Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][CH:19]2[CH2:29][CH2:28][C:22]3([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH2:21][CH2:20]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[CH:13]=2)=[N:6][CH:7]=1.[C:30]([CH2:32][C:33](O)=[O:34])#[N:31].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl.CN(C)C=O.O>[Cl:1][C:2]1[C:3]([NH:18][CH:19]2[CH2:20][CH2:21][C:22]3([CH2:23][CH2:24][N:25]([C:33](=[O:34])[CH2:32][C:30]#[N:31])[CH2:26][CH2:27]3)[CH2:28][CH2:29]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[CH:13]=2)=[N:6][CH:7]=1
Reactant: N#CCC(=O)O
Reactant: Clc1cnc(Nc2cnn(CC3CC3)c2)nc1NC1CCC2(CCNCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCC(=O)N1CCC2(CCC(Nc3nc(Nc4cnn(CC5CC5)c4)ncc3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
To a solution of 5-chloro-N2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine (300.5 mg, 0.72 mmol), 2-cyanoacetic acid (92.2 mg, 1.08 mmol), HOAT (196.5 mg, 1.44 mmol) and EDCI (276.5 mg, 1.44 mmol) in a mixture of dichloromethane (20 mL) and N,N-dimethylformamide (5 mL) was added TEA (146.2 mg, 1.45 mmol). The mixture was stirred at room temperature for 1 h then diluted with water (50 mL), and extracted with DCM/MeOH (10/1, 50 mL×3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1) to give the product as a yellow solid (156.8 mg, 44.94%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:32])[N:13]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[C:14](=[O:23])[C:15]=2[C:16]([N:18]([CH2:20][CH2:21][OH:22])[CH3:19])=[O:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].[H-].[Na+].[Cl-].[NH4+]>O1CCCC1>[C:38]([O:37][C:35]([CH2:34][O:22][CH2:21][CH2:20][N:18]([CH3:19])[C:16]([C:15]1[C:14](=[O:23])[N:13]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[N:12]([CH3:32])[C:11]=1[C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)=[O:17])=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: CN(CCO)C(=O)c1c(-c2ccc(C(C)(C)C)cc2)n(C)n(-c2ccc(C#N)cc2)c1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(CCOCC(=O)OC(C)(C)C)C(=O)c1c(-c2ccc(C(C)(C)C)cc2)n(C)n(-c2ccc(C#N)cc2)c1=O
Temperature: 25 °C
Yield: 39.6 %

Procedure:
To a mixture of 200 mg of 3-(4-t-butylphenyl)-1-(4-cyanophenyl)-4-(N-hydroxyethyl-N-methyl-aminocarbonyl)-2-methyl-2H-pyrazol-5-one, 4 ml of tetrahydrofuran and 108 mg of t-butyl bromoacetate, 12.2 mg of sodium hydride was added at 0° C., and the resulting reaction solution was refluxed under heating for 3 days. After the reaction solution was cooled to room temperature, saturated aqueous ammonium chloride was added, and the reaction solution was extracted with chloroform. The extract was washed with 1N hydrochloric acid and saturated aqueous sodium chloride successively and dried over anhydrous sodium sulfate. The insolubles were filtered off, and the filtrate was concentrated. The resulting residue was recrystallized in chloroform-ether-hexane to give 100 mg of the title compound as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16]>>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH:16][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Br:1]
Reactant: CN(C)CCN
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Product: CN(C)CCNc1ccc([N+](=O)[O-])cc1Br

Procedure:
Prepared from 2-bromo-1-fluoro-4-nitro-benzene and N,N-dimethyl-ethylenediamine
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[N:17]([CH2:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:18](=[O:22])[N:19]([CH3:21])[N:20]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31].C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH:24]1([CH2:23][N:17]2[C:18](=[O:22])[N:19]([CH3:21])[N:20]=[C:16]2[CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:4]3[CH:3]=[C:2]([NH:1][C:30](=[O:32])[CH3:31])[CH:7]=[CH:6][CH:5]=3)[CH2:13][CH2:12]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1nc(CCN2CCN(c3cccc(N)c3)CC2)n(CC2CCCCC2)c1=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(N2CCN(CCc3nn(C)c(=O)n3CC3CCCCC3)CC2)c1
Reaction time: 1 h
Yield: 26.7 %

Procedure:
To a solution of 5-{2-[4-(3-aminophenyl)piperazino]ethyl}-4-(cyclohexylmethyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (D16; 450 mg, 1.129 mmol) in dry pyridine (5 mL), acetic anhydride (0.112 mL, 1.185 mmol) was added at room temperature. The reaction mixture was stirred for 1 h, toluene (30 mL) was added and the solvents were removed in vacuo to afford a light-brown solid. Purification by preparative LC-MS afforded 133 mg (27%) of the title compound as a light brown powder.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]([CH3:39])([CH3:38])[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=O)[CH2:31][CH2:30]1.[NH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([N:50]2[CH2:59][CH2:58][C:57]3[N:56]=[C:55]([CH3:60])[N:54]([CH2:61][C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)[C:53]=3[C:52]3[CH:68]=[CH:69][CH:70]=[CH:71][C:51]2=3)=[O:49])=[CH:44][C:43]=1[CH3:72].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:61]([N:54]1[C:53]2[C:52]3[CH:68]=[CH:69][CH:70]=[CH:71][C:51]=3[N:50]([C:48]([C:45]3[CH:46]=[CH:47][C:42]([CH2:41][NH:40][C:35]([CH:32]4[CH2:31][CH2:30][N:29]([CH2:28][CH2:27][C:26]([CH3:25])([CH3:39])[CH3:38])[CH2:34][CH2:33]4)=[O:37])=[C:43]([CH3:72])[CH:44]=3)=[O:49])[CH2:59][CH2:58][C:57]=2[N:56]=[C:55]1[CH3:60])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: CC(C)(C)CCN1CCC(C(=O)O)CC1
Reactant: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1CNC(=O)C1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
HBTU (175 mg, 0.46 mmol) was added to a solution of 1-(3,3-dimethyl-butyl)-piperidine-4-carboxylic acid (86 mg, 0.34 mmol) in DMF (5 ml). The mixture was stirred at room temperature for 2 h then (4-aminomethyl-3-methyl-phenyl)-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone from Example E121.2 (100 mg, 0.23 mmol) and DIEA (0.12 ml, 0.69 mmol) were added. The mixture was stirred at room temperature for 18 h then solvents were removed in vacuo and azeotroped with toluene. The residue was purified by flash chromatography on silica gel through an isolute (eluant; 5% methanol:95% dichloromethane then 10% methanol:90% dichloromethane) to give a yellow foam identified as the title compound (114 mg, 79%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[N:9]1([CH2:15][C@H:16]2[NH:20][C:19](=[O:21])[CH2:18][CH2:17]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([N:20]2[C@H:16]([CH2:15][N:9]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]3)[CH2:17][CH2:18][C:19]2=[O:21])=[CH:3][CH:4]=1
Reactant: O=C1CC[C@@H](CN2CCCCC2)N1
Reactant: Clc1ccc(Br)cn1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1CC[C@@H](CN2CCCCC2)N1c1ccc(Cl)nc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 44 %

Procedure:
A suspension of 5-bromo-2-chloropyridine a130 (0.75 g, 3.9 mmol, 1 eq), (5S)-5-(piperidin-1-ylmethyl)pyrrolidin-2-one a15 (0.85 g, 4.67 mmol, 1.2 eq), cesium carbonate (1.78 g, 5.46 mmol, 1.4 eq), Xanphos (0.17 g, 0.29 mmol, 0.075 eq), and tris(dibenzylideneacetone) dipalladium (0) (89 mg, 0.097 mmol, 0.025 eq) in dioxane (25 ml) is stirred under an argon atmosphere in a sealed tube for 12 h at 100° C. The mixture is left to cool to room temperature and filtered through a pad of Celite. The solid is washed with ethyl acetate and the resulting soluble fractions are combined and concentrated to dryness. The residue is taken up in ethyl acetate and washed twice with a saturated aqueous solution of sodium hydrogenocarbonate. The organic phase is then dried over magnesium sulfate and concentrated to afford 1.4 g of crude mixture. Purification by chromatography over silicagel (dichloromethane/methanol/ammonia gradient) affords 0.5 g of (5S)-1-(6-chloropyridin-3-yl)-5-(piperidin-1-ylmethyl)pyrrolidin-2-one a131.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[C:15]([OH:17])=O)=[CH:4][CH:3]=1.[CH3:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:20]([CH3:19])[C:15](=[O:17])[CH:14]([C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[OH:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(=O)O
Reactant: CNCc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(=O)N(C)Cc1ccccc1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-hydroxy-acetic acid and N-methyl-benzylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[NH2:16][C@@H:17]([C:19]([OH:21])=[O:20])[CH3:18].C([O-])([O-])=O.[Na+].[Na+].[N+](C1C=CC=C([N+]([O-])=O)C=1C(O)=O)([O-])=O>>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=1[C:6]([NH:16][C@H:17]([CH3:18])[C:19]([OH:21])=[O:20])=[O:7])([O-:3])=[O:2]
Reactant: O=C(Cl)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: C[C@@H](N)C(=O)O
Agent: O=C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@@H](NC(=O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-])C(=O)O

Procedure:
The reaction of 2,6-dinitrobenzoyl chloride (prepared from 2,6-dinitrobenzoic acid, 1.4 g and SOCl2, 15 mL) with D-alanine (0.7 g, 7.92 mmol) in the presence of Na2CO3 (0.83 g, 7.92 mmol) as described in intermediate 2 gave the title compound as a pale brown color solid (1.58 g, 85%), mp 202-204° C. 1H NMR (400 MHz, DMSO-d6): δ 12.79 (1H, br s), 9.24 (1H, d, J=7.6 Hz), 8.45 (2H, d, J=8.4 Hz), 7.93 (1H, t, J=8.4 Hz), 4.48 (1H, pentet, J=7.3 Hz), 1.33 (3H, d, J=7.2 Hz); LC-MS (negative ion mode): m/z 282 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[N:4]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=3)[N:23]=[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:21]=2[CH3:37])[CH2:3]1.Cl[C:40]1[C:45]([Cl:46])=[CH:44][N:43]=[C:42]([NH2:47])[N:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:46][C:45]1[C:40]([C:7]2[CH:6]=[C:5]3[C:10]([C:2]([CH3:38])([CH3:1])[CH2:3][N:4]3[C:20]3[C:29]4[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[C:21]=3[CH3:37])=[CH:9][CH:8]=2)=[N:41][C:42]([NH2:47])=[N:43][CH:44]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: Nc1ncc(Cl)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(-c3nc(N)ncc3Cl)cc21
Temperature: 120 °C

Procedure:
Prepared according to procedure P using 4-(3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl)-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (68.7 mg, 0.14 mmol) (described herein), 4,5-dichloropyrimidin-2-amine (22.1 mg, 0.14 mmol), bis(triphenylphosphine)palladium(ii) chloride (9.5 mg, 0.013 mmol), and sodium carbonate (42.9 mg, 0.41 mmol) in 1,4-dioxane (2.9 mL) and water (0.73 mL), and heating in a microwave at 120° C. for 60 min. After purification 5-chloro-4-(1-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-pyrimidinamine was obtained as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.74 (1H, dd, J=3.9, 1.2 Hz), 8.19 (1H, s), 7.76-7.99 (4H, m), 7.35-7.42 (1H, m), 7.28-7.30 (1H, m), 7.23-7.27 (1H, m), 7.16 (1H, dd, J=7.4, 1.2 Hz), 6.36 (1H, s), 4.94-5.21 (2H, br. s.), 3.76-3.88 (2H, m), 2.37 (3H, s), 1.58 (3H, s), 1.52 (3H, s). Mass Spectrum (ESI) m/e=511 (M+1).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:35]=[CH:34][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:20]=[C:19]([CH:21]([N:23]4C(=O)C5C(=CC=CC=5)C4=O)[CH3:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].O.NN>ClCCl.C(O)C>[CH:1]([O:4][C:5]1[CH:35]=[CH:34][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:20]=[C:19]([CH:21]([NH2:23])[CH3:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(Oc2ccc(-c3cc(C(C)N4C(=O)c5ccccc5C4=O)on3)cc2)cc1
Agent: NN
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CC(C)Oc1ccc(Oc2ccc(-c3cc(C(C)N)on3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 17E (168 g, 3.59 mmol) in dichloromethane (25 ml) and ethanol (2.5 mL) was added hydrazine monohydrate (100 mL, 20.6 mmol). The mixture was stirred at room temperature overnight. The reaction was filtered and the filtrate concentrated. The residue was dissolved in dichloromethane again and filtered. The filtrate was concentrated to give the amine as a colorless oil (1.20 g, theory: 100%).
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([NH2:29])[CH2:27][CH3:28])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([NH:29][CH2:16][CH2:15][C:2]2([OH:1])[CH2:3][CH2:4][C:5]3([O:10][CH2:9][C:8]([CH3:11])([CH3:12])[CH2:7][O:6]3)[CH2:13][CH2:14]2)[CH2:27][CH3:28])=[CH:22][CH:21]=1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Reactant: CC[C@H](N)c1ccc(OC)cc1
Product: CC[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(OC)cc1
Yield: 53 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(4-methoxy-phenyl)-propylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 53% of theory; LC (method 5): tR=1.02 min; Mass spectrum (ESI+): m/z=392 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:17])=O)=[CH:6][C:5]=1[O:20][CH3:21])#[N:2].O=P(Cl)(Cl)Cl>>[CH3:21][O:20][C:5]1[CH:6]=[C:7]([C:8]2[O:17][C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C:11]=3[N:10]=2)[CH:18]=[CH:19][C:4]=1[CH2:3][C:1]#[N:2]
Reactant: COc1cc(C(=O)NC2CCCCC2=O)ccc1CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(-c2nc3c(o2)CCCC3)ccc1CC#N

Procedure:
4-(cyanomethyl)-3-methoxy-N-(2-oxocyclohexyl)benzamide (0.8 g, 2.8 mmol) was treated with POCl3 (5 mL) at reflux for 1 h. The resulting mixture was concentrated and dissolved in dichloromethane (50 mL), washed with sat. NaHCO3 (3×15 mL) and sat. brine (3×15 mL), dried (MgSO4), and concentrated in vacuo. The crude residue was chromatographed on silica gel, eluting with 2:1 hexanes:EtOAc to afford the desired compound, [2-methoxy-4-(4,5,6,7-tetrahydro-1,3-benzoxazol-2-yl)phenyl]acetonitrile, the desired compound, as white solid. 1H NMR (CDCl3, 300 MHz) δ 7.58 (dd, 1H), 7.53 (m, 1H), 7.42 (d, 1H), 3.95 (s, 3H), 3.72 (s, 2H), 2.71 (m, 2H), 2.62 (m, 2H), 1.87 (m, 4H). MS (ESI) 269 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([O:31][C:32]3[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=3[F:39])[CH:26]=[N:25]2)[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@H:17]3[CH2:21][O:20]C(C)(C)[O:18]3)[N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH:1]1([CH2:6][CH:7]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([O:31][C:32]3[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=3[F:39])[CH:26]=[N:25]2)[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@H:17]([OH:18])[CH2:21][OH:20])[N:12]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OC[C@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(Oc4c(F)cccc4F)cc3=O)n2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: O=C(Nc1ccn(C[C@H](O)CO)n1)C(CC1CCCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide (142.4 mg, 0.26 mmol) in methanol (2.6 mL, 0.10M) at 25° C. was treated with para-toluenesulfonic acid monohydrate (7.7 mg, 0.04 mmol). The reaction was stirred at 25° C. overnight. After this time, the reaction was concentrated in vacuo. Silica gel column chromatography (AnaLogix 8 g, 1-10% methanol/methylene chloride) afforded 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((S)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (110.3 mg, 84%) as an off-white solid as a mixture of diastereomers; ES+-HRMS m/e calcd for C24H27N5O5F2 [M+H+] 504.2053 found 504.2053. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.18 (m, 1H) 1.22-1.76 (m, 8H) 1.88-2.01 (m, 1H) 2.17-2.35 (m, 1H) 3.19-3.32 (m, 2H) 3.70-3.80 (m, 1H) 3.82-3.93 (m, 1H) 4.09 (dd, J=13.3, 4.4 Hz, 1H) 4.70 (t, J=5.5 Hz, 1H) 4.94 (dd, J=5.5, 2.5 Hz, 1H) 5.40-5.51 (m, 1H) 6.03 (d, J=3.0 Hz, 1H) 6.36 (d, J=2.1 Hz, 1H) 7.35-7.43 (m, 2H) 7.44-7.51 (m, 1H) 7.53 (d, J=2.1 Hz, 1H) 8.28 (d, J=3.0 Hz, 1H) 10.83 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:16])[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[O:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][O:1][C:2]1[C:3](=[O:16])[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[O:6][CH:7]=1
Reactant: O=c1cc(COC2CCCCO2)occ1O
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=c1cc(COC2CCCCO2)occ1OCCCCBr
Temperature: 80 °C
Yield: 71 %

Procedure:
The compound was prepared according to example 11 using 5-hydroxy-2-(tetrahydro-pyran-2-yloxymethyl)-4H-pyran-4-one (1.00 g, 4.42 mmol), Cs2CO3 (1.58 g, 4.86 mmol) and 1,4-dibromobutane (2.00 mL, 16.7 mmol). The sealed tube was heated at 80° C. for 2 h 30. A white solid 2 was obtained (1.14 g, 71% yield).
Reaction SMILES: Br[C:2]1[C:3]([Cl:8])=[N:4][N:5]([CH3:7])[CH:6]=1.[Cl:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[C:11]=1[C@H:19]([C:21]1[C:29]2[C:24](=[N:25][CH:26]=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:28]=2)[NH:23][CH:22]=1)[CH3:20].C(=O)([O-])[O-].[K+].[K+]>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.O1CCOCC1>[Cl:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[C:11]=1[C@H:19]([C:21]1[C:29]2[C:24](=[N:25][CH:26]=[C:27]([C:2]3[C:3]([Cl:8])=[N:4][N:5]([CH3:7])[CH:6]=3)[CH:28]=2)[NH:23][CH:22]=1)[CH3:20]
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Cn1cc(Br)c(Cl)n1
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: C1COCCO1
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cn(C)nc3Cl)cc12
Temperature: 100 °C

Procedure:
A solution of 4-bromo-3-chloro-1-methyl-1H-pyrazole (0.0136 g, 0.0697 mmol), 3-[(S)-1-(2-chloro-3-fluoro-6-methoxy-phenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.020 g, 0.046 mmol), potassium carbonate (0.0193 g, 0.139 mmol) and Pd(PPh3)4 (5.37 mg, 0.00464 mmol) in previously degassed 4:1 dioxane:water (1.0 mL) was evacuated and charged with N2 (2×) and heated under microwave conditions [Biotage, 100° C., 30 min, high absorption]. This was purified by Gilson HPLC. The combined fractions were concentrated in vacuo resulting in the title compound as off-white solid. 1H NMR (400 MHz, CD3OD): δ=1.80 (d, J=7.3 Hz, 3H), 3.60-3.71 (m, 2H), 3.87 (s, 3H), 5.11 (q, J=7.1 Hz, 1H), 6.89 (dd, J=4.2, 9.0 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 7.34 (d, J=1.3 Hz, 2H), 7.72-7.77 (m, 2H), 7.80 (s, 2H), 8.20 (d, J=1.8 Hz, 2H). MS (ES+): m/z 419.05, 421.03 (76, 24) [MH+]. HPLC: tR=1.84 min (polar—3 min, TOF)
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][N:16]2[CH:22]=1.[CH:23]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([NH:21][C:28]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:29])[CH:18]=[CH:17][N:16]2[CH:22]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(N)cc2n1
Reactant: O=C(O)C1CCCC1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(NC(=O)C3CCCC3)cc2n1
Yield: 10 %

Procedure:
As described for Example 47, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridin-7-ylamine (92 mg, 0.32 mmol) was converted, using cyclopentanecarboxylic acid instead of 3-pyridylacetic acid, to the title compound (11.1 mg, 10%) which was obtained as an off-white solid. MS: m/e=387.1 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][NH:9][C:8]2=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([N:10]2[CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8](=[O:18])[NH:9]2)=[O:28])=[CH:22][C:21]=1[C:29]([F:30])([F:31])[F:32]
Reactant: O=C1NNC(c2ccccc2)C1c1ccccc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=C1NN(C(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)C(c2ccccc2)C1c1ccccc1
Reaction time: 2.3 h
Yield: 85.3 %

Procedure:
4,5-Diphenyl-3-pyrazolidinone (3.00 g, 12.6 mmol) was dissolved in 40 mL THF under nitrogen, then a solution of 4-chloro-3-trifluoromethylphenylisocyanate (2.87 g, 13.0 mmol, 1.03 eq.) in 10 mL THF added over 2 min. After 2.3 hr, solvent was removed in vacuo, and the residue triturated with 25 mL toluene. The resulting solid was pulverized, washed twice with toluene, and dried in vacuo at 65° C. to give 4.94 g (85%) white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[C:3]=1[CH2:14]O.S(Cl)([Cl:18])=O>>[Cl:18][CH2:14][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([Cl:13])[CH:5]=2)[C:10]([Cl:12])=[CH:11][C:2]=1[Cl:1]
Reactant: O=S(Cl)Cl
Reactant: OCc1c(Cl)cc(Cl)c2ccc(Cl)cc12
Product: ClCc1c(Cl)cc(Cl)c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2,4,7-Trichloronaphthalen-1-yl)methanol (1.0 g, 3.8 mmoles) was added portionwise to thionyl chloride (10 ml) with cooling (ice bath). The reaction mixture was stirred at room temperature for 30 minutes and at reflux for 2 hours and then concentrated to dryness in vacuo. The oily residue was taken up in methylene chloride and the solution dried over MgSO4. The solution was filtered and concentrated in vacuo to give 1.0 g of the title compound.