Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:26][C:11]3[CH:12]=[N:13][C:14]([NH:16][C:17]([CH:19]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[O:18])=[CH:15][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH:27]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.O.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH:27]1([C:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:26][C:11]4[CH:12]=[N:13][C:14]([NH:16][C:17]([CH:19]5[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]5)=[O:18])=[CH:15][C:10]=4[N:9]=3)=[CH:4][CH:3]=2)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Nc1ccc(-c2nc3cc(NC(=O)C4CCCCCC4)ncc3[nH]2)cc1
Reactant: O=C(Cl)C1CCCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc2nc(-c3ccc(C(=O)C4CCCCCC4)cc3)[nH]c2cn1)C1CCCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
The amine 19 (0.094 g, 0.27 mmol) was taken in dry Pyridine (5 ml) and cycloheptane carbonyl chloride (0.100 ml, 0.622 mmol) was added and the solution stirred at room temperature overnight. Water was added followed by sat. NaHCO3 solution. The mixture was stirred at room temperature for 1 h. The solid was filtered, dried and passed through a SiO2 gel column, eluting with ethyl acetate afforded a white solid 20 (0.050 g, 39%). M.p. 194° C.; 1H NMR (DMSO-d6, 500 MHz): δ13.40 (1H, brs, NH), 10.09 (2H, s, NH), 8.81 (1H, brs), 8.145 (2H, d, J=9.0 MHz), 7.82 (2H, d, J=9.0 Hz), 2.74 (1H, m), 2.49 (1H, m), 1.91-1.25 (24H, m); EIMS m/z: 474.4 (M+1) and 472.6 (M−1); Anal (C28H35N5O2) C, H, N.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:13][C:12]([CH:22]=[O:23])=[CH:11][C:10]=1[C:24]([CH3:27])([CH3:26])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([Mg]Br)#[CH:29].[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=[CH:13][C:12]([CH:22]([OH:23])[C:28]#[CH:29])=[CH:11][C:10]=1[C:24]([CH3:27])([CH3:26])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Mg]Br
Reactant: Cc1ccc(-c2cc(C=O)cc(C(C)(C)C)c2OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)c1cc(-c2ccc(C)cc2)c(OCc2ccccc2)c(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
780 mg (2.2 mmol) of 6-benzyloxy-5-tert-butyl-4′-methyl-3-biphenylcarbaldehyde are dissolved in 50 mL of THF, and the reaction medium is cooled to 0° C. 5.7 mL (2.8 mmol) of 0.5 M ethynylmagnesium bromide solution are added slowly. The medium is stirred at 0° C. for 2 hours and the reaction is then treated with a saturated ammonium chloride solution. The residue obtained is purified by chromatography on a column of silica (eluent: 9 heptane/1 ethyl acetate). A yellow oil is obtained (m=740 mg; yield=89%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH2:11][CH:12]3[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]3)[N:7]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH2:25])[N:20]=3)[C:6]=2[CH:26]=1.[CH3:27][C:28]1[O:32][N:31]=[C:30]([C:33]([OH:37])([C:35]#[CH:36])[CH3:34])[CH:29]=1.C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:25][C:21]1[N:20]=[C:19]([N:7]2[C:6]3[CH:26]=[C:2]([C:36]#[C:35][C:33]([C:30]4[CH:29]=[C:28]([CH3:27])[O:32][N:31]=4)([OH:37])[CH3:34])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:10][CH2:11][CH:12]2[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]2)[CH:24]=[CH:23][N:22]=1
Reactant: C#CC(C)(O)c1cc(C)on1
Reactant: CC1(C)OCC(COc2nc3ccc(Br)cc3n2-c2ccnc(N)n2)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)(O)C#Cc2ccc3nc(OCC4COC(C)(C)O4)n(-c4ccnc(N)n4)c3c2)no1
Temperature: 70 °C
Reaction time: 1 h
Yield: 17.2 %

Procedure:
A mixture of 4-[6-bromo-2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (150 mg, 0.32 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (300 mg, 1.98 mmol), bis(triphenylphosphine)palladium(II) dichloride (300 mg, 0.43 mmol) and triethylamine (2 mL) in dimethylsulfoxide (3 mL) was stirred for 1 h at 70° C. under a nitrogen atmosphere. The reaction mixture was cooled to room temperature then filtered through a frit filter to remove the catalyst. The filtrate was purified on a C18 column (acetonitrile/water, 5:95-80:20) to yield 27 mg (17%) of 4-[1-(2-aminopyrimidin-4-yl)-2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol as a white solid: 1H NMR (400 MHz, DMSO) delta 8.38 (d, J=5.2 Hz, 1H), 8.18 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.09 (s, 2H), 7.02 (d, J=5.2 Hz, 1H), 6.44 (s, 1H), 6.38 (s, 1H), 4.69-4.54 (m, 3H), 4.11 (t, J=7.4 Hz, 1H), 3.89 (t, J=7.2 Hz, 1H), 2.41 (s, 3H), 1.81 (s, 3H), 1.32 (d, J=16 Hz, 6H); LC-MS: m/z=+491 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20](OC)[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1[NH:28][C:29](=[O:31])[CH3:30].[CH3:32]C1NC2C(C=1CC(O)=O)=CC=CC=2.C(NC1C(Cl)=CC(CN)=CC=1Cl)(=O)C>>[Cl:27][C:4]1[CH:5]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[CH3:32])[CH:7]=[C:2]([Cl:1])[C:3]=1[NH:28][C:29](=[O:31])[CH3:30]
Reactant: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1
Reactant: Cc1[nH]c2ccccc2c1CC(=O)O
Agent: CC(=O)Nc1c(Cl)cc(CN)cc1Cl
Product: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c(C)[nH]c3ccccc23)cc1Cl

Procedure:
In a manner similar to that used in the preparation of the compound of example 2, but using 2-(2-methyl-1H-indol-3-yl)acetic acid in step 11 (A) and 4-acetamido-3,5-dichloro-benzylamine (preparation B) in step 11 (B), the title compound was prepared. MS (ESI) (M+H)+=446.08 1H-NMR (500 MHz, CD3OD) δ 7.36-7.50 (m, 3 H), 7.30 (d, J=7.93 Hz, 1 H), 7.00-7.10 (m, 2 H), 4.52 (s, 2 H), 3.92 (s, 2 H), 2.44 (s, 3 H), 2.19 (s, 3 H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[S:12](Cl)(Cl)(=O)=O.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>CCCCC>[CH2:17]([N:19]([CH2:20][CH3:21])[S:12][S:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:6][CH3:7])[O:8][CH3:9])[CH3:18]
Reactant: CCNCC
Reactant: O=S(=O)(Cl)Cl
Reactant: CO[Si](CCCS)(OC)OC
Solvent: CCCCC
Product: CCN(CC)SSCCC[Si](OC)(OC)OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a 3 liter 3-necked round bottom glass flask fitted with a dry-ice/acetone condenser, stirrer and dropping funnel was charged 196 grams (1.0 moles) 1-mercapto-3-trimethoxysilylpropane and 2 liters of n-pentane. The mixture was stirred until completely homogeneous afterwhich 135 grams (1.0 moles) of sulfuryl chloride was slowly added with stirring at room temperature. Nitrogen was slowly passed through the mixture for about 20 minutes. The liquid contents were transferred to a dropping funnel and slowly added at about 25 C. to a stirred solution of 160 grams (2.19 moles) diethylamine and 0.3 liter n-pentane. After the addition was complete (2 hrs) the mixture was stirred for an additional 0.5 hrs., filtered and the solid residue washed with 0.5 liters n-pentane. The n-pentane solvent was removed under vacuum with nitrogen. Nitrogen was passed through the residue for 16-20 additional hours under atmospheric conditions. The remaining sludge was again filtered to give 204 grams (68 mole % yield) of a liquid product considered to be the desired product. Analysis by GLC indicate 64.13% purity. Elemental analysis based on 64.13% pure C10H25O3NS2Si is: Calc. N, 2.99; S, 13.7. Found N, 3.97; S, 12.9.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([Br:15])[C:12]([F:14])=[CH:13][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-].O>C1COCC1>[Br:15][C:11]1[C:12]([F:14])=[CH:13][C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[S:9][C:8]=2[CH:10]=1
Reactant: COC(=O)c1cc2cc(F)c(Br)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2cc(F)c(Br)cc2s1
Yield: 90.9 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 25 for the preparation of I-25b above, 6-bromo-5-fluoro-benzo[b]thiophene-2-carboxylic acid methyl ester (I-27b: 0.3 g, 1.0 mmol) in THF (10 mL) was hydrolyzed with LiOH (87 mg, 2.04 mmol) and water (2 mL) to afford 250 mg of the product (yield 88%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.C(O)(=O)C.[N:14]([O-])=[O:15].[Na+]>O>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([N:14]=[O:15])=[C:4]([NH2:9])[N:3]=1
Reactant: O=N[O-]
Reactant: Nc1cc(O)nc(N)n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(N)c(N=O)c(O)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of 2,6-diamino-4-hydroxypyrimidine (12.9 g, 102.2 mmoles) in 200 ml of a 10% acetic acid solution in water at 80° C. was added dropwise a solution of NaNO2 (7.05 g, 102.2 mmoles) in 20 ml water. A pink precipitate was formed, which was further stirred for 1 hour at 80° C. The reaction mixture was cooled down in the refrigerator overnight. The precipitate was filtered off and dried over P2O5, providing the title compound as a pink powder (15.43 g, yield: 97%). The spectral data are in accordance with literature data (Landauer et al. in J. Chem. Soc. (1953) 3721-3722).
Reaction SMILES: C(C1C=C2C(=CC=1)N=C(C(OCC)=O)NC2=O)#N.[CH3:19][C:20]1[C:28]2[C:27](=[O:29])[NH:26][C:25]([C:30]([O:32]CC)=O)=[N:24][C:23]=2[S:22][CH:21]=1.NCC1C=C(C=CC=1)N.[NH2:44][CH2:45][C:46]1[CH:47]=[C:48]([CH2:52][NH:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[CH:49]=[CH:50][CH:51]=1>>[CH3:19][C:20]1[C:28]2[C:27](=[O:29])[NH:26][C:25]([C:30]([NH:44][CH2:45][C:46]3[CH:47]=[C:48]([CH2:52][NH:53][C:54](=[O:60])[O:55][C:56]([CH3:58])([CH3:57])[CH3:59])[CH:49]=[CH:50][CH:51]=3)=[O:32])=[N:24][C:23]=2[S:22][CH:21]=1
Reactant: CCOC(=O)c1nc2scc(C)c2c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN)c1
Agent: CCOC(=O)c1nc2ccc(C#N)cc2c(=O)[nH]1
Agent: NCc1cccc(N)c1
Product: Cc1csc2nc(C(=O)NCc3cccc(CNC(=O)OC(C)(C)C)c3)[nH]c(=O)c12

Procedure:
By a method similar to that in Reference Example 45, and using, instead of ethyl 6-cyano-4-oxo-3,4-dihydroquinazoline-2-carboxylate, ethyl 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained according to the method described in U.S. Pat. No. 4,054,656 and using, instead of 3-(aminomethyl)aniline, 1,1-dimethylethyl {[3-(aminomethyl)phenyl]methyl}carbamate, the title compound was obtained as a white powder (2.11 g, 82%).
Reaction SMILES: [Br-].[C:2]1([CH2:8][CH2:9][CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[O:46][N:45]=[C:44]([CH3:47])[C:43]=2[CH:48]=O)=[CH:38][CH:37]=1>C1COCC1.Cl>[Br:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[O:46][N:45]=[C:44]([CH3:47])[C:43]=2[CH:48]=[CH:10][CH2:9][CH2:8][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:40][CH:41]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: c1ccc(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(Br)cc2)c1C=CCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (3-phenylpropyl)triphenylphosphonium bromide (0.956 g, 2.07 mmol) in THF (5 mL) at −78° C. was slowly added n-butyllithium (2.5 M in hexanes, 0.83 mL, 2.07 mmol) and the mixture was stirred for 15 minutes. 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.500 g, 1.88 mmol) in THF (3 mL) was added, and the reaction was warmed to 0° C. and stirred for 1 hour. The solution was diluted with 1 N aqueous HCl and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, decanted, and concentrated. The residue was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the title compound.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[N:21]1[CH:26]=[C:25](B(O)O)[CH:24]=[N:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][C@@H:14]1[CH2:15][CH2:16][CH2:17][N:13]1[C@H:11]1[CH2:12][C@H:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([C:25]4[CH:26]=[N:21][CH:22]=[N:23][CH:24]=4)[CH:20]=[CH:19][C:5]=3[N:6]=2)[CH2:10]1
Reactant: OB(O)c1cncnc1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(-c4cncnc4)cc3s2)C1

Procedure:
A solution of the product of Example 1E (40 mg, 0.114 mmole), pyrimidine-5-boronic acid (CAS #109299-78-7) (21 mg, 0.169 mmole), dichlorobis(triphenylphosphine)palladium(II) (8 mg, 0.01 mmole) and potassium carbonate (47 mg, 0.34 mmole) in 1 ml isopropanol was heated at 85° C. overnight with stirring. The reaction was then quenched with water and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (eluted by 0.35% ammonium hydroxide and 3.5% methanol in dichloromethane) to give 33 mg (82% yield) of title compound. 1H NMR (400 MHz, CDCl3) δ ppm 9.23 (s, 1H), 9.02 (s, 2H), 8.12 (d, J=8.59 Hz, 1H), 8.06 (d, J=1.84 Hz, 1H), 7.67 (dd, J=8.44, 1.99 Hz, 1H), 3.83-3.94 (m, 1H), 3.46-3.62 (m, 1H), 2.99-3.14 (m, 1H), 2.64-2.85 (m, 3H), 2.43-2.64 (m, 2H), 2.23-2.40 (m, 1H), 1.89-2.03 (m, 1H), 1.78-1.91 (m, 1H), 1.67-1.78 (m, 1H), 1.42-1.56 (m, 1H), 1.14 (d, J=4.91 Hz, 3H). MS: (M+H)+=351.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([F:26])=[C:16]([C@@:18]4([CH3:25])[NH:23][C:22](=S)[CH2:21][O:20][CH2:19]4)[CH:17]=3)[CH2:7][CH2:8][C:9]=2[CH:10]=1.C(OO)(C)(C)C.[NH3:33]>CO>[NH2:33][C:22]1[CH2:21][O:20][CH2:19][C@:18]([C:16]2[CH:17]=[C:12]([NH:11][CH:6]3[C:5]4[N:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=4[CH2:8][CH2:7]3)[CH:13]=[CH:14][C:15]=2[F:26])([CH3:25])[N:23]=1
Reactant: N
Reactant: C[C@@]1(c2cc(NC3CCc4cc(Cl)cnc43)ccc2F)COCC(=S)N1
Agent: CC(C)(C)OO
Solvent: CO
Product: C[C@@]1(c2cc(NC3CCc4cc(Cl)cnc43)ccc2F)COCC(N)=N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a pressure tube (R)-5-[5-((RS)-3-chloro-6,7-dihydro-5H-[1]pyrindin-7-ylamino)-2-fluoro-phenyl]-5-methyl-morpholin-3-thione (58 mg, 0.15 mmol) was dissolved in a solution of ammonia in methanol (7M, 0.5 ml). Then tert-butyl hydroperoxide (70% in water) (0.07 ml, 0.74 mmol) was added. The tube was sealed and the mixture stirred for 4 hours at room temperature. For the workup, the solution was evaporated at reduced pressure. NMR analysis showed still starting material. The residue was redissolved in a solution ammonia in methanol (7M, 0.5 ml) and heated to 50° C. for 3 days. Thereafter, another 0.5 ml were added, then after 1 day another 0.071 ml (0.74 mmol) of tert-butyl hydroperoxide. After stirring at room temperature for 4.5 hours the reaction mixture was quenched with a saturated aqueous solution of sodium carbonate, thereafter extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate, then evaporated at reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 0:100 as the eluent. The [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-((RS)-3-chloro-6,7-dihydro-5H-[1]pyrindin-7-yl)-amine was obtained as a white foam (33 mg, 60%); (calculated) C19H20ClFN4O [374.85]; (found) [M+H]+=375.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])=[CH2:2].[NH3:12]>CCOC(C)=O>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:12])=[O:7])=[CH2:2]
Reactant: C=Cc1cccc(C(=O)Cl)c1
Reactant: N
Solvent: CCOC(C)=O
Product: C=Cc1cccc(C(N)=O)c1

Procedure:
3-Vinylbenzoyl chloride is saturated with ammonia gas to afford an immediate precipitate. This mixture is poured into EtOAc and extracted with water and brine. The EtOAc is dried, filtered, and concentrated to afford the title compound: mp=128-130° C.; 1H NMR (CDCl3) δ 7.86 (d, J=1.3 Hz, 1H), 7.66 (dd, J=8.6, 1.0 Hz, 1H), 7.57 (d, 7.8 Hz, 1H), 7.41 (t, 7.8 Hz, 1H), 6.75 (dd, J=17.4, 10.9 Hz, 1H), 6.05 (br s, 1H), 5.83 (d, J=17.9 Hz, 1H), 5.61 (br s, 1H), 5.34 (d, J=10.9 Hz, 1H).
Reaction SMILES: C([O:4][C@H:5]1[CH2:9][C@@H:8]([OH:10])[CH:7]=[CH:6]1)(=O)C.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:19]([Si:16]([CH3:18])([CH3:17])[O:4][C@@H:5]1[CH2:9][C@H:8]([OH:10])[CH:7]=[CH:6]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(=O)O[C@@H]1C=C[C@H](O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,4S)-4-acetoxy-2-cyclopenten-1-ol (1.0 g, 7.03 mmol) (Fluka) and imidazole (960 mg, 14.06 mmol) (Aldrich) in tetrahydrofuran (65 mL) at 0° C. was added tert-butyldimethylsilyl chloride (1.27 g, 8.44 mmol) (Aldrich). The mixture was allowed to warm slowly to room temperature, stirred overnight and then partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to a residue that was dissolved in methanol (approximately 45 mL). To this solution was added potassium carbonate (1.17 g, 8.44 mmol) and the mixture stirred overnight. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to a residue that was purified by silica gel column chromatography with a 0–30% diethyl ether in hexanes gradient to give (+)-(1S,4R)-4-(tert-butyl-dimethyl-silanyloxy)-cyclopent-2-enol as a colorless oil. (Yield 1.43 g, 95%).
Reaction SMILES: C1([C:7]2C=CC3C(=CC(C(=O)C)=CC=3)[N:8]=2)C=CC=CC=1.C(#N)CC#N.[S].N1CCOCC1.[CH:32]([NH2:34])=O.[NH2:35][C:36]1[S:37][CH:38]=[C:39]([C:43]2[CH:52]=[C:51]3[C:46]([CH:47]=[CH:48][C:49]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)=[N:50]3)=[CH:45][CH:44]=2)[C:40]=1C#N>[Cl-].[Na+].O>[C:53]1([C:49]2[CH:48]=[CH:47][C:46]3[C:51](=[CH:52][C:43]([C:39]4[C:40]5[C:32]([NH2:34])=[N:8][CH:7]=[N:35][C:36]=5[S:37][CH:38]=4)=[CH:44][CH:45]=3)[N:50]=2)[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: CC(=O)c1ccc2ccc(-c3ccccc3)nc2c1
Reactant: NC=O
Reactant: N#Cc1c(-c2ccc3ccc(-c4ccccc4)nc3c2)csc1N
Agent: [Cl-]
Agent: [Na+]
Agent: [S]
Solvent: C1COCCN1
Solvent: N#CCC#N
Solvent: O
Product: Nc1ncnc2scc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Temperature: 80 °C

Procedure:
One-pot synthesis from 1-(2-phenylquinolin-7-yl)-ethanone: The mixture of 1-(2-phenylquinolin-7-yl)-ethanone (50 mg, 0.20 mmol), malononitrile (40 mg, 0.60 mmol), sulfur (39 mg, 1.2 mmol), morpholine (0.12 ml), and formamide (1.0 ml) in a sealed tube was heated at 80° C. for 17 h under N2. LC-MS confirmed the formation of 2-amino-4-(2-phenylquinolin-7-yl)-thiophene-3-carbonitrile (MS (ES+): m/z 328.1 (100) [MH+]). The above mixture was then heated to 180° C. for 3 h. The cooled reaction mixture was poured into brine (10 ml) and extracted with EtOAc (3×15 ml). The combined organic extracts were washed with brine (10 ml), dried over MgSO4, filtered, and concentrated to give a brown oil. Purification by TLC on silica gel [eluting with EtOAc/hexane (40/60)], followed by HPLC gave the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([N:5]1[C:12](=[O:13])[C:11]2[CH2:14][CH:15]3[CH2:17][CH:6]1[CH:7]=[C:8]([S:18]([NH2:21])(=[O:20])=[O:19])[S:9][C:10]=2S3)[CH:2]([CH3:4])[CH3:3].OO[S:24]([O-:26])=[O:25].[K+].CO>O>[CH2:1]([N:5]1[C:12](=[O:13])[C:11]2[CH2:14][CH:15]3[CH2:17][CH:6]1[CH:7]=[C:8]([S:18]([NH2:21])(=[O:20])=[O:19])[S:9][C:10]=2[S:24]3(=[O:26])=[O:25])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN1C(=O)C2=C3SC(S(N)(=O)=O)=CC1CC(C2)S3
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)CN1C(=O)C2=C3SC(S(N)(=O)=O)=CC1CC(C2)S3(=O)=O
Reaction time: 24 h

Procedure:
5-Isobutyl-4-oxo-3,4,5,6-tetrahydro-2H-2,6-methanothieno[3,2-g]-1,5-thiazocine-8-sulfonamide (2 g, 5.8 mmol) was added to a mixture of Oxone® (10 g, 16.3 mmol) and methanol (25 ml). After 24 hours, the reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). After drying over sodium sulfate, the solvent was evaporated under reduced pressure to yield 2.13 of a foam. A sample triturated with 1-chlorobutane gave material with mp 239°-241° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[NH4+].[Cl-]>[Zn].CO>[Cl:1][C:2]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[C:13]1([NH2:15])[CH:14]=[CH:2][CH:3]=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(OCc2nccs2)c(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1ccc(OCc2nccs2)c(Cl)c1
Product: Nc1ccccc1
Reaction time: 2 h
Yield: 397.9 %

Procedure:
3-Chloro-4-(thiazol-2-ylmethoxy)-phenylamine is prepared by added Zn dust (55.9 g, 856 mmol) to a mixture of 2-(2-chloro-4-nitro-phenoxymethyl)-thiazole (47.0 g, 190 mmol) in 5:1 MeOH:saturated aqueous NH4Cl solution (600 ml). After 2 h, the reaction mixture is filtered, and the filtrate concentrated. The resulting solid is triturated with water to give 3-chloro-4 thiazol-2-ylmethoxy)-phenylamine (35.2 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:24][C:25](Br)=[O:26].[CH2:28]([NH:35][CH3:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:24][C:25]([N:35]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:36])=[O:26])=[CH:21][CH:22]=1
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(F)cc1)NCC2
Reactant: O=C(Br)CBr
Reactant: CNCc1ccccc1
Product: COc1cc2c(cc1OC)C(Cc1ccc(F)cc1)N(CC(=O)N(C)Cc1ccccc1)CC2

Procedure:
prepared by reaction of 1-(4-Fluoro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with N-benzyl-N-methylamine
Reaction SMILES: [Br:1][C:2]1[C:6]([S:7][C:8]([F:11])([F:10])[F:9])=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[NH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].CC(C)([O-])C.[K+].[CH2:29]([O:31][CH2:32]Cl)[CH3:30]>O1CCCC1.CCOCC.O>[Br:1][C:2]1[C:6]([S:7][C:8]([F:10])([F:9])[F:11])=[C:5]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[N:4]([CH2:32][O:31][CH2:29][CH3:30])[C:3]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CCOCCl
Reactant: FC(F)(F)Sc1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOCn1c(-c2ccc(Cl)cc2)c(SC(F)(F)F)c(Br)c1C(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of 3-bromo-5-(p-chlorophenyl)-2-(trifluoromethyl)-4-[(trifluoromethyl)thio]pyrrole (0.6 g, 1.4 mmol) and potassium tert-butoxide (0.19 g, 1.7 mmol) in tetrahydrofuran is stirred for 15 minutes, treated with chloromethyl ethyl ether (0.16 g, 1.7 mmol), stirred for 30 minutes and diluted with an ether/water mixture. The organic phase is separated, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a residue. Chromatography of the residue using silica gel and a 1:9 ethyl acetate/hexanes solution gives the title product as an amber oil which is identified by 1HNMR and 13CNMR spectral analyses.