Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]([C:17]1[CH:30]=[CH:29][C:20]([O:21][CH2:22][C:23]([OH:28])([CH2:26][CH3:27])[CH2:24][CH3:25])=[C:19]([CH3:31])[CH:18]=1)([C:6]1[S:10][C:9]2[CH:11]=[C:12]([O:15]C)[CH:13]=[CH:14][C:8]=2[CH:7]=1)[CH2:4][CH3:5])[CH3:2].CN(C=O)C>C(OCC)C>[CH2:1]([C:3]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:8]=2[CH:7]=1)([C:17]1[CH:30]=[CH:29][C:20]([O:21][CH2:22][C:23]([CH2:24][CH3:25])([OH:28])[CH2:26][CH3:27])=[C:19]([CH3:31])[CH:18]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(O)(CC)COc1ccc(C(CC)(CC)c2cc3ccc(OC)cc3s2)cc1C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCC(O)(CC)COc1ccc(C(CC)(CC)c2cc3ccc(O)cc3s2)cc1C
Temperature: 100 °C
Yield: 86.3 %

Procedure:
To a solution of 3-{4-[1-ethyl-1-(6-methoxy-benzo[b]thiophen-2-yl)-propyl]-2-methyl-phenoxymethyl}-pentan-3-ol (0.80 g, 1.82 mmol) and DMF (10 mL) is added NaSEt (1.53 g, 18.15 mmol). The resulting solution is heated at 100° C. overnight, diluted with diethyl ether (50 mL), washed with water (3×50 mL), brine (50 mL), dried with MgSO4, filtered and concentrated. The resulting residue is purified by silica gel chromatography (10% to 40% EtOAc gradient) to give the title compound (0.67 g, 1.57 mmol, 87%). 1H NMR (CDCl3), δ 0.75 (t, J=7.2 Hz, 6H), 0.95 (t, J=7.4 Hz, 6H), 1.67 (q, J=15.1, 7.4 Hz, 4H), 2.12-2.24 (m, 7H), 3.82 (s, 2H), 6.73 (d, J=8.6 Hz, 1H), 6.79 (dd, J=9.0, 2.6 Hz, 1H), 6.79 (dd, J=9.0, 2.6 Hz, 1H), 7.00 (s, 1H), 7.05 (d, J=2.2 Hz, 1H), 7.08 (dd, J=8.2, 2.6 Hz, 1H), 7.11 (d, J=2.2 Hz, 1H), 7.49 (d, J=9.0 Hz, 1H). LC/MS (m/z): calcd. for C26H35O3S (M+H)+: 427.2; found: 427.1.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([O:11][CH3:12])[N:5]=[C:4]([O:13][CH3:14])[N:3]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH2:23][C:24]#[N:25])[CH:19]=[C:20]([CH3:22])[CH:21]=1.[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Br:15][C:16]1[CH:17]=[C:18]([CH:23]([C:2]2[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([O:11][CH3:12])[N:5]=[C:4]([O:13][CH3:14])[N:3]=2)[C:24]#[N:25])[CH:19]=[C:20]([CH3:22])[CH:21]=1
Reactant: COc1nc(Cl)c(C(C)C)c(OC)n1
Reactant: Cc1cc(Br)cc(CC#N)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1nc(OC)c(C(C)C)c(C(C#N)c2cc(C)cc(Br)c2)n1
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a stirred mixture of 4-chloro-5-isopropyl-2,6-dimethoxy-pyrimidine (47.63 g, 0.22 M) and (3-bromo-5-methyl-phenyl)-acetonitrile (42 g, 0.2 M) in anhydrous DMF (220 mL) in an ice-water bath under an atmosphere of nitrogen, was added 60% sodium hydride (16 g, 0.4 M) in portions. After stirring for 1 hr, the mixture was stirred at room temperature for overnight. The mixture was neutralized with aqueous saturated ammonium chloride solution. The crude product was extracted with ether and purified by silica gel column chromatography (eluent, ether:hexanes (1:7)) to afford 68 g (87%) of a white solid. m.p. 123-124° C.; 1H NMR (200 MHz, CDCl3) δ 1.11 (3H, d, J=6.9 Hz), 1.15 (3H, D, J=6.9 Hz), 2.32 (3H, s), 2.97 (1H, m), 4.00 (3H, s), 4.01 (3H, s), 5.34 (1H, s), 7.14 (1H, s), 7.28 (1H, s), 7.31 (1H, s).
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[C:5](/[CH:8]=[N:9]/O)=[N:4][CH:3]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C1COCC1>[Br:1][C:2]1[N:6]([CH3:7])[C:5]([C:8]#[N:9])=[N:4][CH:3]=1
Reactant: Cn1c(Br)cnc1/C=N/O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: Cn1c(Br)cnc1C#N
Temperature: 0 °C
Reaction time: 3 h
Yield: 43.4 %

Procedure:
(E)-5-Bromo-1-methyl-1H-imidazole-2-carbaldehyde oxime (Preparation 155, 38 mg, 0.186 mmol) and TEA (39 uL, 0.279 mmol) was stirred in THF (6 mL) and cooled at 0° C., TFAA (28 uL, 0.205 mmol) was added. Then the mixture was stirred at 60° C. under microwave irradiation for 3 hours. The reaction was purified directly by Biotage silica gel column chromatography eluting with 20% EtOAc in cyclohexanes to give the title compound as yellow solid (15 mg, 43%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[N:24]=[C:23]([NH2:25])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[NH:34][S:35](C1C=CC(C2C=C3N=C(CCC4CCCCC(=S)N4)NC3=NC=2)=CC=1)(=[O:37])=[O:36].N>CO>[NH2:25][C:23]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]([CH2:17][CH2:16][C:14]2[NH:13][C:10]3=[N:11][CH:12]=[C:7]([C:1]4[CH:2]=[CH:3][C:4]([S:35]([NH:34][C:28]5[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]=5[F:26])(=[O:36])=[O:37])=[CH:5][CH:6]=4)[CH:8]=[C:9]3[N:15]=2)[N:24]=1
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(-c3cnc4[nH]c(CCC5CCCCC(=S)N5)nc4c3)cc2)c(F)c1
Reactant: NC1=NC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)CCCC1
Agent: N
Solvent: CO
Product: Cc1ccc(NS(=O)(=O)c2ccc(-c3cnc4[nH]c(CCC5CCCCC(N)=N5)nc4c3)cc2)c(F)c1

Procedure:
The title compound is synthesized as described for 7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine (compound 1) from 100 mg of N-(2-fluoro-4-methyl-phenyl)-4-{2-[2-(7-thioxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-benzenesulfonamide (compound A8) and 4.30 ml of methanol containing ammonia (strength: 7.0 M) at 50° C. for 90 hours. Subsequently, the mixture is filtered with suction. The residue is washed with 20 ml of methanol and dried under high vacuum to afford 61 mg of the pure title compound as an amorphous, colorless solid of m.p. 265° C. ESI-MS: 521.2 (MH+), TLC: Rf=0.28 (HPTLC RP-C18; acetonitrile/water 2:1 parts by volume).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([CH:25]=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.Cl.[NH2:28][OH:29].N1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CO.O>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([CH:25]=[N:28][OH:29])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(C=O)c3ccccc23)cc1
Reactant: NO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CO
Product: ON=Cc1ccc(-c2ccc(O)cc2)c2ccccc12
Reaction time: 0.08 h
Yield: 40.7 %

Procedure:
A mixture of 4-[4-(tert-butyldimethylsilanyloxy)-phenyl]-naphthalene-1-carbaldehyde (510 mg, 1.40 mmol), hydroxylamine hydrochloride (196 mg, 2.82 mmol), and anhydrous pyridine (0.228 ml, 2.82 mmol) in MeOH (3.2 ml) was heated to reflux for 3 h. The mixture was then concentrated under reduced pressure and dissolved in ether (5 ml). Then 1.0 M TBAF in THF (5.1 ml, 4.2 mmol) was added and stirred for 5 minutes. To the reaction was added water (5 ml) and then extracted with EtOAc. The organics were dried over anhydrous Na2SO4 and passed through a silica plug. Evaporation of the solvent and purification by column chromatography (10% MeOH-EtOAc) afforded 150 mg (41%) of product as a white solid: mp 200.0–200.5° C.; 1H NMR (300 MHz, DMSO-d6): δ 6.93 (2H, d, J=8.0 Hz), 7.29 (2H, d, J=8.0 Hz), 7.42 (1H, d, J=7.3 Hz), 7.54 (1H, appt, J=7.6 Hz). 7.61 (1H, appt, J=7.6 Hz), 7.83 (1H, d, J=7.3), 7.92 (1H, d, J=8.4 Hz), 8.73 (1H, d, J=8.4 Hz), 8.81 (1H, s), 9.66 (1H,s), 11.45 (1H, s); MS (ESI) m/z 262 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[N:6]=[CH:7]2.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:27]=[CH:26][C:21]([CH2:22][N:23]=[C:24]=[O:25])=[CH:20][CH:19]=1>>[CH3:15][O:14][C:12]([C:5]1[N:6]=[CH:7][C:8]2[C:3]([CH:4]=1)=[C:2]([NH:1][C:24]([NH:23][CH2:22][C:21]1[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:29])[F:28])=[CH:27][CH:26]=1)=[O:25])[CH:11]=[CH:10][CH:9]=2)=[O:13]
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cc2c(N)cccc2cn1
Product: COC(=O)c1cc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)cccc2cn1

Procedure:
Prepared from methyl 5-aminoisoquinoline-3-carboxylate (Description 107) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 404 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7][CH3:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl>[CH3:1][C:2]1[S:6][C:5]([S:7]([CH3:8])=[O:20])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(-c2ccccc2)c(C)s1
Solvent: ClCCl
Product: Cc1sc(S(C)=O)nc1-c1ccccc1
Reaction time: 0.5 h

Procedure:
6.56 g. of 5-methyl-2-methylthio-4-phenylthiazole pre-dissolved in 100 ml. of methylene chloride is cooled in an ice bath. The stirred solution is treated with 6.01 g. of m-chloroperoxybenzoic acid, added in portions over five minutes. After 30 minutes, the reaction is complete and the precipitated m-chlorobenzoic acid is filtered and the filtrate washed successively with a 10% solution of sodium sulfite, saturated aqueous sodium bicarbonate solution and water. After drying, concentration in vacuo and chromatography yields a white solid, m.p. 96°-97° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([OH:16])=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[C:17](Cl)(=O)C(Cl)=O.CO.N1C=CC=CC=1>ClC(Cl)C.CN(C=O)C>[CH3:17][O:13][C:12](=[O:14])[C:11]1[CH:15]=[C:7]([S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:6])=[O:5])[CH:8]=[CH:9][C:10]=1[OH:16]
Reactant: O=C(O)c1cc(S(=O)(=O)C2CC2)ccc1O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: COC(=O)c1cc(S(=O)(=O)C2CC2)ccc1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 7.2 mmol 5-cyclopropanesulfonyl-2-hydroxy-benzoic acid in 20 ml dichloroethane containing a few drops of DMF was added dropwise 8.7 mmol oxalyl chloride. After stirring for 90 min at RT, the reaction mixture was cooled to 0° C. and then 144 mmol methanol was added, followed by 72 mmol pyridine, and stirring continued at RT for 1 h. The mixture was then washed with 1 M aq HCl, dried with Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane gradient) to afford the title compound. MS (m/e): 255.2 ([M−H]−, 100%)
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)=O)=[C:4]([CH3:18])[CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(#N)C>[Br:1][C:2]1[S:6][C:5]([CH2:7][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)=[C:4]([CH3:18])[CH:3]=1
Reactant: CCCc1ccc(C(=O)c2sc(Br)cc2C)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CC#N
Product: CCCc1ccc(Cc2sc(Br)cc2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
To a solution of (5-bromo-3-methylthiophen-2-yl)(4-propylphenyl)methanone (45, 0.95 g, 2.95 mmol) in DCM (9.4 mL) and ACN (9.4 mL) was added triethylsilane (1.42 mL, 8.85 mmol) followed by BF3 etherate (1.11 mL, 8.85 mmol) under nitrogen atmosphere at 0° C. The reaction mixture was allowed warmed to room temperature and stirred for 16 hours. The mixture was poured into a saturated K2CO3 solution (50 mL) and extracted with EtOAc (100 mL). The organic phase was dried over MgSO4 and evaporated under vacuum. The residue was further purified by silica column chromatography (Biotage) to provide 5-bromo-3-methyl-2-(4-propylbenzyl)thiophene (46, 0.86 g, 2.77 mmol, 94%).
Reaction SMILES: [Cl:1][C:2](=[CH2:12])[CH2:3][C:4]1([C:9]([OH:11])=O)[CH2:8][CH2:7][CH2:6][CH2:5]1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.OC(C(F)(F)F)=O.[NH2:49][C@@H:50]([CH2:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[CH:58][CH:57]=1)[C:51]([NH:53][CH3:54])=[O:52]>CN(C=O)C>[C:59]1([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:60]=[CH:61][C:56]([CH2:55][C@H:50]([NH:49][C:9]([C:4]2([CH2:3][C:2]([Cl:1])=[CH2:12])[CH2:5][CH2:6][CH2:7][CH2:8]2)=[O:11])[C:51]([NH:53][CH3:54])=[O:52])=[CH:57][CH:58]=1
Reactant: CNC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: C=C(Cl)CC1(C(=O)O)CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: C=C(Cl)CC1(C(=O)N[C@@H](Cc2ccc(-c3ccccc3)cc2)C(=O)NC)CCCC1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
To a solution of 1-(2-chloroallyl)cyclopentanecarboxylic acid (50 mg, 0.27 mmol) in DMF (1.2 mL) was added EDC.HCl (51 mg, 0.27 mmol), HOAt (29 mg, 0.21 mmol) and triethylamine (0.04 mL, 0.27 mmol). To the mixture stirred at room temperature was added (S)-2-amino-3-(biphenyl-4-yl)-N-methylpropanamide TFA salt (45 mg, 0.18 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was extracted with EtOAc, and the organic layer was washed with water (8 times), brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by TLC preparation plates using 70% EtOAc/heptane to give (S)—N-(3-(biphenyl-4-yl)-1-(methylamino)-1-oxopropan-2-yl)-1-(2-chloroallyl)cyclopentanecarboxamide (38 mg). HPLC retention time=1.69 minutes (condition B); MS (m+1)=425.0; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34-1.64 (m, 6H), 1.79-2.02 (m, 2H), 2.59 (d, J=5.8 Hz, 2H), 2.66 (d, J=4.9 Hz, 3H), 3.05 (d, J=7.3 Hz, 2H), 4.66 (q, J=7.5 Hz, 1H), 4.95 (s, 1H), 5.05 (s, 1H), 6.28-6.35 (m, 1H), 6.37 (d, J=7.7 Hz, 1H), 7.20 (d, J=8.2 Hz, 2H), 7.23-7.30 (m, 1H), 7.34 (t, J=7.5 Hz, 2H), 7.45 (dd, J=14.5, 7.8 Hz, 4H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:38][S:39]([CH2:42][CH2:43][N:44]1[CH2:50][CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:41])=[O:40]>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:47]3[CH2:48][CH2:49][CH2:50][N:44]([CH2:43][CH2:42][S:39]([CH3:38])(=[O:40])=[O:41])[CH2:45][CH2:46]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCN1CCCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCCN(CCS(C)(=O)=O)CC1

Procedure:
[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-[1,4]diazepan-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 1-(2-methanesulfonyl-ethyl)-[1,4]diazepane (example 19) in an analogous manner as described in example 25. LR-MS: 699.4 [(M+H)+]
Reaction SMILES: C[C:2]1[N:3]=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[O:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:5]2[C:10]([CH3:11])=[C:9]([C:12]([NH2:14])=[O:13])[S:8][C:6]=2[N:7]=1.CCN(C(C)C)C(C)C.Cl[CH2:40][C:41]1[N:45]=[CH:44][O:43][N:42]=1.O>CN(C=O)C>[O:43]1[CH:44]=[N:45][C:41]([CH2:40][N:27]2[CH2:28][CH2:29][CH:24]([O:23][C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[NH:15][C:4]3[C:5]4[C:10]([CH3:11])=[C:9]([C:12]([NH2:14])=[O:13])[S:8][C:6]=4[N:7]=[CH:2][N:3]=3)[CH2:25][CH2:26]2)=[N:42]1
Reactant: Cc1nc(Nc2ccc(F)cc2OC2CCNCC2)c2c(C)c(C(N)=O)sc2n1
Reactant: ClCc1ncon1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC3CCN(Cc4ncon4)CC3)c12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
To a suspension of methyl 4-(4-fluoro-2-(piperidin-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxamide (0.06 g, 0.15 mmol) in DMF (2.0 mL) was added Hünigs base (0.06 mL, 0.35 mmol) and 3-(chloromethyl)-1,2,4-oxadiazole (0.035 g, 0.3 mmol) and the mixture was warmed to 60° C. for 18 hours. After cooling to ambient temperature water (2 mL) was added and the mixture stirred for 0.5 hours. The precipitated solid was collected by filtration and triturated from boiling MeCN. The solid was collected by filtration and dried under vacuum to give beige solid (0.046 g, 63%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Al+3].[Cl-].[Cl-].[Cl-].[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(Cl)Cl>[C:14]1([CH2:20][C:21]([C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: c1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1ccccc1)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
Modification of Method A: To a mixture of 1H-pyrrolo[2,3-b]pyridine (1.0 g, 8.46 mmol) and AlCl3 (3.4 g, 25.50 mmol) in dry methylene chloride (20 mL) was added phenyl acetyl chloride (3.27 g, 21.15 mmol) at room temperature. The solution was then stirred at room temperature (RT) for 4 hrs. The mixture was poured into iced water and extracted with methylene chloride (3×20 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated. The residue was then dissolved in MeOH (20 mL) and treated with 6N NaOH (5 mL) at RT for 2 hrs. Evaporated most of the solvent, the residue was acidified with 6N HCl and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and evaporated. The residue was purified by flash column to give desired product (1.3 g, 65%). MS (ES−): m/e=235.2 (M−H); LC/Method A/2.86 min.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[O:17])=[CH:19][CH:20]=1)([O-:11])=[O:10]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(F)cc1
Product: O=C(Nc1ccc(F)cc1)c1ccc([N+](=O)[O-])cc1
Yield: 65.7 %

Procedure:
Using 4-fluoroaniline (1.0 ml, 9.93 mmol) and 4-nitrobenzoic acid (1.58 g, 9.36 mmol), the procedure of Reference Example 16 was repeated to obtain 1.60 g (65.8%) of the title compound in the form of light yellow needle crystals.
Reaction SMILES: [Cr](O)(O)(=O)=O.[F:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][C:10]([CH3:28])([CH3:27])[N:11]=[C:12]2[C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2.S([O-])([O-])=[O:30].[Na+].[Na+].C(=O)([O-])O.[Na+]>O.C(O)(=O)C>[F:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=[O:30])[C:10]([CH3:28])([CH3:27])[N:11]=[C:12]2[C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2
Reactant: CC1(C)Cc2c(F)cccc2C(c2cnc3ccccc3c2)=N1
Reactant: O=S([O-])[O-]
Agent: O=[Cr](=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)N=C(c2cnc3ccccc3c2)c2cccc(F)c2C1=O
Reaction time: 0.5 h
Yield: 6 %

Procedure:
Chromic acid (4.9 g) was added to an acetic acid (50 mL) solution of 3-(5-fluoro-3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)quinoline (5.0 g, 16.4 mmol), followed by heating and refluxing for 14 hours, pouring water, aqueous sodium sulfite solution and aqueous sodium hydrogencarbonate solution. After stirring for 30 minutes, extracting with ethyl acetate, and applying the resulting residue to chromatography to obtain 0.3 g (yield 6%) of the target compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[CH2:31]([O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)[CH3:32]>COCCOC>[CH2:31]([O:33][C:34]1[CH:39]=[C:38]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:37]=[CH:36][CH:35]=1)[CH3:32]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Reactant: CCOc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOc1cccc(-c2ccccc2CCC(=O)N(NC(=O)c2ccccc2)C(C)C)c1
Yield: 21.4 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 3-ethoxy-phenylboronic acid (42 mg, 0.26 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient and then by RP HPLC to afford the product as a solid (12 mg, 22%). LC-MS m/e 431.27 (M+H+)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]2[CH2:33][CH2:32][N:31]([C:13]([C:9]3[CH:10]=[N:11][O:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[O:15])[CH2:30]2)=[CH:27][CH:28]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: Clc1ccc(C2CCNC2)cc1
Agent: O=C(O)C(=O)O
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(c3ccc(Cl)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-(4-chlorophenyl)pyrrolidine oxalate (16.3 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (4.4 mg). Calcd for C21H19ClN2O2: 366.1135, found 366.1138.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8]O)[CH:7]=1.O=S(Cl)[Cl:14]>C1(C)C=CC=CC=1>[Cl:14][CH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:10][CH3:11]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(F)cc1CO
Solvent: Cc1ccccc1
Product: COc1ccc(F)cc1CCl
Temperature: 60 °C
Yield: 61 %

Procedure:
Neat (5-Fluoro-2-methoxy-phenyl)-methanol (19.587 g, 1 equiv.) was added to neat SOCl2 (42.2 mL, 4.6 equiv.) at −78° C. under a nitrogen atmosphere and the solution was then allowed to warn to room temperature and stirred until evolution of gas had ceased. An equivalent volume of anhydrous toluene was added to the flask and the solution heated to 60° C. On cooling the reaction solution was poured onto ice water. The toluene layer was separated and dried (MgSO4) and the solvent removed under reduced pressure. The crude material was sublimed (60-80° C./0.05 mBarr) to give the title compound as a white solid (13.40 g, 61%). 1H NMR (300 MHz, CDCl3): δ 3.87 (s, 3H), 4.60 (s, 2H), 6.79-7.20 (m, 3H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH2:4][OH:5].[C:16]([N:20]=[C:21]=[S:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C(O)C.C(OCC)(=O)C>[C:16]([NH:20][C:21]([NH:2][C@H:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH2:4][OH:5])=[S:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)N=C=S
Reactant: N[C@@H](CO)Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=S)N[C@@H](CO)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 0.92 g of (2R)-2-amino-3-(3-nitrophenyl)-1-propanol hydrochloride and 0.6 cm3 of tert-butyl isothiocyanate in 10 cm3 of ethanol is cooled to a temperature in the region of 0° C. and 0.56 cm3 of triethylamine is then added. The mixture is stirred for 18 hours at room temperature and is then heated at a temperature in the region of 60° C. for 2 hours; the suspension thus dissolves. 0.6 cm3 of tert-butyl isothiocyanate is added and heating is continued for 3 hours, after which the reaction medium is concentrated under reduced pressure (2 kPa) at a temperature in the region of 50° C. The yellow oil obtained is dissolved in 50 cm3 of ethyl acetate, after which the organic solution is washed with twice 50 cm3 of sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1.2 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(3-nitrobenzyl)-ethyl]thiourea are obtained in the form of a yellow oil. 1H NMR spectrum (300 MHz, (CD3)2SO-d6 with addition of a few drops of CD3COOD-d4, δ in ppm): 1.39 (s: 9H); 2.98 (limiting AB: 2H); 3.38 (limiting AB: 2H); 4.48 (mt: 1H); 7.60 (t, J=8 Hz: 1H); 7.74 (broad d, J=8 Hz: 1H); 8.09 (broad d, J=8 Hz: 1H); 8.16 (broad s: 1H).