[C:17]([F:36])[CH:16]=3)[CH:9]=[C:10]([C:11](=[O:14])[CH2:12][O:55][CH2:54][CH2:53][CH2:52][N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(C(=O)CBr)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Reactant: OCCCN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Nc1ncnn2c(C(=O)COCCCN3CCOCC3)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Temperature: 40 °C
Reaction time: 17 h
Yield: 16.6 %

Procedure:
To a stirred solution of Example 257 (200 mg, 0.351 mmol) in DMSO (1 mL), was added diisopropylethylamine (435 μL, 2.64 mmol) and 3-morpholin-4-ylpropan-1-ol (364 μL, 2.64 mmol) at rt. The reaction was allowed to stir at 40° C. for 17 hr. The mixture was allowed to cool and purified by preparative HPLC using a gradient elution from 10% to 70% acetonitrile to obtain 37 mg (17%) of the desired product. 1H-NMR (DMSO-d6) δ 9.62 (br s, 1H), 9.47 (br s, 1H), 8.65 (dd, J=2.4, 7.2 Hz, 1H), 8.23 (t, J=8.4 Hz, 1H), 7.92 (s, 1H), 7.54-7.47 (m, 1H), 7.42-7.38 (m, 1H), 7.31 (dd, J=2.1, 12.3 Hz, 1H), 7.22 (d, J=8.1 Hz, 1H), 6.88 (s, 1H), 4.24 (d, J=11.7 Hz, 2H), 4.05-3.96 (m, 4H), 3.86-3.77 (m, 4H), 3.43 (t, J=5.7 Hz, 2H), 3.24-3.20 (m, 2H), 1.91-1.85 (m, 2H); MS [M+H]+=634.2; LCMS RT=2.75 min.
Reaction SMILES: O1CCOCC1.Cl[C:8]1[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]2[CH2:17][CH2:16]2)[C:9]=1[NH2:18].C(=O)([O-])[O-].[Na+].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>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.O>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:17][CH2:16]3)[C:9]=2[NH2:18])=[CH:28][CH:27]=1
Reactant: Nc1c(Cl)ncnc1NC1CC1
Reactant: OB(O)c1ccc(Cl)cc1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1c(NC2CC2)ncnc1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
In a reactor carousel test tube which had been dried by heating and preheated to 100° C., the degassed diluent mixture dioxane (20 ml)/water (7 ml) was added to 6-chloro-N-cyclopropylpyrimidine-4,5-diamine (10 g, 54.1 mmol) and sodium carbonate (17.22 g, 162 mmol). 5 mol % of tetrakis(triphenylphosphine)palladium(0) and 4-chlorophenylboronic acid (108.2 mmol) were added, and the reaction mixture was stirred at 90° C. overnight. The solution was cooled, filtered and concentrated and the residue was recrystallised from acetonitrile.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].C(=O)C.N1C(O[BH3-])=NN=1.[Na+].C(Cl)Cl>ClCCCl.C(O)(=O)C>[CH2:2]([N:33]1[CH2:34][CH2:35][CH:30]([C:28]2[CH:27]=[CH:26][C:23]3[C:24]4[N:18]([CH:17]=[C:16]([C:15]5[N:11]([CH:8]([CH3:10])[CH3:9])[N:12]=[CH:13][N:14]=5)[N:25]=4)[CH2:19][CH2:20][O:21][C:22]=3[CH:29]=2)[CH2:31][CH2:32]1)[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Agent: CC=O
Agent: [BH3-]OC1=NN=N1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCN1CCC(c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)CC1
Yield: 12 %

Procedure:
To a stirred suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoro acetate (189 mg, 0.37 mmol) in DCE (3 mL) was added acetic acid (3 drops, catalytic) acetaldehyde (0.023 mL, 0.41 mmol) and sodium triazetoxyborohydride (94 mg, 0.44 mmol). After stirring for 2 h at RT DCM was added and the mixture washed with saturated aqueous sodium hydrogen carbonate, water and then brine before being dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 20% methanol in DCM) then freeze dried from methanol/water and triturated in petroleum ether to give 314 as a brown solid (18 mg, 12%). LCMS: RT=2.73 min, [M+H]+=407. 1H NMR 400 MHz (DMSO-d) δ: 8.32 (1H, d, J=8.29 Hz), 7.90 (2H, d, J=2.38 Hz), 7.06 (1H, d, J=8.41 Hz), 6.90 (1H, s), 5.90-5.89 (1H, m), 4.49 (4H, d, J=7.47 Hz), 2.97 (2H, d, J=10.98 Hz), 2.34 (2H, q, J=7.20 Hz), 1.95 (2H, t, J=11.47 Hz), 1.76 (2H, d, J=12.54 Hz), 1.72-1.54 (3H, m), 1.48 (6H, d, J=6.59 Hz), 1.02 (3H, t, J=7.20 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14](O)[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26]([CH:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:27])[CH3:24].CP(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([C:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])([C:26]([O:25][CH2:23][CH3:24])=[O:27])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[C:19]([CH3:21])([CH3:22])[CH3:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(O)CCC2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CP(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCCc2nc(C(C)(C)C)n(Cc3ccc(Cl)cc3)c21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of Intermediate 54 (82 mg) and triethylmethanetricarboxylate (0.11 mL) in anhydrous toluene (3 mL) and anhydrous tetrahydrofuran (3.00 mL) under a nitrogen atmosphere was added trimethylphosphine, 1M in toluene (0.52 mL). The reaction was then cooled to −78° C. and diisopropyl azodicarboxylate (0.11 mL) added dropwise via syringe over 1 min. The reaction was stirred at −78° C. under an atmosphere of nitrogen for 60 mins before being allowed to warm to ambient temperature and stirred for a further 16 hr. The reaction was concentrated in vacuo. The residue was taken up in dichloromethane (40 mL) and washed with water (40 mL), dried (hydrophobic frit) and concentrated in vacuo. The sample was loaded in dichloromethane and purified on silica 0-100% ethyl acetate-cyclohexane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product (100 mg). LC/MS MH+533, Rt 2.18 mins (5 min run).
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:11])[CH:8]=2)[C:3]1=O.[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([NH2:25])=[S:24])[CH2:15][CH2:14]1>C(O)C>[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][NH:22][C:23]2[S:24][C:2]3[CH2:10][C:9]4[CH:8]=[C:7]([F:11])[CH:6]=[CH:5][C:4]=4[C:3]=3[N:25]=2)[CH2:15][CH2:14]1
Reactant: O=C1c2ccc(F)cc2CC1Br
Reactant: NC(=S)NCCCN1CCOCC1
Solvent: CCO
Product: Fc1ccc2c(c1)Cc1sc(NCCCN3CCOCC3)nc1-2
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.7 %

Procedure:
3.5 g of 2-bromo-5-fluoro-1-indanone and 3.1 g of N-(3-morpholinopropyl)thiourea were added to 40 ml of ethanol. The resulting mixture was refluxed for 10 minutes, agitated for 24 hours at room temperature to precipitate crystals which were collected by filtration. The thus collected crystals were washed with ethanol, dried, incorporated with 40 ml of a 5% aqueous solution of NaOH, extracted with ethyl acetate, washed with water, dried, distilled at a reduced pressure and then recrystallized from ethyl acetate-isopropyl ether thereby to obtain 3.9 g of 2-(3-morpholinopropyl)amino-6-fluoro-8H-indeno[1.2-d]thiazole. The thus obtained compound had a melting point of 113° to 115° C. and the following analysis.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[F:22][C:23]1[CH:24]=[C:25]([N+:30]([O-:32])=[O:31])[CH:26]=[CH:27][C:28]=1F>C(OCC)(=O)C>[F:22][C:23]1[CH:24]=[C:25]([N+:30]([O-:32])=[O:31])[CH:26]=[CH:27][C:28]=1[N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CCN(c3ccccc3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 105 h
Yield: 96.33 %

Procedure:
50 ml of ethyl acetate, 13.5 ml of 4-phenyl piperazine, and 15.30 ml of diisopropyl ethyl amine were added into a 250 ml triple-neck flask. After magnetic stirring at room temperature, 9.0 ml of 3,4-difluoro-nitrobenzene was added. The reaction was carried out for 105 hours, followed by extraction with 150 ml of ethyl acetate for three times (150 ml×3). The extract was washed three times with saturated NaCl solution (150 ml×3), dried with anhydrous magnesium sulfate (MgSO4), and evaporated to dryness. An orange yellow solid was obtained which was recrystallized with a mixture of acetone and water in volumetric ratio of 9:1 to produce orange yellow crystals (23.66 g) with a yield of 96.33%.
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[CH2:3][C:4]1[N:8]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:7]=[C:6]([C:17]([OH:19])=O)[CH:5]=1.[NH2:22][C@@H:23]([CH3:40])[CH2:24][N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:37]=[C:36]([F:38])[C:33]([C:34]#[N:35])=[C:32]([Cl:39])[CH:31]=2)=[N:26]1>>[Cl:39][C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][N:25]([CH2:24][C@@H:23]([NH:22][C:17]([C:6]3[CH:5]=[C:4]([CH2:3][C:2]([OH:1])([CH3:21])[CH3:20])[N:8]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[N:7]=3)=[O:19])[CH3:40])[N:26]=2)[CH:37]=[C:36]([F:38])[C:33]=1[C:34]#[N:35]
Reactant: CC(C)(O)Cc1cc(C(=O)O)nn1COCC[Si](C)(C)C
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(CC(C)(C)O)n(COCC[Si](C)(C)C)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 5-(2-hydroxy-2-methylpropyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-pyrazole-3-carboxylic acid (1.59 mmol, 500 mg) and (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.59 mmol, 442 mg). The product was purified by flash-chromatography. Yield 295 mg. 1H-NMR (400 MHz; DMSO-d6): δ −0.13 (s, 9H), 0.68 (t, 2H), 1.06 (s, 3H), 1.08 (s, 3H), 1.20 (d, 3H), 2.61 (s, 2H), 3.40 (t, 2H), 4.23-4.42 (m, 3H), 4.51 (s, 1H), 5.54 (d, 1H), 5.68 (d, 1H), 6.72 (s, 1H), 7.01 (d, 1H), 7.84-7.87 (m, 2H), 7.96 (s, 1H), 8.40 (d, 1H). LC-MS: [M+1]=575.01.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21].[CH2:23]([CH:25]([NH2:28])[CH2:26][CH3:27])[CH3:24]>CS(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH:28][CH:25]([CH2:26][CH3:27])[CH2:23][CH3:24])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21]
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(Cl)cc1C
Reactant: CCC(N)CC
Solvent: CS(C)=O
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Temperature: 120 °C

Procedure:
A mixture of 4-chloro-6-methyl-2-(4-Chloro-2,6-dimethyl-phenoxy)-nicotinic acid methyl ester (77 mg, 0.226 mmol) and 1-ethyl-propyl-amine in DMSO was heated at 120° C. for 4 hr. The mixture was quenched with sat. ammonium chloride, water, brine and extracted with ethyl acetate. The organic layer was dried and concentrated to give 140 mg of yellow solid. 1HNMR(CDCl3) d 8.10(d,1H), 7.03(s,2H), 6.09(s,1H), 3.88(s,3H), 3.35(m,1H), 2.10(s,3H), 2.08(s,6H), 1.5-1.7(m,4H), 0.96(t,6H) ppm.