Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[CH2:23]([N:27]1[C:36](=[O:37])[C:35]2[CH:38]=[CH:39][CH:40]=[C:33]3[C:34]=2[C:29](=[CH:30][CH:31]=[CH:32]3)[C:28]1=[O:41])[CH2:24][C:25]#[CH:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:26]#[C:25][CH2:24][CH2:23][N:27]3[C:36](=[O:37])[C:35]4[CH:38]=[CH:39][CH:40]=[C:33]5[C:34]=4[C:29](=[CH:30][CH:31]=[CH:32]5)[C:28]3=[O:41])[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Reactant: C#CCCN1C(=O)c2cccc3cccc(c23)C1=O
Product: Cc1nnc2n1-c1sc(C#CCCN3C(=O)c4cccc5cccc(c45)C3=O)cc1C(c1ccccc1Cl)=NC2

Procedure:
Coupling of 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno[3,2-f][1,2,4] triazolo[4,3-a][1,4]diazepine with 2-(3-butyn-1-yl)-1H-benz[de]isoquinoline-1,3(2H)-dione as described in Example 37 yielded after chromatography and crystallization from ethyl acetate light yellow crystals of the title compound with m.p. 175°-179° C. A higher melting crystalline modification with m.p. 227°-229° C. was also observed.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].[Cl:32][CH2:33]/[CH:34]=[CH:35]/[CH2:36]Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:36]/[CH:35]=[CH:34]/[CH2:33][Cl:32])[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7]
Reactant: ClC/C=C/CCl
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(C[C@@H]2CN(C/C=C/CCl)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (1.0 g), (E)-1,4-dichloro-2-butene (0.31 ml) and powdered potassium carbonate (0.4 g) in dry acetonitrile (10 ml) was heated at 50° C. After 4 hours, the reaction mixture was cooled and then filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel using a mixture of toluene and ethyl acetate (4:1) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(E)-4-chloro-2-butenyl]piperazine (0.53 g) as an oil.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH2:15][C:16]1[C:21]2[CH:22]=[CH:23][O:24][C:20]=2[C:19]([Cl:25])=[CH:18][CH:17]=1>C1COCC1>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH2:15][C:16]1[C:21]2[CH:22]=[CH:23][O:24][C:20]=2[C:19]([Cl:25])=[CH:18][CH:17]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: Clc1ccc(CBr)c2ccoc12
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(Cl)c2occc12)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diethyl malonate (1.7 ml) was added dropwise to a suspension of sodium hydride (60%; 0.3 g) in dry THF (40 ml) at 0° under nitrogen. The mixture was allowed to warm to room temperature over 15 mins. Then a solution of 4-bromomethyl-7-chloro-benzofuran in dry THF (10 ml) was added in one portion and the mixture stirred for 1 h; then partitioned between water (100 ml) and ethyl acetate (3×50 ml). The combined organic extracts were washed with brine (50 ml), dried (MgSO4) and evaporated to give the title compound as a pale yellow oil (2.466 g)
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[N+](C)([O-])=O>[CH:9]1([C:15]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COc1ccccc1
Reactant: O=C(Cl)C1CCCCC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(=O)C2CCCCC2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
To commercially available nitromethane (5 ml) were added commercially available anisole (0.5 ml), commercially available cyclohexanecarbonyl chloride (0.63 ml) and commercially available ytterbium(III) trifluoromethanesulfonate (288 mg), and the admixture was stirred at 60° C. for 3 hours. The reaction mixture was partitioned between water and chloroform, and the chloroform layer was washed with saturated aqueous sodium hydrogen carbonate and brine and then dried with anhydrous sodium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by chromatography on silica gel eluting with chloroform to obtain 517 mg of the title compound (yield: 51%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:31])[N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]([C:32]([OH:34])=[O:33])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd].C(O)(=O)C>[C:32]([OH:34])(=[O:33])[CH3:13].[C:25]1([N:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:17]([N:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH:13]2[C:32]([OH:34])=[O:33])=[O:31])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: [H][H]
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)N(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)C1CNCCN1C(=O)N(c1ccccc1)c1ccccc1

Procedure:
A solution of 109 mg. (0.24 mmole) of (±)-4-(benzyloxycarbonyl)-1-(diphenylcarbamoyl)piperazine-2carboxylic acid (from Step A) in 3 ml of methanol containing 3 drops of acetic acid and 50 mg of 10% Pd/C was hydrogenated with rocking at 40 psi of hydrogen for 16 hours. The mixture was filtered through Celite and the solution was concentrated in vacuo to 66 mg (71%) of solid which was homogeneous by TLC (1:1:1:1 n-butyl alcohol-acetic acid-water-ethyl acetate, Rf =0.70). 1H NMR (CDCl3, 300 MHz, ppm): δ2.05 (s, 3H), 2.72 (m, 1H), 2.96 (m, 1H), 3.12 (m, 1H), 3.26 (m, 1H), 3.67 (m, 1H), 3.79 (m, 1H), 4.78 (br.s, 1H), 7.0-7.3 (m, 10H).
Reaction SMILES: S1C=CC=C1S([NH:9]C1C=CC=CC=1N)(=O)=O.[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26]>>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25](=[O:26])[NH2:9]
Reactant: O=C=Nc1ccccc1Br
Reactant: Nc1ccccc1NS(=O)(=O)c1cccs1
Product: NC(=O)Nc1ccccc1Br
Yield: 134.9 %

Procedure:
The urea was synthesized from 2-(2-thiophene sulfonyl amino) aniline(1 mmol) and 2-bromo phenyl isocyanate(1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.29 g, 64%). EI-MS m/z 450(M-H)-
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]([CH3:21])=[CH:19][C:18]3[C:17]([CH3:23])([CH3:22])[CH2:16][CH2:15][C:14]([CH3:25])([CH3:24])[C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:26](=[CH2:30])[C:27]([OH:29])=[O:28].CO.[CH2:33]1COCC1.S(=O)(=O)(O)O>O>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]([CH3:21])=[CH:19][C:18]3[C:17]([CH3:23])([CH3:22])[CH2:16][CH2:15][C:14]([CH3:25])([CH3:24])[C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:26](=[CH2:30])[C:27]([O:29][CH3:33])=[O:28]
Reactant: C1CCOC1
Reactant: C=C(C(=O)O)c1cc(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)ccc1OCOC
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: C=C(C(=O)OC)c1cc(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)ccc1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.9 g (4.35 mmol) of 2-methoxymethoxy-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenylacrylic acid, 20 ml of methanol and 30 ml of THF are introduced into a round-bottomed flask. 2.8 ml of concentrated sulphuric acid are added and the mixture is stirred at room temperature for 12 hours. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, washed with water, dried over magnesium sulphate and evaporated. 1.63 g (95%) of methyl 2-hydroxy-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenylacrylate are collected.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]([C:19]([OH:21])=O)[C:12]2=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:36]([NH2:40])[CH2:37][CH2:38][CH3:39].[Cl-].[Na+]>CN(C)C=O>[CH2:36]([NH:40][C:19]([C:13]1[C:12](=[O:22])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([NH:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:10]=2)[NH:15][CH:14]=1)=[O:21])[CH2:37][CH2:38][CH3:39]
Reactant: CCCCN
Reactant: O=C(O)c1c[nH]c2ccc(NCc3ccccc3)nc2c1=O
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCNC(=O)c1c[nH]c2ccc(NCc3ccccc3)nc2c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a solution of 6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (53 mg, 0.2 mmol) and triethylamine (59 ml, 0.42 mmol) in N,N-dimethylformamide (1 mL) at 0° C. was added ethyl chloroformate (39 mL, 0.41 mmol). After stirring at 0° C. for 1 h, n-butylamine 99 mL, 1.0 mmol) was added. The reaction mixture was stirred an additional 2 h at 0° C., then poured into saturated aqueous sodium chloride. The mixture was cooled in an ice bath, the precipitate collected, rinsed with water and ether, then dried to afford 49 mg of N-n-butyl 6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide as a brown solid. Compound 1. An alternate name for this compound is: N-butyl(4-oxo-6-(benzylamino)(3-hydro-5-azaquinolyl))formamide.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[N:5][N:4]=[C:3]1[S:13][CH3:14].O.[C:16]([OH:20])(=[O:19])[CH:17]=[O:18]>C(OCC)(=O)C>[CH3:14][S:13][C:3]1[N:2]([NH:1][CH:17]([OH:18])[C:16]([OH:20])=[O:19])[C:7](=[O:8])[C:6]([C:9]([CH3:11])([CH3:10])[CH3:12])=[N:5][N:4]=1
Reactant: O=CC(=O)O
Reactant: CSc1nnc(C(C)(C)C)c(=O)n1N
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1nnc(C(C)(C)C)c(=O)n1NC(O)C(=O)O
Reaction time: 3 h
Yield: 87.4 %

Procedure:
21.4 g (0.1 mol) of 4-amino-6-tert.-butyl-3-methylthio-1,2,4-triazin-5-one and 10.1 g (0.11 mol) of glyoxylic acid monohydrate were stirred in 250 ml of ethyl acetate for 12 hours at room temperature, whereby a clear solution was produced. The mixture was then left to stand; after about 3 hours, the product began to crystallize out. It was filtered off and the filtrate was concentrated, whereupon further material crystallized out. The combined filter residues were washed with ether and dried. 25.2 g (87.5% of theory) of N-(3-methylthio-6-tert.-butyl-1,2,4-triazin-5-on-4-yl)- α-hydroxy-glycine of melting point 161° C (decomposition) were obtained.
Reaction SMILES: [F:1][CH:2]([F:45])[N:3]1[CH:7]=[C:6]([C:8]2[C:13]3[C:14](=[O:28])[N:15](CC4C=CC(OC)=CC=4OC)[CH2:16][C:12]=3[C:11]([F:29])=[C:10]([NH:30][C@@H:31]3[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]3[NH:37]C(=O)OC(C)(C)C)[N:9]=2)[CH:5]=[N:4]1.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>>[NH2:37][C@H:32]1[CH2:33][CH2:34][CH2:35][CH2:36][C@H:31]1[NH:30][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[N:4][N:3]([CH:2]([F:1])[F:45])[CH:7]=2)[C:13]2[C:14](=[O:28])[NH:15][CH2:16][C:12]=2[C:11]=1[F:29].[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4cnn(C(F)F)c4)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCCC[C@H]1Nc1nc(-c2cnn(C(F)F)c2)c2c(c1F)CNC2=O

Procedure:
A solution of tert-butyl (1S,2R)-2-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (36 mg, 0.057 mmol) in TFA (2 mL) was heated at 60° C. for 2 h. After removal of the solvent, the residue was diluted in MeOH (2 mL) and was purified by preparative HPLC. The fractions were collected and stripped to dryness via rotary evaporation to yield the title compound as a TFA salt (18.7 mg, 86%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.40-1.52 (m, 2H), 1.58-1.76 (m, 3H), 1.75-1.94 (m, 3H), 3.67 (br s, 1H), 4.44 (d, J=4.88 Hz, 2H), 4.53 (br s, 1H), 6.86 (d, J=6.83 Hz, 1H), 7.71 (br s, 2H), 7.79-8.12 (m, 1H), 8.53 (s, 2H), 9.41 (s, 1H). [M+H] calc'd for C17H19F3N6O, 381. found, 381.
Reaction SMILES: [C:1]([O-])(=O)[CH:2]=C.[CH2:6]=[C:7]([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH2:9]>C1(C)C=CC=CC=1>[C:7]1([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][CH2:2][CH2:1][CH2:9][CH:8]=1
Reactant: C=CC(=O)[O-]
Reactant: C=CC(=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: C[Si](C)(C)OC1=CCCCC1
Temperature: 150 °C

Procedure:
In a pressure vessel, a solution of acrylate (1 eq), (buta-1,3-dien-2-yloxy)trimethylsilane (1.1 eq) in toluene was flushed with nitrogen, sealed and heated at 150° C. for 1-3 days. The reaction mixture was cooled to RT and concentrated in vacuo to give crude product which was used for the next step without purification.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[NH:8][C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].[CH2:21](I)[CH2:22][CH2:23][CH3:24]>CN(C=O)C>[CH2:21]([N:8]1[C:7]2[N:6]=[CH:5][N:4]([CH2:1][CH:2]=[CH2:3])[C:12]=2[C:11](=[O:13])[NH:10][C:9]1=[O:14])[CH2:22][CH2:23][CH3:24]
Reactant: C=CCn1cnc2[nH]c(=O)[nH]c(=O)c21
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CCCC
Reaction time: 48 h
Yield: 68.7 %

Procedure:
A stirred solution of 7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (10 g, 52 mmol) in anhydrous DMF (100 ml) was treated with K2CO3 (7.91 g, 57.2 mmol) and, after 10 minutes, BuI (6.51 ml, 57.2 mmol). After reacting for 2 days the reaction mixture was partitioned between 2M HCl(aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated in vacuo to give an off-white solid. This was washed with hot cyclohexane and dried under vacuum to give the title compound (8.87 g, 68%); m/z 249.3[MH+].
Reaction SMILES: [H-].[Na+].[CH3:3]I.[Br:5][C:6]1[CH:7]=[C:8]([CH2:11][OH:12])[S:9][CH:10]=1>O1CCCC1>[Br:5][C:6]1[CH:7]=[C:8]([CH2:11][O:12][CH3:3])[S:9][CH:10]=1
Reactant: OCc1cc(Br)cs1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cc(Br)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add sodium hydride (737 mg, 29.23 mmol, 1.10 equivalents, 95%) to a solution containing methyl iodide (1.65 mL, 26.57 mmol, 1.00 equivalents) and (4-bromo-thiophen-2-yl)-methanol (5.13 g, 26.57 mmol, 1.00 equivalents) in tetrahydrofuran (dry, 25 mL). Stir the resulting mixture at room temperature overnight and evaporate. Partition the residue between water (100 mL) and dichloromethane (100 mL). Extract the aqueous layer with dichloromethane (100 mL), combine the organic layers, dry over magnesium sulfate, filter and evaporate to yield the desired product as a yellow oil.
Reaction SMILES: [Br-].[C:2]1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:31]([O:33][C:34]([N:36]1[CH2:42][CH2:41][C:40]2[C:43](Br)=[C:44]([C:46](=O)[C:47]([F:50])([F:49])[F:48])[S:45][C:39]=2[CH2:38][CH2:37]1)=[O:35])[CH3:32]>C1COCC1.CCOC(C)=O>[CH2:31]([O:33][C:34]([N:36]1[CH2:42][CH2:41][C:40]2[CH:43]=[C:44]([C:46]([C:47]([F:50])([F:49])[F:48])=[CH2:2])[S:45][C:39]=2[CH2:38][CH2:37]1)=[O:35])[CH3:32]
Reactant: CCOC(=O)N1CCc2sc(C(=O)C(F)(F)F)c(Br)c2CC1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(c1cc2c(s1)CCN(C(=O)OCC)CC2)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
Triphenyl phosphonium bromide (393 mg, 1.1 mmol) was stirred in 7 mL THF. KHMDS (199 mg, 1.0 mmol) was added and the yellow solution was stirred for 30 minutes at room temperature. The product of step (a) (180 mg, 0.56 mmol) was dissolved in 7 mL THF and added to the above reaction. The solution was allowed to stir for 1 hour at room temperature, then diluted with EtOAc (25 mL) and washed with water (2×20 mL). The crude product was purified by silica gel chromatography (30% EtOAc in Hex) to give 100 mg of the sub-title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([S:19]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=2[CH3:30])(=[O:21])=[O:20])[CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=1)=[O:4].Br[C:32]1[C:37]([CH3:38])=[CH:36][N:35]=[C:34]([Cl:39])[CH:33]=1.CO.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.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>[CH3:1][O:2][C:3]([C:5]1[N:6]([S:19]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=2[CH3:30])(=[O:20])=[O:21])[CH:7]=[C:8]([C:32]2[C:37]([CH3:38])=[CH:36][N:35]=[C:34]([Cl:39])[CH:33]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cn1S(=O)(=O)c1c(C)cc(C)cc1C
Reactant: Cc1cnc(Cl)cc1Br
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: CCOC(C)=O
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1cc(-c2cc(Cl)ncc2C)cn1S(=O)(=O)c1c(C)cc(C)cc1C
Yield: 43.1 %

Procedure:
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2,4,6-trimethylbenzensulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester (125 mg, 0.29 mmol, 0.6 equiv.) and 4-bromo-2-chloro-5-methylpyridine (96 mg, 0.47 mmol, 1.0 equiv.) were dissolved in benzene (4 mL). After adding methanol (0.94 mL) and aqueous Na2CO3, Pd(PPh3)4 (108 mg, 0.094 mol, 0.2 equiv.) was then added and the resulting mixture was heated at reflux for 16 hours. The reaction mixture was dissolved in ethyl acetate and washed with water. After drying the organic layer over Na2SO4, the solvent was removed under reduced pressure. The crude material was purified by reversed phase HPLC (acetonitrile/water/TFA), yielding the title compound as a colorless solid (54 mg, 0.125 mmol, HPLC Rt 9.087 min, ES+433.0, ES−431.0).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8](Cl)[N:7]=1)[CH3:2].[CH2:18]([N:25]1[CH2:32][CH2:31][NH:30][CH2:29][C:26]21[CH2:28][CH2:27]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC([O-])(C)C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([N:30]2[CH2:29][C:26]3([CH2:28][CH2:27]3)[N:25]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:32][CH2:31]2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1nc(Cl)cc2ccccc12
Reactant: c1ccc(CN2CCNCC23CC3)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: CCOC(=O)Cc1nc(N2CCN(Cc3ccccc3)C3(CC3)C2)cc2ccccc12
Temperature: 85 °C
Reaction time: 0.42 h

Procedure:
(3-Chloro-isoquinolin-1-yl)-acetic acid ethyl ester (2.50 g, 10.01 mmol), 4-benzyl-4,7-diaza-spiro [2.5]octane (2.23 g, 11.01 mmol), NaOtBu (1.06 g, 11.01 mmol), BINAP (249 mg, 0.40 mmol) and Palladium(II)-acetate (180 mg, 0.80 mmol) are mixed under argon. After addition of degassed, dry dioxane (36 ml), the suspension is heated to 85° C. After 25 minutes at 85° C., HPLC analysis indicates a conversion of 71%. The mixture is cooled to RT, diluted with EtOAc, and washed with H2O and sat. aq. NH4Cl (back extracted). The combined organic layers are dried over Na2SO4, the solvent is removed and the residue purified by FCC (hexane/EtOAc 100:0 to 96:4 to 93:7 to 90:10 to 85:15) to afford the title compound. 1H NMR (DMSO, 400 MHz) δ 0.58 -0.61 (m, 2H), 0.70 -0.73 (m, 2H), 1.18 (t, J=8.8, 3H), 2.98 (t, J =5.5, 2H), 3.39 (s, 2H), 3.49 (t, J=5.5, 2H), 3.86 (s, 2H), 4.12 (s, 2H), 4.12 (q, J=8.8, 2H), 5.59 (s, 1H), 7.14 -7.19 (m, 6H), 7.39 (t, J=8.8, 1H), 7.51 (d, J=9.9, 1H), 7.78 (d, J=9.9, 1H); ES-MS: 417 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]([C:10]#[N:11])=[N:6][CH:7]=[CH:8][CH:9]=1)#[N:2].[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][C:1]1[CH:3]=[C:4]2[C:5](=[C:10]([NH2:11])[N:2]=1)[N:6]=[CH:7][CH:8]=[CH:9]2
Reactant: N#CCc1cccnc1C#N
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2cccnc2c(N)n1
Yield: 9.4 %

Procedure:
To a 1 L round bottom flask was added 3-(cyanomethyl)picolinonitrile (63.6 mmol), MeOH (500 mL), followed by sodium methoxide (76.3 mmol). The mixture was heated at reflux for 18 h, after which time the solvent was removed. The residue was diluted with water (400 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The resultant crude residue was purified by silica gel to yield 6-methoxy-1,7-naphthyridin-8-amine (1.05 g, 5.99 mmol, 9.4%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.50 (d, J=2.75 Hz, 1H), 7.95 (d, J=8.24 Hz, 1H), 7.48 (dd, J=8.25, 4.40 Hz, 1H), 7.05 (s, 2H), 6.16 (s, 1H), 3.79 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])[C:5]([CH:23]=O)=[C:4](Cl)[N:3]=1.C(O)(C)C.O.[NH2:31][NH2:32]>O>[NH2:1][C:2]1[N:3]=[C:4]2[NH:31][N:32]=[CH:23][C:5]2=[C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])[N:7]=1
Reactant: Nc1nc(Cl)c(C=O)c(NCC(=O)Nc2cccc(C(F)(F)F)c2)n1
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: Nc1nc(NCC(=O)Nc2cccc(C(F)(F)F)c2)c2cn[nH]c2n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
In a disposable sealed tube was added 2-(2-Amino-6-chloro-5-formyl-pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide (96.0 mg, 0.25 mmol, 1.0 eq.), isopropanol (2.0 mL), and hydrazine monohydrate (0.02 mL, 0.35 mmol, 1.4 eq.). The reaction was sealed and heated to 80° C. After 2 hrs, the reaction was spiked with 0.01 mL of hydrazine monohydrate, resealed, and allowed to continue stirring at 80° C. overnight. The reaction was then cooled to RT and the resulting yellow precipitate was filtered and rinsed with cold EtOH to give crude 2-(6-amino-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide. The crude precipitate was then sonicated in 1.0 mL H2O, filtered, rinsed with an additional 1 mL H2O, and lyophilized overnight to give pure 2-(6-amino-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide as a pale yellow solid (30 mg, 34%). LC/MSD (HP Series 1100 MSD): Expected MW: 351, Observed M+H, 352.1, Retention time: 1.19 min. ANALYTICAL HPLC: >90%, Retention time: 3.58 min (8 minute run). 1H-NMR (d6-DMSO): 12.5 (br s, 1H), 10.42 (s, 1H), 8.15 (s, 1H), 7.80 (m, 2H), 7.59 (t, 1H), 7.41 (d, 1H), 6.01 (br s, 2H), 4.40 (rotamer d, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:18])[C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])[CH:5]=[CH:4][N:3]=1.[Cl:19][CH:20]1[CH2:22][CH:21]1[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:17])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:23]([C@H:21]2[CH2:22][C@H:20]2[Cl:19])=[O:24])[CH:7]=1)=[O:18]
Reactant: O=C(O)C1CC1Cl
Reactant: Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccnc(NC(=O)[C@H]2C[C@H]2Cl)c1)c1c(Cl)cccc1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
To a solution of N-(2-aminopyridin-4-yl)-2,6-dichlorobenzamide (150 mg, 0.54 mmol), 2-chlorocyclopropanecarboxylic acid (66 mg, 0.54 mmol) and HATU (381 mg, 1.08 mmol) in dry DMF (4.5 mL) was added DIPEA (144 mg, 1.08 mmol). The mixture was stirred at 110° C. in a microwave reactor for 1 hour. The mixture was cooled to room temperature and diluted with EtOAc (30 mL). The organic solution was washed with water (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give the desired compounds.