Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BrH:1].[CH2:2]([NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[C:12]=2[NH2:16])[CH2:7]1)[CH2:3][CH3:4].[CH:18](O)=[O:19].C(OC(=O)C)(=O)C>C(OCC)C>[BrH:1].[CH2:2]([NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[C:12]=2[NH:16][CH:18]=[O:19])[CH2:7]1)[CH2:3][CH3:4]
Reactant: CCCNC1CCc2c(ccc(O)c2N)C1
Reactant: O=CO
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CCCNC1CCc2c(ccc(O)c2NC=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.9 g of 2-propylamino-5-amino-6-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide are introduced into a mixture of 6 ml of formic acid and 0.67 ml of acetic anhydride, kept in an ice-bath for 1/2 hour. The mixture is stirred for 3 hours at ambient temperature and then poured into diethyl ether. The precipitate which has formed is filtered off and washed with hot isopropyl alcohol. After drying, 1.7 g of the final compound are obtained, which melts at 210° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[S:11][C:12]([CH:15]=O)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:17]([NH:21][OH:22])([CH3:20])([CH3:19])[CH3:18]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[S:11][C:12]([CH:15]=[N+:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[O-:22])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Sc2ccc(C=O)s2)cc1
Reactant: CC(C)(C)NO
Solvent: ClC(Cl)Cl
Product: COc1ccc(Sc2ccc(C=[N+]([O-])C(C)(C)C)s2)cc1
Yield: 16.8 %

Procedure:
2-(4-Methoxyphenylthio)-5-thiophenecarboxaldehyde from Step A was mixed with N-tert-butylhydroxylamine (10 g, 112.11 mmol), molecular sieves (4A, 50 g), silica gel (10 g) and chloroform (200 mL). The mixture was refluxed for 15 h, filtered and rotary evaporated. The residue obtained was purified by chromatography over silica gel eluting with hexanes/EtOAc (2:1, v:v) to provide a slightly pinkish powder (4.60 g, yield 16.8%), m.p.100.9° C. (Rf =0.19 on a silica gel plate using hexanes/EtOAc, 2:1, v:v, as the eluant).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[C:11](#[N:15])[CH2:12][C:13]#[N:14].N1CCCCC1.[NH2:22][C:23]1[C:28]([NH2:29])=[CH:27][CH:26]=[CH:25][C:24]=1[OH:30]>C(O)C.O>[C:13]([C:12]1[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=2)[C:25]2[C:24](=[C:23]([NH2:22])[C:28]([NH2:29])=[CH:27][CH:26]=2)[O:30][C:11]=1[NH2:15])#[N:14]
Reactant: COc1cccc(C=O)c1
Reactant: Nc1cccc(O)c1N
Reactant: N#CCC#N
Solvent: CCO
Solvent: O
Solvent: C1CCNCC1
Product: COc1cccc(C2C(C#N)=C(N)Oc3c2ccc(N)c3N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a mixture of m-anisaldehyde (544 mg, 4.0 mmol) and malononitrile (264 mg, 4.0 mmol) in ethanol (10 mL) was added piperidine (0.4 mL) and 2,3-diaminophenol (496 mg, 4.0 mmol). The mixture was stirred at room temperature under argon for 2 h, then it was diluted with water (20 mL). The precipitate was filtered to yield 1.08 g (88%) of the title compound as a brown solid. 1H NMR (CD3OD): 8.02 (s, 1H), 7.05 (t, J=7.8 Hz, 1H), 6.58–6.66 (m, 3H), 6.30 (d, J=7.8 Hz, 1H), 6.08 (d, J=7.8 Hz, 1H), 4.41 (s, 1H), 3.60 (s, 3H).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([O:17]C)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:19])[CH:2]=1.B(Br)(Br)Br.C(Cl)Cl>>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:19])[CH:2]=1
Reactant: COc1cccc2c1cc(C)n2Cc1cccc(-c2ccccc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(O)cccc2n1Cc1cccc(-c2ccccc2)c1
Yield: 86.5 %

Procedure:
By the method used in Example 1, Part D, 1.25 g (3.8 mmol) of 1- ([1,1′-biphenyl]-3-ylmethyl)-4-methoxy-2-methyl-1H-indole was O-demethylated by creating it with 15.2 mL of 1M BBr3/CH2Cl2 to give 1.03 g (87% yield) of crude 1-([1,1′-biphenyl]-3-ylmethyl)-4-hydroxy-2-methyl-1H-indole.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=[CH:13][C:14]2=[O:17])[CH2:9]1)C1C=CC=CC=1.Cl[C:31]([O:33][CH:34]=[CH2:35])=[O:32]>ClCCCl>[C:24]1([C:11]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]3[CH:15]([CH2:16][N:8]([C:31]([O:33][CH:34]=[CH2:35])=[O:32])[CH2:9]3)[C:14](=[O:17])[CH:13]=[CH:12]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1C=CC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC12
Reactant: C=COC(=O)Cl
Solvent: ClCCCl
Product: C=COC(=O)N1CC2C(=O)C=CC(c3ccccc3)(c3ccccc3)C2C1

Procedure:
A mixture of 2-benzyl-7,7-diphenyl-2,3,3a,4,7,7a-hexahydro-4-1H-isoindolone (3.4 g) and vinyl chloroformate (0.92 cc) in 1,2-dichloroethane (80 cc) is refluxed for 1 hour; the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from ethyl ether (20 cc). 7,7-Diphenyl-2-vinyloxycarbonyl-2,3,3a,4,7,7a-hexahydro-4-1H-isoindolone (2.6 g) melting at 162° C. is obtained.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.ClC1N=CN=C2C=1NC=N2.Cl.[OH:28][C:29]1[C:36]([OH:37])=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32].C(N(CC)CC)C>C(O)CC>[OH:28][C:29]1[C:36]([OH:37])=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][NH:32][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: NCc1cccc(O)c1O
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Agent: Clc1ncnc2nc[nH]c12
Solvent: CCCO
Solvent: CCN(CC)CC
Product: Oc1cccc(CNc2ncnc3c2ncn3C2CCCCO2)c1O
Yield: 60 %

Procedure:
A mixture of 10 mmol (2387 mg) 6-chloro-9-(tetrahydropyran-2-yl)purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (2100 mg) 2,3-dihydroxybenzylamine hydrochloride, and 7 mL of triethylamine was refluxed in n-propanol for 3 hrs. After removal of the n-propanol by vacuum evaporation, the resulting material was treated with water and extracted into ethyl acetate. The ethyl acetate solvent was evaporated and the residuum subsequently washed with 30 ml of petroleum ether. The solid residue was filtered off and the crude product crystallized from methanol. Yield 60%, white solid. TLC (CHCl3:methanol) (4:1) (v:v): single spot; HPLC: purity>98%. 1H-NMR (300 MHz, DMSO): 1.57m (2H); 1.71 m (1H); 1.95m (2H); 2.27qq (1H, Ja=12 Hz, Jb=4.0 Hz); 3.67m (1H); 4.00d (1H, J=11.7 Hz); 4.58bs (2H); 5.63dd (1H, Ja=11.2 Hz, Jb=1.9 Hz); 6.55tt (1H, Ja=7.7 Hz, Jb=1.5 Hz); 6.63dd (1H, Ja=7.7 Hz, Jb=1.8 Hz); 6.66dd (1H, Ja=7.7 Hz, Jb=1.8 Hz); 8.24s (1H); 8.27bs (1H); 8.37s (1H), 8.96bs (1H), 9.53bs (1H). MS (ES): [M+H]+=342 (100).
Reaction SMILES: C(OC([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[N:11]([CH3:19])[C:10](=[O:20])[CH2:9]1)=O)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[CH3:19][N:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[CH2:14][NH:8][CH2:9][C:10]1=[O:20]
Reactant: CN1C(=O)CN(C(=O)OC(C)(C)C)Cc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)CNCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 1-methyl-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (70 mg, 0.25 mmol) in dry DCM (10 mL), was added trifluoroacetic acid (0.75 mL, 3 mL/mmol). The mixture was stirred at r.t. for 1 h. After the completion of the reaction as confirmed by TLC, excess of TFA and DCM were evaporated in vacuo to afford trifluoroacetic acid salt of 1-methyl-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-one (70 mg, 95%) as a gummy solid which was used as such for next coupling.
Reaction SMILES: [Mg].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br.[CH:11]12[O:17][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16]2>O1CCCC1>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[OH:17]
Reactant: C1CCC2OC2C1
Reactant: COc1ccccc1Br
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccccc1[C@@H]1CCCC[C@H]1O
Temperature: -30 °C
Yield: 61.5 %

Procedure:
A mixture of 3.24 g (0.1 35 mol) of magnesium and 20 ml of tetrahydrofuran was charged into a three-necked flask of 300 ml and stirred. Then, a solution of 25.3 g (0.135 mol) of o-methoxyphenylbromide in 80 ml of tetrahydrofuran was added dropwise at a temperature of 60° C. or less. After the dropping was stopped, the mixture was cooled to -30° C., 0.65g of cuprous chloride was added, and the mixture was stirred for 10 minutes. To the mixture, a solution of 13.3 g (0.135 mol) of cyclohexene oxide in 15 ml tetrahydrofuran was added dropwise. After the dropping was stopped, the temperature was raised to 0° C., and the mixture was stirred for three hours at 0° C. After the temperature was raised to room temperature, the mixture was charged into a separatory funnel and extracted with 600 ml of methylene chloride, and the organic layer was washed with 600 ml of saturated ammonium sulfate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled away under reduced pressure. The concentrate was distilled under reduced pressure to obtain 17.11 g (0.083 mol ) of (±)-trans-2-(2-methoxyphenyl)-1-cyclohexanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[CH2:9][C:10]1[N:18]2[C:13]([C:14]([NH2:19])=[N:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1)=[O:5])[CH3:2].[Br:20]C1C(=O)C(C)(C)C(Br)C1=O>C1COCC1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[CH2:9][C:10]1[N:18]2[C:13]([C:14]([NH2:19])=[N:15][CH:16]=[N:17]2)=[C:12]([Br:20])[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC1Cc1ccc2c(N)ncnn12
Reactant: CC1(C)C(=O)C(Br)C(=O)C1Br
Solvent: C1CCOC1
Product: CCOC(=O)C1CC1Cc1cc(Br)c2c(N)ncnn12
Temperature: -20 °C
Reaction time: 2 h
Yield: 102.8 %

Procedure:
To a solution of 2-(4-amino-pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl)-cyclopropanecarboxylic acid ethyl ester (4.5 g, 17.2 mmol) in THF (73 mL) cooled to −20° C. was added 2,5-dibromo-4,4-dimethyl-cyclopentane-1,3-dione (2.4 g, 8.6 mmol) in four portions over 15 mins. The mixture was allowed to stir at −20° C. for 2 hours. The mixture was quenched with sodium thiosulfate solution (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was washed with water, brine, dried by Na2SO4, filtered and concentrated. The residue was purified by Biotage® to give 3.0 g (51%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.80 (s, 1 H), 8.75 (bs, 2 H), 6.60 (s, 1 H), 4.0 (m, 2 H), 2.9 (d, 2 H), 1.5 (m, 2 H), 1.2 (t, 3 H), 1.0 (m, 2 H); ES-MS m/z 339.19 [M+H]+, HPLC RT (min) 2.58.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[CH:10][N:11]=[C:5]2[CH:4]=1.O=P(Cl)(Cl)Cl.CN(C)[CH:19]=[O:20]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([CH:19]=[O:20])=[CH:10][N:11]=[C:5]2[CH:4]=1
Reactant: COc1ccn2ccnc2c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccn2c(C=O)cnc2c1
Temperature: 90 °C
Yield: 69 %

Procedure:
7-Methoxyimidazo[1,2-a]pyridine (621 mg, 4.2 mmol) was mixed with POCl3 (16.8 mmol) in dimethylformamide (4 mL). The reaction mixture was heated at 90° C. for 24 h and then cooled to room temperature. After the solvent was removed in vacuo, an oil was obtained. The oil was purified on a silica gel column eluting with EtOAc/Hexane (1:1) to afford 7-methoxyimidazo[1,2-a]pyridine-3-carbaldehyde (508 mg, 69%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[NH:23][CH:24]=[CH:25][C:18]=34)=[C:12]([F:26])[CH:11]=2)[CH:3]=1.C(N(C(C)C)C(C)C)C.[NH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>C(O)CCC>[F:26][C:12]1[CH:11]=[C:10]([NH:9][C:4]2[CH:3]=[C:2]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[N:7]=[C:6]([NH2:8])[N:5]=2)[CH:15]=[CH:14][C:13]=1[O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[NH:23][CH:24]=[CH:25][C:18]=12
Reactant: C1CNCCN1
Reactant: Nc1nc(Cl)cc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)cc(N2CCNCC2)n1

Procedure:
75 mg (0.20 mmol) of 6-chloro-N4-[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-phenyl]pyrimidine-2,4-diamine (from example 60) are dissolved in 3 ml of 1-butanol. 0.35 ml of N-ethyldiisopropylamine and 70 mg (0.81 mmol) of piperazine are added, and the mixture is heated at reflux for 5 hours. The solvent is then removed under reduced pressure and the residue is purified by preparative HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([S:17](C)(=O)=O)[CH2:14][C@H:13]2[C:21](=S)[OH:22])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].P([O-])([O-])(O)=O.[Na+].[Na+].C(N(CC)CC)C>C(Cl)Cl.O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]3[CH2:14][C@H:13]2[C:21](=[O:22])[S:17]3)=[O:11])=[CH:24][CH:25]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)[C@@H]1C[C@@H](C(O)=S)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1S[C@H]2C[C@@H]1N(C(=O)OCc1ccc([N+](=O)[O-])cc1)C2

Procedure:
For example, (2S,4R)-1-p-nitrobenzyloxycarbonyl -4-methanesulfonyl-2-pyrrolidinethiocarboxylic acid is allowed to react with disodium hydrogenphosphate or triethylamine in methylene chloride or tetrahydrofuran, thereby to give (1S,4S)-5-p-nitrobenzyloxycarbonyl-2-thia-5-azabicyclo[2.2.1]heptan-3-one.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH2:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[C:22]([Cl:29])[N:21]=1>CO>[Cl:29][C:22]1[N:21]=[C:20]([NH:11][CH:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=3)[CH2:6][CH2:7]2)[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=1
Reactant: NC1CCc2ccc(F)cc21
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=[N+]([O-])c1ccc(Cl)nc1NC1CCc2ccc(F)cc21
Yield: 52 %

Procedure:
Dissolve 6-fluoroindan-1-ylamine (8.50 g, 56.22 mmol) in methanol (200 mL) and triethylamine (8.62 mL, 61.84 mmol). Add 2,6-dichloro-3-nitropyridine (10.85 g, 56.22 mmol) and stir under nitrogen for 14 hours. Filter the reaction mixture and wash the solids with methanol and hexanes to give the title compound as a yellow solid (9.00 g, 52%). MS (ES) m/z=308 [M+1].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([CH:28]3[CH2:33][CH2:32][N:31]([C:8]([NH:7][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)=[O:15])[CH2:30][CH2:29]3)[S:26][CH:27]=2)=[CH:19][CH:18]=1
Reactant: O=C(Nc1cnccn1)OCC(Cl)(Cl)Cl
Reactant: Fc1ccc(-c2csc(C3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1cnccn1)N1CCC(c2nc(-c3ccc(F)cc3)cs2)CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 69.1 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyrazin-2-ylcarbamate (227 mg, 0.839 mmol), 4-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperidine (200 mg, 0.762 mmol) and diisopropylethylamine (0.266 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 6 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and ethyl acetate to give the desired product (202 mg, 69.2%) as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([F:30])[C:6]([NH:20][CH:21]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:37]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[CH:21]([NH:20][C:6]1[C:5]([F:30])=[CH:4][C:3]([C:1]([NH2:2])=[O:37])=[C:8]([NH:9][C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:7]=1)[CH2:25][C:26]([F:29])([F:27])[F:28]
Reactant: CC(=O)O
Reactant: N#Cc1cc(F)c(NC(CC(F)(F)F)C(N)=O)nc1Nc1cnc2ccccc2c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1cc(F)c(NC(CC(F)(F)F)C(N)=O)nc1Nc1cnc2ccccc2c1
Reaction time: 0.33 h

Procedure:
To a solution of crude 2-(5-cyano-3-fluoro-6-(quinolin-3-ylamino)pyridin-2-ylamino)-4,4,4-trifluorobutanamide (180 mg) in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1 mL) and aq. H2O2 (50%, 1 mL) were added. The mixture was stirred for 20 min. HOAc (0.5 mL) was added. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (44 mg). MS 437.3 (M+H); UV 202.2, 224.1, 295.2 nm; t 0.482 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10](OS(C)(=O)=O)[CH3:11])=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C=O)C>[N:23]([CH:10]([CH:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:11])=[N+:24]=[N-:25]
Reactant: CC(OS(C)(=O)=O)C(Cc1ccc(Cl)cc1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])C(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-chlorophenyl)-2-methanesulfonyloxy-3-phenylbutane (Step F, 12 g, 34 mmol) in DMF (50 mL) was added sodium azide (11 g, 0.17 mol). After stirring at 120° C. for 1 h, the reaction mixture was poured into water (200 mL), and the product was extracted with ether (2×100 mL). The combined organic extracts were washed with water, dried over MgSO4, filtered and concentrated to dryness, and the residue was purified on a silica gel column eluting with hexane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@@H:6]([CH3:13])[N:5]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:4]=2[N:3]=1.C(N(CC)CC)C.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:7](=[O:12])[C@@H:6]([CH3:13])[N:5]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[C:4]=2[N:3]=1
Reactant: C[C@@H]1C(=O)Nc2cnc(Cl)nc2N1C1CCCCC1
Reactant: OB(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1C(=O)N(c2ccccc2)c2cnc(Cl)nc2N1C1CCCCC1
Temperature: 25 °C
Yield: 39 %

Procedure:
To a solution of (7R)-2-chloro-8-cyclohexyl-7-methyl-7,8-dihydropteridin-6(5H)-one (280 mg, 1.0 mmol) in 10 mL of dry dichloromethane was added triethylamine (1.39 mL, 10 mmol), cupric acetate (363 mg, 2.0 mmol), phenylboronic acid (244 mg, 2.0 mmol) and 4 Å molecular sieves (2.0 g). The reaction mixture was allowed to stir at room temperature with air balloon on. The reaction mixture was then filtered over Celite, washed with dichloromethane and the organic layer was washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel flash chromatography, using dichloromethane-methanol mixture (v:v=99:1) as eluent, to give titled compound (yield: 39%). 1HNMR (300 MHz, CDCl3): δ 1.20-1.22 (m, 1H), 1.47-1.49 (m, 6H), 1.72-1.77 (m, 3H), 1.87-1.89 (m, 2H), 2.10-2.13 (m, 1H), 4.44-4.49 (m, 2H), 7.17 (s, 1H), 7.20-7.24 (m, 2H), 7.48-7.56 (m, 3H).
Reaction SMILES: [CH3:1][Si:2]([O:7][CH3:8])([O:5][CH3:6])[O:3][CH3:4].[CH2:9]([Si:12]([CH3:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])CC.[CH2:20]([Si](C)(Cl)Cl)[CH2:21][CH3:22].[OH-:27].[K+:28]>O.C(O)C.CO>[CH3:1][Si:2]([O:7][CH3:8])([O:5][CH3:6])[O:3][CH3:4].[CH2:20]([CH:17]([O:16][Si:12]([CH3:9])([CH3:19])[O:13][CH2:14][CH3:15])[CH3:18])[CH2:21][CH3:22].[OH-:27].[K+:28]
Reactant: CCC[Si](C)(OCC)OCC
Reactant: CCC[Si](C)(Cl)Cl
Agent: CO[Si](C)(OC)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CO
Product: CCCC(C)O[Si](C)(C)OCC

Procedure:
A 500 ml 5-neck round-bottom flask, inertized with nitrogen and fitted with paddle stirrer, dropping funnel, thermometer, and water separator with reflux condenser, is charged with 27 g (0.198 mol) of methyltrimethoxysilane (available commercially from Wacker Chemie AG), 3.9 g (0.02) of n-propyl(methyl)diethoxysilane (prepared in the laboratory by reacting n-propyl(methyl)dichlorosilane with ethanol) and 20 g of Isopar E (isoparaffinic hydrocarbon mixture with a boiling range of 113-143° C., available commercially from ExxonMobil). The water separator is filled to the brim with Isopar E. Accompanied by stirring at 350 rpm, a solution of 12.4 g (0.188 mol) of potassium hydroxide (85% form, available commercially from AppliChem) in 7.9 g (0.44 mol) of demineralized water is metered in over 12 minutes. The mixture heats up to 48° C. It is heated to boiling temperature. The distillate separates off as the bottom phase in the water separator. Up to a boiling temperature of 95° C., 19.4 g of colorless, slightly turbid distillate accumulate, containing—according to analysis by gas chromatography—78.5% of methanol, 7.5% of ethanol, 3.5% of water, and 8.2% of Isopar E. The bottom phase is drained off from the water separator, which is made up completely with Isopar E again, and water is removed in circulation at a boiling temperature of up to 131° C. This produces 6.2 g of distillate as bottom phase, which according to GC analysis contains 46.9% of methanol, 4.7% of ethanol, and 48.4% of water. During the distillation, a pastelike white solid separates out in the reaction mixture, and breaks down increasingly into fine particles and forms a suspension. 10 g of cyclohexane are added and the suspension is filtered through a Beco KD3 filter plate in a pressure suction filter, and nitrogen is passed through to constant weight. This gives 21.4 g of fine, white, free-flowable powder with a solids content of 99.5% (determined using the HR73 halogen moisture analyzer from Mettler Toledo at 160° C.). A 50% strength aqueous solution prepared with this solid exhibits no precipitation even after storage at room temperature for two weeks in the absence of air.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][SH:15].O.O.O.C([O-])(=O)C.[Na+]>C(O)C.O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]2[NH:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][S:15]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: N[C@@H](CS)C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(C2N[C@H](C(=O)O)CS2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.9 %

Procedure:
4-Cyanobenzaldehyde (500 mg, 3.8 mmol) was dissolved in 5 ml of ethanol (96%) and L-(+)-cysteine hydrochloride (460 mg, 3.8 mmol) and natriumacetate trihydrate (468 mg, 5.7 mmol) dissolved in 5 ml of water was added. The reaction mixture was stirred for 16 hours at room temperature and the white crystals were collected by filtration and washed twice with 15 ml of water:ethanol (1:1), to afford 400 mg of 2-(RS)-(4-cyanophenyl)thiazolidine-4-(R)-carboxylic acid (48) in 44% yield. 1H-NMR (MEOH, 300 MHz) δ: 7.69 (m, 4H); 5.81 (s, ½H); 5.60 (s, ½H); 4.23 (dd, ½H); 4.02 (dd, ½H); 3.52-3.17 (m, 2H).