Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[C@H:24]1[CH2:29][C@@H:28]([OH:30])[CH2:27][CH2:26][NH:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:39]([O:41][CH3:42])=[O:40]>O1CCCC1.CCOCC>[CH3:42][O:41][C:39]([N:25]1[CH2:26][CH2:27][C@H:28]([OH:30])[CH2:29][C@@H:24]1[C:10]1[CH:11]=[CH:12][C:13]([C:15]([CH3:22])([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:40]
Reactant: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2)c(OCc2ccccc2)c1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2C(=O)OC)c(OCc2ccccc2)c1
Reaction time: 0.67 h
Yield: 89.9 %

Procedure:
To a 0° C. solution of 193 mg (0.471 mmole) of cis-2-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidinol and 0.29 ml triethylamine in 2.2 ml tetrahydrofuran is added dropwise 40 microliters (0.518 mmole) of methyl chloroformate. The reaction is stirred 40 minutes and then another 10 microliters of methyl chloroformate is added. The reaction is stirred 40 minutes longer, diluted with ether and filtered. The filtrate is washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate and evaporated to an oil. The crude product is purified via column chromatography on 10.4 g of silica gel eluting in 3 ml fractions with 1:3 ethyl ether/hexane to yield (fractions 16-30) 198 mg (80%) of the title compound as an oil.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.Cl.[NH2:24][CH2:25][C:26]1[CH:31]=[C:30]([C:32]2[N:37]=[C:36]([NH:38][S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][N:43]=3)(=[O:41])=[O:40])[C:35]([O:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[O:56][CH3:57])=[C:34]([O:58][CH3:59])[N:33]=2)[CH:29]=[CH:28][N:27]=1>CN(C=O)C>[CH3:59][O:58][C:34]1[C:35]([O:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[O:56][CH3:57])=[C:36]([NH:38][S:39]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][N:43]=2)(=[O:41])=[O:40])[N:37]=[C:32]([C:30]2[CH:29]=[CH:28][N:27]=[C:26]([CH2:25][NH:24][C:1](=[O:4])[CH3:2])[CH:31]=2)[N:33]=1
Reactant: CC(=O)O
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(CN)c2)nc1OC
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(CNC(C)=O)c2)nc1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6.6 mg of acetic acid and 22.3 mg of 4-methylmorpholin in DMF (5 ml) were added under ice-cooling 22.3 g of 2-Chloro-4,6-dimethoxy-1,3,5,-triazine and the solution was then stirred for 90 minutes at RT. Then 60 mg of 5-methyl-pyridine-2-sulfonic acid [2-(2-aminomethyl-pyridin-4-yl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide hydrochloride were added and stirring was continued for 12 h at RT. The mixture was partitioned between cold diluted HCl and EtOAc. The layers were separated the organic layer washed with water, dried over Na2SO4 and the solvent removed in vacuo to give N-{4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridin-2-ylmethyl}-acetamide as a light yellow crystalline solid. ISN mass spectrum, m/e 549.1 (M−1 calculated for C26H26N6O6S: 549).
Reaction SMILES: [CH:1]([CH2:3][CH2:4][C:5]12[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:6]1[C:7]([NH:9][C:10]2=[O:11])=[O:8])=[O:2].[CH3:20][NH:21][CH2:22][CH2:23][C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=2)[CH:27]=[N:26][CH:25]=1>>[OH2:2].[CH3:20][N:21]([CH2:22][CH2:23][C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=2)[CH:27]=[N:26][CH:25]=1)[CH2:1][CH2:3][CH2:4][C:5]12[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:6]1[C:7]([NH:9][C:10]2=[O:11])=[O:8].[CH3:20][N:21]([CH2:1][CH2:3][CH2:4][C:5]12[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:6]1[C:7]([NH:9][C:10]2=[O:11])=[O:8])[CH2:22][CH2:23][C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=2)[CH:27]=[N:26][CH:25]=1
Reactant: COC1=C(OC)C2C(=O)NC(=O)C2(CCC=O)C=C1
Reactant: CNCCc1cncc2cc(OC)c(OC)cc12
Product: COC1=C(OC)C2C(=O)NC(=O)C2(CCCN(C)CCc2cncc3cc(OC)c(OC)cc23)C=C1
Product: O

Procedure:
Prepared from 2-(2-formyl-ethyl)-5,6-dimethoxy-phthalimide and 4-(2-methylamino-ethyl)-6,7-dimethoxy-isoquinoline analogously to Example 4.
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[C:14]([O:16]C)[CH:13]=[C:12]([O:18][CH3:19])[C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C(=O)([O-])[O-].[Na+].[Na+]>[Cl:2][C:3]1[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]([O:18][CH3:19])[C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COc1cc(Cl)c(CN2CCCCC2)c(OC)c1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cc(O)cc(Cl)c1CN1CCCCC1
Temperature: 60 °C
Yield: 0.1 %

Procedure:
Hydroiodic acid (57% solution, 5 mL) was added to 1-(2-chloro-4,6-dimethoxybenzyl)-piperidine (360 mg, 1.3 mol) and the mixture heated at 60° C. for 2 h. The reaction mixture was cooled to ambient temperature, diluted with saturated aqueous sodium carbonate solution (20 mL) and extracted with DCM (3×30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford an beige solid that was then purified by flash chromatography (silica, 12 g column, ISCO, 0-15% (2N ammonia in methanol) in DCM) to afford the title compound as a white solid (277 mg, 88%). 1H NMR (CDCl3, 400 MHz): 6.08 (d, J=2.2 Hz, 1H), 5.96 (d, J=2.2 Hz, 1H), 3.61 (s, 3H), 3.59 (s, 2H), 3.31 (br s, 1H), 2.74-2.64 (m, 4H), 1.70-1.62 (m, 4H), 1.60-1.43 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:16]=3)[N:11]([CH:23]([CH3:25])[CH3:24])[CH:10]=2)[S:5][C:6]=1[C:7]#[N:8].[F-:26].[Cs+]>CS(C)=O.CCOC(C)=O>[C:7]([C:6]1[S:5][C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:16]=3)[N:11]([CH:23]([CH3:25])[CH3:24])[CH:10]=2)=[CH:3][C:2]=1[F:26])#[N:8]
Reactant: CC(C)n1cc(-c2cc(Cl)c(C#N)s2)c2ccc(NS(C)(=O)=O)cc21
Reactant: [F-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)n1cc(-c2cc(F)c(C#N)s2)c2ccc(NS(C)(=O)=O)cc21
Temperature: 21 °C
Yield: 3.5 %

Procedure:
Heat a mixture of N-[3-(4-Chloro-5-cyano-thiophen-2-yl)-1-isopropyl-1H-indol-6-yl]-methanesulfonamide (Example 118) (0.15 g, 0.381 mmol) and CsF (0.324 g, 2.13 mmol) in DMSO (5 ml) at 150° C. for 6 hours under N2. Cool the mixture to 21° C. and dilute with EtOAc. Wash the mixture with water, brine, and dried over MgSO4. Filter the material and concentrate to dryness. Purify the crude product by reverse phase chromatography to yield 5 mg of the title compound. MS: 378.0 (MH+)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1.[C:18](=O)([O-])[O-].[K+].[K+].CI.Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:18][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2c1ncc[nH]1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccnc1N1CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
230 mg 1-(1H-imidazol-2-yl)-5-nitro-2,3-dihydro-1H-indole are dissolved in 6 ml dimethylformamide, combined with 200 mg potassium carbonate and 75 μl methyl iodide and stirred overnight at ambient temperature. The mixture is divided between ethyl acetate and 2 N hydrochloric acid and the aqueous phase is washed twice with dichloromethane. Then the pH of the aqueous phase is adjusted to 12 by the addition of 40% sodium hydroxide solution and it is extracted with dichloromethane. The organic phase is washed with saturated sodium chloride solution and dried on magnesium sulphate. The solvents are eliminated in vacuo and the residue is chromatographed on silica gel (dichloromethane/methanol 99:1 to 90:10).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[OH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](=O)[CH3:38]>O1CCCC1>[OH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([CH3:38])=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: CC(=O)CCCCCCCO
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=CCCCCC(=O)O)CCCCCCCO
Reaction time: 0.5 h
Yield: 111.2 %

Procedure:
45.7 g (0.1 mol) of (5-carboxypentyl)triphenylphosphonium bromide were placed in 200 ml of tetrahydrofuran and 25 g (0.22 ol) of potassium t-butylate in 100 l of tetrahydrofuran were added dropwise at 0° C. Then, 15.8 g (0.1 mol) of 9-hydroxy2-nonanone were added. After stirring for 30 minutes and usual work up, 28.5 g of crude 14-hydroxy-7-methyltetradec-6-enoic acid were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([NH2:10])[CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:17][C:18](Br)=[O:19].CCOC(C)=O>C(Cl)(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[O:9][CH2:17][C:18](=[O:19])[NH:10][C:4]=2[CH:3]=1
Reactant: Cc1cc(N)c(O)cc1C
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1C)OCC(=O)N2
Reaction time: 2 h
Yield: 79.7 %

Procedure:
A solution of 4,5-dimethyl-2-aminophenol (1.73 g, 12.6 mmol) in chloroform (50 mL) was added to a rapidly stirred saturated solution of sodium bicarbonate. Bromoacetyl bromide (1.1 mL, 2.54 g, 12.6 mmol) in chloroform (15 mL) was added dropwise to the rapidly stirring mixture. Stirring continued for 2 h. EtOAc was added. Layers separated and the EtOAc solution washed with H2O (1×), brine (1×), dried (MgSO4) and concentrated to give a brown solid, which was dissolved in DMF (85 mL). CsCO3 (4.1 g, 12.6 mmol) was added and the mixture heated at 80 deg. C. for 1 h, then poured into ice-H2O (200 mL). The crystallized product was collected, washed with H2O, and dried to give a tan solid (1.78 g, 80%). MS (ES) m/e 178[M+H]+.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C([O-])([O-])=O.[Cs+].[Cs+].S(O[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(C1C=CC(C)=CC=1)(=O)=O.O>CN(C=O)C>[C:33]([NH:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][N:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3])([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccn(CCCCCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Temperature: 40 °C
Yield: 70 %

Procedure:
Uracil (0.087 g, 0.776 mmol) was stirred with Cs2CO3 (0.169 g, 0.519 mmol) in DMF (4 mL) at room temperature for 1 h. A solution of O-tosyl-6-tritylaminohexanol (0.250 g, 0.487 mmol) in DMF (2 mL) was then added dropwise. The reaction mixture was heated at 40° C. for 64 h, left to cool to room temperature, poured into cold water (15 mL) and extracted with EtOAc (25 mL). The organic extracts were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo. Further purification was carried out by flash column chromatography (ISOLUTE SI column) using a gradient elution of 20→50% EtOAc in hexane. The fractions with Rf=0.49 (10% CH3OH/CHCl3) gave the title compound slightly contaminated with DMF as a white solid (0.111 g, ca 50%). Remaining traces of DMF could be removed by recrystallisation from CH3OH or alternatively by water wash with a purification yield of 70-80%.
Reaction SMILES: F[C:2]1[N:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])[CH:8]=1)=[O:5].Cl.Cl.[NH:29]1[C:33]2=[N:34][CH:35]=[CH:36][C:37]([CH2:38][NH2:39])=[C:32]2[CH:31]=[CH:30]1>>[NH:29]1[C:33]2=[N:34][CH:35]=[CH:36][C:37]([CH2:38][NH:39][C:2]3[N:26]=[CH:25][CH:24]=[CH:23][C:3]=3[C:4]([NH:6][C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([OH:22])([C:14]([F:16])([F:15])[F:17])[C:18]([F:21])([F:20])[F:19])[CH:8]=3)=[O:5])=[C:32]2[CH:31]=[CH:30]1
Reactant: O=C(Nc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1)c1cccnc1F
Reactant: NCc1ccnc2[nH]ccc12
Agent: Cl
Product: O=C(Nc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1)c1cccnc1NCc1ccnc2[nH]ccc12

Procedure:
The titled compound was prepared from 2-fluoro-N-[3-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-nicotinamide and C-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 510 (M+H). Calc'd. for C23H17F6N5O2—509.41.
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:18][C:19]([F:44])([F:43])[CH2:20][NH:21][C:22]([C:24]1([CH2:38][CH2:39][CH2:40][CH2:41]Br)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[S:31][C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]>>[F:44][C:19]([F:18])([F:43])[CH2:20][NH:21][C:22]([C:24]1([CH2:38][CH2:39][CH2:40][CH2:41][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=2[S:31][C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:23]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Sc2ccccc21
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Product: CCOC(=O)c1ccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4Sc4ccccc43)CC2)cc1

Procedure:
Step (b) of Example 1 was repeated, except that the compound prepared in step (a) of Example 80 and the compound prepared in step (d) of Example 133 were used as the starting compounds. Thus, ethyl 4-[4-[4-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-thioxanthen-9-yl]butyl]piperazin-1-yl]benzoate was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:39])[NH:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:41][O:42][C:43](=[O:68])[NH:44][CH:45]([C:49]([N:51]1[CH2:55][CH2:54][CH2:53][CH:52]1[C:56]1[NH:57][C:58]([C:61]2[CH:66]=[CH:65][C:64](Br)=[CH:63][CH:62]=2)=[CH:59][N:60]=1)=[O:50])[CH:46]([CH3:48])[CH3:47].C(=O)([O-])[O-].[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:40])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:39])[NH:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:25]=[CH:26][C:27]([C:64]3[CH:65]=[CH:66][C:61]([C:58]4[NH:57][C:56]([CH:52]5[CH2:53][CH2:54][CH2:55][N:51]5[C:49](=[O:50])[CH:45]([NH:44][C:43]([O:42][CH3:41])=[O:68])[CH:46]([CH3:48])[CH3:47])=[N:60][CH:59]=4)=[CH:62][CH:63]=3)=[CH:28][CH:29]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1C(=O)Nc1cccc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1C(=O)Nc1cccc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)c1)C(C)C
Temperature: 85 °C
Yield: 5.1 %

Procedure:
(2-Methyl-1-{2-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-3-ylcarbamoyl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (135 mg, 0.246 mmol), (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (110 mg, 0.246 mmol), Pd(PPh3)4 (14 mg, 0.0123 mmol) and a 2 M aqueous solution of potassium carbonate (0.246 mL, 0.492 mmol) were degassed in 1,2-dimethoxyethane (2.5 mL) for 13 min. The stirred suspension was heated to 85° C. for 3 hours then concentrated, brought up in DMF/water and purified by reverse phase preparative HPLC to provide {1-[2-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-[1,1′; 4′,1″]terphenyl-3″-ylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (10 mg, 5%). (MeOH-d4, 400 MHz) 7.90 (s, 1H), 7.82-7.66 (m, 8H), 7.54-7.51 (m, 1H), 7.40-7.37 (m, 2H), 4.59 (m, 1H), 4.24 (m, 1H), 4.02-3.73 (m, 4H), 3.66 (s, 3H), 3.65 (s, 3H), 2.36-2.02 (m, 10H), 1.15-0.88 (m, 12H); MS (ESI) m/z 792 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C@H:17]([CH3:18])[CH2:16][C:15]2[C:10](=[C:11]([O:21][CH3:22])[CH:12]=[C:13]([O:19][CH3:20])[CH:14]=2)[C@H:9]1[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24]Br>C(Cl)Cl>[CH2:1]([N:8]1[C@H:17]([CH3:18])[CH2:16][C:15]2[C:10](=[C:11]([O:21][CH3:22])[CH:12]=[C:13]([O:19][CH3:20])[C:14]=2[Br:24])[C@H:9]1[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: COc1cc2c(c(OC)c1)[C@@H](C)N(Cc1ccccc1)[C@H](C)C2
Solvent: ClCCl
Product: COc1cc(OC)c2c(c1Br)C[C@@H](C)N(Cc1ccccc1)[C@@H]2C
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
Into a 25 mL round bottom flask was placed N-benzyl-(1R, 3R)-1,2,3,4-tetrahydro-6,8-dimethoxy-1,3-dimethylisoquinoline (288 mg, 0.9 mmol) dissolved in methylene chloride (3 mL). Bromine (156 mg, 1.0 mmol) in methylene chloride (1 mL ) was added to the solution. The mixture was stirred for 3 h at room temperature and then diluted with methylene chloride (20 mL) and washed with H2O (2×5 ml). The organic layer was dried with sodium sulfate and concentrated in vacuo to yield 360 mg of crude material. Separation on MPLC (hexane/ethyl acetate; 9:1, 3% Et3N) gave N-benzyl-(1R, 3R)-5-bromo-1,2,3,4-tetrahydro-6,8-dimethoxy-1,3-dimethylisoquinoline [106] (282 mg, 78%) as light yellow oil; 1H-NMR (CDCl3, 200 MHz): δ7.31 [m, 5H, Ph], 6.4 [s, Ar-H(7)], 3.97 [q, J=6.6 Hz, CHCH3 ], 3.91 [s, OMe] 3.84, [d, J=14.4 Hz, CHcHdPh], 3.76 [s, OMe], 3.52 [ddq, J=11.6, 6.0, and 4.6 Hz, CH2CHCH3 ], 3.19 [d, J=14.4 Hz, CHcHdPH], 2.74 [dd, J=17.7 and 4.6 Hz, CHaHbCHCH3 ], 2.45 [dd, J=17.7 and 11.6 Hz, CHaHbCHCH3 ], 1.35 [d, J=6.0 Hz, CH2CHCH3 ], and 1.31 [d, J=6.6 Hz, CHCH3 ]; 13C-NMR (CDCl3, 200 MHz): δ157.0, 154.4, 140.9, 136.1, 128.3 [2C], 128.0 [2C], 126.3, 122.1, 104.5, 94.3, 56.3, 55.3 [2C], 51.3, 49.4, 45.7, 33.1, and 19.8; LRMS (EI): m/z 374 (M+ -15, 70), 360, 294, 268, 226, 203, 190, 162, 145 (all <5), 91 (100), 65, and 39.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]([S:45]([C:48]1[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=1)(=[O:47])=[O:46])[CH2:9][CH2:10][N:11]([S:35]([C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:12][CH2:13][N:14]([S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[O:7])[CH2:2][CH2:3][CH3:4].CCN(CC)CC.[C:62]1([CH3:72])[CH:67]=[CH:66][C:65]([S:68](Cl)(=[O:70])=[O:69])=[CH:64][CH:63]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[S:68]([O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:14]([S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:13][CH2:12][N:11]([S:35]([C:38]1[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][CH:43]=1)(=[O:36])=[O:37])[CH2:10][CH2:9][N:8]([C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[S:45]([C:48]1[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=1)(=[O:46])=[O:47])([C:65]1[CH:66]=[CH:67][C:62]([CH3:72])=[CH:63][CH:64]=1)(=[O:70])=[O:69]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCOC(=O)N(CCN(CCN(CCCCCCCCCO)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)N(CCN(CCN(CCCCCCCCCOS(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
To 5.47 g of 16-butoxycarbonyl-10, 13,16-tri(p-toluenesulfonyl)-10, 13,16-triazahexadecanol in 200 ml of CH2Cl2, 2.95 g of Et3N was added and the mixture was cooled to 0° C. To the well stirred solution was added dropwise at 0° C. 0.22 g of 4-dimethylaminopyridine and then 1.67 g of p-toluenesulfonyl chloride in 100 ml of CH2Cl2 was added. The reaction was continued overnight at room temperature. A 0.04 g amount of 4-dimethylaminopyridine and 0.33 g of p-toluenesulfonyl chloride were added at 7° C. and stirring was continued for 4 hours. The mixture was extracted with water twice. The organic layers were dried over MgSO4, filtered and evaporated under reduced pressure and eluted with CH2Cl2 and CH2Cl2/ethyl acetate (100/1 v/v). About 4.21 g of product was obtained. The preparation scheme is shown below:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.O=S(Cl)[Cl:13]>>[ClH:1].[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Cl)nc1
Product: Cl
Product: O=C(Cl)c1ccc(Cl)nc1
Yield: 93 %

Procedure:
A solution of 6-chloronicotinic acid (10.00 g, 63.5 mmol) in SOCl2 (37 mL) was heated to reflux for 2 h. The SOCl2 was evaporated to dryness, to afford 12.56 g of the desired product (yield: 93%).
Reaction SMILES: [OH:1][C:2]1([CH2:8][O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[O:24])[CH:18]=3)=[C:12]([CH3:25])[CH:11]=2)[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1.O1CCCC1.[BH4-].[Na+]>CO>[OH:24][CH2:23][C:19]1[CH:18]=[C:17]([C:13]2[C:12]([CH3:25])=[CH:11][C:10]([O:9][CH2:8][C:2]3([OH:1])[CH2:7][CH2:6][S:5][CH2:4][CH2:3]3)=[CH:15][C:14]=2[CH3:16])[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc(OCC2(O)CCSCC2)cc(C)c1-c1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCC2(O)CCSCC2)cc(C)c1-c1cccc(CO)c1
Reaction time: 0.33 h
Yield: 87.7 %

Procedure:
To a solution of 4′-[(4-hydroxytetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6′-dimethylbiphenyl-3-carbaldehyde (2.12 g, 5.95 mmol) in a mixed solvent of tetrahydrofuran (8 mL) and methanol (4 mL) was added sodium borohydride (0.225 g, 5.95 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 20 min. The reaction solution was concentrated under reduced pressure, aqueous ammonium chloride solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (1.87 g, yield 88%) as colorless crystals.
Reaction SMILES: [CH:1]([C:3]1[C:7]2[NH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:6]=2[O:5][CH:4]=1)=O.Cl.[NH2:15]O>CN(C=O)C>[C:1]([C:3]1[C:7]2[NH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:6]=2[O:5][CH:4]=1)#[N:15]
Reactant: O=Cc1coc2cc(C(=O)O)[nH]c12
Reactant: NO
Agent: Cl
Solvent: CN(C)C=O
Product: N#Cc1coc2cc(C(=O)O)[nH]c12
Temperature: 125 °C
Yield: 2 %

Procedure:
To a solution of 3-formyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid (0.20 g, 0.2 M, 1.12 mmol) in DMF (6.0 mL) was added hydroxylamine hydrochloride (0.16 g, 2.24 mmol). The reaction mixture was heated at 125° C. overnight, then cooled to rt. The mixture was partitioned between EtOAc (20 mL) and H2O (20 mL). The aqueous phase was extracted with EtOAc (3×20 mL). The combined organic phases were washed with H2O and saturated aq NaCl, filtered and concentrated in vacuo. The crude product was chromatographed over silica gel (0 to 40% MeOH in CH2Cl2 over 30 min) to give 3-cyano-4H-furo[3,2-b]pyrrole-5-carboxylic acid 51 (4 mg, 2.1%) as a brown solid. 1H NMR (400 MHz, CD3OD) δ ppm 6.65 (d, J=0.68 Hz, 1H) 7.33 (d, J=0.68 Hz, 1H). LCMS m/e 175 (M−H).