Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH3:19])[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:10])[CH:5]=[CH:6][CH:7]=1.C[Li].C([Li])(C)(C)C.[B:27](OC)([O:30]C)[O:28]C>O1CCCC1.CCCCC>[CH2:12]([NH:11][C:9](=[O:10])[N:8]([C:4]1[CH:3]=[C:2]([B:27]([OH:30])[OH:28])[CH:7]=[CH:6][CH:5]=1)[CH3:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(Br)c1
Reactant: COB(OC)OC
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(B(O)O)c1
Yield: 36 %

Procedure:
In a manner similar to that of Example (18a), by reaction of 113 g (0.345 mol, 1 eq) of 1-(3-bromophenyl)-3-heptyl-1-methylurea in 1.13 L of tetrahydrofuran, 127 mL (0.38 mol, 1.1 eq) of methyllithium, 530 mL (0.76 mol, 2.2 eq) of a 1.7M solution of tert-butyllithium in pentane and 97 mL (0.904 mol, 2.2 eq) of trimethyl borate, and after purification by chromatography on silica gel (50/50 heptane/ethyl acetate) and crystallization from ethyl acetate/heptane, 36.0 g of 3-(3-heptyl-1-methylureido)phenylboronic acid are obtained in the form of a pinkish powder. Yield=36%
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[N:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:19].[OH-].[Na+]>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])=[N+:6]([O-:19])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(OCC(F)(F)F)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc(OCC(F)(F)F)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 23.5 %

Procedure:
A mixture of 5-methyl-2-(2,2,2-trifluoroethoxy)pyridine (0.55 g, 2.88 mmol, Step-1) and m-chloroperoxybenzoic acid (1.66 g, 5.77 mmol) in dichloromethane (50 mL) is stirred at room temperature for 20 hours. The reaction mixture is poured into 2M sodium hydroxide and extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with ethyl acetate/methanol (10:1) to give 0.14 g (24% yield) of the title compound as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[OH:11])=[CH:9][C:4]=2[O:3][CH2:2]1>C(Cl)Cl.O=[Mn]=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc(C(O)c2ccc3c(c2)OCO3)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc3c(c2)OCO3)cc1

Procedure:
To a stirred solution of benzo[1,3]dioxol-5-yl-(4-methoxy-phenyl) -methanol (2.54 g crude, 9.1 mmol) in CH2Cl2 (20 mL) at room temperature was added activated MnO2 powder (4.0 g, 45.5 mmol) and kept adding 2˜3 equivalents of MnO2 every 3˜5 h until HPLC showed disappearance of the starting material. The black suspension was filtered through a Celite pad, concentrated in vacuo to give benzo[1,3]dioxol-5-yl-(4-methoxy-phenyl)-methanone as a yellow solid (2.47 g, 106% crude yield, HPLC purity 93%): 1H NMR (CDCl3) δ 3.89 (s, 3H, —OCH3), 6.06 (s, 2H, CH2), 6.76-6.98 (m, 3H, Ar), 7.26-7.39 (m, 2H, Ar), 7.75-7.80 (m, 2H, Ar). The product was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH2:10][C:11]([O:13]C)=[O:12].N1C=CC=CC=1.[OH-].[Na+]>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:10][C:11]([OH:13])=[O:12]
Reactant: COC(=O)CBr
Reactant: Sc1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: O=C(O)CSc1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
2-Bromothiophenol (4.00 g, 21.6 mmol) was added to a solution of methyl 2-bromoacetate (2.20 mL, 23.3 mmol) and pyridine (1.88 mL, 23.3 mmol) in DMSO (50 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc (300 mL) and the resulting solution was washed with water (2×250 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was dissolved in THF (50 mL), aqueous 1 N NaOH solution (25 mL, 25 mmol) was added and the mixture was stirred at room temperature for 45 min. The mixture was concentrated and the aqueous solution was diluted with aqueous 1 N NaOH solution. The solution was cooled to 0° C. and was slowly rendered acidic (pH=2) by addition of aqueous 1 N HCl solution. The resulting suspension was filtered, the solid was washed with water and dried under reduced pressure to give the title compound (3.71 g, 71% yield) as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[CH2:17]([N:19]([CH2:20][CH3:21])[C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=1)[CH3:18]
Reactant: O=C(O)c1cccc(I)c1
Reactant: CCNCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
3-Iodobenzoic acid (55.5 g, 0.224 mol) was dissolved in tetrahydrofuran (220 mL) and oxalyl chloride (22 mL, 0.252 mol). Catalytic dimethylformamide (4 drops) was added, the solution was stirred at room temperature for 1 hour, and the solvent was removed under vacuum. The residue was dissolved in 220 mL petroleum ether (35°-60° C. boiling range) and cooled to 0° C. in an ice bath. Diethylamine (55 mL, 0.532 mol) was then added dropwise over 15 minutes. The reaction mixture was stirred an additional 15 minutes in the ice bath, then diluted with ethyl acetate (100 mL) and washed with saturated sodium chloride solution (50 mL). The organic layer was separated, dried over magnesium sulfate, and concentrated in vacuo to approximately half of the original volume. The solution was then filtered through a small pad of silica gel, using ethyl acetate to wash the pad. All volatiles were removed in vacuo, and the product was dried under high vacuum to give 65.69 g (97%) of N,N-diethyl-3-iodobenzamide as an amber oil. NMR (300 MHz, CDCl3): δ 1.11 (br s, 3H); 1.21 (br s, 3H); 3.23 (br s, 2H); 3.51 (br s, 2H); 7.13 (ddd, J1 =0.8 Hz, J2 =7.6 Hz, J3 =7.6 Hz, 1H); 7.32 (ddd, J1 =1.3 Hz, J2 =1.3 Hz, J3 =7.5 Hz, 1H); 7.71 (d, J=1.2 Hz, 1H); 7.72 (ddd, J1 =1.3 Hz, J2 =1.3 Hz, J3 =approx. 8.0 Hz (partially obstructed), 1H). Mass spectrum (CI--CH4) m/e: 304 (M+1, 100%). Calc. for C11H14NOI: C, 43.58; H, 4.65; N, 4.62; I, 41.86. Found: C, 43.68; H, 4.64; N, 4.64; I, 41.92.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.C[Si](C)(C)CCOC[N:26]1[CH:30]=[C:29]([C:31]([OH:35])([C:33]#[CH:34])[CH3:32])[N:28]=[CH:27]1>>[F:19][C:3]1[C:2]([C:34]#[C:33][C:31]([OH:35])([C:29]2[N:28]=[CH:27][NH:26][CH:30]=2)[CH3:32])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)c1cn(COCC[Si](C)(C)C)cn1
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1c[nH]cn1

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)but-3-yn-2-ol and following removal of the SEM protecting group (nBu4F, THF) gave the titled compound as an off-white solid. (1.5 mg, 3%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](O)=[O:11]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: COC(=O)CCCCCCC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCCCCCCO
Reaction time: 8 h

Procedure:
A solution of suberic acid monomethyl ester (1.5 g, 7.97 mmol, 1.0 equiv.) in tetrahydrofuran (THF) (32.0 mL, 0.25M) at −20° C. was treated dropwise with BH3 THF (1M solution in THF, 7.97 mL, 7.97 mmol, 1.0 equiv.). The reaction mixture was stirred overnight and was subsequently allowed to reach room temperature. The reaction mixture was then diluted with ethyl acetate (100 mL) and quenched with methanol (10 mL) and 10% HCl (10 mL). Extraction with NaHCO3 (1×20 mL), water (2×10 mL), and brine (1×10 mL), afforded methyl-8-hydroxy-octanoate (7) as a crude white solid.
Reaction SMILES: N(C(C)C)(C(C)C)CC.[N:10]([CH2:19][C:20]#[CH:21])([Si:15]([CH3:18])([CH3:17])[CH3:16])[Si:11]([CH3:14])([CH3:13])[CH3:12].I[Si:23]([CH3:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH3:16][Si:15]([CH3:18])([CH3:17])[N:10]([CH2:19][C:20]#[C:21][Si:23]([CH3:26])([CH3:25])[CH3:24])[Si:11]([CH3:12])([CH3:13])[CH3:14]
Reactant: C[Si](C)(C)I
Reactant: C#CCN([Si](C)(C)C)[Si](C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C[Si](C)(C)C#CCN([Si](C)(C)C)[Si](C)(C)C
Yield: 177.9 %

Procedure:
A reactor with a capacity of 40 mL, equipped with a magnetic stirrer was filled, under argon atmosphere, with 0.0085 g (0.015 mmol) of [{Ir(μ-Cl)(CO)2}2], and then with 25 mL of anhydrous and deoxidized toluene and 0.7 g (5.4 mmol) of NEt(i-Pr)2. The whole mixture was stirred until the starting iridium(I) complex was dissolved, and then 0.598 g (3 mmol) of (Me3Si)2NCH2C≡CH and 0.96 g (4.8 mmol) of ISiMe3 were added to the resulting mixture. The reaction was carried out at a temperature of 80° C. until complete conversion of (Me3Si)2NCH2C≡CH. After the reaction was completed, in order to remove the catalyst from the reaction mixture the solvent was evaporated at a reduced pressure along with any residual unreacted substrates, and then anhydrous pentane was added to the residue. The resulting suspension was filtered and the resulting deposit was rinsed with two portions of a solvent. The solvent was initially evaporated from the filtrate, and the residual product was distilled by means of the “trap-to-trap” technique at a reduced pressure to obtain 1.45 g of 1-(N,N-bis(trimethyl-silyl)amino)-3-trimethylsilylprop-2-yne, obtained with a yield of 96%.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:31])[C@H:7]([CH2:27][CH:28]([CH3:30])[CH3:29])[N:8]([CH3:26])[C:9](=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[N:17]=[C:16]1[CH3:24])C>C(O)C>[CH3:26][N:8]([C:9](=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[N:17]=[C:16]1[CH3:24])[C@H:7]([C:6]([OH:31])=[O:5])[CH2:27][CH:28]([CH3:29])[CH3:30]
Reactant: CCOC(=O)[C@H](CC(C)C)N(C)C(=O)CCCCCn1c(C)nc2cnccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2cnccc2n1CCCCCC(=O)N(C)[C@@H](CC(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
2M Potassium hydroxide (2.5 ml) was added to a solution of N-methyl-N-6-(2-methylimidazo[4,5-c]pyridin-1-yl)hexanoyl-L-leucine ethyl ester (200 mg, 0.50 mmol) in ethanol (70 ml). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and water was added to the residue. The pH of the resulting solution was adjusted to pH 6 by the addition of 2M HCl, the mixture was saturated with sodium chloride and extracted with DCM. The combined organic extracts were dried over anhydrous sodium sulphate, filtered and evaporated to give N-methyl-N-6-(2-methylimidazo[4,5-c]pyridin-1-yl)hexanoyl-L-leucine (70 mg, 38%) as a white foam.
Reaction SMILES: Br[CH:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]2[C:7]([OH:18])=[CH:6][CH:5]=[CH:4][C:3]1=2.[SH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23]>ClCCl>[CH3:25][O:24][C:22]([CH2:21][CH2:20][S:19][CH:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]2[C:7]([OH:18])=[CH:6][CH:5]=[CH:4][C:3]1=2)=[O:23]
Reactant: COC(=O)CCS
Reactant: O=C1c2c(O)cccc2C(Br)c2cccc(O)c21
Solvent: ClCCl
Product: COC(=O)CCSC1c2cccc(O)c2C(=O)c2c(O)cccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
10-Bromo-1,8-dihydroxy-9-anthrone (122 mg) was dissolved in dichloromethane (8 ml) and then methyl 3-mercaptopropionate (0.05 ml) was added. The red-brown solution became yellow-green immediately after addition of the thiol. The solution was stirred at room temperature for 5 hours. Removal of the solvent and recrystallisation of the residue from hexane gave the product (107.5 mg, 78%) as yellow needles, melting point 92°-94° C. (with decomposition).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[N:16]3[CH:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]3=[C:14]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:24][CH:23]=3)[N:13]=2)[CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH:8]1[CH2:9][CH:10]([C:12]2[N:16]3[CH:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]3=[C:14]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:24][CH:23]=3)[N:13]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn23)C1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nccn2c(C3CNC3)nc(-c3ccc(Oc4ccccc4)cc3)c12
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
Into a round bottom flask at 0° C. was added 3-[8-amino-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]-azetidine-1-carboxylic acid tert-butyl ester (30 mg, 0.00006 mol) and 4 M of HCl in 1,4-Dioxane (2 mL) and the suspension was stirred at 0° C.→RT for 3-4 h. The solvent was concentrated in vacuo and purification by prep TLC using 10% NH3 in MeOH in DCM afforded the compound as a yellow solid. The compound was dissolved in MeOH and passed through an SPE cartridge. The compound was registered as OSIP 700588 AA. 1H NMR (400 MHz, CDCl3): δ=4.17-4.28 (m, 2H), 4.42 (d, J=3.03 Hz, 3H), 7.05-7.10 (m, 2H), 7.10-7.15 (m, 3H), 7.15-7.19 (m, 1H), 7.20 (d, J=5.05 Hz, 1H), 7.34-7.41 (m, 2H), 7.55-7.65 (m, 2H). MS (ES+): m/z 358.12 [MH+]. HPLC: tR=0.65 min (Open Lynx, polar—5 min).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([C@@H:13]2[CH2:17][C@H:16]([S:18][C:19]3[C@H:20]([CH3:43])[C@@H:21]4[C@@H:38]([C@H:39]([OH:41])[CH3:40])[C:37](=[O:42])[N:22]4[C:23]=3[C:24]([O:26]CC3C=CC([N+]([O-])=O)=CC=3)=[O:25])[CH2:15][N:14]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)=[O:12])[CH2:6][CH2:5]1.[ClH:57]>O1CCCC1.O>[ClH:57].[F:1][CH2:2][CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([C@@H:13]2[CH2:17][C@H:16]([S:18][C:19]3[C@H:20]([CH3:43])[C@@H:21]4[C@@H:38]([C@H:39]([OH:41])[CH3:40])[C:37](=[O:42])[N:22]4[C:23]=3[C:24]([OH:26])=[O:25])[CH2:15][NH:14]2)=[O:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCCN(CCF)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCCN(CCF)CC4)C3)[C@H](C)[C@H]12

Procedure:
500 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[4-(2-fluoroethyl)-1-homopiperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 12 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 0.62 ml of 1N aqueous hydrochloric acid was added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 500 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 15(b), to give 96 mg of the title compound, as a powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:30]([NH:33][CH2:34][C:35](O)=[O:36])(=[O:32])[CH3:31].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CC#N.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:35]([CH2:34][NH:33][C:30](=[O:32])[CH3:31])=[O:36])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: CC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)CNC(C)=O)c1
Temperature: 25 °C

Procedure:
(1R,2S)-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 200 mg, 0.51 mmol) (1) and N-acetylglycine (59.8 mg, 0.51 mmol) were dissolved in dry DMF (2 ml). O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate (213 mg, 0.56 mmol) was added followed by N,N-diisopropylethylamine (270 μL, 1.53 mmol). The reaction was stirred at r.t. over night. The crude solution was diluted by MeCN/H2O and the product was purified on preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([CH3:26])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([CH:23]([CH3:25])[CH3:24])[CH:16]=1)[CH:5]=[N:6][NH:7][C:8]([NH2:10])=[O:9].[S]Cl>C(OCC)(=O)C.C(O)(=O)C>[CH:23]([C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH3:22])[O:14][C:13]1[C:2]([CH3:1])=[CH:3][C:4]([C:5]2[NH:10][C:8](=[O:9])[NH:7][N:6]=2)=[CH:11][C:12]=1[CH3:26])([CH3:24])[CH3:25]
Reactant: COc1ccc(Oc2c(C)cc(C=NNC(N)=O)cc2C)cc1C(C)C
Agent: [S]Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2c(C)cc(-c3n[nH]c(=O)[nH]3)cc2C)cc1C(C)C
Yield: 24.2 %

Procedure:
A solution of the title compound of Step A (20 mg, 0.055 mmol) and sulfur monochloride (26.7 μl, 0.33 mmol) in ethyl acetate/acetic acid (2.4 ml/0.6 ml) was heated to reflux for about eight hours. The mixture was concentrated and the residue was purified by preparative TLC (5% methanol in dichloromethane) to afford the title compound (4.7 mg) as a white solid. MS (APCI+) Calc: 353.2, found: 354.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.[Cl-].[NH4+].C(OCC)(=O)C.O1CCCC1.C(OCC)(=O)C.CCCCCC>C(O)C.O.[Fe]>[NH2:23][C:21]1[CH:20]=[CH:19][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:22]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1)N1CCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)c(F)c1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
To 4-(2-fluoro-4-nitrophenoxy)-2-[(pyrrolidin-1-yl)carbonylamino]pyridine (2.927 g) dissolved in ethanol (100 ml)-water (20 ml) were added electrolytic iron powder (3.0 g) and ammonium chloride (6.0 g), followed by heating under reflux for 1 hr. The reaction mixture was cooled down to room temperature, and then ethyl acetate-tetrahydrofuran (1:1) was added thereto, followed by stirring. An insoluble portion was filtered through celite, and washed with ethyl acetate and water. The organic layer of the filtrate was separated, washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, to which ethyl acetate-hexane was added to suspend. Crystals was filtered off and dried under aeration to provide the titled compound (2.378 g, 89%) as pale brown crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7](C1C=CC=C(O)C=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].S([O:39][CH2:40][CH:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:48])[CH2:43][CH2:42]1)(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:7][CH:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:39][CH2:40][CH:41]1[CH2:42][CH2:43][N:44]([C:47]([O:49][CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)=[O:48])[CH2:45][CH2:46]1)=[O:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)c1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a stirred solution of tert-butyl(3-hydroxyphenyl)(phenyl)methylcarbamate. (the second eluting isomer from Chiral Example 1 Step 4, 1.00 g, 3.34 mmol) in DMF (15 mL), was added potassium carbonate (0.554 g, 4.01 mmol). The reaction mixture was stirred for 10 minutes, and benzyl 4-((tosyloxy)methyl)piperidine-1-carboxylate (prepared according to Bioorganic & Medicinal Chemistry Letters, 20(1), 380-382; 2010, which is incorporated herein by reference in its entirety, 1.48 g, 3.67 mmol) added. The reaction mixture was heated at 60° C. for 2 days followed by 80° C. for 5 days. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine (×2). The organic phase was dried with anhydrous magnesium sulfate, and the solvent evaporated at reduced pressure. The crude material was purified by silica gel chromatography eluting with 100% iso-hexane to 50% ethyl acetate in iso-hexane to afford the title compound (1.12 g, 63%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][N:18]=1>C(Cl)Cl>[Cl:16][C:17]1[N:18]=[CH:19][C:20]([C:21]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:22])=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(Cl)nc1
Temperature: 25 °C

Procedure:
To a solution of t-butyl (2-aminophenyl)carbamate A1 (10 g, 48.0 mmol) in CH2Cl2 (200 mL) was added 6-chloronicotinoyl chloride (8.5 g, 48.0 mmol). The reaction mixture was concentrated after 2 hours of stirring at room temperature and purified by flash chromatography (10-75% EtOAc/hexanes) to give the Boc-protected nicotinamide B1 confirmed by MS (ESI+): cal'd [M+Na]+ 370.1, obs'd 370.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:13]([F:16])([F:15])[C:12](=[O:17])[CH:11]=[CH:10][C:9]=2[N:8]=[CH:7][C:6]=1[OH:18])=[O:4].[C:19](OC(=O)C)(=[O:21])[CH3:20].C(OCC)(=O)C>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:13]([F:16])([F:15])[C:12](=[O:17])[CH:11]=[CH:10][C:9]=2[N:8]=[CH:7][C:6]=1[O:18][C:19](=[O:21])[CH3:20])=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1c(O)cnc2c1C(F)(F)C(=O)C=C2
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(OC(C)=O)cnc2c1C(F)(F)C(=O)C=C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.2 %

Procedure:
A solution of 5,5-difluoro-3-hydroxy-6-oxo-5,6-dihydro-quinoline-4-carboxylic acid methyl ester (11.1 g, 43.50 mmol, 1.0 eq) in acetone (100 mL) is cooled to 0° C. before the addition of acetic anhydride (8.2 mL, 87.0 mmol, 2.0 eq). After 3 hours stirring at room temperature, solvent is evaporated and the crude product is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1, v/v) to afford 3-acetoxy-5,5-difluoro-6-oxo-5,6-dihydro-quinoline-4-carboxylic acid methyl ester as a white solid (5.2 g, 40% yield).