Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.O1CCOCC1.[N:8]([C@H:11]1[C@@H:16]([CH3:17])[CH2:15][N:14]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N:24](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)[CH2:13][C@H:12]1[NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[N+:9]=[N-:10].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[NH2:24][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:18]=1[N:14]1[CH2:15][C@H:16]([CH3:17])[C@H:11]([N:8]=[N+:9]=[N-:10])[C@H:12]([NH:39][C:40](=[O:41])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:13]1
Reactant: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A solution of 4 M HCl in dioxane (30.0 equiv.) was added to tert-butyl (4-((3R,4S,5S)-4-azido-3-((tert-butoxycarbonyl)amino)-5-methylpiperidin-1-yl)pyridin-3-yl)(tert-butoxycarbonyl)carbamate (1.0 equiv.). The solution started to go homogeneous for a few minutes, but then a ppt formed and the solution went very thick. After sitting at rt for 1 hour, the volatiles were removed in vacuo and the solid was pumped on for 5 minutes on the high vac. To the residue was added CH2Cl2 (0.11 M), TEA (5.0 equiv.) and Boc2O (1.0 equiv.). The solution was left stirring at rt for 1 hr. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat), NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield tert-butyl ((3R,4S,5S)-1-(3-aminopyridin-4-yl)-4-azido-5-methylpiperidin-3-yl)carbamate in 33% yield. LC/MS (m/z)=348.2 (MH+), Rt=0.70 min. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.02-1.18 (m, 3 H), 1.36-1.54 (m, 10 H), 2.19 (qd, J=6.91, 3.91 Hz, 1 H), 2.57 (q, J=10.96 Hz, 2 H), 2.96 (d, J=9.00 Hz, 1 H), 3.20 (dd, J=11.15, 3.72 Hz, 1 H), 3.55-3.73 (m, 2 H), 3.90 (br. s., 1 H), 4.01 (br. s., 1 H), 4.81 (d, J=8.61 Hz, 1 H), 6.72-6.83 (m, 1 H), 7.96 (d, J=5.09 Hz, 1 H), 8.02 (s, 1 H).
Reaction SMILES: [OH:1][CH:2]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])[CH2:7][C@@H:6]1[C:22]([O:24]C)=[O:23].[OH-].[Na+]>O1CCOCC1.ClCCl>[OH:1][CH:2]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])[CH2:7][C@@H:6]1[C:22]([OH:24])=[O:23]
Reactant: COC(=O)[C@H]1CN(CC#Cc2cccc(F)c2F)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CC#Cc4cccc(F)c4F)C[C@@H]3C(=O)O)c2c1
Temperature: 60 °C
Reaction time: 17 h
Yield: 59.7 %

Procedure:
A mixture of 0.810 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylate in 8 cm3 of dioxane to which had been added 1.3 cm3 of 5N aqueous sodium hydroxide solution was stirred for 17 hours at a temperature in the region of 60° C. After cooling to approximately 20° C., the reaction mixture was evaporated under reduced pressure (5 kPa) at a temperature in the region of 50° C. The residue obtained was purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μm; diameter 3 cm; mass 45 g), elution was carried out with a dichloromethane/methanol (92/8 by volume) mixture. A fraction of 275 cm3 was first collected, followed by 20-cm3 fractions. Fractions 12 to 46 were collected. These fractions were combined and concentrated under reduced pressure (5 kPa) at a temperature in the region of 35° C. The residue obtained was taken up in dichloromethane and filtered. The filtrate was evaporated as above and then the new residue obtained was triturated in 10 cm3 of diisopropyl ether. The mixture was stirred for 1 hour at a temperature in the region of 20° C. and then left for 16 hours. The solid precipitate was separated by filtration and washed with 2 times 10 cm3 of the same solvent and then with 2 times 10 cm3 of pentane. 0.47 g of (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid was obtained in the form of a solid with a white color melting at 92° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[CH3:20][C:21]1(C)[C:25](C)(C)OB(C(C)=C)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.O.O1CCOCC1>[CH3:20][CH:21]([C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19])[CH3:25]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccnnc1Cl
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1nnccc1CN1C(=O)c2ccccc2C1=O
Temperature: 110 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
2-[(3-Chloropyridazin-4-yl)methyl]-1H-isoindole-1,3(2H)-dione (137 mg, 0.5 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (252 mg, 0.28 mL, 1.5 mmol), tetrakis(triphenylphosphine)palladium (57.8 mg, 0.05 mmol) and sodium carbonate (106 mg, 2.00 mmol) were mixed with water (0.2 mL) and 1,4-dioxane (0.9 mL) and stirred at 110° C. for 8 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and the solvent was removed by vacuum distillation. The resulting residue was mixed with 4 M hydrogen chloride/1,4-dioxane (5 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2). The obtained colorless solid (76 mg) and 10% palladium-carbon (50 wt %, 100 mg) were stirred in methanol (5 mL) under hydrogen atmosphere (1 atm) at room temperature for 16 hours. After filtering through celite, the filtrate was evaporated under reduce pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give the desired product (76.3 mg, 54% yield).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[S:14])SC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:11]([SH:14])=[N:17][N:16]=[N:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CSC(=S)NCCCc1ccccc1
Agent: [Na+]
Product: Sc1nnnn1CCCc1ccccc1
Yield: 20.6 %

Procedure:
Methyl N-(3-phenylpropyl)dithiocarbamate (0.044 mol) and sodium azide (0.062 mol) were reacted substantially as described in Example 1C above to obtain 2.0 g (21%) colorless crystals: mp 75°-76° (pet. ether).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][NH:10][CH2:11][CH2:12][C:13]#[N:14]>S(=O)(=O)(O)O.O.S([O-])([O-])(=O)=O.[Fe+3].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Fe+3].S([O-])([O-])(=O)=O.[Fe+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1/[N:9]=[N:10]/[CH2:11][CH2:12][C:13]#[N:14]
Reactant: N#CCCNNc1cc(F)ccc1F
Agent: [Fe+2]
Agent: [Fe+3]
Agent: O=S(=O)(O)O
Solvent: O
Product: N#CCC/N=N/c1cc(F)ccc1F
Yield: 90.8 %

Procedure:
To a solution of 3-(2-(2,5-difluorophenyl)hydrazinyl)propanenitrile (790 mg) in 15 mL of 2N sulfuric acid was added 2.0 g of iron(III) sulfate hydrate. The reaction mixture was stirred at ambient temperature for 30 min as the iron sulfate slowly dissolved and a yellow oil precipitated. The reaction mixture was extracted with ether, and the extracts were washed with water, brine, dried over sodium sulfate, filtered through a plug of silica gel and concentrated to give 710 mg (91%) of (E)-3-((2,5-difluorophenyl)diazenyl)propanenitrile. LCMS (ESI) m+H=196.2. 1H NMR (400 MHz, CDCl3) δ 7.34-7.08 (m, 3H), 4.54-4.31 (m, 2H), 2.99 (t, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)([OH:12])[CH2:10][CH3:11].[Cl:18][CH2:19][C:20](Cl)=[O:21]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:20](=[O:21])[CH2:19][Cl:18])=[C:3]([C:9]([OH:12])([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:10][CH3:11])[CH:4]=1
Reactant: O=C(Cl)CCl
Reactant: CCC(O)(c1cccs1)c1cc(Br)ccc1N
Product: CCC(O)(c1cccs1)c1cc(Br)ccc1NC(=O)CCl

Procedure:
The title compound was prepared from 1-(2-amino-5-bromophenyl)-1-thiophen-2-yl-propan-1-ol and chloroacetyl chloride using the procedure described in example 1. 1H-NMR (CDCl3) δ 10.23 (s, 1H), 8.11 (d, J=8.7 Hz, 1H), 7.46 (dd, J=8.7, 2.3 Hz, 1H), 7.37 (d, J=2.3 Hz, 1H), 7.29 (dd, J=5.1, 1.0 Hz, 1H), 6.97 (m, 1H), 6.90 (dd, J=3.5, 1.0 Hz, 1H), 4.09 (m, 2H), 2.80 (s, 1H), 2.43 (m, 2H), 1.03 (t, J=7.3 Hz, 3H); MS (ES) m/z 386 (M−H)−; Anal Calc. For C15H15BrClNO2S: C, 46.35, H, 3.89; N, 3.60. Found: C, 46.67, H, 3.80; N, 3.52.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[C:12]([C:11]([F:10])([F:21])[F:22])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(N)cc1Br
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-4-methylbenzenamine (0.82 g, 4.4 mmol) in anhydrous CH2Cl2 (40 mL) was added 3-(trifluoromethyl)benzoyl chloride (0.72 ml, 4.85 mmol) and triethylamine (2.5 ml, 17.6 mmol). The mixture was stirred overnight at room temperature. The saturated NaHCO3 (80 mL) was added and the mixture was stirred for 5 min. The organic layer was separated and aqueous was extracted with CH2Cl2 (3×20 mL). The combined organic solution was dried (Na2SO4). The solvent was removed in vacuo. The title compound was afforded as a yellow solid (1.48 g, 94%).
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:25]=[CH:24][C:23]3[N:22]=[CH:21][C:20]4[N:26]([CH3:40])[C:27](=[O:39])[N:28]([C:29]5[C:30]([CH3:38])=[N:31][N:32]([CH2:34][C:35]([OH:37])=O)[CH:33]=5)[C:19]=4[C:18]=3[CH:17]=2)=[CH:12][CH:11]=1.[B-](F)(F)(F)F.[CH3:46][N:47](C(ON1C(=O)C=CC=C1)=[N+](C)C)[CH3:48].CCN(C(C)C)C(C)C.C1COCC1>CC(N(C)C)=O>[CH3:8][O:9][C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:25]=[CH:24][C:23]3[N:22]=[CH:21][C:20]4[N:26]([CH3:40])[C:27](=[O:39])[N:28]([C:29]5[C:30]([CH3:38])=[N:31][N:32]([CH2:34][C:35]([N:47]([CH3:48])[CH3:46])=[O:37])[CH:33]=5)[C:19]=4[C:18]=3[CH:17]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(CC(=O)O)nc2C)c(=O)n4C)cn1
Reactant: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: COc1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(CC(=O)N(C)C)nc2C)c(=O)n4C)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of {4-[8-(6-Methoxy-pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-3-methyl-pyrazol-1-yl}-acetic acid TFA salt (Example 101, 60 mg, 0.107 mmol), TPTU (128 mg, 0.430 mmol) and DIPEA (0.094 ml, 0.537 mmol) in DMA (1.5 ml) was stirred under argon at rt for 20 min. Then dimethtylamine in THF 2 M (Aldrich, Buchs, Switzerland, 0.242 ml, 0.483 mmol) was added and the RM was stirred at rt for 3 h. The RM was directly purified by Prep.HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 50:50). The fractions containing products were collected together and basified with NaHCO3 (0.3 g), before being concentrated. The resulting layer was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give the title compound as a white solid. (HPLC: tR 2.57 min (Method A); M+H=472 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.95 (s, 1H), 8.50-8.43 (m, 1H), 8.14-8.04 (m, 2H), 8.01-7.96 (m, 1H), 7.95-7.90 (m, 1H), 7-77-7.71 (m, 1H), 6.87-6.81 (m, 1H), 5.25-5.09 (m, 2H), 3.86 (s, 3H), 3.56 (s, 3H), 3.05 (s, 3H), 2.88 (s, 3H), 1.93 (s, 3H))
Reaction SMILES: [CH:1]([C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([NH:15][C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:4]=1[CH3:23])=[O:2].[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[OH:2][CH:1]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]1[C:11]2[O:10][C:9]([CH3:12])([CH3:13])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([NH:15][C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:4]=1[CH3:23]
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(C)O2
Reactant: Br[Mg]c1ccccc1
Product: Cc1c2c(c(C(O)c3ccccc3)c(C)c1NC(=O)CC(C)(C)C)OC(C)(C)C2

Procedure:
Using N-(7-formyl-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethyl-butanamide obtained in Example 340 and phenylmagnesium bromide, the title compound was synthesized in the same manner as in Example 239. The yield was quantitative. Amorphous substance.
Reaction SMILES: O1[C:5]2([CH2:9][CH2:8][CH:7]([C:10]3[CH:19]=[C:18]4[C:13]([C:14](=[O:28])[C:15]([C:23]([O:25]CC)=[O:24])=[CH:16][N:17]4[CH:20]4[CH2:22][CH2:21]4)=[CH:12][C:11]=3[F:29])[CH2:6]2)[O:4]CC1>C(O)C.Cl>[O:4]=[C:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:28])[C:15]([C:23]([OH:25])=[O:24])=[CH:16][N:17]3[CH:20]3[CH2:22][CH2:21]3)=[CH:12][C:11]=2[F:29])[CH2:6]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(C3CCC4(C3)OCCO4)c(F)cc2c1=O
Agent: Cl
Solvent: CCO
Product: O=C1CCC(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Yield: 191.9 %

Procedure:
A solution of 20 g (50 mmol) of 7-(1,4-dioxaspiro[4.4]non-7-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro4-oxoquinoline-3-carboxylic acid, ethyl ester in 150 ml of ethanol and 100 ml of 6.0 M hydrochloric acid was heated at reflux for 6 hours. The solvent was removed in vacuo to give 31.6 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([NH:9][C@@H:10]2[C:24](=[O:25])[N:23]3[CH2:26][C@H:27]([O:29][C:30]4[N:31]=[C:32]5[C:37](=[C:38]6[C:43]=4[CH:42]=[CH:41][CH:40]=[CH:39]6)[CH:36]=[CH:35][CH:34]=[CH:33]5)[CH2:28][C@H:22]3[C:21](=[O:44])[NH:20][C@:19]3([C:46]([O:48]CC)=[O:47])[CH2:45][C@H:18]3[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[CH:3]=1.O.O.[OH-].[Li+]>O1CCCC1.C(O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([NH:9][C@@H:10]2[C:24](=[O:25])[N:23]3[CH2:26][C@H:27]([O:29][C:30]4[N:31]=[C:32]5[C:37](=[C:38]6[C:43]=4[CH:42]=[CH:41][CH:40]=[CH:39]6)[CH:36]=[CH:35][CH:34]=[CH:33]5)[CH2:28][C@H:22]3[C:21](=[O:44])[NH:20][C@:19]3([C:46]([OH:48])=[O:47])[CH2:45][C@H:18]3[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[CH:3]=1
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)c1cc(C)on1)C(=O)N1C[C@H](Oc3nc4ccccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)c1cc(C)on1)C(=O)N1C[C@H](Oc3nc4ccccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: Cc1cc(C(=O)N[C@H]2CCCCC/C=C\[C@@H]3C[C@@]3(C(=O)O)NC(=O)[C@@H]3C[C@@H](Oc4nc5ccccc5c5ccccc45)CN3C2=O)no1
Agent: [Li+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N[C@H]2CCCCCC=C[C@@H]3C[C@@]3(C(=O)O)NC(=O)[C@@H]3C[C@@H](Oc4nc5ccccc5c5ccccc45)CN3C2=O)no1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of (2R,6S,13aS,14aR,16aS,Z)-ethyl 6-(5-methylisoxazole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (Example 18c, 3.4 g, 5.0 mmol) in tetrahydrofuran (16.7 ml), ethanol (8.4 mL), and water (8.4 mL) was added lithium hydroxide monohydrate (1.36 g, 32.5 mmol). The mixture was stirred at 50° C. for 2 h, the solvent was evaporated under reduced pressure, and the residue partitioned between water and ethyl acetate. The aqueous layer was separated, diluted with ethyl acetate, and washed with 1N HCl. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give (2R,6S,13aS,14aR,16aS,Z)-6-(5-methylisoxazole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (3.05 g, 94% yield)as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]([CH3:32])[C:9]([N:11]([C:20]2[C:25]([Cl:26])=[C:24]([O:27][CH3:28])[CH:23]=[C:22]([O:29][CH3:30])[C:21]=2[Cl:31])[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:10])[CH:3]=1.[CH3:33][N:34]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[C:39]([N+:44]([O-:46])=[O:45])[CH:38]=1)[CH3:35].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO>[Cl:26][C:25]1[C:24]([O:27][CH3:28])=[CH:23][C:22]([O:29][CH3:30])=[C:21]([Cl:31])[C:20]=1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:19])[CH3:17])[C:9]([N:8]([C:4]1[CH:3]=[C:2]([NH:43][C:40]2[CH:41]=[CH:42][C:37]([CH2:36][N:34]([CH3:35])[CH3:33])=[CH:38][C:39]=2[N+:44]([O-:46])=[O:45])[N:7]=[CH:6][N:5]=1)[CH3:32])=[O:10]
Reactant: CN(C)Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(Cl)ncn2)c1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(Nc3ccc(CN(C)C)cc3[N+](=O)[O-])ncn2)c1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 29.4 %

Procedure:
To a stirred solution of 1-(6-chloro-pyrimidin-4-yl)-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-urea (procedure L, step b; 260 g, 0.5 mmol) in toluene (5 mL) was added 4-dimethylaminomethyl-2-nitro-phenylamine (100 g, 0.5 mmol), Cs2CO3 (400 g, 1.25 mmol), Pd2(dba)3 (46 g, 0.05 mmol), xantphos (90 g, 0.15 mmol). The solution was stirred at 100° C. overnight. LCMS showed major product peak. The solution was evaporated with silica gel and purified by flash chromatography on silica eluting with EtOAc (w(/0.5% TEA):MeOH (w/0.5% TEA)=10-10:0.5 to afford the desired product (100 mg, yield: 30%). MS (ESI): 680 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH3:9])=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:35]1[C:36]2[C:37]3[CH:50]=[CH:49][S:48][C:38]=3[C:39](=[O:47])[NH:40][C:41]=2[CH:42]=[CH:43][C:44]=1[O:45][CH3:46]>>[CH:11]1([NH:10][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:35]3[C:36]4[C:37]5[CH:50]=[CH:49][S:48][C:38]=5[C:39](=[O:47])[NH:40][C:41]=4[CH:42]=[CH:43][C:44]=3[O:45][CH3:46])=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(NC1CCCC1)c1ccc(Br)cc1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)NC2CCCC2)cc1
Yield: 97.3 %

Procedure:
Following General Procedure E, N-[1-(4-bromophenyl)ethyl]cyclopentanamine (600 mg, 2.3 mmol) was reacted with bis(pinacolato)diboron (410 mg, 1.6 mmol) to afford the crude boronic ester which was reacted with 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (250 mg, 0.81 mmol) to afford the desired product (330 mg, 97%) as a brown solid: 1H NMR (300 MHz, CD3OD) δ 7.73-7.64 (m, 2H), 7.60-7.50 (m, 2H), 7.47-7.34 (m, 3H), 6.01 (d, J=5.4 Hz, 1H), 4.57 (q, J=6.8 Hz, 1H), 3.74 (s, 3H), 3.62-3.45 (m, 1H), 2.30-2.02 (m, 2H), 1.93-1.85 (m, 2H), 1.81 (d, J=6.7 Hz, 3H), 1.77-1.51 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][CH2:32][OH:33])[C:6]=2[CH:34]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][CH2:32][O:33][S:36]([CH3:35])(=[O:38])=[O:37])[C:6]=2[CH:34]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCCO)c3cc(Cl)ccc32)cn1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCCOS(C)(=O)=O)c3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7-chloro-5-(2-hydroxyethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in pyridine (5 ml) is added with stirring methanesulfonyl chloride (0.11 ml) under ice-cooling, and the mixture is stirred at room temperature for two hours. Water is added to the reaction solution, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-methanesulfonyloxyethoxyl)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.55 g) as colorless amorphous.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:48][S@@](C(C)(C)C)=O)([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[CH2:16][C:17]2[N:18]=[N:19][N:20]([C:22](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:21]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.Cl>CO.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@:15]([C:41]2[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=2)([NH2:48])[CH2:16][C:17]2[N:18]=[N:19][N:20]([CH3:22])[N:21]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:11])[F:12])[CH:7]=1
Reactant: CC(C)(C)[S@@](=O)N[C@](Cc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cn1nnc(C[C@@](N)(c2ccc(F)cc2)c2cc(F)cc(OC(F)(F)C(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29.3 %

Procedure:
To a solution of (R)—N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2-trityl-2H-tetrazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide (60 mg, 0.079 mmol) in MeOH (3 mL) was added 4 N HCl in dioxane (1 mL). The reaction mixture was stirred at room temperature for 20 min, then concentrated to yield (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2H-tetrazol-5-yl)ethanamine LCMS: RT=2.66 min [M+H] 418.55 (Phenomenex Luna C18 4.6×50 mm column, eluting with 10-90% MeOH/H2O containing 0.1% TFA, 4 min gradient, flow rate 4 mL/min, wavelength 220 nm). To a solution of ((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2H-tetrazol-5-yl)ethanamine in THF (3 mL) and MeOH (0.5 mL) was added (diazomethyl)trimethylsilane (2.0 M in hexanes, 0.05 mL). After stirring at room temperate for 20 min, the reaction mixture was concentrated and purified by ISCO flash column chromatography (silica gel, EtOAc) to give ((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)ethanamine (10 mg, yield: 30%). LCMS: RT=2.83 min [M+H] 432.57 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).