Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([NH:45][C:46](=[O:58])[C@@H:47]([N:49]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH3:50])[CH3:48])[C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30]3[CH:31]=[N:32][CH:33]=[C:34]([C:36](=[O:44])[C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=4)[CH:35]=3)=[O:24])C3C(=CC=CC=3)C=2C=CC=1.CNC>C1COCC1>[C:54]([O:53][C:51](=[O:52])[N:49]([C@H:47]([C:46](=[O:58])[NH:45][C@H:22]([C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[C:30]1[CH:31]=[N:32][CH:33]=[C:34]([C:36](=[O:44])[C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[CH:35]=1)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][NH2:17])[CH3:48])[CH3:50])([CH3:55])([CH3:56])[CH3:57]
Reactant: C[C@@H](C(=O)N[C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1CCC[C@H]1c1cncc(C(=O)c2ccc(F)cc2)c1)N(C)C(=O)OC(C)(C)C
Agent: CNC
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1c1cncc(C(=O)c2ccc(F)cc2)c1)N(C)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
To ((S)-5-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-6-{(S)-2-[5-(4-fluoro-benzoyl)-pyridin-3-yl]-pyrrolidin-1-yl}-6-oxo-hexyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (I-1c: 2.98 g, 3.7 mmol) was added 2M dimethylamine in THF (20 mL) and the mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo and purification was accomplished with semi-preparative reverse phase HPLC (300×50 mm) eluting w/10-60% acetonitrile/water over 45 minutes, followed by lyophilization of the desired fractions to provide [(S)-1-((S)-5-amino-1-{(S)-2-[5-(4-fluoro-benzoyl)-pyridin-3-yl]-pyrrolidine-1-carbonyl}-pentylcarbamoyl)-ethyl]-methyl-carbamic acid tert-butyl ester (1.5 g, 69% over 4 steps).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11].[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:5](=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccccc1
Reactant: O=C(Cl)CCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a 2-liter three-necked flask equipped with a stirring device, a thermometer and a nitrogen substituting device, 700 milliliters of benzene was introduced and 177.0 g of aluminum chloride was added with ice cooling. Then, a solution of 101.6 g of adipoyl chloride in 300 milliliters of benzene was added dropwise for 35 minutes. After stirring for one day and one night with warming back to the room temperature, the solution was poured in 3 liters of ice water containing dilute hydrochloric acid, and extracted with 2.5 liters of toluene. Thereafter, the solution was washed with a 0.5N aqueous solution of sodium hydroxide and water, and then dried with anhydrous magnesium sulfate. After removing off the solvent by a rotary evaporator, 128.4 g of 1,6-diphenylhexane-1,6-dione was obtained as crystals by recrystallizing the obtained crystals from ethyl acetate.
Reaction SMILES: C([O:8][C:9]1[C:17]2[N:16]=[C:15]([NH:18][CH3:19])[N:14]([CH3:20])[C:13]=2[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1.[B-](Br)(Br)(Br)[S+](C)C.C(Cl)(Cl)Cl.CO>ClCCl>[OH:8][C:9]1[C:17]2[N:16]=[C:15]([NH:18][CH3:19])[N:14]([CH3:20])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CNc1nc2c(OCc3ccccc3)cccc2n1C
Agent: C[S+](C)[B-](Br)(Br)Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNc1nc2c(O)cccc2n1C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
To a suspension of 4-benzyloxy-1-methyl-2-methylamino-1H-benzimidazole (150 mg) in dichloromethane (2 ml) was added boron tribromide-methyl sulfide complex (211 mg) in dryice-aceton bath, and the mixture was stirred for 1 hour under ice-cooling and then at ambient temperature overnight. To the reaction mixture were added chloroform-methanol (3:1, v/v) and saturated sodium bicarbonate solution, and insoluble material was filtered off. The separated organic layer was concentrated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=8:1, v/v) to give 4-hydroxy-1-methyl-2-methylamino-1H-benzimidazole (49 mg).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][O:7][CH2:6]1.N1C=CC=CC=1.[S:25](Cl)([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26]>C(Cl)Cl.CCOC(C)=O>[CH3:32][C:31]1[CH:33]=[CH:34][C:28]([S:25]([O:1][CH2:2][C@@H:3]([NH:11][C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])[CH2:4][C@H:5]2[CH2:10][CH2:9][CH2:8][O:7][CH2:6]2)(=[O:27])=[O:26])=[CH:29][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C[C@H]1CCCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H](C[C@H]2CCCOC2)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
The above crude product tert-butyl (S)-1-hydroxy-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate was dissolved in anhydrous DCM (22 mL). To this solution was added pyridine (2 mL) and TsCl (1.230 g, 6.45 mmol). After stirred at rt for 4 hr, another batch of pyridine (3 mL) and TsCl (0.700 g, 3.67 mmol) was added and stirred for another 12 hr. The reaction mixture was diluted with EtOAc (80 mL), washed with 1N HCl (75 mL), followed by H2O (2×30 mL), saturated aq. NaHCO3, brine, and dried over anhydrous Na2SO4, and filtered, and concentrated under reduced pressure. The resulted slurry was purified through flash chromatography on silica gel (eluted with gradient system: 0-35% EtOAc in hexane) to afford (S)-2-(tert-butoxycarbonylamino)-3-((R)-tetrahydro-2H-pyran-3-yl)propyl 4-methylbenzenesulfonate, 670 mg, yield 75% for two steps. MS ESI+ve m/z 436 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[S:17][C:16]2[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=2[CH:14]=1)=[O:12].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[S:17][C:16]3[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=3[CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=C(CBr)c1cc2c(s1)CCCC2
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(Cl)cnc1=O)c1cc2c(s1)CCCC2
Temperature: 25 °C
Yield: 33.1 %

Procedure:
A mixture of 5-chloropyrimidin-2-one (370 mg) and 2-bromoacetyl-4,5,6,7-tetrahydrobenzo[b]thiophene (740 mg) in ethanol (15 ml) was treated with triethylamine (0.6 ml, 4.76 mmol) and then stirred at room temperature. After 1.5 h the mixture was concentrated to ca 5 ml and then diluted with ethyl acetate (50 ml). The resulting solution was washed with water (×3), dried (MgSO4) and evaporated to a pale yellow foam. The foam was subjected to preparative thin-layer chromatography on silica developing with chloroform-ethanol (29:1) (two runs). Elution of the major band with ethyl acetate gave a white solid which was crystallised from ethyl acetate to give the title pyrimidinone (290 mg), m.p. 206°-208° C., λmax (EtOH) 225 nm (ε 10,160), 268.5 nm (ε 9,570), 314 nm (ε 12,260).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH3:13])=[CH:5][C:4]=1F)[CH3:2].[CH3:15][S:16]([CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:18])=[O:17].C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH3:13])=[CH:5][C:4]=1[N:24]1[CH2:25][CH2:26][CH:21]([CH2:20][CH2:19][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:22][CH2:23]1)[CH3:2]
Reactant: CS(=O)(=O)CCC1CCNCC1
Reactant: CCc1cc([N+](=O)[O-])c(OC)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCc1cc([N+](=O)[O-])c(OC)cc1N1CCC(CCS(C)(=O)=O)CC1
Temperature: 100 °C
Yield: 68 %

Procedure:
To 1-ethyl-2-fluoro-4-(methyloxy)-5-nitrobenzene (Example 187, Step C) (0.20 g, 1.0 mmol), 4-[2-(methylsulfonyl)ethyl]piperidine (Example 101, Step D) (0.23 g, 1.2 mmol), and K2CO3 (0.49 g, 3.5 mmol) was added DMSO (10 mL). The reaction was heated to 100° C. for two days. The reaction was determined to be complete by TLC. The reaction mixture was diluted with H2O and extracted with DCM and EtOAc sequentially for two iterations. The organic was dried (MgSO4), filtered, and rotovapped down. Purification by flash chromatography provided the title compound of Step A (0.25 g, 0.68 mmol, 68%). 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 6.56 (s, 1H), 3.92 (s, 3H), 3.22 (d, J=11.5 Hz, 2H), 3.00-3.14 (m, 2H), 2.92 (s, 3H), 2.69 (t, J=11.7 Hz, 2H), 2.57 (q, J=7.4 Hz, 2H), 1.76-1.97 (m, 4H), 1.35-1.70 (m, 3H), 1.24 (t, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:24][CH2:23]4)=[CH:18][C:17]=3[CH:25]3[CH2:27][CH2:26]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33]>>[CH:25]1([C:17]2[CH:18]=[C:19]([CH:22]3[CH2:24][CH2:23]3)[CH:20]=[CH:21][C:16]=2[N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:30]4[CH2:31][CH2:32][O:28][C:29]4=[O:33])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)[CH2:27][CH2:26]1
Reactant: O=C1NCCO1
Reactant: O=C(c1ccc(Br)nc1)N1CCN(c2ccc(C3CC3)cc2C2CC2)CC1
Product: O=C(c1ccc(N2CCOC2=O)nc1)N1CCN(c2ccc(C3CC3)cc2C2CC2)CC1
Yield: 75.9 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(2,4-dicyclopropylphenyl)piperazin-1-yl]methanone (500 mg) described in Preparation Example 141 and oxazolidin-2-one (148 mg), the title compound (385 mg) was obtained.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[CH2:11]([O:18][NH:19][CH2:20][C@@H:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])[C:22]([OH:24])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH:1]([N:19]([CH2:20][C@@H:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])[C:22]([OH:24])=[O:23])[O:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:2]
Reactant: O=CO
Reactant: C=CCCCC[C@H](CNOCc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: C=CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cold solution of HCO2H (3.2 mL) and dichloromethane (10 mL) at 0° C. was added acetic anhydride (1.2 mL, 12.9 mmol). The mixture was stirred for 1 hour at 0° C. To the resulting mixture was added slowly a solution of (2R)-2-({N-benzoxy-amino}methyl)-7-octenoic acid (358 mg, 1.29 mmol) in dichloromethane (10 mL). The mixture was stirred at 0° C. for 3 hours. The volatiles were removed by evaporation under vacuum. Dichloromethane (20 mL) was added to it. It was washed with brine (20 mL×2), and dried over MgSO4. Filtration and evaporation under vacuum provided the title compound. MH+306.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:22][C:23]([C:25]2[CH:34]=[C:33]([OH:35])[C:32]3[C:27](=[CH:28][C:29]([CH3:36])=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:38]([O:45][C:46](=[O:49])[CH2:47]Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:22][C:23]([C:25]2[CH:34]=[C:33]([O:35][CH2:47][C:46]([O:45][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:49])[C:32]3[C:27](=[CH:28][C:29]([CH3:36])=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)c3ccc(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3 g of 4-{(S)-3-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester and 1.5 g of Bromo-acetic acid benzyl ester in 38 ml of DMF, 2 g of cesium carbonate was added. The reaction mixture was stirred for 4 h at RT, diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 2.8 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[N:14]3[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:30](O)=[O:31])[CH:25]=4)[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:33][C@H:34]1[CH2:39][CH2:38][CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:18])[F:19])[N:14]3[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:30]([NH:33][C@H:34]5[CH2:39][CH2:38][CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35]5)=[O:31])[CH:25]=4)[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4ccnc(C(=O)O)c4)cc3N2)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Product: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4ccnc(C(=O)N[C@H]5CCCN(C(=O)OC(C)(C)C)C5)c4)cc3N2)cc1OC
Yield: 42.9 %

Procedure:
Example ER-897036 was prepared in two steps from 4-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)picolinic acid (25 mg, 0.056 mmol) and commercially available (S)-tert-butyl 3-aminopiperidine-1-carboxylate (33 mg, 0.167 mmol) in a manner similar to that of example D-6 to afford intermediate (3S)-tert-butyl 3-(4-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)picolinamido)piperidine-1-carboxylate (15 mg, 0.024 mmol, 43% yield). Then, this intermediate (13 mg, 0.021 mmol) was treated with HCl in a manner similar to that of example ER-897560 to afford the desired product ER-897036 (12 mg, 96% yield.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]([OH:16])[C:8]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[N:4]=[CH:3][CH:2]=1.[C:17](Cl)(=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[C:17]([O:9][C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][N:15]=1)=[C:7]([O:16][C:17](=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:5]1[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=1)(=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: O=C(c1ccccn1)C(O)c1ccccn1
Product: CCCCCCCCCC(=O)OC(=C(OC(=O)CCCCCCCCC)c1ccccn1)c1ccccn1
Yield: 9.9 %

Procedure:
To 21.0 g (0.1 mole) of pulverized α-pyridoin (commercially available, e.g. from Aldrich Chemical Co.) was added 9.5 g (0.05 mole) decanoyl chloride. The reaction mixture was mixed for 30 minutes, after which it became solid. The solid was extracted with acetonitrile and the acetonitrile solution evaporated to yield an oily semisolid. Recrystallization from 70% cyclohexanone-30% acetone yielded 1.3 g (9.9%) white fine needles of compound NA-IV, m.p. 89°-90° C.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]1[C:38](B(O)O)=[CH:37][CH:36]=[CH:35][N:34]=1>O>[Cl:32][C:33]1[C:38]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)=[CH:37][CH:36]=[CH:35][N:34]=1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: OB(O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc(COc2ccc(-c3cccnc3Cl)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A first stock solution was prepared consisting of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1; 1.77 g, 4.8 mmol), bis(tri-cyclohexyl-phosphine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 168 mg, 0.25 mmol), and dioxane (approximately 100 mL). A second stock solution was prepared consisting of potassium carbonate (1.99 g, 14.4 mmol) and water (approximately 10 mL). The solutions were sonicated and degassed by bubbling nitrogen gas through them. 4 mL of the first stock solution and 0.4 mL of the second stock solution were added to a reaction vial containing 2-chloropyridine-3-boronic acid (ASDI Incorporated, Newark, Del.; 94 mg, 0.6 mmol). The mixture was heated in a microwave oven at 170 degrees for 25 min and then passed through a silica gel column (1 g of silica), and washed with dioxane (1 mL) and dimethylacetamide (1 mL). 2 M potassium hydroxide solution (0.4 mL) was added. The mixture was stirred at room temperature overnight, and then 1 M HCl (0.8 mL) was added and the solvents were removed in the Genevac. Aqueous methanol (50%; approximately 2 mL) was added, then the vial was centrifuged and the solvent was removed. This process was repeated and then the sample was dried overnight in the oven to give 3-[4-(2-chloro-pyridin-3-yl)-phenoxymethyl]-benzoic acid. Mass spectrum MH+=340.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C(OCC)(=O)C.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]>[CH3:15][O:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1
Reactant: COc1cnccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1cc(Br)ccc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cnccc1-c1ccc([N+](=O)[O-])c(OC(C)C)c1
Yield: 94.9 %

Procedure:
A mixture of 2.5 g of 4-bromo-1-nitro-2-(propan-2-yloxy)benzene, 2.58 g of 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 9.4 g of caesium carbonate and 703 mg of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in 27 ml of dioxane and 8.8 ml of water, is microwave-heated at 130° C. for 20 minutes. The mixture is diluted with ethyl acetate and water. The aqueous phase is extracted with ethyl acetate (2×) and then with dichloromethane (2×10 ml). The combined organic phases are dried over magnesium sulfate and concentrated under vacuum. The residue is purified on 100 g of silica, elution being carried out with heptane/ethyl acetate (50/50 to 0/100), so as to obtain 2.63 g of 3-methoxy-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridine in the form of a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@@H:4]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:12])[C@H:5]([N:7]=[N+]=[N-])[CH3:6]>CO>[CH3:1][O:2][C:3](=[O:27])[C@@H:4]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:12])[C@H:5]([NH2:7])[CH3:6]
Reactant: CCc1ccc(-c2ccc(C(=O)N[C@H](C(=O)OC)[C@@H](C)N=[N+]=[N-])cc2)cc1
Solvent: CO
Product: CCc1ccc(-c2ccc(C(=O)N[C@H](C(=O)OC)[C@@H](C)N)cc2)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of biphenyl azido-Thr methyl ester (6) (244 mg, 0.67 mmol) in MeOH (10 ml) was made by sonicating until the milky precipitate cleared. After bubbling nitrogen through the reaction solution for 30 sec., 10% Pd/C was added in one portion. The reaction was stirred under nitrogen at RT. The reaction was exposed to aspirator vacuum to remove the nitrogen and then opened to the hydrogen gas at balloon pressure (˜1 atm). The reaction stirred for 3 h at which time the hydrogen was exchanged for nitrogen. The reaction was filtered through a pad of celite to remove the palladium. The celite pad was washed with MeOH (30 ml). The combined fractions of MeOH were evaporated under reduced pressure and dried in vacuo to give 225 mg (99% yield) of pure produce (7) as a white solid.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:29])[N:11]3[C:25]([O:27][CH3:28])=[O:26])[CH2:4][CH2:3][CH2:2]1.Br[C:31]1[N:32]=[C:33]([C:36]2([F:49])[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)[S:34][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+].O1CCOCC1.O>[C:45]([O:44][C:42]([N:39]1[CH2:40][CH2:41][C:36]([C:33]2[S:34][CH:35]=[C:31]([C:15]3[C:6]([O:5][CH:1]4[CH2:2][CH2:3][CH2:4]4)=[C:7]4[C:12](=[CH:13][CH:14]=3)[N:11]([C:25]([O:27][CH3:28])=[O:26])[C@@H:10]([CH3:29])[CH2:9][CH2:8]4)[N:32]=2)([F:49])[CH2:37][CH2:38]1)=[O:43])([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2nc(Br)cs2)CC1
Reactant: COC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)c(OC3CCC3)c2CC[C@@H]1C
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)N1c2ccc(-c3csc(C4(F)CCN(C(=O)OC(C)(C)C)CC4)n3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 100 °C
Yield: 57.4 %

Procedure:
A mixture of (S)-methyl 5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.099 g, 0.247 mmol), tert-butyl 4-(4-bromothiazol-2-yl)-4-fluoropiperidine-1-carboxylate (0.082 g, 0.224 mmol), XPhos Precatalyst 2nd Generation (0.018 g, 0.022 mmol), and cesium carbonate (0.219 g, 0.673 mmol) in 1,4-dioxane (1.0 mL) and water (0.2 mL) was heated at 100° C. for 2 h. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, and concentrated. The residue was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 25-50% ethyl acetate-hexane) to afford (S)-methyl 6-(2-(1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.072 g, 57%). MS (ESI, pos. ion) m/z 558 [M+H]+.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:17]([O:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH:32]=O)[CH:30]=2)[C:25](=[O:34])[N:24]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:23]=1[CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:18][CH2:19][CH3:20].O>CN(C)C=O>[CH2:17]([O:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29](/[CH:32]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:30]=2)[C:25](=[O:34])[N:24]([CH2:35][C:36]([CH3:37])([CH3:38])[CH3:39])[C:23]=1[CH2:40][NH:41][C:42]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:48])[CH2:18][CH2:19][CH3:20]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(C=O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(/C=C/C(=O)OCC)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.7 %

Procedure:
To a solution of ethyl diethylphosphonoacetate (1.1 mL, 5.5 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (0.22 g, 5.5 mmol) (60% in oil), and the mixture was stirred at room temperature for 10 min. To the obtained mixture was added a solution of tert-butyl (4-butoxy-6-formyl-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (2.45 g, 5.5 mmol) in N,N-dimethylformamide (10 mL) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl (E)-3-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenate (2.03 g, 71.7%), as an amorphous.