Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:30])[CH:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:46]1([CH2:52][C:53]([N:55]=[C:56]=[S:57])=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(OCC)C>C(O)C.C1(C)C=CC=CC=1.CCCCCC>[F:30][C:4]1[CH:3]=[C:2]([NH:1][C:56]([NH:55][C:53](=[O:54])[CH2:52][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[S:57])[CH:29]=[CH:28][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: Nc1ccc(Oc2cc(NC(=O)N3CCC(CN4CCCC4)CC3)ncn2)c(F)c1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOCC
Solvent: CCO
Solvent: CCCCCC
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCC(CN4CCCC4)CC3)ncn2)c(F)c1
Reaction time: 0.08 h
Yield: 26.4 %

Procedure:
4-(Pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (100 mg) was dissolved in ethanol (1.0 ml) under a nitrogen atmosphere, and then (S)-(+)-10-camphorsulfonic acid (56 mg) was added thereto, followed by for stirring 5 min. A 0.25 M solution of phenylacetyl isothiocyanate in toluene (1.45 ml) was added thereto, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (30 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (20 ml), water (20 ml), brine (20 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; heptane:ethyl acetate=1:3). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (1.5 ml) and hexane (2.0 ml) in this order were then added to suspend. The solid was filtered off, and dried under aeration to provide the titled compound (37.6 mg, 26.4%) as pale yellow powder.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([F:6])([F:5])I.C[Li].[Br-].[Li+].[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22](N(OC)C)=[O:23])[CH:17]=[CH:18][CH:19]=1>>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22](=[O:23])[C:3]([F:6])([F:5])[C:2]([F:8])([F:7])[F:1])[CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)(F)C(F)(F)I
Reactant: CON(C)C(=O)C=Cc1cccc(Br)c1
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Product: O=C(C=Cc1cccc(Br)c1)C(F)(F)C(F)(F)F
Reaction time: 0.33 h
Yield: 85.3 %

Procedure:
To a saturated solution of pentafluoroiodoethane (0.84 M, in diethyl ether) (102.0 mL, 85.5 mmol), was slowly added a solution of methyllithium/lithium bromide (1.5 M, in diethyl ether) (57.0 mL, 85.5 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 20 minutes and then a solution of 3-(3-bromo-phenyl)-N-methoxy-N-methylacrylamide (7.7 g, 28.5 mmol, in diethyl ether 50.0 mL) prepared in Step 1 of Preparation 4 was slowly added thereto at −78° C. The reaction mixture was stirred at room temperature for 1 hour, quenched with distilled water, acidified by a 10% potassium hydrogen sulfate solution (pH=5), and then extracted with diethyl ether. The extract was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30) to give 8.0 g of the titled compound as a yellow liquid.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].[CH2:26]([C:33]1[CH:37]=[CH:36][S:35][C:34]=1[C:38](=O)[C:39]([O:41][CH3:42])=[O:40])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>C1COCC1>[CH2:26]([C:33]1[CH:37]=[CH:36][S:35][C:34]=1/[C:38](=[CH:2]\[O:3][CH3:4])/[C:39]([O:41][CH3:42])=[O:40])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)C(=O)c1sccc1Cc1ccccc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO/C=C(/C(=O)OC)c1sccc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (methoxymethyl)triphenylphosphonium chloride and sodamide (0.4 g of a 1:1 molar mixture) in dry THF was added a solution of methyl 2-(3-benzyl-2-thienyl)-2-oxoacetate (220 mg, 0.8 mmol) in dry THF (5 ml). The reaction mixture was stirred at room temperature for 30 minutes. More (methoxymethyl)triphenylphosphonium chloride and sodamide (0.2 g of a 1:1 molar mixture) were added and stirring was continued for a further one hour. The reaction mixture was poured into water and then extracted with ether. The combined ether layers were washed with water and brine and then dried. Filtration through a pad of silica gel to remove triphenylphosphine oxide, followed by HPLC (eluent dichloromethane) afforded (Z)-methyl 2-(3-benzyl-2-thienyl)-3-methoxypropenoate, an oil (100 mg), 1H nmr: delta 3.64 (3H, s), 3.78 (6H,s), 6.75 (1H,d), 7.0-7.4 (6H,m), 7.60 (1H,s) ppm; and (E)-methyl 2-(3-benzyl-2-thienyl)-3-methoxypropenoate, an oil (30 mg), 1H nmr: delta 3.64 (3H.s), 3.80 (3H,s), 3.82 (3H,s), 6.56 (1H,s), 6.75 (1H,d), 7.0-7.3 (6H,m) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[N:25][OH:26])=[CH:19][CH:18]=1.C(N(CC)CC)C>O1CCCC1>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[CH:2]=[C:1]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=3)[O:26][N:25]=2)=[CH:19][CH:18]=1
Reactant: ON=C(Cl)Cc1ccc(COc2ccccn2)cc1
Reactant: C#Cc1cccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: c1ccc(OCc2ccc(Cc3cc(-c4cccnc4)on3)cc2)nc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 24 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynylpyridine (10 mg, 0.097 mmol) and (4-(pyridin-2-yloxymethyl)-phenyl)-acetohydroximoyl chloride (42.9 mg, 0.155 mmol) described in Manufacturing Example 2-1-5 was added triethylamine (54.1 μL, 0.388 mmol), which was stirred for 2.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4 to 1:2, then 1:1) to obtain the title compound (8 mg, 24%).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8]C(C)(C)C)[C@H:3]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:24])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:8])[OH:13])[C@H:3]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)OCc2ccccc2)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C(=O)OCc2ccccc2)[C@@H]1/C=C\C(=O)O
Yield: 73.5 %

Procedure:
A mixture of 5 g of the product of Step A, 250 mg of p-toluene sulfonic acid and 30 ml of toluene was refluxed for one hour and was cooled and chromatographed over silica gel. Elution with a 1-1 hexane-ethyl acetate mixture containing 1% of acetic acid and crystallization from isopropyl ether yielded 3.05 g of benzyl(1R,cis,Z)2,2-dimethyl-3- [3-oxo-3-hydroxy-1-propenyl]-cyclopropane-carboxylate melting at 69° C.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[N:3]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: C1=COCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Clc1cc2nc(Cl)n(C3CCCCO3)c2cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.1 %

Procedure:
To a solution of 2,5,6-trichlorobenzimidazole (2.07 g, 9.33 mmol) in tetrahydrofuran (20 mL) were added 3,4-dihydro-2H-pyran (2.55 mL, 28.0 mmol) and camphor sulfonic acid (216 mg, 0.93 mmol). The mixture was stirred at room temperature for 3 hours, and the reaction mixture was neutralized by addition of 0.1M aqueous sodium hydroxide, then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (C-300, hexane:ethyl acetate=4:1) to give the title compound (487 mg, 9%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([Cl:17])=[CH:6][C:7]=1[C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15].[C:18](=O)([O:20]CC)[NH2:19]>[Cl-].[Zn+2].[Cl-]>[CH3:1][N:2]1[C:3]2[S:4][C:5]([Cl:17])=[CH:6][C:7]=2[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[N:19][C:18]1=[O:20]
Reactant: CNc1sc(Cl)cc1C(=O)c1ccccc1F
Reactant: CCOC(N)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: Cn1c(=O)nc(-c2ccccc2F)c2cc(Cl)sc21
Temperature: 200 °C

Procedure:
A mixture of 700 mg of 2-methylamino-3-(o-fluorobenzoyl)-5-chlorothiophene, 700 mg of ethyl carbamate and 50 mg of zinc chloride is heated at 200°C for 1 hour. After cooling, the reaction mixture is extracted with chloroform. The extracts are combined, washed with water, dried over sodium sulfate and concentrated under reduced pressure to give a residue, which is chromatographed on silica gel using chloroform as an eluent to give crystals of 1-methyl-4-(o-fluorophenyl)-6-chloro-1,2-dihydrothieno[2,3-d]pyrimidin-2-one as crystals having a melting point of 192° - 194°C (after recrystallization from ethanol).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:12]=[C:11]([N:13]3[C:21]4[CH:20]=[CH:19][N:18]=[CH:17][C:16]=4[N:15]=[CH:14]3)[S:10][C:9]=2[C:22]([O:24]C)=O)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH3:32]>CO>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:12]=[C:11]([N:13]3[C:21]4[CH:20]=[CH:19][N:18]=[CH:17][C:16]=4[N:15]=[CH:14]3)[S:10][C:9]=2[C:22]([NH2:32])=[O:24])=[C:4]([C:28]([F:30])([F:29])[F:31])[CH:3]=1
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccc(F)cc1C(F)(F)F
Reactant: N
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccc(F)cc1C(F)(F)F

Procedure:
In a similar manner as described for example 33, 45.5 mg of methyl 3-{[4-fluoro-2-(trifluoromethyl)benzyl]oxy}-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate and 5 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([O:14][C:15]([C@:17]1([N:39]=[N+:40]=[N-:41])[C@H:22]([S:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:21][C@@H:20]2[C@H:18]1[C@@:19]2([F:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:16])[CH3:13]>ClCCl>[CH2:12]([O:14][C:15]([C@:17]1([N:39]=[N+:40]=[N-:41])[C@H:22]([S:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)=[O:9])[CH2:21][C@@H:20]2[C@H:18]1[C@@:19]2([F:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:16])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](SCc3ccc(Cl)c(Cl)c3)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Solvent: ClCCl
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](S(=O)Cc3ccc(Cl)c(Cl)c3)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Reaction time: 1 h
Yield: 83.5 %

Procedure:
32 mg of 3-chloroperbenzoic acid was added to 73 mg of (1R,2S,3R,5R,6R)-2-azido-3-(3,4-dichlorobenzylsulfanyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 1.46 mL of dichloromethane and the mixture was stirred for 1 hour in a dry ice-acetone bath. The mixture was stirred for 3.5 hours in an ice bath, and further stirred for 11 hours at room temperature. 15 mg of 3-chloroperbenzoic acid was further added thereto, and the mixture was stirred for 1 hour in a dry ice-acetone bath, and then stirred for 4 hours in an ice bath. The reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200 (made by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=4:1 to 2:1), thereby yielding 63 mg of (1R,2S,3R,5R,6R)-2-azido-3-(3,4-dichlorobenzylsulfinyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester and 12 mg of (1R,2S,3R,5R,6R)-2-azido-3-(3,4-dichlorobenzylsulfonyl-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: ClC[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.O1CCN(NC(=S)[S-])CC1>CO>[C:6]1([CH2:9][C:10]([OH:12])=[O:11])[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1
Reactant: O=C(O)Cc1ccc(CCl)cc1
Agent: S=C([S-])NN1CCOCC1
Solvent: CO
Product: O=C(O)Cc1ccccc1

Procedure:
A solution of 1.85 g (0.01 mole) of 4-chloromethylphenyl acetic acid and 6.25 g (0.025 mole) of freshly prepared morpholinodithiocarbamate salt in 250 ml of methanol was stirred under nitrogen for 20 hours at room temperature. The solvent was evaporated, water was added and the solution was acidified to pH 1 using aqueous 10% hydrochloric acid then extracted with ethylacetate, dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from ethylacetate to give p-morpholinodithiocarbamatemethyl)phenylacetic acid. M.P. 163° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]3[N:14]=[C:13]([Cl:15])[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11][N:6]3[N:7]=2)[CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[Cl:15][C:13]1[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][N:6]2[N:7]=[C:8]3[C:4]([CH:3]=[C:2]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)[CH:10]=[CH:9]3)=[C:5]2[N:14]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Clc1nc2c3cc(Br)ccc3nn2cc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Fc1ccc(-c2ccc3nn4cc(-c5ccccc5)c(Cl)nc4c3c2)cc1

Procedure:
300 mg (0.84 mmol) 9-Bromo-2-chloro-3-phenylpyrimido[1,2-b]indazole, (intermediate example Int-1-2), 128.7 mg (0.92 mmol) (4-fluorophenyl)boronic acid, 68.3 mg (0.084 mmol) bis(diphenylphosphino)ferrocenedichloropalladium(II) and 1.5 mL aqueous sodium carbonate solution (10%) in 10 mL dimethoxyethane were heated in the microwave oven for 45′ at 110° C. The reaction mixture was poured on water/dichloromethane and stirred vigorously for 30′. The organic phase was separated and washed twice with brine. After drying and filtration the solvent was evaporated and the residue (194 mg), a mixture (according to UPLC/MS) of the title compound, the regioisomer 9-bromo-2-(4-fluorophenyl)-3-phenyl-pyrimido[1,2-b]indazole and the bisproduct 2,9-bis-(4-fluorophenyl)-3-phenyl-pyrimido[1,2-b]indazole, was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:32]([OH:34])=O)[CH2:20][CH2:19][N:18]([C:21]([C:23]3([CH3:31])[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25][CH2:24]3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:35][N:36]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.NO>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:32]([NH:36][OH:35])=[O:34])[CH2:20][CH2:19][N:18]([C:21]([C:23]3([CH3:31])[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25][CH2:24]3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(=O)C3(C)COC(C)(C)OC3)CC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)NO)CCN(C(=O)C3(C)COC(C)(C)OC3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxamide was prepared following the procedure Example 64 (step 6). Starting from 4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxylic acid (280 mg, 0.57 mmol) in dimethylformamide (6 ml), 1-hydroxybenzotriazole (92 mg, 0.57 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (153 mg, 0.80 mmol), N-methylmorpholine (0.094 ml, 0.85 mmol), and hydroxylamine (0.174 ml, 2.85 mmol), 180 mg (62%) of the product was isolated as a solid. HR-MS: m/z Calculated for C24H32N2O8S 531.1771; Found 531.1768.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][NH2:6])[CH2:3][NH2:4].[ClH:8].[NH2:9][C:10](N)=N>C(O)C>[ClH:8].[CH3:1][C:2]1([CH3:7])[CH2:5][NH:6][C:10]([NH2:9])=[N:4][CH2:3]1
Reactant: N=C(N)N
Reactant: CC(C)(CN)CN
Agent: Cl
Solvent: CCO
Product: CC1(C)CN=C(N)NC1
Yield: 104.9 %

Procedure:
2.5 g of 2,2-dimethylpropane-1,3-diamine and 2.17 g of guanidine hydrochloride are heated to 140° C. under argon for 4 h. After returning to RT, add ethanol and dry evaporate. 3.9 g (yield=95%) of 5,5-dimethyl-1,4,5,6-tetrahydropyrimidin-2-amine hydrochloride are obtained as a white powder used as such.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][O:6][C:5](=[O:8])[N:4]1[C:9]1[CH:14]=[CH:13][C:12]([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])=[CH:11][N:10]=1.[CH3:32]I>>[CH3:32][O:1][CH2:2][C@@H:3]1[CH2:7][O:6][C:5](=[O:8])[N:4]1[C:9]1[CH:14]=[CH:13][C:12]([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])=[CH:11][N:10]=1
Reactant: CI
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)nc3)CC2)nc1C
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3nc(C)c(C)cc3C)CC2)cn1

Procedure:
By reaction and treatment in the same manner as in Example 73 and using (R)-4-hydroxymethyl-3-{5-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}oxazolidin-2-one (200 mg) described in Example 254 and methyl iodide (35 μL), the title compound (158 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]1[N:5]([CH2:18][CH2:19][CH3:20])[N:6]=[C:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[C:8]2[NH2:17].Cl.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>>[NH2:17][C:8]1[C:7]2=[N:6][N:5]([CH2:18][CH2:19][CH3:20])[C:4]([CH2:3][C:2]([NH:1][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)([CH3:21])[CH3:22])=[C:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NC(=O)c1ccncc1
Yield: 67.9 %

Procedure:
Using the method of Example 68, 1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 64, 770 mg, 2.59 mmol) was reacted with isonicotinoyl chloride hydrochloride (1.15 mg, 6.48 mmol). The crude product was purified as described in Example 68 to provide 708 mg of N-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]isonicotinamide as an off-white solid, mp 148-150° C. MS (APCI) m/z 403 (M+H)+; Anal. Calcd for C23H26N6O: C, 68.63; H, 6.51; N, 20.88. Found: C, 68.30; H, 6.49; N, 20.92.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]2[C:10]=1[C:9](=O)[N:8]=[CH:7][N:6]=2.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[NH:4][N:3]=[C:2]([CH3:1])[C:10]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1=C2C(=O)N=CN=C2N=N1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1n[nH]c2ncnc(Cl)c12

Procedure:
To a stirred suspension of 3-methyl-pyrazolo[3,4-d]pyrimidin-4-one (7.50 g, 50.0 mmol, Example 2) in phosphorus oxychloride (150 mL) was added diisopropylethylamine (31 mL, 175 mmol, Aldrich). The mixture was heated at reflux for 2.5 hours before the solvent was evaporated under reduced pressure. The residue was treated with ice (200 g) and made slightly basic with 4N aqueous sodium hydroxide solution and extracted with ethyl acetate (3×250 mL). The combined organic extracts were washed with water, brine, dried and concentrated to give 4-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine as a white solid. (Yield 6.38 g).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][N:15]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[N:23]1[CH:24]=[CH:25][C:20]([NH:19][N:15]2[CH2:14][CH2:13][C:12]3[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=3)[CH2:16]2)=[CH:21][CH:22]=1
Reactant: c1ccc(COc2ccc3c(c2)CN(Nc2ccncc2)CC3)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Oc1ccc2c(c1)CN(Nc1ccncc1)CC2
Temperature: 25 °C
Yield: 82.2 %

Procedure:
A mixture of 7-benzyloxy-2-(4-pyridinylamino)-1,2,3,4-tetrahydroisoquinoline (5.68 g) and 5% palladium-on-carbon (1.1 g) in methanol (85 mL) was shaken on a parr hydrogenation apparatus at ambient temperature, starting at an initial pressure of 55 psi. After 2 hrs an additional 1.1 g of catalyst was added, the pressure was increased to 55 psi, and the mixture was shaken for an additional 5 hrs. An additional 0.75 g of catalyst was added, the pressure was increased to 55 psi, and the mixture was shaken until hydrogen uptake ceased. The reaction mixture was filtered through a pad of Celite, and the pad was washed with methanol. Concentration of the filtrate gave 3.4 g (82%) of product. Recrystallization from ethanol gave the analytical sample, mp 236-239° C. (dec).
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:2].[ClH:15].[CH2:16]([O:18]CC)[CH3:17].C(O)C>>[ClH:15].[CH2:16]([O:18][C:1](=[NH:2])[CH2:3][N:4]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:17]
Reactant: CCOCC
Reactant: CCOC(=O)c1ccc(C)n1CC#N
Agent: Cl
Solvent: CCO
Product: CCOC(=N)Cn1c(C)ccc1C(=O)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
A high pressure reaction vessel charged with ethyl 1-(cyanomethyl)-5-methyl-1H-pyrrole-2-carboxylate (848 mg, 4.41 mmol) cooled to 0° C. was treated with a 2M solution of hydrochloric acid in diethyl ether (30 mL, 60 mmol) and absolute ethanol (406 mg, 8.82 mmol). The mixture was stirred at 0° C. for 10 min and then was warmed to room temperature where it stirred over the weekend. At this time, the mixture was diluted with hexanes. The resulting precipitate was collected by filtration to afford ethyl 1-(2-ethoxy-2-iminoethyl)-5-methyl-1H-pyrrole-2-carboxylate hydrochloride (1.16 g, 95.7%) as a white solid. LC-MS calcd. for C12H19N2O3 [(M+H)+] 239, obsd. 239.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[CH:9]1([CH2:15][C@H:16]([N:20]2[C:24](=[O:25])[C@H:23]([CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[NH:22][C:21]2=[O:33])[C:17](O)=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1([CH2:15][C@H:16]([N:20]2[C:24](=[O:25])[C@H:23]([CH2:26][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)[NH:22][C:21]2=[O:33])[C:17]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=2)=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1C(=O)N[C@@H](CC2CCCCC2)C1=O
Reactant: Cc1ccc(N)nc1
Product: Cc1ccc(NC(=O)[C@H](CC2CCCCC2)N2C(=O)N[C@@H](CC3CCCCC3)C2=O)nc1

Procedure:
By using the conditions described in Step (iv) of Example 17, 2-amino-5-methylpyridine was condensed with (S,S)-3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidinyl]propanoic acid [Example 17, Step (iii)] to give the title compound as a colorless foam: EI-HRMS m/e calcd. for C25H36N4O3 (M+) 441.2866, found 441.2869.