Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][N:14]=[C:8]3[CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:15]#[N:16].Cl.[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH2:21].Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCCO)C>[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH:21][C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][N:14]=[C:8]3[CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:15]#[N:16]
Reactant: N#Cc1cnc2c(c1Cl)C=C1N=CN=C1C2
Reactant: COc1ccc(Cl)c(N)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1ccc(Cl)c(Nc2c(C#N)cnc3c2C=C2N=CN=C2C3)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
A mixture of 0.2 g (0.87 mmol) of 8-chloroimidazo[4,5-g]quinoline-7-carbonitrile, 0.22 g (1.04 mmol) of 2-chloro-5-methoxyaniline hydrochloride and 0.1 g (0.87 mmol) of pyridine hydrochloride in 5.0 mL of 2-ethoxyethanol is heated at reflux temperature for 1 hour, cooled to room temperature, poured into a saturated solution of sodium bicarbonate and stirred for 0.5 hour. The solid is collected by filtration, washed with water and dried. The solid is purified by silica gel chromatography utilizing a gradient of methylene chloride/methanol (97:3 to 90:10) to yield 0.19 g of 8-(2-chloro-5-methoxy-phenylamino)imidazo[4,5-g]quinoline-7-carbonitrile as beige solid, mp 296–298° C.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][N:7]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C@H:6]([C:22]([C:24]2[N:25]=[CH:26][N:27]3[CH:31]=[CH:30][S:29][C:28]=23)=[O:23])[CH2:5]1)=[N+:2]=[N-:3].[CH2:32]([Sn:36](Cl)([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH3:35].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>>[N:1]([C@@H:4]1[CH2:8][N:7]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C@H:6]([C:22]([C:24]2[N:25]=[CH:26][N:27]3[CH:31]=[C:30]([Sn:36]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:32][CH2:33][CH2:34][CH3:35])[S:29][C:28]=23)=[O:23])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)c2ncn3ccsc23)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)[C@@H]3C[C@H](N=[N+]=[N-])CN3C(=O)OCc3ccc([N+](=O)[O-])cc3)c2s1

Procedure:
The title compound (321 mg) was prepared in substantially the same manner as in step c) of Synthesis Example 1, except that 585 mg of 7-[(2S,4S)-4-azido-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]carbonylimidazo[5,1-b]thiazole, 0.396 ml of tri-n-butylstannyl chloride, and 2.8 ml of a 1.0 N lithium bis(trimethylsilyl)amide/THF solution were used as the starting materials.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)[CH:9]=[CH:10][CH:11]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:20][C:18]1[CH:17]=[CH:16][N:15]2[CH:21]=[C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:7]=3)[N:13]=[C:14]2[CH:19]=1
Reactant: C1CCNCC1
Reactant: Cc1ccn2cc(-c3cccc(OCCCCl)c3)nc2c1
Product: Cc1ccn2cc(-c3cccc(OCCCN4CCCCC4)c3)nc2c1
Temperature: 25 °C

Procedure:
The product of Step C (271 mg) and piperidine (2.0 mL) were heated at 100° C. for 2 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous portion was extracted with a fresh portion of ethyl acetate (10 mL) and the organic portions combined and washed with brine (10 mL). The organic portions were dried over magnesium sulfate, filtered and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (193 mg). 1H-NMR (CD3OD) 8.27 (d, J=7.0 Hz, 1H), 8.08 (s, 1H), 7.46 (m, 2H), 7.31 (m, 2H), 6.88 (m, 1H), 6.76 (m, 1H), 4.09 (t, J=6.0 Hz, 2H), 2.58 (m, 6H), 2.42 (s, 3H), 2.04 (m, 2H), 1.65 (m, 4H), 1.51 (m, 2H).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][O:11][C:12](=[O:49])[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][C@@H:19]1[C@@H:23](/[CH:24]=[CH:25]/[C@@H:26]([O:34]C2CCCCO2)[C:27]([CH3:33])([CH3:32])[CH2:28][CH2:29][CH2:30][CH3:31])[C@H:22]([O:41]C2CCCCO2)[CH2:21][C@@H:20]1O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH3:10][O:11][C:12](=[O:49])[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][C@@H:19]1[C@@H:23](/[CH:24]=[CH:25]/[C@@H:26]([OH:34])[C:27]([CH3:33])([CH3:32])[CH2:28][CH2:29][CH2:30][CH3:31])[C@H:22]([OH:41])[CH2:21][C@H:20]1[F:7]
Reactant: CCCCC(C)(C)[C@@H](/C=C/[C@@H]1[C@@H](CC/C=C\CCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC(C)(C)[C@H](O)/C=C/[C@@H]1[C@@H](CC/C=C\CCC(=O)OC)[C@H](F)C[C@H]1O
Temperature: -70 °C
Reaction time: 3.5 h

Procedure:
0.56 ml of diethylaminosulfur trifluoride (DAST) is instilled in a solution of 2.05 g of (4Z,13E)-(9S,11R,15R)-9-hydroxy-16,16-dimethyl-11,15-bis-(tetrahydropyran-2-yloxy)-4,13-prostadienoic acid methyl ester in 43 ml of methylene chloride and 1.1 ml of pyridine at −70° C. and stirred for 3.5 hours at −70° C. Then it is added to 200 ml of 5% sodium bicarbonate solution cooled to 0° C. and allowed to stir vigorously for 10 minutes. Then it is extracted several times with methylene chloride, the extract is washed with water, dried over MgSO4 and concentrated by evaporation in a vacuum. The residue is stirred for 24 hours at 20° C. with 60 ml of a mixture of acetic acid/water/tetrahydrofuran (65/35/10), concentrated by evaporation in a vacuum after addition of toluene and the raw product is purified by chromatography on silica gel with toluene/0-10% isopropanol. 306 mg of the title compound is obtained as oil.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[Cl:5][C:6]1[N:11]=[C:10](Cl)[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][N:7]=1>CCO>[Cl:5][C:6]1[N:11]=[C:10]([S:1][C:2]#[N:3])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][N:7]=1
Reactant: N#C[S-]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: [K+]
Solvent: CCO
Product: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
(compound known, e.g. WO 2003/032994) Potassium thiocyanate (0.97 g, 10 mM) was added to a solution of 2,4-dichloro-5-nitropyrimidine (1.94 g 10, mM) in EtOH (40 mL) cooled to 0° C. via an ice bath. The solution was stirred at 0° C. for 30 min, then the bath was removed and the resulting suspension allowed to come to RT over 60 min, when water (100 mL) was added. The precipitate was collected via filtration, washed with ice cold water, dissolved with DCM, dried (MgSO4), filtered and evaporated to yield the titled compound (1.7 g). 1H-NMR (300 MHz, CDCl3) δ 9.4 (s, 1H).
Reaction SMILES: [CH:1]([N:4]1[CH:12]=[C:11]2[C:6]([C:7](=[O:25])[NH:8][C:9]3([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH2:10]2)=[N:5]1)([CH3:3])[CH3:2].[ClH:26]>C(OCC)(=O)C.O1CCOCC1>[ClH:26].[CH:1]([N:4]1[CH:12]=[C:11]2[C:6]([C:7](=[O:25])[NH:8][C:9]3([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[CH2:10]2)=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cc2c(n1)C(=O)NC1(CCN(C(=O)OC(C)(C)C)CC1)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)n1cc2c(n1)C(=O)NC1(CCNCC1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 2′-isopropyl-7′-oxo-2′,4′,6′,7′-tetrahydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridine]-1-carboxylate (130 mg, 0.37 mmol) in ethyl acetate (5 mL) was added 4 M hydrochloric acid (2 mL) in 1,4-dioxane. The reaction mixture was stirred 3 hours at room temperature, the volatiles were removed under reduced pressure and the resultant residue was triturated with 10 mL heptane. The solid was dried under reduced pressure to yield 2′-isopropyl-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one hydrochloride (105 mg) as an off-white solid. +ESI (M+H) 249.1; 1H NMR (500 MHz, DMSO-d6, δ): 7.91 (s, 1H) 7.69 (s, 1H) 4.48-4.62 (m, 1H) 3.02-3.28 (m, 4H) 2.78 (s, 2H) 1.74-1.89 (m, 4H) 1.41 (d, J=6.59 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[N:6][CH:5]=[C:4]([NH2:9])[N:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>COC(OC)C>[NH2:1][C:2]1[C:7]([Br:8])=[N:6][CH:5]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[N:3]=1
Reactant: Nc1cnc(Br)c(N)n1
Reactant: CC(=O)OC(C)=O
Agent: COC(C)OC
Product: CC(=O)Nc1cnc(Br)c(N)n1

Procedure:
A mixture of 2,6-diamino-3-bromopyrazine (10.509, 0.056 mole) in dry 1,1-dimethoxyethane (168 ml) and acetic anhydride (7.91 ml, 8.56 g, 0.084 mole) was refluxed under nitrogen for 2.50 hrs. The cooled mixture was evaporated in vacuo. The residue was triturated with ether, filtered and dried in vacuo Yield 10.31 g (80%), M.p. 218-221° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.CCN(C(C)C)C(C)C.Br[C:19]1[C:28]2[C:23](=C[CH:25]=[C:26](OC)[N:27]=2)[N:22]=[CH:21]C=1N>CN(C)C=O>[CH3:19][C@@H:28]1[CH2:23][N:22]([CH3:21])[CH2:25][CH2:26][N:27]1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1
Reactant: COc1ccc2ncc(N)c(Br)c2n1
Reactant: Nc1cc(Cl)ncn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(C)CCN1c1cc(N)ncn1
Temperature: 220 °C
Yield: 23.8 %

Procedure:
A mixture of 6-chloro-4-pyrimidinamine (200 mg, 1.544 mmol), Hunig's base (1.2 ml, 6.95 mmol) and (3R)-1,3-dimethylpiperazine (Ref.: WO2009061879 (A1)) (433 mg, 2.316 mmol) in N,N-dimethylformamide (DMF) (2 ml) was heated to 220° C. via a microwave reactor for 15 min. The reaction mixture was purified by RP-HPLC to yield 6-[(2R)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinamine (76 mg, 0.367 mmol, 24% yield). MS (ES+) m/z 208.0 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:17]=[N:16][N:15]([CH3:18])[C:14]=3[C:19]([OH:21])=O)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.Cl.Cl.[CH3:31][N:32]1[CH2:37][CH2:36][CH2:35][CH:34]([NH2:38])[CH2:33]1>>[CH3:18][N:15]1[C:14]([C:19](=[O:21])[NH:38][CH:34]2[CH2:35][CH2:36][CH2:37][N:32]([CH3:31])[CH2:33]2)=[C:13]([NH:12][C:10]([C:8]2[C:7]([NH:22][C:23]3[CH:28]=[N:27][CH:26]=[N:25][CH:24]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:9]=2)=[O:11])[CH:17]=[N:16]1
Reactant: CN1CCCC(N)C1
Reactant: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)O
Agent: Cl
Product: CN1CCCC(NC(=O)c2c(NC(=O)c3nc(C4CC4)cnc3Nc3cncnc3)cnn2C)C1

Procedure:
The product was obtained starting from 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid (25 mg, 66 μmol; example 236, step 3) and 1-methyl-piperidin-3-ylamine dihydrochloride (12 mg, 66 μmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (11 mg, 33%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[CH:5][C:6]([N+:17]([O-:19])=[O:18])=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=1.[CH:24]([C:27]1[CH:28]=[CH:29][C:30]([O:36][CH3:37])=[C:31](B(O)O)[CH:32]=1)([CH3:26])[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1>[CH:24]([C:27]1[CH:28]=[CH:29][C:30]([O:36][CH3:37])=[C:31]([C:7]2[CH:8]=[C:3]([O:2][CH3:1])[C:4]([C:20]([F:23])([F:22])[F:21])=[CH:5][C:6]=2[N+:17]([O-:19])=[O:18])[CH:32]=1)([CH3:26])[CH3:25]
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])cc1C(F)(F)F
Reactant: COc1ccc(C(C)C)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)C)cc1-c1cc(OC)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
Trifluoromethanesulfonic acid 5-methoxy-2-nitro-4-trifluoromethyl-phenyl ester (2.6 g) is dissolved in 1,4-dioxane (20 ml) and thereto is added 5-isopropyl-2-methoxybenzene boronic acid (1.5 g), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (575 mg) and cesium carbonate (3.44 g), and the mixture is stirred under nitrogen atmosphere at 80° C. overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and a saturated aqueous sodium bicarbonate solution, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=49:1→17:3) to give 5′-isopropyl-5,2′-dimethoxy-2-nitro-4-trifluoromethyl-biphenyl (2.35 g). MS (m/z): 370 [M+H]+
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:4]([CH:5]=[CH:6][C:7](=[O:20])[C:8]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[CH:3]=1.[Br-].[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH2:25][Zn+]>C1COCC1.C(OCC)(=O)C.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>[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH2:25][C:2]1[CH:11]=[CH:10][C:9]2[N:4]([CH:5]=[CH:6][C:7](=[O:20])[C:8]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[CH:3]=1
Reactant: Fc1ccc(C[Zn+])c(F)c1
Reactant: O=c1ccn2cc(Br)ccc2c1-c1c(F)cccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1ccn2cc(Cc3ccc(F)cc3F)ccc2c1-c1c(F)cccc1F
Temperature: 90 °C

Procedure:
To a solution of 7-bromo-1-(2,6-difluorophenyl)-2H-quinolizin-2-one (100 mg, 0.3 mmole) was added 2,4-difluorobenzylzincbromide (0.5 N in THF, 1.2 ml), and tetrakis (15 mg) in THF. The mixture was heated to 90° C. until reaction complete. The mixture was diluted with ethyl acetate, washed with 1N HCl, brine and dried over MgSO4. Upon concentration, the mixture was purified by gel chromatography (100% ethyl acetate) to yield the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])([NH:25][C:26](=[O:35])[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[C:17]1=[O:43])=[O:14])(C)(C)C>C(Cl)Cl>[Cl:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[Cl:33])[C:26]([NH:25][C:18]1([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]([CH2:15][C:13]([OH:14])=[O:12])[C:17]1=[O:43])=[O:35]
Reactant: CCOC(=O)CCC1(NC(=O)c2ccc(Cl)c(Cl)c2)C(=O)N(CC(=O)OC(C)(C)C)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCC1(NC(=O)c2ccc(Cl)c(Cl)c2)C(=O)N(CC(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.9 %

Procedure:
5 ml of trifluoroacetic acid was added to a solution of 700 mg of ethyl 3-[1-(t-butoxycarbonylmethyl)-3-(3,4-dichlorobenzoylamino)-2,3-dihydro-2-oxo-1H-indol-3-yl]propionate in methylene chloride (20 ml). The mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated to dryness under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to afford 651 mg of 2-[3-(3,4-dichlorobenzoylamino)-2,3-dihydro-3-(2-ethoxycarbonylethyl)-2-oxo-1H-indol-1-yl]acetic acid as colorless prism crystals. Melting point: 219° to 220° C., IR (Nujol) (cm-1): 3280, 1735, 1720, 1705, 1670, 1610, FAB-MS (m/z): 481 & 479 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:21]1[CH:22]=[CH:23][N:24]2[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][C:25]=12.C(N(CC)C(C)C)(C)C>C(#N)C>[N:21]1[CH:22]=[CH:23][N:24]2[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:2]3[C:3]4[CH2:11][N:10]([C:12]5[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=5[C:14]#[N:15])[CH2:9][CH2:8][C:4]=4[N:5]=[CH:6][N:7]=3)=[CH:26][C:25]=12
Reactant: NCc1ccn2ccnc2c1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(NCc4ccn5ccnc5c4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (300 mg, 1.05 mmol) and imidazo[1,2-a]pyridin-7-ylmethanamine (400 mg, 2.31 mmol) in acetonitrile (10 mL) and N,N-diisopropylethylamine (1.0 mL, 5.7 mmol) was subjected to microwave irradiation at 185° C. for 2.5 h. The reaction mixture was concentrated and purified by semi-preparative HPLC (100×20.2 mm, C18 column; 30-60% CH3CN-water [10 mM Et2NH]) to yield a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:25]([CH:29]1[CH2:34][CH2:33][CH:32](OS(C)(=O)=O)[CH2:31][CH2:30]1)([CH3:28])([CH3:27])[CH3:26].CC(=O)CC>CC(O)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:32]3[CH2:33][CH2:34][CH:29]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:30][CH2:31]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc2C1
Reactant: CC(C)(C)C1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2cc(OC3CCC(C(C)(C)C)CC3)ccc2C1
Yield: 58.6 %

Procedure:
A mixture of 6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.1 g, 4.4 mmol), cesium carbonate (4.3 g, 13 mmol), and methanesulfonic acid 4-tert-butyl-cyclohexyl ester (2.2 g, 8.8 mmol). in t-BuOH (12 mL) and 2-butanone (6.0 mL) was heated in a sealed vial at 100° C. overnight. The mixture was partitioned between water and ether. The organic phase was washed with water, dried over MgSO4, filtered and concentrated. The residue was purified via a silica gel column eluted with EtOAc in hexanes from 0 to 30% to give white precipitate (1.0 g, yield: 58%). 1H NMR (400 MHz, CDCl3) δ 6.99 (d, 1H), 6.74 (dd, 1H), 6.67 (d, 1H), 4.49 (s, 2H), 4.07 (m, 1H), 3.61 (s, 2H), 2.78 (m, 2H), 2.18 (d, 2H), 1.85 (d, 2H), 1.48 (s, 9H), 1.37 (m, 2H), 1.18-1.00 (m, 3H), 0.87 (s, 9H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1)=[N+:2]=[N-:3].Cl.[NH2:14][OH:15].C(N(CC)CC)C>CO>[OH:15][NH:14][C:9]([C:8]1[CH:7]=[N:6][C:5]([CH2:4][N:1]=[N+:2]=[N-:3])=[CH:12][CH:11]=1)=[NH:10]
Reactant: NO
Reactant: N#Cc1ccc(CN=[N+]=[N-])nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: [N-]=[N+]=NCc1ccc(C(=N)NO)cn1
Temperature: 65 °C
Yield: 100 %

Procedure:
To a solution of the azide of Example 51 (11-3) (6.46 g, 40.6 mmol) in methanol (100 ml) was added hydroxylamine hydrochloride (3.95 g, 56.84 mmol), followed by triethylamine (9.6 ml). The solution was heated to 65° C. for four hours. The solvent was removed under reduced pressure and the remaining residue was extracted with ethylacetate (300 ml) and water (100 ml). The water layer was re-extracted with ethylacetate (2×200 ml). The combined organic extracts were washed with brine (2×100 ml), dried over MgSO4 and evaporated to yield the title product (11-4) (7.8 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C:9]2=[O:14])[CH:7]=1.[S:32]1(=[O:38])(=[O:37])[CH2:36][CH2:35][CH2:34][NH:33]1>>[O:37]=[S:32]1(=[O:38])[CH2:36][CH2:35][CH2:34][N:33]1[C:2]1[CH:3]=[CH:4][C:5]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C:9]2=[O:14])[CH:7]=1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Cl)cc3N3CCN(C)C3=O)CC2)nc1C
Reactant: O=S1(=O)CCCN1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N3CCN(C)C3=O)CC2)nc1C
Yield: 41.2 %

Procedure:
Using 1-{5-chloro-2-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-methylimidazolidin-2-one (57 mg) described in Preparation Example 259 and isothiazolidine 1,1-dioxide (24 mg) and by the reaction and treatment in the same manner as in Example 666, the title compound (28 mg) was obtained.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C@@H:13]2[CH2:15][C@H:14]2[CH2:16][NH2:17])=[N:5]1.C(N(CC)CC)C.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>O1CCCC1>[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:17][CH2:16][C@@H:14]2[CH2:15][C@H:13]2[C:10]2[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=2)=[N:5][N:4]([CH3:3])[CH:12]=3)=[O:31])=[CH:28][CH:27]=1
Reactant: Cn1cc2c([C@@H]3C[C@H]3CN)cccc2n1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1cc2c([C@@H]3C[C@H]3CNC(=O)c3ccc(Br)cc3)cccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a solution of 1-[(1R,2R)-2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methanamine dihydrochloride (200 mg, 0.729 mmol) and triethylamine (407 μL, 2.92 mmol) in tetrahydrofuran (7 mL) was added 4-bromobenzoyl chloride (192 mg, 0.875 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→90/10) to give the title compound (247 mg, yield 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([F:13])=[C:11]2[C:6]([C:7](=[O:14])[CH2:8][O:9][CH2:10]2)=[CH:5][CH:4]=1.[F:15][C:16]([F:23])([F:22])[C:17](OCC)=[O:18].C[O-].[Na+].CO.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([F:13])=[C:11]2[C:6]([C:7](=[O:14])[CH:8]([C:17](=[O:18])[C:16]([F:23])([F:22])[F:15])[O:9][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1F)COCC2=O
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1F)COC(C(=O)C(F)(F)F)C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
A solution of 7-methoxy-8-fluoroisochroman-4-one from Step 2 (370 mg, 1.76 mmol) and ethyl trifluoroacetate (290 mg, 2.04 mmol) in 8 mL of anhydrous tetrahydrofuran was treated with a solution of 25% sodium methoxide in methanol (570 mg, 2.64 mmol). The solution was stirred at room temperature for 16 hours, treated with excess 3N hydrochloric acid, and extracted with ether. The ethereal extract was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford 450 mg (88%) of pure 7-methoxy-8-fluoro-3-(trifluoroacetyl)isochroman-4-one which was used directly in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][N:12]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:44][O:45][C:46]1[C:47]2[N:60]=[C:59]([NH2:61])[S:58][C:48]=2[C:49]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[N:50][CH:51]=1>C1COCC1>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][N:12]=1)[C:7]([NH:61][C:59]1[S:58][C:48]2[C:49]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)=[N:50][CH:51]=[C:46]([O:45][CH3:44])[C:47]=2[N:60]=1)=[O:9]
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: COc1cc(C(=O)O)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cc(C(=O)Nc2nc3c(OC)cnc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-methoxy-isonicotinic acid hydrochloride, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 402 (M+H+, 100).