Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:27]=[CH:26][C:14]([O:15][C:16]2[C:21]([F:22])=[C:20](F)[C:19]([F:24])=[C:18]([F:25])[N:17]=2)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:28]([C:31]1[CH:37]=[CH:36][C:34]([O-:35])=[CH:33][C:32]=1[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([O-:30])=[O:29].[K+].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[K+]>CS(C)=O>[N+:28]([C:31]1[CH:37]=[CH:36][C:34]([O:35][C:20]2[C:19]([F:24])=[C:18]([F:25])[N:17]=[C:16]([O:15][C:14]3[CH:13]=[CH:12][C:11]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])=[CH:27][CH:26]=3)[C:21]=2[F:22])=[CH:33][C:32]=1[O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([O-:30])=[O:29]
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2nc(F)c(F)c(F)c2F)cc1
Reactant: O=[N+]([O-])c1ccc([O-])cc1OCc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)c1ccc(Oc2nc(F)c(F)c(Oc3ccc([N+](=O)[O-])c(OCc4ccccc4)c3)c2F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
40 g of the 2-(4-benzyloxycarbonylphenoxy)-3,4,5,6-tetrafluoropyridine (0.106 mol) prepared as described in Example 6 and 30 g of potassium 4-nitro-3-benzyloxyphenoxide (0.106 mol) are dissolved in 500 ml of dimethyl sulfoxide. 30 g of potassium carbonate (0.22 mol) are added in portions to the solution. The mixture is then stirred at room temperature for 24 hours, then heated at 60° C. for 24 hours, and 15 g of potassium hydrogencarbonate (0.15 mol) are then added. The reaction solution is then cooled to room temperature and filtered through a fluted filter. The crude product is extracted by shaking with 300 ml of ethyl acetate and 700 ml of water, and the organic phase is washed three times with water and evaporated in a rotary evaporator until the reaction product precipitates out. The reaction product is then recrystallized from a mixture of ethyl acetate and n-hexane (volume ratio 1:1) and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 92%).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26](OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.[F:40][C:41]([F:54])([F:53])[O:42][C:43]1[CH:48]=[CH:47][C:46]([CH:49]=[CH:50]C=O)=[CH:45][CH:44]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH:50]=[CH:49][C:46]4[CH:45]=[CH:44][C:43]([O:42][C:41]([F:40])([F:53])[F:54])=[CH:48][CH:47]=4)[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCN(C[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)CC2)CC1
Reactant: O=CC=Cc1ccc(OC(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(CN2CCN(C3CCN(CC=Cc4ccc(OC(F)(F)F)cc4)CC3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 48.8 %

Procedure:
Tert-butyl (S)-4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]piperidine-1-carboxylate (750 mg, 1.66 mmol) was dissolved in methylene chloride (5 ml), trifluoroacetic acid (5 ml) was added followed by stirring at room temperature for 1.5 hours. The reaction mixture was concentrated. To the residue, methylene chloride (5 ml) and triethylamine (5 ml) were added, and the mixture was stirred at room temperature for 10 minutes and then concentrated. The residue was dissolved in 1,2-dichloroethane (20 ml), 3-(4-trifluoromethoxyphenyl)propenal (396 mg, 1.83 mmol) and sodium triacetoxyborohydride (564 mg, 2.66 mmol) were added followed by stirring at room temperature for 3.5 hours. The reaction solution was washed with a saturated sodium hydrogencarbonate solution (15 ml), water (20 ml), and a saturated saline solution (20 ml) in this order, and then dried over sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=10/1) and then recrystallized from methanol/water to obtain (S)-2-methyl-6-nitro-2-[4-{1-[3-(4-trifluoromethoxyphenyl)-2-propenyl]piperidin-4-yl}piperazin-1-ylmethyl]-2,3-dihydroimidazo[2,1-b]oxazole (446 mg, 49%) as a light yellow powder.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]1([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([CH:22]=2)[C:18](OC)=[O:19])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>C1COCC1>[N:7]1([C:13]2[CH:22]=[C:17]([CH2:18][OH:19])[CH:16]=[N:15][CH:14]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: COC(=O)c1cncc(N2CCOCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cncc(N2CCOCC2)c1
Yield: 80 %

Procedure:
To a suspension of LAH (1 g, 0.027 mol) in dry THF (70 mL) was added methyl 5-morpholin-4-ylnicotinate (4 g, 0.018 mol) in dry THF (10 mL) at −40° C. under stirring. The reaction mixture was stirred at this temperature for 2 h and then quenched with 6 mL of 10% aqueous NaOH solution at −40° C. The reaction mixture was allowed to stir at RT for 30 min, filtered through celite, washed with THF and concentrated to afford 2.8 g, (80%) of the title compound as a liquid.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[NH:12][C:11](=[O:13])[C:10]2([CH3:15])[CH3:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:16]I.[Cl-].[NH4+]>O1CCCC1>[CH3:16][N:12]1[CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]([CH3:15])([CH3:14])[C:11]1=[O:13]
Reactant: CC1(C)C(=O)NC1c1ccccc1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1C(=O)C(C)(C)C1c1ccccc1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Sodium hydride (60% oil) (0.48 g, 12 mmol) was added at 0° C. to a tetrahydrofuran (40 ml) solution of 4-phenyl-3,3-dimethyl-2-azetidinone (1.75 g, 10 mmol) as prepared in Example 2-(2) and the mixture was reacted at 0° C. for 15 minutes. To the reaction solution, methyl iodide (0.74 ml, 12 mol) was added dropwise and the temperature of the mixture was returned to room temperature. The reaction was performed for 2 hours and stopped by adding a saturated aqueous solution of ammonium chloride. The reaction mixture was extracted 2 times with ethyl acetate and washed 3 times with a saturated aqueous solution of NaCl. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained oil was applied to a silica gel column and eluted with a mixed solution (hexane:ethyl acetate=2:1). The desired fractions were collected and the solvents were distilled off to yield N-methyl-4-phenyl-3,3-dimethyl-2-azetidinone (1.89 g, quant.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]([CH2:19][CH2:20][CH:21]([C:25]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=2)[C:22]([OH:24])=O)C(O)=O)[CH:6]=[C:7]([S:13][CH3:14])[C:8]=1[O:9][CH2:10][CH2:11][CH3:12].BrC1C=C(C2CCC(C3C=C(OC)C(OC)=C(OC)C=3)C2=O)C=C(OC)C=1OCCC>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]2[CH2:19][CH2:20][CH:21]([C:25]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=3)[C:22]2=[O:24])[CH:6]=[C:7]([S:13][CH3:14])[C:8]=1[O:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCOc1c(OC)cc(C(CCC(C(=O)O)c2cc(OC)c(OC)c(OC)c2)C(=O)O)cc1SC
Agent: CCCOc1c(Br)cc(C2CCC(c3cc(OC)c(OC)c(OC)c3)C2=O)cc1OC
Product: CCCOc1c(OC)cc(C2CCC(c3cc(OC)c(OC)c(OC)c3)C2=O)cc1SC

Procedure:
Following substantially the same procedure of Step I but substituting 2-(3-bromo-5-methoxy-6-propoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1,6-hexanedioic acid for 2-(3-methoxy-5-(methylthio)-4-propoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1,6-hexanedioic acid there was prepared a 1:4 cis:trans mixture of 2-(3-bromo-5-methoxy-4-propoxyphenyl-5-(3,4,5-trimethoxyphenyl)cyclopentanone as an oil in a 15% yield.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([S:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH:24]([P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])[P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[C:12]1([S:18]([CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH:24]([P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])[P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[O:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOP(=O)(OCC)C(NCCCCSc1ccccc1)P(=O)(OCC)OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(NCCCCS(=O)c1ccccc1)P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
m-Chloroperbenzoic acid (487 rag) was added in small portions to a solution of tetraethyl 4-(phenylthio)butylaminomethylenebisphosphonate (1.20 g) in dichloromethane (10 ml) with ice-cooling, and then the mixture was stirred at 0° C. for 2 hours. The reaction mixture was washed successively with aqueous sodium bisulfite, saturated aqueous sodium bicarbonate, and water and then dried (MgSO4), and concentrated. The residue was chromatographed on silica gel. Tetraethyl 4-(phenylsulfinyl)butylaminomethylenebisphosphonate was obtained as a colorless oil (1.05 g, 85%) from the fraction eluted with chloroformmethanol (50:1, v/v).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[N:22]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:23]3[N:22]=[C:21]([CH3:20])[O:25][N:24]=3)[CH:27]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1nc(-c2cccc(C=O)c2)no1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2noc(C)n2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.81 min.; [M+H]+: 408.04 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:19](=[O:36])[N:20]([C:27]2[O:35][C:31]3=[CH:32][CH:33]=[CH:34][C:30]3=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][C:39]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O.Cl[Pd]Cl>[CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:19](=[O:36])[N:20]([C:27]2[O:35][C:31]3=[CH:32][CH:33]=[CH:34][C:30]3=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12]2[CH:17]=[CH:16][C:15]([C:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]=3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CC(C(=O)N(c2ccccc2)c2ccc3cccc-3o2)c2ccc(Br)cc2)cc1
Reactant: OB(O)C1=CCCCC1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(CC(C(=O)N(c2ccccc2)c2ccc3cccc-3o2)c2ccc(C3=CCCCC3)cc2)cc1
Temperature: 130 °C
Yield: 102.1 %

Procedure:
A mixture of 4-[2-(4-benzofuran-2yl-phenylcarbamoyl)-2-(4-bromo-phenyl)-ethyl]-benzoic acid methyl ester (0.4 g, 0.74 mmol), cyclohexen-2-ylboronic acid (0.23 g, 1.85 mmol), PdCl2 (o-tolylphosphine) (75 mg, 0.096 mmol), and Na2CO3 (390 mg, 3.70 mmol) in DME/EtOH/H2O (4:2:1) (17.5 mL) was heated in an oil bath at 130° C. for 2 h, cooled to rt, filtered and washed with EtOAc (20 mL). The solvent was removed under reduced pressure. The crude mixture was extracted with ethyl acetate (100 mL) and the organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography on silica gel, eluting with ethyl acetate:hexanes (3:2) to afford 4-[2-(4-benzofuran-2-yl-phenylcarbamoyl)-2-(4-cyclohex-1-enyl-phenyl)-ethyl]-benzoic acid methyl ester as a white solid (0.42 g). 1H NMR (300 MHz, CDCl3): δ 10.23 (s, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.54-7.65 (m, 4H), 7.21-7.34 (m, 8H), 6.10 (bt, 1H), 4.02 (m, 1H), 3.78 (s, 3H), 3.45 (dd, J=8.7, 13.5 Hz, 1H), 3.04 (dd, J=6.6, 13.5 Hz, 1H), 2.25-2.40 (m, 2H), 2.10-2.20 (m, 2H), 1.64-1.72 (m, 2H), 1.54-1.59 (m, 2H); LC-MS m/z=556 [C37H33NO4+H]+; TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate/hexanes (2:1); Rf=0.45.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[C:21]4[CH2:20][N:19]([CH2:22][C:23]5[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=5)[C:18](=[O:31])[NH:17][C:16]=4[N:15]=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[N:4]([CH3:32])[N:3]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46](O)=[O:47])[C:41]2=[O:49])=[CH:36][CH:35]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:19]2[CH2:20][C:21]3[C:12]([O:11][C:7]4[CH:6]=[C:5]5[C:10]([C:2]([NH:1][C:46]([C:42]6[C:41](=[O:49])[N:40]([C:37]7[CH:36]=[CH:35][C:34]([F:33])=[CH:39][CH:38]=7)[CH:45]=[CH:44][CH:43]=6)=[O:47])=[N:3][N:4]5[CH3:32])=[CH:9][CH:8]=4)=[CH:13][CH:14]=[N:15][C:16]=3[NH:17][C:18]2=[O:31])=[CH:24][CH:25]=1
Reactant: COc1ccc(CN2Cc3c(Oc4ccc5c(N)nn(C)c5c4)ccnc3NC2=O)cc1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3c(Oc4ccc5c(NC(=O)c6cccn(-c7ccc(F)cc7)c6=O)nn(C)c5c4)ccnc3NC2=O)cc1
Yield: 18.9 %

Procedure:
A solution of compound 276 (100.00 mg; 0.23 mmol; 1.00 eq.), 1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (59.59 mg; 0.26 mmol; 1.10 eq.), pybop (157.16 mg; 0.30 mmol; 1.30 eq.), DMF (4.00 ml), and N,N-diisopropylethylamine (115.48 μl; 0.70 mmol; 3.00 eq.) was stirred at room temperature for 22 hours. The reaction was concentrated, redissolved in DMSO and purified via prep HPLC to afford 28 mg (16%) of 278 as an off-white solid. LC-MS (M+H=646, obsd.=646).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([NH:12][CH2:13][C:14]([OH:16])=O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:38][O:39][C:40](=[O:50])[C@H:41]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[NH2:42]>C1COCC1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:38][O:39][C:40](=[O:50])[C@H:41]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[NH:42][C:14](=[O:16])[CH2:13][NH:12][C:10](=[O:11])[CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To N-Boc-glycylglycine (696 mg, 3.00 mmol, 1.00 equiv) in THF (10.0 mL) at 0° C. was added EDCI (1.15 g, 6.00 mmol, 2.00 equiv), HOBt (810 mg, 6.00 mmol, 2.00 equiv), n,n-diisopropylethyl amine (1.56 mL, 9.00 mmol, 3.00 equiv) and 4-(Dimethylamino)pyridine (36 mg, 0.030 mmol, 0.10 equiv) and L-phenylalanine methyl ester (647 mg, 3.00 mmol, 1.00 equiv). The reaction mixture was stirred for 1 hr at 0° C. and stirred for 12 h at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and dried (Na2SO4). The filtrate is concentrated in vacuo and the residue is purified by chromatography on silica gel eluting with DCM/MeOH 10:1 (v/v) to afford 1.10 g of the title compound as a colorless oil (93% yield).
Reaction SMILES: CS(Cl)(=O)=O.O[C@@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]1[N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[CH2:22]([N:24](CC)CC)C>C(Cl)Cl>[CH3:22][NH:24][C@@H:9]1[C:14]2[C:15](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:16][CH2:7][C@H:8]1[N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCN(CC)CC
Reactant: O[C@@H]1CCc2ccccc2[C@H]1N1CCCC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CN[C@@H]1c2ccccc2CC[C@H]1N1CCCC1
Yield: 56.8 %

Procedure:
A solution of methanesulfonyl chloride (10.3 g) in methylene chloride (50 ml) was added rapidly in drops to a stirred and cooled (0.5° C.) solution of trans-1,2,3,4-tetrahydro-2-hydroxy-1-(pyrrolidin-1yl)naphthalene (10.3 g) and triethylamine (10 g) in methylene chloride (100 ml). After the addition was complete, the mixture was stirred at room temperature for 3 hours and then evaporated under reduced pressure. The residue was treated carefully with a 33% solution of methylamine in ethanol (125 ml) and the mixture was stirred at reflux for 2 hours followed by evaporation of the solvent under reduced pressure. The residue was treated with water and extracted twice with ether. The combined ether extracts were washed with 2N sodium hydroxide and then with water, dried over magnesium sulfate and evaporated under reduced pressure. The residual viscous liquid was distilled under vacuum to yield trans-1,2,3,4-tetrahydro-1-methylamino-2-(pyrrolidin-1-yl)naphthalene (6.2 g), b.p. 126°-134°/0.25 torr.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[C:5]2[CH:12]1[CH2:14][CH2:13]1.C(Cl)Cl.CC([O-])=O.[K+].Br[C:24]1[S:25][C:26]2[C:32]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)=[C:31]([C@H:40]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:41]([O:43]CC)=[O:42])[C:30]([CH3:51])=[CH:29][C:27]=2[N:28]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>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].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.CCO.O1CCOCC1>[C:47]([O:46][C@@H:40]([C:31]1[C:30]([CH3:51])=[CH:29][C:27]2[N:28]=[C:24]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([CH3:11])[N:6]=[C:5]4[CH:12]3[CH2:14][CH2:13]3)[S:25][C:26]=2[C:32]=1[C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)[C:41]([OH:43])=[O:42])([CH3:50])([CH3:48])[CH3:49]
Reactant: Cn1nc(C2CC2)c2cc(Br)ccc21
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1cc2nc(-c3ccc4c(c3)c(C3CC3)nn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 100 °C

Procedure:
A vial was charged with 5-bromo-3-cyclopropyl-1-methyl-1H-indazole (49 mg, 0.19 mmol), bis-pinacolatodiboron (53 mg, 0.21 mmol), PdCl2(dppf).DCM (15 mg, 19 μmol), KOAc (62 mg, 0.62 mmol), and dioxane (1.6 mL). The reaction was sealed and heated to 100° C. for 2 h. (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (94 mg, 0.190 mmol), Pd(PPh3)4 (22 mg, 19 μmol), and 2 M aq K2CO3 (400 μL) were added; the reaction was heated at 100° C. for 1.5 h. The reaction was treated with absolute EtOH (2 mL) and 10 M aq NaOH (2 mL). After heating to 100° C. for 1 h, the reaction was cooled to 23° C., and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C31H30ClN3O3S: 560.2, 562.2 (M+H+); Found: 560.2, 562.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 8.37 (s, 1H), 7.99 (dd, J=8.8, 1.3 Hz, 1H), 7.77 (s, 1H), 7.72-7.66 (m, 1H), 7.58 (d, J=3.2 Hz, 3H), 7.49 (d, J=8.9 Hz, 1H), 5.25 (s, 1H), 3.93 (s, 3H), 2.59 (s, 3H), 2.26 (ddd, J=13.1, 8.3, 5.2 Hz, 1H), 1.16-0.98 (m, 4H), 0.97 (s, 9H).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:11][C:12]([NH:14][C@H:15]1[CH2:18][C@H:17]([C:19]([O:21]C)=O)[CH2:16]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[NH:2]([C:19]([C@H:17]1[CH2:18][C@H:15]([NH:14][C:12](=[O:13])[O:11][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:16]1)=[O:21])[NH2:3]
Reactant: COC(=O)[C@H]1C[C@H](NC(=O)OCc2ccccc2)C1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)[C@H]1C[C@H](NC(=O)OCc2ccccc2)C1
Reaction time: 24 h

Procedure:
Hydrazine monohydrate (10 ml) was added to a methanol (50 ml) solution of methyl trans-3-{[(benzyloxy)carbonyl]amino}cyclobutanecarboxylate (Neurochemical Research, 1980, 5, 393-400) (995 mg, 3.78 mmol) at room temperature and the resulting mixture was stirred for 24 hours. The precipitated solid was collected by filtration, washed with water and then dried to give 760 mg (76%) of the title compound as a colorless solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7](=[O:10])[O:8][CH2:9][C:2]=12.[N:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1.C[O-].[Na+].N#N>CO.C(OCC)(=O)CC.O>[N:11]1[CH:16]=[CH:15][C:14]([CH:17]2[C:9](=[O:8])[C:2]3[N:1]=[CH:6][CH:5]=[CH:4][C:3]=3[C:7]2=[O:10])=[CH:13][CH:12]=1
Reactant: O=Cc1ccncc1
Reactant: O=C1OCc2ncccc21
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(=O)CC
Product: O=C1c2cccnc2C(=O)C1c1ccncc1

Procedure:
To a suspension of 20.27 g (150 mmol) furo[3,4-b]pyridin-5(7H)-one (for preparation see Synthesis 1997, 113) and 14.13 ml (150 mmol) 4-pyridinecarbaldehyde in 120 ml methanol and 75 ml ethyl propionate, 27.8 ml (150 mmol) of a 5.4 M solution of sodium methylate in methanol is added dropwise under ice cooling (and N2 atmosphere). The mixture is heated for 15 min to RT and then for 2 h to reflux temperature. The suspension temporarily goes into solution before a solid forms again. After cooling, 120 ml water is added, before stirring, filtering and washing the product with water. Further product is obtainable from the filtrate by acidification with acetic acid: FAB MS (M+H)+=225.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C@@:10]2([NH:15][C:16]([C@@H:18]3[CH2:22][C@@H:21]([O:23][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:27]([O:34][CH3:35])=[CH:26][N:25]=4)[CH2:20][N:19]3C(OC(C)(C)C)=O)=[O:17])[CH2:12][C@H:11]2[CH:13]=[CH2:14])=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([S:4]([NH:7][C:8]([C@@:10]2([NH:15][C:16]([C@@H:18]3[CH2:22][C@@H:21]([O:23][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:27]([O:34][CH3:35])=[CH:26][N:25]=4)[CH2:20][NH:19]3)=[O:17])[CH2:12][C@H:11]2[CH:13]=[CH2:14])=[O:9])(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2ncc(OC)c3ccccc23)CN1C(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2ncc(OC)c3ccccc23)CN1)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
To a solution of (2S,4R)-tert-butyl 2-(((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-((4-methoxyisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (1.3 g, 2.1 mmole) in DCM was added trifluoroacetic acid (TFA, 5 mL) at room temperature. The reaction mass was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure to get crude compound (2S,4R)—N-((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-4-((4-methoxyisoquinolin-1-yl)oxy)pyrrolidine-2-carboxamide (1.05 g, 97.2%) as a TFA salt. The crude compound was taken to the next step without further purification. MS: MS m/z 501.3 (M++1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:27](=[CH:28][CH:29]=1)[CH2:26][C:8]1([C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:9]1=[O:25])[CH2:7]2)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:27](=[CH:28][CH:29]=1)[CH2:26][C:8]1([C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24])[C:9]1=[O:25])[CH2:7]2
Reactant: C[Si](C)(C)CCOCN1C(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)c2cccnc21
Agent: [Pd]
Solvent: CCO
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3ccc(N)cc3C2)c2cccnc21
Reaction time: 18 h

Procedure:
A mixture of 10% Pd/C (3 g) and (±)-5-nitro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step A (19.1 g, 46.4 mmol) was stirred vigorously in EtOH (400 mL) under an atmosphere of hydrogen (ca. 1 atm). After 18 h, the mixture was filtered through a pad of Celite, washing extensively with MeOH, and the filtrate was concentrated in vacuo to give the title compound. MS: m/z=382 (M+1).