Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:6]([CH3:20])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][CH:13]=2)[C:9]=1[CH3:10].[CH2:22]([Mg]Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>O1CCCC1>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:6]([CH3:20])=[N:7][N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]([OH:19])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:16][CH:17]=2)[C:9]=1[CH3:10]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(C=O)cc2)c1C
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)Cc1c(C)nn(Cc2ccc(C(O)Cc3ccccc3)cc2)c1C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
[1-(4-Formyl-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-acetic acid methyl ester (intermediate 15.1.1, 500 mg, 1.8 mmol) was dissolved in 5 ml tetrahydrofuran, cooled to −78° C., and benzyl magnesium chloride (1.92 ml, 2 M solution in tetrahydrofuran) was added to the solution. After 30 min at this temperature, the mixture was warmed to room temperature within 12 h, and ice and 4 N aqueous HCl was added to the solution. After dilution with ethyl acetate, the organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by MPLC (silica gel, CH2Cl2/methanol 98:2).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH2:9](I)[CH3:10]>>[CH2:9]([N:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]1=[O:8])[CH3:10]
Reactant: O=c1cc(I)cc[nH]1
Reactant: CCI
Product: CCn1ccc(I)cc1=O

Procedure:
1-ethyl-4-iodopyridin-2(1H)-one was prepared from 4-iodopyridin-2(1H)-one and ethyl iodide following a procedure analogous to that described in Example 628 Step 1.
Reaction SMILES: [C:1]([S:9]/[CH:10]=[CH:11]\[C:12]([OH:14])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.C(Cl)(=O)C([Cl:23])=O>ClCCl>[C:1]([S:9]/[CH:10]=[CH:11]\[C:12]([Cl:23])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)/C=C\SC(=O)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)/C=C\SC(=O)c1ccccc1
Yield: 98.5 %

Procedure:
To a mixture of 7.0 g (0.0336 mol) of cis-3-(benzoylthio)propenoic acid and 0.5 ml of N,N-dimethylformamide in 100 ml of dichloromethane under nitrogen was added 2.93 ml (0.0336 mol) of oxalyl chloride. After 12 h the solvents were removed to give 7.5 g (99% yield) of cis-3-(benzoylthio)propenoyl chloride as a pale yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:30])[NH:17][C:18]2[S:26][C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:20]=3[C:19]=2[C:27]([NH2:29])=[O:28])=[CH:11][CH:10]=1.C(O)(=O)C.[CH:35]1([CH:38]=O)[CH2:37][CH2:36]1.C([BH3-])#N.[Na+]>CO.O1CCCC1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:30])[NH:17][C:18]2[S:26][C:21]3[CH2:22][N:23]([CH2:38][CH:35]4[CH2:37][CH2:36]4)[CH2:24][CH2:25][C:20]=3[C:19]=2[C:27]([NH2:29])=[O:28])=[CH:13][CH:14]=1
Reactant: O=CC1CC1
Reactant: NC(=O)c1c(NC(=O)Nc2ccc(Cl)cc2)sc2c1CCNC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)c1c(NC(=O)Nc2ccc(Cl)cc2)sc2c1CCN(CC1CC1)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.8 %

Procedure:
To a slurry of compound A4 (300 mg, 0.645 mmol) in methanol (4 mL) and tetrahydrofuran (2 mL) two drops of glacial acetic acid and cyclopropanecarbaldehyde (94.0 mg, 1.34 mmol) were added. After stirring at room temperature for 5 min, sodium cyanoborohydride (122 mg, 1.94 mmol) was added and the reaction mixture was stirred for an additional 3 h. After this time, the reaction was quenched with water (25 mL) and saturated aqueous sodium bicarbonate (50 mL). The resulting mixture was extracted with ethyl acetate (100 mL). The extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was triturated with methylene chloride to afford compound A5 as a white solid (245 mg, 94%): 1H NMR (500 MHz, DMSO-d6) δ 10.95 (s, 1H), 10.16 (s, 1H), 7.54-7.40 (m, 3H), 7.33 (d, J=9.0 Hz, 2H), 6.83 (bs, 1H), 3.54 (s, 2H), 2.84-2.78 (m, 2H), 2.78-2.69 (m, 2H), 2.36 (s, 2H), 0.95-0.87 (m, 1H), 0.53-0.45 (m, 2H), 0.17-0.09 (m, 2H). MS (M+H) 405.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[N:6][CH:7]=1>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(CCOc2ccc([N+](=O)[O-])cc2)nc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(CCOc2ccc(N)cc2)nc1
Yield: 92.8 %

Procedure:
A solution of 4-[2-(5-methyl-2-pyridyl)ethoxy]nitrobenzene (15.0 g) in methanol (150 ml) was subjected to catalytic reduction under 1 atmospheric pressure in the presence of 10% Pd-C (50% wet, 2.0 g). The catalyst was filtered off, and the filtrate was concentrated to give 4-[2-(5-methyl-2-pyridyl)ethoxy]aniline as crystals (12.3 g, 92.5%). Recrystallization from ethyl acetate-hexane gave colorless prisms, m.p. 74°-75° C.
Reaction SMILES: [CH2:1]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CS(O)(=O)=O.O.[CH2:32]([C:38]1([CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[C:50]2[CH:49]=[C:48]([C:51]3(O)[C:63]4[CH:62]=[C:61]([Br:64])[CH:60]=[CH:59][C:58]=4[C:57]4[C:52]3=[CH:53][C:54]([Br:65])=[CH:55][CH:56]=4)[CH:47]=[CH:46][C:45]=2[C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>ClCCl>[CH2:20]([C:7]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:19]2[CH:18]=[C:17]([C:51]3([C:48]4[CH:47]=[CH:46][C:45]5[C:44]6[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=6)[C:38]([CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:50]=5[CH:49]=4)[C:63]4[CH:62]=[C:61]([Br:64])[CH:60]=[CH:59][C:58]=4[C:57]4[C:52]3=[CH:53][C:54]([Br:65])=[CH:55][CH:56]=4)[CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCC1(CCCCCC)c2ccccc2-c2ccc(C3(O)c4cc(Br)ccc4-c4ccc(Br)cc43)cc21
Reactant: CCCCCCC1(CCCCCC)c2ccccc2-c2ccccc21
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: O
Product: CCCCCCC1(CCCCCC)c2ccccc2-c2ccc(C3(c4ccc5c(c4)C(CCCCCC)(CCCCCC)c4ccccc4-5)c4cc(Br)ccc4-c4ccc(Br)cc43)cc21

Procedure:
In a 2 L round-bottom flask, 50 g of the compound (1) and 200 g of 9,9-dihexylfluorene were dissolved in 1000 ml of dichloromethane, and then the temperature was decreased to 0° C. The reaction solution was slowly added with a s olution of 10 ml of methane sulfonic acid dissolved in 100 ml of dichloromethane with stirring, followed by further stirring for 2 hours. The resulting reaction solution was poured into water, after which an extraction was performed using diethyl ether. The solvent was evaporated using a rotary evaporator. A column chromatography separation resulted in 60 g (58%) of (9,9-di(9,9-dihexylfluoren-2-yl)-2,7-dibromofluorene) (2).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CS(O)(=O)=O.[N-:16]=[N+]=[N-].[Na+].[OH-].[Na+]>C(Cl)Cl>[NH:16]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2][C:1]1=[O:10]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCc2ccccc21
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1CCc2ccccc2N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
Step 1 A solution of 2,3-dihydro-1H-inden-1-one (1 g, 7.57 mmol) in DCM (10 mL) was treated with methanesulfonic acid (10 mL) and cooled to 0° C. Sodium azide (0.984 g, 15.13 mmol) was added and the mixture was stirred at 0° C. for 2 h, then at rt overnight. The mixture was made basic with 20% aqueous sodium hydroxide and extracted with DCM. The organic phase was washed with water, dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc) to provide 3,4-dihydroquinolin-2(1H)-one as a white solid (655 mg, 60%). 1H NMR (400 MHz, methanol-d4) δ 7.08-7.19 (2H, m), 6.92-6.99 (1H, m), 6.85 (1H, d, J=7.9 Hz), 5.47 (1H, s), 2.92 (2H, t, J=7.6 Hz), 2.49-2.58 (2H, m). Mass spectrum m/z 148.1 (M+H)+. Also obtained was 3,4-dihydroisoquinolin-1(2H)-one as a colorless oil (162 mg, 15%). 1H NMR (400 MHz, methanol-d4) δ 7.93 (1H, dd, J=7.8, 1.0 Hz), 7.44-7.52 (1H, m), 7.35 (1H, td, J=7.6, 1.2 Hz), 7.29 (1H, d, J=7.7 Hz), 3.50 (2H, t, J=6.6 Hz), 2.98 (2H, t, J=6.7 Hz). Mass spectrum m/z 148.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:24]([OH:26])[CH3:25])=[N:14][N:15]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:29]I.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:24]([O:26][CH3:29])[CH3:25])=[N:14][N:15]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)c1nn(C2CCCCO2)c2cc(OCc3ccccc3)ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(C)c1nn(C2CCCCO2)c2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1-(6-(Benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-indazol-3-yl) ethanol (10 mg) which can be prepared according to the method described in Reference example 24, etc. was dissolved in dehydrated DMF (0.12 mL; manufactured by Kanto Chemical Co., Inc.), added with sodium hydride-comprising 400 oil (2.0 mg; manufactured by Kanto Chemical Co., Inc.), followed by stirring at room temperature for 5 minutes. To the reaction solution, methyl iodide (4.87 μL; manufactured by Tokyo Chemical Industry, Co., Ltd.) was added and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, which was then extracted twice with ethyl acetate. The organic layer was washed twice with water and once with brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (“COLUMN-F”; n-hexane:ethyl acetate=5:1) to obtain the title compound (10.2 mg).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[N:22][C:21]([CH3:24])=[N:20]1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=1>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[CH:23]=[N:22][C:21]([CH3:24])=[N:20]2)=[O:11])=[N:27][CH:28]=1
Reactant: Cc1ccc(-n2cnc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Fc1ccc(Br)nc1
Product: Cc1ccc(-n2cnc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(F)cn2)c1

Procedure:
The title compound was synthesized following the same general protocol as described in Example A44, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanone and 2-bromo-5-fluoropyridine. ESI-MS (m/z): 423 [M+1]+.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][CH:66]([CH2:80][C:81]([F:84])([F:83])[F:82])[C:67](=[O:79])[C:68]([NH:70][C:71]1[CH:76]=[CH:75][C:74]([CH3:77])=[CH:73][C:72]=1[CH3:78])=[O:69])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29]C(C)(C)C)=[O:23])[CH2:14][C:15](=[O:21])[O:16]C(C)(C)C)=[O:11])=[O:7])(C)(C)C>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][CH:66]([CH2:80][C:81]([F:82])([F:83])[F:84])[C:67](=[O:79])[C:68]([NH:70][C:71]1[CH:76]=[CH:75][C:74]([CH3:77])=[CH:73][C:72]=1[CH3:78])=[O:69])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:29])[OH:34])=[O:23])[CH2:14][C:15](=[O:16])[OH:21])=[O:11])([OH:7])=[O:5]
Reactant: Cc1ccc(NC(=O)C(=O)C(CC(F)(F)F)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc2ccccc2C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(C)(C)C)c(C)c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)C(=O)C(CC(F)(F)F)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc2ccccc2C)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CCC(=O)O)C(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
50 mg (0.042 mmol) of 3(RS)-[[N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-5,5,5-trifluoro-2′,4′-dimethyl-2-oxovaleranilide were dissolved in 3 ml of trifluoroacetic acid and the solution was stirred at room temperature for 30 minutes. The solution was then diluted with 10 ml of toluene and the solvent was removed by evaporation. The solid was triturated with diethyl ether to give 29 mg of 3(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-α-aspartyl]-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-5,5,5-trifluoro-2′,4′-dimethyl-2-oxovaleranilide as a white solid, MS: m/e 1020.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[N:11]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:17]N1C(=O)CCC1=O>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[N:11]=2)=[O:9])=[CH:6][C:5]([Br:17])=[CH:4][N:3]=1
Reactant: Nc1ncccc1C(=O)c1cccc(Br)n1
Reactant: O=C1CCC(=O)N1Br
Product: Nc1ncc(Br)cc1C(=O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
To a suspension of (2-aminopyridin-3-yl)(6-bromopyridin-2-yl)methanone (5.76 g, 20.7 mmol) in acetonirile (120 ml) was added N-bromosuccinimide (4.05 g, 22.77 mmol). The resulting mixture was stirred at room temperature for 1 hour before mixture was concentrated in vacuo to approximately 20 ml. The solid was then collected by filtration and washed with minimal acetonitrile and dried to leave title compound as a brown solid (4.23 g, 57%). 1H NMR (DMSO-d6) 7.93-7.89 (4H, m), 8.03-7.99 (1H, m), 8.22 (1H, d), 8.36 (1H, d). ES+ 357.99.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=1.[OH:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][N:18]=[CH:19]2>>[CH:19]1[C:20]2[C:15](=[C:14]([O:13][CH2:2][C:3]3[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=3)[CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:17][N:18]=1
Reactant: Oc1cccc2cnccc12
Reactant: COC(=O)c1ccc(CBr)cc1
Product: O=C(O)c1ccc(COc2cccc3cnccc23)cc1

Procedure:
Methyl 4-(bromomethyl)benzoate was alkylated with commercially available 5-hydroxyisoquinoline using the analogous procedure as used for Example 202. MS found: (M+H)=280.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:11][CH2:10]2)(=O)=O.[CH3:29]O>>[CH3:29][O:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:11][CH2:10]2
Reactant: CCOC(=O)C1c2ccc(COS(C)(=O)=O)cc2CCN1C(=O)OC(C)(C)C
Reactant: CO
Product: CCOC(=O)C1c2ccc(COC)cc2CCN1C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a solution of 1-ethyl 2-tert-butyl 6-(((methylsulfonyl)oxy)methyl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (500 mg, 1.21 mmol) in MeOH (5 mL) was added TEA (0.337 mL, 2.42 mmol), and the mixture was stirred at 70° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (solvent gradient; 3→60% ethyl acetate/hexane) to give 1-ethyl 2-tert-butyl 6-(methoxymethyl)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (169 mg, 0.484 mmol, 40.0%) as a colorless oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12](/[CH:13]=[CH:14]/[C:15]#[C:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)=[CH:11][C:10]([CH3:29])([CH3:28])[CH2:9][CH:8]=1)(=O)=O.FC(F)(F)S(O[C:38]1[C:43](/C=C/CCC2C=CC(C(OCC)=O)=CC=2)=[CH:42][C:41](C)([CH3:59])[CH2:40][CH:39]=1)(=O)=O>>[CH3:59][C:41]1[CH:42]=[CH:43][C:38]([C:7]2[C:12](/[CH:13]=[CH:14]/[C:15]#[C:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)=[CH:11][C:10]([CH3:29])([CH3:28])[CH2:9][CH:8]=2)=[CH:39][CH:40]=1
Reactant: CCOC(=O)c1ccc(CC/C=C/C2=CC(C)(C)CC=C2OS(=O)(=O)C(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(C#C/C=C/C2=CC(C)(C)CC=C2OS(=O)(=O)C(F)(F)F)cc1
Product: CCOC(=O)c1ccc(C#C/C=C/C2=CC(C)(C)CC=C2c2ccc(C)cc2)cc1

Procedure:
Following General Procedure A, ethyl (E)-4-(4-(2-(trifluoromethanesulfonyl)oxy-5,5-dimethyl-1,3-cyclohexadien-3-yl)but-3-ene-1-yn-1-yl)benzoate (Compound 21, 46 mg, 0.098 mmol) was converted into the title compound.
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N+:16]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCCCCC.CCOC(C)=O>[Pd].CCO>[NH2:16][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]2[O:12][CH2:11][C:10]([CH3:14])([CH3:15])[C:9]=2[CH:8]=1
Reactant: CC(C)(C)c1cc([N+](=O)[O-])cc2c1OCC2(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: CC(C)(C)c1cc(N)cc2c1OCC2(C)C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
A suspension of 7-tert-butyl-2,3-dihydro-3,3-dimethyl-5-nitro-benzofuran (2.2 g, 8.8 mmol) and 10% palladium on carbon (200 mg) in absolute EtOH (60 mL) is hydrogenated at 40 psi of H2 pressure on a Parr hydrogenation apparatus for 3 h at 22° C. The reaction is judged complete by TLC (hexane:EtOAc, 19:1; visualized with Dragendorff reagent). The reaction mixture is filtered through Celite and evaporated to yield the title compound as a purple solid (1.7 g, 88%), which is used without further purification.
Reaction SMILES: [F:1][CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11]C(=O)OC(C)(C)C)[CH2:7][CH2:6]1.Cl>O1CCOCC1>[F:1][CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OCC(F)c2ccccc2F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CC[C@H](OCC(F)c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1 g of tert-butyl {trans-4-[2-fluoro-2-(2-fluorophenyl)ethoxy]-cyclohexyl}carbamate an 10 mL of 4N HCl in dioxane was stirred at room temperature for 3 h then concentrated to dryness under reduced pressure. The white crystalline hydrochloride salt could be converted into the free base by partitioning between 25 mL of 3N sodium hydroxide and 3×25 mL portions of chloroform. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. Further drying under vacuum gave 0.72 g of product as an oil which crystallized on standing: MS (m+1)=256.4; 1H NMR (400 MHz, CDCl3) 7.45 (m, 1H), 7.3 (m, 1H), 7.17 (m, 1H), 7.04 (m, 1H), 5.85 (dd, JHF=47 Hz, 1H), 3.75 (m, 2H), 3.3 (m, 1H), 2.7 (m, 1H), 2.02 (m, 2H), 1.85 (m, 2H), 1.3 (m, 2H), 1.05 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5](O)=[O:6].Cl.[CH3:13][NH:14][CH3:15].CCN(C(C)C)C(C)C>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([N:14]([CH3:15])[CH3:13])=[O:6]
Reactant: O=C(O)c1cc(Br)cc(I)c1
Reactant: CNC
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cc(Br)cc(I)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A solution of 3-bromo-5-Iodo-benzoic acid (4.0 g, 12.2 mmol) in 100 mL of thionyl chloride was heated under reflux for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting solid was then dissolved in 80 mL of CH2Cl2. Dimethylamine hydrochloride (1.5 g, 18.3 mmol) and DIPEA (4.3 mL, 24.5 mmol) was added and the reaction mixture was stirred at room temperature for 3 h. The resulting solution was concentrated under reduced pressure and the crude material was purified by column chromatography (Isco™ 330 g) using 50% hexanes/EtOAc as eluting solvent to afford 3.8 g (88%) of 3-bromo-5-iodo-N,N-dimethyl-benzamide as a white solid.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:9](=[O:10])[O:8][C:7]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[N:6]1)C.[C:21]([O:25][C:26](=[O:34])[NH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([CH3:24])([CH3:23])[CH3:22]>O1CCCC1>[C:21]([O:25][C:26](=[O:34])[NH:27][CH:28]1[CH2:33][CH2:32][N:31]([CH:4]=[C:5]2[C:9](=[O:10])[O:8][C:7]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][CH:12]=3)=[N:6]2)[CH2:30][CH2:29]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CCOC=C1N=C(c2cccc3ccccc23)OC1=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(C=C2N=C(c3cccc4ccccc34)OC2=O)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-ethoxymethylene-2-naphthalen-1-yl-4H-oxazol-5-one (6.30 g, 23.7 mmol) in tetrahydrofuran, piperidin-4-yl-carbamic acid tert-butyl ester (4.70 g, 23.7 mmol) was added, and the mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure to yield [1-(2-naphthalen-1-yl-5-oxo-oxazol-4-ylidenemethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester.
Reaction SMILES: [CH:1]1([C@H:7]([OH:30])[C@H:8]([N:19]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCO.O.NN>CCOCC>[NH2:19][C@@H:8]([C@H:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[OH:30])[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15]
Reactant: CN(C[C@H]([C@@H](O)C1CCCCC1)N1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Agent: NN
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CN(C[C@@H](N)[C@@H](O)C1CCCCC1)C(=O)OC(C)(C)C
Temperature: 55 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
tert-butyl (2R,3S)-3-cyclohexyl-2-(1,3-dioxoisoindolin-2-yl)-3-hydroxypropyl(methyl)carbamate (500 mg, 1.20 mmol) was dissolved into a minimal volume of EtOH (12 mL) and hydrazine monohydrate (85% in EtOH, 0.35 mL, 6.00 mmol) was added. The solution was heated at 55° C. for 45 min and then the reaction temperature was raised to reflux for 2 h. A white solid formed. The reaction was cooled to rt, Et2O (50 mL) was added and the reaction was filtered. The filtrate was stripped and the residue was stirred in Et2O (15 mL) for 1 h and filtered. The filtrate was stripped to afford tert-butyl (2R,3S)-2-amino-3-cyclohexyl-3-hydroxypropyl(methyl)carbamate (300 mg, yield 87%), which was pure enough to use directly in the next step. MS (E/Z): 287 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C:11]12([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:16][CH:15]1[CH2:14][NH:13][CH2:12]2>>[C:20]([O:19][C:18](=[O:24])[NH:17][C:11]12[CH2:16][CH:15]1[CH2:14][N:13]([C:2]1[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH2:12]2)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC12CNCC1C2
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Product: CC(C)(C)OC(=O)NC12CC1CN(c1ccc([N+](=O)[O-])nc1)C2
Yield: 95.2 %

Procedure:
Following general N—C coupling procedure 1, 5-bromo-2-nitropyridine (50 mg, 0.246 mmol), was combined with tert-butyl 3-azabicyclo[3.1.0]hexan-1-ylcarbamate (48.8 mg, 0.246 mmol), which gave 75 mg of [3-(6-Nitro-pyridin-3-yl)-3-aza-bicyclo[3.1.0]hex-1-yl]-carbamic acid tert-butyl ester in 95% yield. MS (ESI) m/e (M+H+): 321.3