Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([Si](C)(C)[O:6][CH:7]1[CH2:31][CH2:30][C:10]2([CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:11]2)[CH2:9][CH2:8]1)(C)C.C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1C=CN=CC=1.F.C([O-])(O)=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[OH:6][CH:7]1[CH2:8][CH2:9][C:10]2([CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:11]2)[CH2:30][CH2:31]1
Reactant: CCOC(=O)C1CC2(CCC(O[Si](C)(C)C(C)(C)C)CC2)CN1C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: F
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CCOC(=O)C1CC2(CCC(O)CC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3-ethyl 2-(phenylmethyl) 8-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-azaspiro[4.5]decane-2,3-dicarboxylate (111) (5.73 g, 12.05 mmol) in THF (60 mL) was added glacial acetic acid (1.38 mL, 24.0 mmol) followed by TBAF (24 mL) as a 1 M solution in THF. The reaction was stirred at room temperature for 72 h. The reaction was partitioned between EtOAc and water (250 mL) each, the organic layer was separated and washed with saturated NaHCO3 (100 mL) and dried (MgSO4) and concentrated in vacuo. The reaction was found to be incomplete by TLC. The residue was dissolved in dry THF (60 mL), cooled to 0° C. and treated with HF-pyridine (1.6 mL, 18.0 mmol), warmed to room temperature and stirred for 2 h under nitrogen. The reaction was poured into saturated NaHCO3 (100 mL) and solid potassium carbonate was added until gas evolution ceased. Extracted with EtOAc (2×150 mL), the organic layers were combined and washed with 0.1 N HCl (100 mL), dried (MgSO4) and concentrated in vacuo to afford the title compound in quantitative yield as a yellow oil which was used in subsequent reactions without additional purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C1COCC1.[NH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.CCN(C(C)C)C(C)C>CCOC(C)=O>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:6]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: NCc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCc1cccnc1)c1ccc(Cl)nc1Cl
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
A mixture of 2,6-dichloronicotinic acid (19.2 g, 0.1 mol), N,N′-carbonyldiimidazole (CDI, 17.8 g, 0.11 mmol) and THF (1 L) was stirred at 60° C. for 30 min and cooled to room temperature. To the mixture was added 3-aminomethylpyridine (10.2 mL, 0.1 mol) and DIEA (21 mL, 0.12 mol). The reaction mixture was stirred at room temperature for 4 hrs, and diluted with EtOAc. The organic layer was washed with H2O, brine, dried over Na2SO4. Concentration of the organic solution gave 2,6-dichloro-N-(pyridin-3-ylmethyl)nicotinamide (20.5 g, 73%). LRMS (M+H+) m/z 282.0; (M+2+H+) m/z 283.9.
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH3:12][O:13][C:14](=[O:20])[CH2:15][C:16](=[O:19])[CH2:17][CH3:18].[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH2:29]Cl>O1CCCC1.O>[CH3:12][O:13][C:14](=[O:20])[CH:15]([CH2:29][C:23]1[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=1[Cl:21])[C:16](=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)CC(=O)OC
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCC(=O)C(Cc1ccc(Cl)cc1Cl)C(=O)OC
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A suspension of potassium tert-butoxide (8.4 g) in anhydrous tetrahydrofuran (180 mL) at 0° C. was treated with a mixture of tert-butanol (0.4 mL) and 3-oxopentanoic acid methyl ester (9.8 g). After stirring at room temperature for 30 minutes a solution of 2,4-dichloro-1-chloromethylbenzene (14.7 g) in tetrahydrofuran (20 mL) was added and the resulting mixture warmed to room temperature and then stirred at this temperature for 6 days. The mixture was diluted with water (200 mL), extracted with ethyl acetate and the combined extracts washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of pentane and dichloromethane (1:0 to 1:1 by volume) to afford title compound as a white solid, 7.0 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][CH:24]([CH2:27][OH:28])[CH2:23][CH2:22]1.CCN(CC)CC>CS(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH2:27][OH:28])[CH2:23][CH2:22]3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2Cl)CC1
Reactant: OCC1CCNCC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nccnc2N2CCC(CO)CC2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 4-(3-chloro-pyrazin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (39) (297 mg, 1 mmol) and piperidin-4-yl-methanol (35) (126.5 mg, 1.1 mmol) in DMSO (6 mL) was added Et3N (202 mg, 2 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (30 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel to give compound (40) (302 mg, 0.8 mmol, yield 80.32%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16][CH2:17][C:18]([OH:20])=O)[CH3:15])=[CH:10][CH:9]=1.C(N1C=CN=C1)([N:23]1C=CN=C1)=O.N.[N-]1C=CN=C1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16][CH2:17][C:18]([NH2:23])=[O:20])[CH3:15])=[CH:10][CH:9]=1
Reactant: CC(SCC(=O)O)c1ccc(-c2ccccc2Cl)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Agent: c1c[n-]cn1
Solvent: C1CCOC1
Product: CC(SCC(N)=O)c1ccc(-c2ccccc2Cl)cc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
63.0 gm (0.205 mol) of [1-(2'-chloro-4-biphenylyl)-ethylthio]-acetic acid were dissolved in 630 ml of dry tetrahydrofuran, and 33.3 gm (0.246 mol) of carbonyldiimidazole were added. After stirring the mixture for 1/2 hour, dry ammonia was introduced into 300 ml of the obtained solution of the imidazolide (corresponding to 0.0683 mol), while cooling slightly, until the mixture was saturated. Subsequently, the mixture was stirred for 2.5 hours more and then evaporated in vacuo. The residue was distributed between water and ethyl acetate, and washed several times with dilute hydrochloric acid. The organic layer was dried and evaporated. Yield: 100% of theory; oil, Rf -value: 0.2 on carrier 1 with cyclohexane/ethyl acetate = 1:1.
Reaction SMILES: [OH:1][CH2:2][C:3]1O[CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7](=[O:9])[CH:8]=1.[C:29]1([CH:35]([NH2:37])[CH3:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].[K+].[Br-]>C(O)C.O>[OH:1][CH2:2][C:3]1[N:37]([CH:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:36])[CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7](=[O:9])[CH:8]=1
Reactant: CC(N)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCOc1coc(CO)cc1=O
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1cn(C(C)c2ccccc2)c(CO)cc1=O

Procedure:
A mixture of 8.0 g (0.02 Mol) 2-hydroxymethyl-5-octadecyloxy-4-pyranone, 4.8 g (0.04 Mol) (±)-1-phenylethylamine, 1.5 g Na2CO3, 10 mL water and 100 mL ethanol is boiled under reflux for 72 hours. After cooling the solvent and the excess of amine is removed under vacuum and the residue is mixed with water and extracted with dichloromethane. The organic phase is dried over Na2SO4, evaporated and the obtained resin is purified by column chromatography on silica gel with dichloromethane with 1-2% methanol to give a yellow oil, which is changing to wax-like consistency. IR (KBr): 1630 (C=O), MS (m/l) 497 (M+).
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:4][CH2:3]2.[CH3:49][C:50]1([C:53]([OH:55])=O)[CH2:52][CH2:51]1>>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:44][CH2:45][N:46]([C:53]([C:50]3([CH3:49])[CH2:52][CH2:51]3)=[O:55])[CH2:47][CH2:48]1)[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C(=O)O)CC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)C4(C)CC4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound (0.9 mg) was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure as described above using 1-methylcyclopropane-1-carboxylic acid as the acylating agent. LCMS: m/e 724.8 (M+H)+, 4.49 min (method 15). 1H NMR (500 MHz, METHANOL-d4) δ 7.89 (d, J=8.2 Hz, 2H), 7.16 (d, J=8.2 Hz, 2H), 5.30 (d, J=4.6 Hz, 1H), 4.78 (s, 1H), 4.67 (s, 1H), 3.90-3.63 (m, 4H), 3.09-2.98 (m, 1H), 2.96-2.82 (m, 2H), 2.81-2.73 (m, 1H), 2.71-2.61 (m, 3H), 2.54 (br. s., 2H), 2.24-2.12 (m, 1H), 2.11-1.82 (m, 5H), 1.75 (s, 3H), 1.72-1.14 (m, 16H), 1.32 (s., 3H), 1.23 (s., 3H), 1.11 (s, 3H), 1.06 (s, 3H), 0.97 (s, 3H), 0.97 (s, 3H), 0.93-0.88 (m, 2H), 0.68-0.58 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:19])([F:18])[F:17])[CH:6]=[CH:7][CH:8]=1)=O.[O:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[F:17][C:16]([F:19])([F:18])[O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3](/[CH:1]=[C:24]2/[C:23](=[O:25])[NH:22][C:21](=[O:26])[O:20]/2)[CH:4]=1
Reactant: O=C1COC(=O)N1
Reactant: O=Cc1cccc(-c2ccccc2OC(F)(F)F)c1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=C1NC(=O)/C(=C/c2cccc(-c3ccccc3OC(F)(F)F)c2)O1

Procedure:
The title compound was prepared by reacting 3-formyl-(2′-trifluoromethoxy-1,1′-biphenyl) (from Example 56, Step A) with 2,4-oxazolidinedione in toluene in the presence of piperidine and benzoic acid as described in Example 56, Step B.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:26][CH2:25][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]4[CH2:24][CH2:23]4)[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:27])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:52]1[CH:61]=[C:60]2[C:55]([CH:56]=[CH:57][C:58]([CH3:62])=[N:59]2)=[CH:54][CH:53]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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(Cl)Cl>[CH:22]1([N:17]2[CH2:16][C:15]3([CH2:25][CH2:26][N:12]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:52]5[CH:61]=[C:60]6[C:55]([CH:56]=[CH:57][C:58]([CH3:62])=[N:59]6)=[CH:54][CH:53]=5)=[CH:3][C:4]=4[F:27])[C:9]([NH2:11])=[O:10])[CH2:13][CH2:14]3)[O:20][CH2:19][C:18]2=[O:21])[CH2:24][CH2:23]1
Reactant: NC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reactant: Cc1ccc2ccc(Br)cc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc2ccc(-c3ccc(C(C(N)=O)N4CCC5(CC4)CN(C4CC4)C(=O)CO5)c(F)c3)cc2n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
A solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (0.341 mmol) in dry 1,4-dioxane (1.5 mL) was treated with bis(pinacolato)diboron (0.409 mmol), potassium acetate (0.499 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.017 mmol). The solution was degassed with a stream of nitrogen for three minutes, at which point the reaction vessel was purged with nitrogen and sealed, and the mixture stirred in an oil bath at 100° C. overnight. At this point the reaction was cooled to room temperature and 7-bromo-2-methylquinoline (0.341 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.017 mmol), and 2M aq potassium carbonate (1.022 mmol) were added. The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120° C. for 15 min. The resulting black mixture was diluted with water (100 mL) and brine (30 mL) and was extracted with ethyl acetate three times. The combined organic layers were treated with Silicycle Si-thiol (20 mg), dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-9% methanol/dichloromethane) followed by chiral HPLC (Chromegachiral CC4, methanol) and lyophilization from water (w/25% acetonitrile) afforded the title compound as a white solid in >98% ee (38 mg, 21% yield). MS(ES)+ m/e 503.0 [M+H]+. αD=+48 deg (c=0.04, methanol).
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH2:20][CH3:21])=[N:9][C:8]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH2:32][CH3:33])=[O:30])=[CH:24][CH:23]=3)=[N:7][C:6]=2[CH2:5]1)(=O)[CH3:2].Cl.[OH-].[Na+].CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1>O1CCCC1>[CH2:32]([NH:31][C:29]([NH:28][C:25]1[CH:24]=[CH:23][C:22]([C:8]2[N:9]=[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH2:20][CH3:21])[C:11]3[CH2:12][CH2:13][N:4]([CH2:1][CH3:2])[CH2:5][C:6]=3[N:7]=2)=[CH:27][CH:26]=1)=[O:30])[CH3:33]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCN(C(C)=O)C3)cc1
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCN(CC)C3)cc1
Temperature: 25 °C

Procedure:
(S)-1-(4-(7-acetyl-4-(3-ethylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea (0.106 g, 0.000234 mol) in dry Tetrahydrofuran (2.10 mL, 0.0259 mol) at 0° C. was added 1.0 M of Borane-THF complex in Tetrahydrofuran (0.92 mL) dropwise. The reaction mixture was warmed to room temperature and for 1 hour. The reaction mixture was cooled at 0° C. then about 1 mL 1M HCl dropwise then added 1M NaOH until pH10. The reaction mixture was extracted three times with 10% MeOH in dichloromethane, dried over Magnesium sulfate, filtered, concentrated, was chromatographed through silica gel (12 g, 0-5% MeOH on dichloromethane), and submitted for purification. 1H NMR (400 MHz, DMSO) δ 8.61 (s, 1H), 8.15 (d, J=8.7, 2H), 7.46 (d, J=8.8, 2H), 6.15 (t, J=5.5, 1H), 3.97 (s, 1H), 3.85 (d, J=10.4, 1H), 3.78 (d, J=11.3, 1H), 3.74-3.62 (m, 3H), 3.55 (t, J=11.2, 1H), 3.40 (t, J=13.4, 2H), 3.18-3.05 (m, 2H), 2.85-2.69 (m, 2H), 2.63-2.47 (m, 3H), 2.43 (d, J=9.0, 1H), 1.76 (ddt, J=38.0, 13.8, 7.1, 2H), 1.11 (t, J=7.1, 3H), 1.06 (t, J=7.2, 3H), 0.82 (t, J=7.4, 3H). LC/MS-m/z+439.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](O)=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:21].C1C=[C:26]2[N:28]=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C>>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:28][CH3:26])=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:21]
Reactant: O=C(O)c1c(-c2ccc(F)cc2)oc2ccc(O)c(F)c12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(O)c(F)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 4-fluoro-2-(4-fluorophenyl)-5-hydroxybenzofuran-3-carboxylic acid (73 mg, 0.252 mmol), methylamine, HCl (25.5 mg, 0.377 mmol), HOBT hydrate (65.5 mg, 0.428 mmol) and EDC hydrochloride (87 mg, 0.453 mmol) at r.t. under N2 was added N,N-diisopropylethylamine (0.220 mL, 1.258 mmol). The mixture was stirred at r.t. for 16 hours. After concentration, the mixture was added with 5 ml 1N HCl, and then 14 ml H2O. The white solid was filtered and washed with 3×5 ml H2O and dried (64 mg). 1H NMR (500 MHz, CD3OD) δ 7.89 (dd, J=8.09, 5.34, 2H), 7.25 (t overlapping with dd, 2H), 7.23 (dd, 1H), 6.99 (t, J=8.55, 1H), 2.96 (s, 3H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O—0.1% TFA, Solvent B=90% MeOH-10% H2O—0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=304.06, HPLC Rt=1.262 min.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:16]([O-])=O)[C:8]([O:14][CH3:15])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>CCOC(C)=O.O>[C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[C:7]([CH:6]=1)[NH2:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [S-2]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(N)cc(C(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 29 %

Procedure:
To a suspension of 5-tert-butyl-2-methoxy-1,3-dinitrobenzene (10.2 g, 0.04 mol) in EtOAc (150 mL) was added in a single portion a solution of sodium sulfide nonahydrate (19.2 g, 0.08 mol) in water (200 mL). Aliquate 336 (0.8 g, 5 mole %) was added in a single portion, and the two-phase mixture was brought to a reflux. All solids dissolved, and the mixture became red/brown. After about 3 h, TLC (3:1 hexanes:EtOAc) revealed almost complete loss of starting material. The mixture was filtered warm through a pad of diatomaceous earth to remove insolubles, and the filter cake was washed with fresh EtOAc. The clarified two-phase mixture was separated, and the organic layer was washed with sodium carbonate solution, followed by water and then saturated sodium chloride solution. After drying over magnesium sulfate, the solution was concentrated under reduced pressure to a thick, dark oil. This oil was extracted three times with refluxing hexanes, leaving behind a dark residue. The orange extract deposited some more dark oil, from which the warm supernatant was decanted. The resulting orange solution was heated back to reflux, and treated with both activated charcoal and diatomaceous earth. The solution was filtered hot, and the filter cake washed with hot hexanes. Re-heating the orange filtrate resulted in a clear solution. Quickly cooling the solution in an ice/acetone bath and scratching the flask with a glass rod resulted in the deposition of an orange/yellow precipitate. The suspension was allowed to cool for 1 h, and then filtered. The filter cake was washed with a small portion of cold hexanes, and then dried on the filter, providing the title compound as a yellow/orange powder (2.6 g, 30%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[CH2:12][CH2:11][CH2:10][CH:9]([NH:13][C:14](=[O:29])[CH2:15][C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH3:28])[CH2:8]1.I[C:31]1[CH:40]=[CH:39][CH:38]=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1(C)C=CC=CC=1>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[S:20][C:16]([CH2:15][C:14]([NH:13][CH:9]3[CH2:10][CH2:11][CH2:12][N:7]([C:31]4[CH:40]=[CH:39][CH:38]=[CH:37][C:32]=4[C:33]([O:35][CH3:36])=[O:34])[CH2:8]3)=[O:29])=[C:17]([CH3:28])[N:18]=2)=[CH:26][CH:25]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CC(=O)NC1CCCNC1
Reactant: COC(=O)c1ccccc1I
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1N1CCCC(NC(=O)Cc2sc(-c3ccc(Cl)cc3)nc2C)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
In an argon atmosphere, tri(dibenzylideneacetone)dipalladium (4.85 mg, 0.00530 mmol), 1,1′-bis(diphenylphosphino)ferrocene (9.09 mg, 0.0159 mmol) and cesium carbonate (48.2 mg, 0.148 mmol) were added to a toluene solution (1 mL) containing N-(piperidin-3-yl)-2-[2-(4-chlorophenyl)-4-methylthiazol-5-yl]acetamide (37.2 mg, 0.106 mmol) and methyl 2-iodobenzoate (27.8 mg, 0.106 mmol). This reaction mixture was stirred at 100° C. for 8 hours. Subsequently, the mixture was allowed to cool and was filtered through Celite. The filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=2:1->1:1) to give 23.0 mg (45%) of the desired compound as a colorless oil.
Reaction SMILES: N([O-])=O.[Na+].S(=O)(=O)(O)O.[Cl:10][C:11]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([Cl:19])[C:12]=1N.C(=O)([O-])[O-].[Na+].[Na+].[C-:26]#[N:27].[K+]>C(O)(=O)C.O.O.O.O.O.O.O.[Ni](Cl)(Cl)Cl>[Cl:10][C:11]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([Cl:19])[C:12]=1[C:26]#[N:27]
Reactant: Cc1cc(Cl)c(N)c(Cl)c1
Reactant: [C-]#N
Agent: Cl[Ni](Cl)Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(Cl)c(C#N)c(Cl)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
Powdered sodium nitrite (20.8 g, 650 mmol) was added in portions to stirred concentrated sulfuric acid (146 ml) at 5° C. The mixture was stirred 30 minutes at ambient temperature and 30 minutes at 50° C., cooled to 5° C., and treated dropwise with a solution of 2,6-dichloro-4-methylaniline (47.0 g, 267 mmol) in acetic acid (158 ml). The mixture was stirred 3 hours at 15° C., slowly poured into a solution of sodium carbonate (253 g, 2.39 mole), potassium cyanide (93.5 g, 1.44 mole), and nickel (III) chloride hexahydrate (45.4 g, 166 mmol) in water (1.3 L). After gas evolution subsided the mixture was stirred for 1 hour at 35° C., cooled, and extracted with diethyl ether. The combined extracts were washed with water, dried over anhydrous magnesium sulfate, and evaporated under vacuum. The residue was dissolved in dichloromethane and chromatographed on a column of silica gel (300 g) eluted with dichloromethane. After a forerun (600 ml), 1 liter of eluent was collected and evaporated under vacuum. The residue was crystallized from n-hexane (200 ml) to provide 14.8 g 2,6-dichloro-4-methylbenzonitrile. The mother liquor was diluted with diethyl ether and chromatographed on silica gel (500 g) using a preparative high-performance liquid chromatograph to provide 7.3 g of product (total yield: 22.1 g [44%]), m.p. 99°-102° C.