Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][CH2:13][C:14]1[NH:15][CH:16]=[CH:17][N:18]=1)(=[O:10])=[O:9].[C:19]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27])([CH3:22])([CH3:21])[CH3:20].[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34]>CO.C(OCC)(=O)C>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[NH:18]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:13][CH2:12][NH:11][S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([C:19]([CH3:21])([CH3:20])[CH3:22])[CH:24]=1)(=[O:10])=[O:9]
Reactant: CC(C)(C)c1cccc(C(=O)Cl)c1
Reactant: Nc1ccccc1S(=O)(=O)NCCc1ncc[nH]1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)c1cccc(C(=O)Nc2ccccc2S(=O)(=O)NCCc2ncc[nH]2)c1
Yield: 84.2 %

Procedure:
The titled compound was prepared substantially in accordance with the method detailed in Example 1C using 2.80 g (0.0107 mol) of 2-amino-N-[2-(1H-imidazol-2-yl)-ethyl] benzene sulfonamide and 4.20 g (0.0213 mol) of meta-t-butylbenzoyl chloride with the exception that, after reducing the reaction solution to dryness under reduced pressure the resultant residue was dissolved in methanol. The resulting solution was heated to reflux for approximately one hour and then reduced to dryness under reduced pressure. The resultant residue was redissolved in an ethyl acetate/aqueous sodium bicarbonate mixture. The resulting layers were separated and the organic layer was washed with water and then a saturated sodium chloride solution, dried over anhydrous sodium sulfate and then reduced to dryness under reduced pressure. The resultant residue was purified using preparatory high performance liquid chromatography (8000 ml of a gradient of methylene chloride to 10% methanol and 0.5% ammonium hydroxide in methylene chloride). Fractions containing the free base form of the desired titled compound were combined and then reduced to dryness under reduced pressure to provide an oil. This oil was dissolved in methanol and 0.36 g of oxalic acid were added, with stirring. The resulting solution was reduced to dryness under reduced pressure to provide a foam. This foam was crystallized from a 1:10 solution of methanol/ethyl acetate to provide 1.74 g of the desired titled compound (m.p. 191°-193.5° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]2[C:20]([CH3:35])=[N:21][N:22](S(C3C=CC(C)=CC=3)(=O)=O)[C:23]=2[CH3:24])=[CH:8][CH:7]=1.C[O-].[Na+].Cl>CO>[CH3:1][O:2][C:3](=[O:36])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]2[C:20]([CH3:35])=[N:21][NH:22][C:23]=2[CH3:24])=[CH:10][CH:11]=1
Reactant: COC(=O)/C=C/c1ccc([C@@H]2CCCN2CCc2c(C)nn(S(=O)(=O)c3ccc(C)cc3)c2C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)/C=C/c1ccc([C@@H]2CCCN2CCc2c(C)n[nH]c2C)cc1
Yield: 30 %

Procedure:
To a solution of (E)-3-[4-((S)-1-{2-[3,5-dimethyl-1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]-ethyl}-pyrrolidin-2-yl)-phenyl]-acrylic acid methyl ester (200 mg, 0.394 mmol) in methanol (10 mL) was added sodium methoxide in methanol (25 wt %, 1.0 mL). The mixture was subjected to microwave irradiation for 10 minutes, neutralized with 1 N HCl, and concentrated in vacuo. The remaining aqueous layer was extracted with ethyl acetate and dichloromethane, and the organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo to give (E)-3-(4-{(S)-1-[2-(3,5-dimethyl-1H-pyrazol-4-yl)-ethyl]-pyrrolidin-2-yl}-phenyl)-acrylic acid methyl ester as a yellow crude oil (126 mg) that was directly used in the next step.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([S:23][CH3:24])[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(O)CC.CN1C(=O)CCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:11]([C:8]3[N:6]4[CH:7]=[C:2]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[N:3]=[C:4]([S:23][CH3:24])[C:5]4=[N:10][CH:9]=3)=[CH:12][CH:13]=2)[CH2:20][CH2:19]1
Reactant: OB(O)c1ccccc1
Reactant: CSc1nc(Br)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCO
Solvent: CN1CCCC1=O
Product: CSc1nc(-c2ccccc2)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Temperature: 120 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
To a stirred solution of 4-(6-bromo-8-methylsulfanyl-imidazo[1,2-a]pyrazin-3-yl)-N-cyclopropyl-benzamide (7.34 g, 18.2 mmol) in n-propanol (270 mL) and NMP (15 mL) was subsequently added 27.3 mL 2M potassium carbonate solution, 4.44 g phenylboronic acid (36.4 mmol, 2 eq), triphenylphosphine (238.7 mg, 0.91 mmol, 0.05 eq), 1.28 g bis(triphenylphosphin)palladium(II)chloride (1.82 mmol, 0.1 eq) in one portion at rt under argon atmosphere. After stirring for 2 h at 120° C., the mixture was concentrated in vaccuo (50% v/v), triturated with water and extracted with DCM. The organic phase was dried over sodium sulphate, filtered and the solvent was evaporated. Purification by flash chromatography (ethyl acetate/n-hexane) followed by crystallization from ethyl acetate yielded 5.87 g (80.5%)N-Cyclopropyl-4-(8-methylsulfanyl-6-phenyl-imidazo[1,2-a]pyrazin-3-yl)-benzamide: 1H-NMR (300 MHz, CDCl3): δ=8.30 (1H, s), 7.94 (4H, d), 7.77 (1H, s), 7.65 (2H, d), 7.50-7.37 (3H, m), 6.38 (1H, bs), 2.95 (1H, m), 2.80 (3H, s), 1.04 (6H, d), 0.92 (2H, m), 0.67 (2H, m) ppm.
Reaction SMILES: FC(F)C1C=CC([C@@H](NCCC2(O)CCC3(OCC(C)(C)CO3)CC2)C)=CC=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[F:41][CH:42]([F:70])[C:43]1[CH:48]=[CH:47][C:46]([C@@H:49]([N:51]2[CH2:56][CH2:55][C:54]3([CH2:68][CH2:67][C:59]4(OCC(C)(C)C[O:60]4)[CH2:58][CH2:57]3)[O:53][C:52]2=[O:69])[CH3:50])=[CH:45][CH:44]=1>>[F:70][CH:42]([F:41])[C:43]1[CH:48]=[CH:47][C:46]([C@@H:49]([N:51]2[CH2:56][CH2:55][C:54]3([CH2:68][CH2:67][C:59](=[O:60])[CH2:58][CH2:57]3)[O:53][C:52]2=[O:69])[CH3:50])=[CH:45][CH:44]=1
Reactant: C[C@@H](c1ccc(C(F)F)cc1)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Agent: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(C(F)F)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: C[C@@H](c1ccc(C(F)F)cc1)N1CCC2(CCC(=O)CC2)OC1=O

Procedure:
The title compound is prepared from 9-{2-[(S)-1-(4-difluoromethyl-phenyl)-ethylamino]-ethyl}-3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2; the crude product, a mixture of the title compound and 3-[(S)-1-(4-difluoromethyl-phenyl)-ethyl]-12,12-dimethyl-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one, obtained thereafter is treated as described in Step 10 of Intermediate 2 to convert the intermediate to the title compound as well. Yield: 58% of theory; LC (method 8): tR=1.10 min; Mass spectrum (ESI+): m/z=338 [M+H]+.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.Cl.[NH2:13][CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:18]2=[O:33].[O:34]=[C:35]1[N:39]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45](O)=[O:46])[CH2:38][CH2:37][O:36]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(#N)C>[O:32]=[C:26]1[CH:25]([N:19]2[C:18](=[O:33])[C:17]3[C:21](=[CH:22][CH:23]=[C:15]([CH2:14][NH:13][C:45](=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][N:39]4[CH2:38][CH2:37][O:36][C:35]4=[O:34])[CH:16]=3)[C:20]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C(O)CCCCCN1CCOC1=O
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCCl
Product: O=C(CCCCCN1CCOC1=O)NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42 %

Procedure:
DBU (1.2 g, 8.1 mmol) was added to a stirred suspension of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.0 g, 3.1 mmol) in acetonitrile (35 mL), resulting in the formation of a clear solution. The mixture was stirred at room temperature for 10 minutes, and then, 6-(2-oxo-oxazolidin-3-yl)-hexanoic acid (2.0 g, 10 mmol) and HOBt (0.5 g, 3.7 mmol) were added, followed by EDC (0.89 g, 4.7 mmol). After stirring for an additional 16 hours, the mixture was evaporated under vacuum. The residue was partitioned between ethyl acetate (50 mL) and water (100 mL), and the aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic layers were evaporated. The residue was chromatographed on silica, using a methylene chloride-methanol gradient, eluting 0.61 g of the product at 93:7 methylene chloride-methanol, in 42% yield; mp 178-180° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 25/75 CH3CN/0.1% H3PO4, 3.36 (98.33%); 1H NMR (DMSO-d6) δ 1.26-1.28 (m, 2H), 1.43-1.61 (m, 4H), 2.04-2.08 (m, 1H), 2.18 (t, J=7.4 Hz, 2H), 2.46-2.63 (m, 2H), 2.83-2.96 (m, 1H), 3.12 (t, J=7.1 Hz, 2H), 3.49 (t, J=8.0 Hz, 2H), 4.42 (t, J=8.0 Hz, 2H), 4.43 (d, J=5.8 Hz, 2H), 5.15 (dd, J=12.9 Hz, J=5.4 Hz, 1H), 7.72-7.77 (m, 2H), 7.89 (d, J=7.8 Hz, 1H), 8.51 (t, J=5.8 Hz, 1H), 11.12 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 24.8, 25.7, 26.4, 30.9, 35.1, 41.9, 43.3, 43.8, 49.0, 61.5, 121.8, 123.5, 129.7, 131.6, 133.3, 147.8, 157.8, 167.0, 167.1, 169.8, 172.4, 172.7; Anal. Calcd for C23H26N4O7+0.3H2O: C, 58.05; H, 5.63; N, 11.77. Found: C, 58.05; H, 5.42; N, 11.62.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].[C:31]([N:34]1[CH2:39][CH2:38][CH:37]([O:40][C:41]2[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][CH:42]=2)[CH2:36][CH2:35]1)(=O)[CH3:32]>>[CH2:1]([N:3]([CH2:45][C:44]1[CH:43]=[CH:42][C:41]([O:40][CH:37]2[CH2:38][CH2:39][N:34]([CH2:31][CH3:32])[CH2:35][CH2:36]2)=[CH:48][CH:47]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(=O)N1CCC(Oc2ccc(C=O)cc2)CC1
Product: CCN1CCC(Oc2ccc(CN(CC)c3cc(OC)c(OC)cc3[C@@H]3CCc4cc(O)ccc4C3)cc2)CC1
Yield: 49.1 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 4-(1-acetylpiperidin-4-yloxy)benzaldehyde (57 mg) according to an analogous synthetic method to Example 264 and purified by LC-MS, the title compound (13 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[C:8]=2[C:12]([F:15])([F:14])[F:13])[C:3]=1[C:18]([NH2:20])=[O:19].[H-].[Na+].Cl[C:24]([O:26][CH3:27])=[O:25].[NH4+].[Cl-]>C1COCC1.O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[C:8]=2[C:12]([F:14])([F:15])[F:13])[C:3]=1[C:18]([NH:20][C:24](=[O:25])[O:26][CH3:27])=[O:19]
Reactant: COC(=O)Cl
Reactant: COc1ccc2c(C(N)=O)c(Br)ccc2c1C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)NC(=O)c1c(Br)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
2-Bromo-6-methoxy-5-(trifluoromethyl)-1-naphthalenecarboxamide (4.18 g, 12.01 mmol) was added to a stirred suspension of sodium hydride (50% dispersion in mineral oil, 632 mg, 1.1 eq) in anhydrous THF (110 mL) precooled in an ice bath under a dry N2 atmosphere. The ice bath was removed and the suspension was stirred at ambient temperature for 30 minutes, warmed to 40° C. and stirred an additional 20 minutes. The reaction mixture was cooled to room temperature and methyl chloroformate (0.93 mL, 1.0 eq) in THF (25 mL) was added dropwise over a 10 minute period. After an additional 20 minutes, saturated aqueous NH4Cl (35 mL) was added. The reaction mixture was added to water (400 mL) and extracted with ether (2×300 mL). The combined ether extracts were washed with saturated aqueous NaCl (300 mL). Silica gel (25 mL) was added to the ether solution and the solvent was removed. The silica absorbate was flash chromatographed (3:2 petroleum ether:ethyl acetate, silica) to provide the title compound as a white solid (2.71 g, 56%) m.p. 180°-182° C.
Reaction SMILES: C=O.[Cl:3][C:4]1[N:5]=[C:6]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:7]2[N:13]=[C:12]([CH2:14][NH:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])[CH:11]=[CH:10][C:8]=2[N:9]=1.[C:27]([BH3-])#N.[Na+].CO>C(Cl)Cl.C(OCC)(=O)C>[Cl:3][C:4]1[N:5]=[C:6]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:7]2[N:13]=[C:12]([CH2:14][N:15]([CH3:27])[CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])[CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: [BH3-]C#N
Reactant: CC(C)(O)CNCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(Cc1ccc2nc(Cl)nc(N3CCOCC3)c2n1)CC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Paraformaldehyde (20 mg, 1.5 eq) was added to a solution of 1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methylamino)-2-methylpropan-2-ol (0.16 g) in DCM (2.5 mL). The reaction was stirred for 5 minutes before addition of sodium cyanoborohydride (1.2 eq). Methanol (1 mL) was added to the reaction mixture which was then stirred overnight at room temperature. The reaction was diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated to give 0.12 g of 1-(((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-2-methylpropan-2-ol as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:20])([CH:17]([F:19])[F:18])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][NH:13][C:12]2=[O:16])=[CH:7][CH:6]=1.[H-].[Na+].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](=[O:41])[C@@H:31](OS(C(F)(F)F)(=O)=O)[CH3:32].C(O)(=O)C>CN1CCCC1=O.O1CCCC1.C(OCC)(=O)C.C(OC(C)C)(C)C>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](=[O:41])[C@H:31]([N:13]1[CH:14]=[CH:15][N:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:20])[CH:17]([F:19])[F:18])=[CH:6][CH:7]=2)[C:12]1=[O:16])[CH3:32]
Reactant: C[C@H](OS(=O)(=O)C(F)(F)F)C(=O)c1ccccc1F
Reactant: O=c1[nH]ccn1-c1ccc(OCC(F)(F)C(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: C[C@H](C(=O)c1ccccc1F)n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.2 %

Procedure:
1-[4-(2,2,3,3-Tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (4.6 g) was dissolved in 30 ml of 1-methyl-2-pyrrolidone, to which 0.6 g of 60% sodium hydride in oil was added. The mixture was stirred at room temperature for 0.5 hours. The reaction solution was ice-cooled and added dropwise under nitrogen atmosphere over the period of 5 minutes to a solution of 5.3 g of (2S)-2'-fluoro-2-trifluoromethanesulfonyloxypropiophenone in 50 ml of tetrahydrofuran which was cooled to -40° C. Then, the reaction solution was stirred at -40° to -35° C. for 20 minutes. To the reaction solution was added 2 ml of acetic acid. The mixture was diluted with a mixture of 300 ml of ethyl acetate and 150 ml of diisopropyl ether, washed with 80 ml of water, 0.5N-hydrochloric acid (80 ml×2) and 40 ml of an aqueous solution of sodium chloride successively, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 200 g, eluent; hexane:ethyl acetate:acetic acid=2:1:0.03) and crystallized from diisopropyl ether to give 2.6 g of 1-[(1R)-2-(2-fluorophenyl)-2-oxo-1-methylethyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone as colorless powdery crystals.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11].I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:13]1([NH:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc2ccccc2c1
Reactant: Ic1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccc3ccccc3c2)cc1
Temperature: 120 °C
Yield: 43 %

Procedure:
A mixture of 2-naphthylamine (8.0 g, 55.9 mmol), iodobenzene (12.24 g, 60 mmol), Pd(dppf)Cl2 (0.731 g, 1 mmol) and sodium tert-butoxide (NaOBut) (5.76 g, 60 mmol) in toluene (200 mL) was degassed and heated at 120° C. overnight. The whole was poured into ethyl acetate (250 mL), washed with brine, dried over Na2SO4, loaded on silica gel and purified by flash column (hexanes to hexanes/dichloromethane 10:1). The desired fraction was collected, and concentrated. A white solid precipitated, which was filtered to give the product (Compound 20) (5.30 g, in 43% yield).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:5][C:4]=2[CH:3]=1.[CH3:19][C:20]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][N:22](C(OC(C)(C)C)=O)[N:21]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:6]1[NH:7][C:8](=[O:11])[C:9]2[S:10][C:2]([C:24]3[CH:23]=[N:22][NH:21][C:20]=3[CH3:19])=[CH:3][C:4]=2[N:5]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=c1[nH]c(-c2ccccc2Cl)nc2cc(Br)sc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1[nH]ncc1-c1cc2nc(-c3ccccc3Cl)[nH]c(=O)c2s1
Temperature: 100 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
6-Bromo-2-(2-chlorophenyl)thieno[3.2-d]pyrimidin-4 (3H)-one (157 mg), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (425 mg), sodium carbonate (138 mg), 1,2-dimethoxyethane (4.0 mL) and water (2.0 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1) (38 mg) was added, and the atmosphere in the flask was purged again with argon. The reaction system was stirred at 100° C. for 1 hr, 8M aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at 100° C. for 30 min. After stirring, the mixture was extracted with ethyl acetate/tetrahydrofuran mixture, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained pale-yellow solid was crystallized from methanol/ethyl acetate to give the title compound (43 mg) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]1[O:32][C:31]2[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][C:24]=2[O:23]1.C(=O)(O)[O-].[Na+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:27][C:26]2[CH:29]=[CH:30][C:31]3[O:32][CH2:22][O:23][C:24]=3[CH:25]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Reactant: ClCc1ccc2c(c1)OCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)Cc1ccc2c(c1)OCO2

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.29 g--see Preparation 3), 3,4-methylenedioxybenzyl chloride (0.18 g--commercially available), sodium bicarbonate (0.1 g) and acetonitrile (20 ml) was heated under reflux for 3 hours. The mixture was partitioned between dichloromethane and 10% aqueous sodium carbonate, the layers separated and the dichloromethane layer dried (MgSO4). The solution was concentrated in vacuo and the residue purified by column chromatography on silica, eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil, yield 0.22 g.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][C:22]#[N:23])[C@H:17]([O:24][CH3:25])[CH2:16]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:25][O:24][C@@H:17]1[CH2:16][C@@H:15]([NH:14][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH:11]=[CH:12][S:13][C:3]=23)[CH2:20][CH2:19][C@@H:18]1[CH2:21][C:22]#[N:23]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: CO[C@@H]1C[C@@H](N)CC[C@@H]1CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CO[C@@H]1C[C@@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC[C@@H]1CC#N
Temperature: 90 °C
Yield: 78.7 %

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (381 mg, 1.78 mmol), [(1R,2R,4S)-4-amino-2-methoxycyclohexyl]acetonitrile (racemic) (310 mg, 1.8 mmol) and N,N-diisopropylethylamine (1.2 mL, 7.1 mmol) in isopropyl alcohol (4.2 mL) was heated at 90° C. for 2 h. The crude was concentrated and purified with flash chromatography to give the desired product (485 mg, 78%). LCMS calculated for C15H19N4O3S (M+H)+: m/z=347.1. Found: 347.0.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([O:18][C:19]([C:21]1[C:30]([Cl:31])=[CH:29][C:28]2[C:23](=[C:24](O)[CH:25]=[CH:26][CH:27]=2)[CH:22]=1)=[O:20])[CH3:17].O>N1C=CC=CC=1>[CH2:16]([O:18][C:19]([C:21]1[C:30]([Cl:31])=[CH:29][C:28]2[C:23](=[C:24]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:25]=[CH:26][CH:27]=2)[CH:22]=1)=[O:20])[CH3:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1cc2c(O)cccc2cc1Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2c(OS(=O)(=O)C(F)(F)F)cccc2cc1Cl
Reaction time: 1 h

Procedure:
Trifluoromethanesulfonic anhydride (2.46 g, 8.73 mmol, 1.2 equiv) was added at −20° C. under an atmosphere of argon to a solution of 3-chloro-8-hydroxy-naphthalene-2-carboxylic acid ethyl ester (1.82 g, 7.28 mmol) in pyridine (55 ml). After 1 hour at 0° C., an additional portion of trifluoromethanesulfonic anhydride (2.46 g, 8.73 mmol, 1.2 equiv) was added, and stirring was continued at 0° C. for another 1.5 hours. Cold water (4° C., 100 ml) was carefully added, and the reaction mixture was extracted with EtOAc (1 liter in total). The combined organic layers were washed with concentrated aqueous NH4Cl solution and brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (slow gradient of hexane/EtOAc 100:0 to 90:10) afforded the title compound (2.45 g, 88%, inseparable 1:1.3 mixture of regioisomers A:B) as an oil. 1H NMR (400 MHz, CDCl3): δ=8.56 (s, 1H isomer B), 8.40 (s, 1H isomer A), 8.12 (s, 1H isomer A), 8.01 (s, 1H isomer B), 7.93-7.91 (m, 1H isomer A), 7.81 (d, J=8.6 Hz, 1H isomer B), 7.62-7.51 (m, 2H isomer A+2H isomer B), 4.47 (q, J=7.1 Hz, 2H isomer A+2H isomer B), 1.45 (t, J=7.1 Hz, 3H isomer A+3H isomer B). 19F NMR (377 MHz, CDCl3): δ=−73.02. MS (ES+): 383 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[OH:12][C:13]1[CH:18]=[C:17]([CH3:19])[O:16][C:15](=[O:20])[CH:14]=1.C1CCC(N=C=NC2CCCCC2)CC1.[Na].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.C(O)C>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[CH2:8][C:9]([C:14]1[C:15](=[O:20])[O:16][C:17]([CH3:19])=[CH:18][C:13]=1[OH:12])=[O:11]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: Cc1cc(C)c(CC(=O)O)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(O)c(C(=O)Cc2sc(C)cc2C)c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 3.82 g (22.4 mmol) of 3,5-dimethylthiopheneacetic acid, 2.87 g (22.7 mmol) of 4-hydroxy-6-methyl-2-pyrone and 5.13 g (24.8 mmol) of DCC were suspended in 70 ml of toluene, then 273 mg (2.23 mmol) of DMAP added and stirring carried out overnight at 90° C. The reaction liquid was cooled to room temperature and the insoluble material filtered off. The mother liquor was concentrated and the residue purified by column chromatography. The solid obtained was recrystallized from ethanol and Compound 12 (684 mg, 2.45 mmol, 11%) obtained. This was converted to the sodium salt with an equivalent quantity of sodium hydrogen carbonate.