Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:7]([CH3:19])=[C:8]([CH3:18])[C:9]2[O:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:10]=2[C:16]=1[CH3:17].C(N(CC)CC)C.O>O1CCCC1>[C:1]([NH:5][C:6]1[C:7]([CH3:19])=[C:8]([CH3:18])[C:9]2[O:13][C:12]([CH3:14])([CH3:15])[CH2:11][C:10]=2[C:16]=1[CH3:17])(=[O:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(C)O2
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Nc1c(C)c(C)c2c(c1C)CC(C)(C)O2
Reaction time: 4 h
Yield: 76.4 %

Procedure:
Acetyl chloride (460 mg, 5.84 mmol) was added dropwise with ice cooling to a solution of 5-amino-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran (100 g, 4.87 mmol) and triethylamine (640 mg, 6.33 mmol) in tetrahydrofuran (20 ml). After the addition was completed, the mixture was stirred for 4 hours. Water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with saturated sodium bicarbonate solution and saturated saline, dried and concentrated. The residue was purified by column chromatography on silica gel (chloroform-methanol, 97:3) to obtain the desired compound (920 mg, yield: 76.4%). A part of it was recrystallized from dichloromethane-isopropyl ether, m.p. 190° C. (dichloromethane-isopropyl ether).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C(S)C.[N:8]1([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:27]([C:28]4[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=4)=[CH:26][CH:25]=[C:24]([CH3:36])[N:23]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1>ClCCCl>[N:8]1([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:27]([C:28]4[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=4)=[CH:26][CH:25]=[C:24]([CH3:36])[N:23]=3)=[CH:20][CH:21]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COc1ccc(-c2ccc(C)nc2-c2ccc(OCCN3CCCC3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCS
Product: Cc1ccc(-c2ccc(O)cc2)c(-c2ccc(OCCN3CCCC3)cc2)n1
Reaction time: 0.25 h
Yield: 89 %

Procedure:
The AlCl3 (3.6 g, 27 mmol) was stirred in 100 mL of DCE at 0° C., ethanethiol (3 mL, 38 retool) was added, and the mixture stirred for 15 min. The 2-[4-[2-(1-pyrrolidinyl) ethoxy]phenyl]-3- (4-methoxyphenyl) -6-methylpyridine (1.5 g, 3.9 mmol) in 50 mL DCE was added dropwise to the reaction mixture and stirred for 2 h as it was allowed to come to rt, then quenched with 75 mL THF at 0° C., followed by 50 mL 1N HCl and worked up. The crude product was triturated with Et2O, filtered, and dried in vacuo to give 1.3 g (90 % yield) of an off-white solid: mp 159°-161° C.; 1H NMR (CDCl3) d 1.80-184 (bs, 4H, pyrrolidine), 2.61 (s, 3H, pyr-CH3), 2.67-2.69 (bs, 4H, pyrrolidine), 2.93-2.97(m, 2H, CH2N), 4.08-4.10 (m, 2H, OCH2), 6.60-6.65 (m, 4H, ArH), 6.90-6.93 (d, 2H, J=8 Hz, ArH), 7.08-7.11 (d, 1H, J=8 Hz, ArH), 7.23-7.26 (m, 2H, ArH), 7.50-7.53 (d, 1H, J=8 Hz, ArH); MS(FD) 374(M+). Anal. Calcd for C24H26N2O2 : C, 76.98; H, 7.00; N, 7.48. Found: C, 76.70; H, 7.07; N, 7.36.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][N:5]1[CH:10]=[C:9]([C:11]2[S:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[O:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][C:22]=3[F:30])[CH:12]=2)[CH:8]=[CH:7][C:6]1=[O:31].[BH4-].[Na+]>CO.C1COCC1.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:17]2[CH:16]=[CH:15][N:14]=[C:13]3[CH:12]=[C:11]([C:9]4[CH:8]=[CH:7][C:6](=[O:31])[N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:32])[CH:10]=4)[S:19][C:18]=23)=[C:22]([F:30])[CH:23]=1
Reactant: CN(C)CCn1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)ccc1=O
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCn1cc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)ccc1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 27 %

Procedure:
To a solution of the nitro compound 421 (0.103 g, 0.227 mmol) in methanol (2 mL) and THF (2 ml) at 0° C. was added nickel chloride hexahydrate (0.162 g, 0.681 mmol) followed by sodium borohydride (28 mg, 0.749 mmol). After one hour of stirring at 0° C. another portion of nickel chloride hexahydrate (0.108 g, 0.458 mmol) and sodium borohydride (19 mg, 0.50 mmol) were added. The reaction mixture was then stirred at room temperature for 5 hours before it was concentrated and treated with 1N HCl(aq) and dichloromethane. The mixture was stirred for 10 minutes and then basified to pH 10 by the addition of NH4OH. The basified solution was then extracted with dichloromethane. The extract was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (eluent a gradient of 10 to 100% methanol in ethyl acetate) to give the title compound 422 as yellow solid (26 mg, 27% yield). MS (m/z): 425.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]([OH:12])[C:8]([F:11])([F:10])[F:9])[S:5][CH:6]=1.CC1(C)COB([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][CH:24]=[N:23]3)OC1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[F:9][C:8]([F:11])([F:10])[CH:7]([C:4]1[S:5][CH:6]=[C:2]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][CH:24]=[N:23]3)[CH:3]=1)[OH:12]
Reactant: OC(c1cc(Br)cs1)C(F)(F)F
Reactant: CC1(C)COB(c2ccc3nccnc3c2)OC1
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: CN(C)C=O
Product: OC(c1cc(-c2ccc3nccnc3c2)cs1)C(F)(F)F
Temperature: 90 °C

Procedure:
A mixture of the alcohol (E1) (1.0 eq.) and the crude boronic ester (E2) (1.3 eq.) in DMF (1.0M), together with 2N Na2CO3 aqueous solution (2.0 eq.) was degassed with a stream of Ar for 10 min. Pd(PPh3)4 (0.05 eq) was added and the reaction heated overnight at 90° C. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica using 500% EtOAc/Petroleum ether to yield the desired compound as a power. 1H NMR (400 MHz, CDCl3, 300K) δ 8.81 (2H, m), 8.20 (1H, d, J=2.0 Hz), 8.10 (1H, d, J=8.8 Hz), 7.98 (1H, dd, J=8.8, 2.0 Hz), 7.68 (1H, s), 7.61 (1H, s), 5.38 (1H, q, J=6.4 Hz). MS (ES) C14H9F3N2OS requires: 310, found: 311 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20](=O)[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (14 g, 42.7 mmol) in dichloroethane (150 mL) was added acetaldehyde (3.75 g, 85.2 mmol) and acetic acid (15.3 g, 256 mmol). The resulting reaction mixture was stirred at room temperature for 15 minutes. The mixture was cooled to 0° C. and sodium triacetoxyborohydride (27 g, 128 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. Upon completion of the reaction as determined by TLC, aqueous sodium bicarbonate solution was added to the reaction mixture until a pH 7-8 was obtained, the organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (100-200 mesh silica gel) eluting with ethyl acetate:hexane to afford the desired compound as a viscous liquid (14 g, 93%). 1H NMR (DMSO-d6, 400 MHz) δ 7.62 (s, 1H), 7.52 (s, 1H), 3.80 (bs, 5H), 3.31 (t, 2H), 2.97-3.05 (m, 2H), 2.87-2.96 (m, 1H), 2.38 (s, 3H), 1.52-1.61 (m, 2H), 1.37-1.50 (m, 2H), 0.87 (t, 3H, J=6.8 Hz).
Reaction SMILES: [N:1]1([C:7]([NH:9][C:10]2([C:16]([OH:18])=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:19][C:20]([NH:23][C:24](=[O:33])[CH:25]([OH:32])[C@@H:26]([NH2:31])[CH2:27][CH2:28][CH2:29][CH3:30])([CH3:22])[CH3:21].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C(Cl)Cl.C(OCC)(=O)C>[OH:32][CH:25]([C@@H:26]([NH:31][C:16]([C:10]1([NH:9][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)=[O:18])[CH2:27][CH2:28][CH2:29][CH3:30])[C:24]([NH:23][C:20]([CH3:19])([CH3:21])[CH3:22])=[O:33]
Reactant: CCCC[C@H](N)C(O)C(=O)NC(C)(C)C
Reactant: O=C(NC1(C(=O)O)CCCCC1)N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCC[C@H](NC(=O)C1(NC(=O)N2CCOCC2)CCCCC1)C(O)C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
0.26 g (1.26 mmol) of 1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxylic acid (1.26 mmol), 0.27 g (1.26 mmol) of (2RS,3S)-N-(2-methyl-2-propyl)-3-amino-2-hydroxyheptanamide and 0.24 g (1.5 mmol) of 1-hydroxybenzotriazole were dissolved in 15 ml of anhydrous methylen chloride and then, under air current of nitrogen, 0.29 g (1.5 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide was added thereto at 0° C. Thereafter, the reaction solution was warmed to the room temperature and stirred overnight. The reaction solution was concentrated under reduced condition. The residue thus obtained was dissolved in 100 ml of ethyl acetate and washed successively with water, aqueous solution of 10% potassium hydrogensulfate, aqueous solution of saturated sodium hydrogencarbonte and saturated brine. After drying over anhydrous magnesium sulfate, the reaction mixture was concentrated under reduced pressure. The residue was separated out with the silicagel column chromatography, whereby 0.35 g of N-[(2RS,3S)-2-hydroxy-1-[N-(2-methyl-2-propyl)amino]-1-oxo-3-heptyl]-1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxamide was obtained.
Reaction SMILES: [NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:2]([C:9](O)=[O:10])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:52]([O:56][C:57](=[O:86])[NH:58][CH:59]([CH:80]1[CH2:85][CH2:84][CH2:83][CH2:82][CH2:81]1)[C:60]([N:62]1[CH2:66][CH2:65][CH:64]2[NH:67][CH2:68][CH:69]([C:70]3[C:78]4[C:73](=[CH:74][C:75]([F:79])=[CH:76][CH:77]=4)[NH:72][CH:71]=3)[CH:63]12)=[O:61])([CH3:55])([CH3:54])[CH3:53]>CN1C(=O)CCC1.C(OCC)C>[C:52]([O:56][C:57](=[O:86])[NH:58][CH:59]([CH:80]1[CH2:81][CH2:82][CH2:83][CH2:84][CH2:85]1)[C:60]([N:62]1[CH2:66][CH2:65][CH:64]2[N:67]([C:9](=[O:10])[CH:2]([NH:1][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)[CH2:68][CH:69]([C:70]3[C:78]4[C:73](=[CH:74][C:75]([F:79])=[CH:76][CH:77]=4)[NH:72][CH:71]=3)[CH:63]12)=[O:61])([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCC2NCC(c3c[nH]c4cc(F)ccc34)C21)C1CCCCC1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC(C(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1)C1CCCCC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 82.4 %

Procedure:
To a solution containing Boc-Chg-OH (167 mg, 0.64 mmol) in anhydrous NMP (6 mL) was cooled to 0° C. HATU (247 mg, 0.64 mmol) and DIPEA (94 mg, 0.73 mmol) were added followed by the addition of crude 49 (300 mg, 0.62 mmol). The reaction mixture was slowly warmed to ambient temperature. After 16 h, the reaction mixture was diluted with diethyl ether and washed successively with water, 1M HCl, water, aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (2:1-1:1 hexanes/EtOAc) to afford 370 mg (82%) of 121 as a white solid. 1H NMR (300 MHz, CDCl3), mixture of rotomers: δ8.32 (dd, J=5.4, 8.7 Hz, 0.4H, minor rotomer), 8.21 (dd, J=5.7, 9.0 Hz, 1.6H, major rotomer), 8.12 (br s, 0.4H), 8.06 (br s, 1.6H), 7.06 (m, 2H), 7.01 (m, 2H), 6.98 (m, 2H), 6.94 (m, 2H), 5.31 (app d, J=9.3 Hz, 2H), 5.22 (app d, J=9.6 Hz, 2H), 4.60 (d, J=5.1 Hz, 2H), 4.46-4.32 (m, 10H), 4.04 (d, J=5.7 Hz, 2H), 3.64 (dd, J=6.0, 10.8 Hz, 2H), 3.33 (m, 2H), 2.43 (dd, J=5.4, 13.4 Hz, 2H), 1.89-1.55 (m, 10H), 1.47 (s, 3.6H, minor rotomer), 1.44 (s, 14.4H, major rotomer), 1.28-1.02 (m, 10H) ppm. Mass spectrum, m/z [724.5] (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[O:7][CH:8]=[CH:9][N:10]=1.CS[C:13](=[NH:18])[NH:14][N+:15]([O-:17])=[O:16]>>[N+:15]([NH:14][C:13]([NH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[O:7][CH:8]=[CH:9][N:10]=1)=[NH:18])([O-:17])=[O:16]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: NCCCSc1ncco1
Product: N=C(NCCCSc1ncco1)N[N+](=O)[O-]

Procedure:
Reacting 2-(3-aminopropylthio)oxazole with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[3-(2-oxazolyl)thiopropyl]guanidine. Similarly, reaction of the same starting material with N,S-dimethyl-N'-nitroisothiourea by the procedure of Example 2(iii) gives N-methyl-N'-nitro-N"-[3-(2-oxazolyl)thiopropyl]guanidine.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.Br[C:17]1[N:21]([CH3:22])[CH:20]=[N:19][CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:22][N:21]1[C:17]([N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=3)[C:10]2=[O:13])=[CH:18][N:19]=[CH:20]1
Reactant: O=C1NCCc2ccc(C(F)(F)F)cc21
Reactant: Cn1cncc1Br
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1cncc1N1CCc2ccc(C(F)(F)F)cc2C1=O
Yield: 24.7 %

Procedure:
Using analogous conditions as described for the preparation of Example 1A above, 7-(trifluoromethyl)-3,4-dihydroisoquinolin-1(2H)-one (I-4-d: 150 mg, 0.6849 mmol) was reacted with 5-bromo-1-methyl-1H-imidazole (165 mg, 1.0273 mmol), 1,4-dioxane (3 mL), copper iodide (13.01 mg, 0.0685 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (29.17 mg, 0.205 mmol) and potassium phosphate (434.6 mg, 2.05 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 50 mg of the product (24.75% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].C(N(CC)CC)C.O>CN(C=O)C>[OH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([O:11][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C(O)COc1ccc(CO)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(COc1ccc(CO)cc1)OCC(=O)c1ccccc1
Reaction time: 8 h

Procedure:
182 g of 4-hydroxymethylphenoxyacetic acid and 199 g of α-bromoacetophenone are dissolved in 600 ml of dry DMF, and then, at 0° C., 138 ml of triethylamine are rapidly added dropwise. The mixture is allowed to reach room temperature, and is stirred overnight. The DMF solution is poured into 3.5 1 of water, and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and concentrated. The product precipitates out on evaporation. It is filtered off with suction, washed with ethyl acetate/n-hexane 1:1 and dried under high vacuum.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=O)=[CH:26][CH:25]=1>>[F:18][C:17]([F:19])([F:20])[C:4]1[C:3]([C:1]#[N:2])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:12][C:13]1[N:16]=[C:28]([C:27]2[CH:31]=[CH:32][C:24]([O:23][C:22]([F:21])([F:33])[F:34])=[CH:25][CH:26]=2)[O:15][N:14]=1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(OC(F)(F)F)cc3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 4-[(trifluoromethyl)oxy]benzoic acid: MS (ESI): m/z 453 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:28].[Na+].O.OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:28])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(CCO)cc3)cc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC#N
Solvent: O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(CCO)cc3)cc12
Temperature: 0 °C
Reaction time: 20 h
Yield: 22.2 %

Procedure:
To a mixture of 6-chloro-5-[4-(2-hydroxyethyl)phenyl]-1H-indole-3-carbaldehyde (150 mg, 0.50 mmol) in acetonitrile (5 mL) and tert-butanol (5 mL) was added 2-methyl-2-butene (5 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (900 mg, 10.0 mmol) and sodium phosphate monobasic hydrate (1.4 g, 10 mmol) in water (5 mL) dropwise via additional funnel. Then ice bath was removed, and the reaction was stirred at room temperature for 20 hours. The solvent was removed in vacuo to give a residue, which was purified by pre-HPLC (Kromasil Eternity-5-C18 150×30 mm×5 μm Mobile phase: from 26% MeCN in water (0.1% TFA) to 41% MeCN in water (0.1% TFA); Wavelength: 220 nm Flow rate: 30 mL/min) to give 6-chloro-5-[4-(2-hydroxyethyl)phenyl]-1H-indole-3-carboxylic acid (35 mg, 25% yield) as a white solid. MS (ES+) 337.9 (M+Na)+. 1H NMR (400 MHz, CD3OD) δ 8.01-7.99 (m, 2 H), 7.57 (s, 1 H), 7.37 (d, 2 H), 7.30 (d, 2 H), 3.80 (t, 2 H), 2.91 (t, 2 H).
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[CH2:7][CH2:6][CH:5]1O)=[N+:2]=[N-:3].COCCN(S(F)(F)[F:32])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[N:1]([CH:4]1[CH:5]([F:32])[CH2:6][CH2:7][N:8]([C:11]2[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[CH2:9][CH2:10]1)=[N+:2]=[N-:3]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CCn1ncc([N+](=O)[O-])c1N1CCC(O)C(N=[N+]=[N-])CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCn1ncc([N+](=O)[O-])c1N1CCC(F)C(N=[N+]=[N-])CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-azido-1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ol (1.25 g, 4.2 mmol) in dry DCM (20 ml) was added dropwise deoxo-Fluor® (3.8 mL, 10.6 mmol, 50% in THF) and the mixture was stirred at room temperature for 16 hr. The mixture was cooled in an ice bath, saturated aqueous NaHCO3 solution (40 mL) was added slowly (effervescence observed) and the mixture was extracted with DCM (2×20 mL). The organic layer was washed with saturated aqueous NaHCO3 solution (2×10 mL), passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane) to give 4-azido-5-fluoro-1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepane as a yellow gum (0.91 g). A solution of this gum (0.9 g, 3.0 mmol) in THF/water (20 mL/4 mL) was treated with triphenylphosphine (0.8 g, 3.0 mmol) and the mixture was heated at 60° C. for 16 hr. The mixture was cooled and concentrated to 4 mL under reduced pressure, diluted with EtOAc (30 mL) and extracted with 1M HCl (4×10 mL). The combined aqueous extracts were washed with EtOAc (20 mL) and then basified with 6N NaOH and extracted with DCM (3×20 mL) The combined organic layers were separated, dried over MgSO4 and concentrated under reduced pressure to give 5-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-amine as a yellow oil (0.82 g). To a solution of this oil (0.8 g, 2.9 mmol) and DIPEA (0.77 mL, 4.4 mmol) in DCM (25 mL) was added di-tert-butyl-dicarbonate (0.97 g, 4.4 mmol) and the mixture stirred at room temperature for 16 hr. Water (15 mL) was added and the organic phase separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave tert-butyl 1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)-5-fluoroazepan-4-ylcarbamate as a yellow solid (1.1 g, 70% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 4.96 (s, 1H), 4.74 (td, J=7.4, 3.6 Hz, 1H), 4.65-4.58 (m, 1H), 4.16-4.05 (m, 3H), 3.42-3.29 (m, 2H), 3.16 (d, J=11.4 Hz, 2H), 2.31-2.18 (m, 2H), 2.20-2.06 (m, 2H), 1.94-1.82 (m, 1H), 1.60-1.45 (m, 10H).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[CH:6]1([Mg]Cl)[CH:10]=[CH:9][CH:8]=[CH:7]1>>[CH2:2]([C:10]1[CH2:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH:4]=[CH2:5]
Reactant: Cl[Mg]C1C=CC=C1
Reactant: C=CCCBr
Product: C=CCCC1=CC=CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 4-bromo-1-butene (100 g of 97 wt %, 0.719 mop was added cyclopentadienyl magnesium chloride (800 mL of 1 M solution in THF, 0.8 mol) at 0° C. in 50 minutes. After stirring for an additional 15 minutes at 0° C., the mixture was warmed to room temperature. After stirring overnight, the reaction was quenched with a mixture of ice and water. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at room temperature gave a brown liquid (94.2 g, crude but-3-enylcyclopentadiene). To the crude but-3-enylcyclopentadiene (94.2 g) dissolved in THF (500 mL) was added n-BuLi (70 mL of 10 M in hexanes, 0.7 mol at −78° C. The mixture was warmed up to room temperature and stirred overnight. The anion solution was added to benzophenone (133.8 g, 0.735 mol) dissolved in THY (400 mL) at 0° C. in 35 minutes. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with a mixture of ice and 10% HCl aqueous solution. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at 40° C. gave a dark red viscous oil. The oil was dissolved in heptane and filtered through silica gel. The product was collected by washing the silica gel with 5-10% CH2Cl2 in heptane. Removal of the solvent gave the desired product (152 g, 74.4% yield based on 4-bromo-1-butene) as a dark red viscous oil. 1H NMR (300 MHz, CDCl3) δ 7.29-7.41 (m, 10H), 6.50-6.53 (dd, J=5.2 Hz, 1.4 Hz, 1H), 6.29-6.31 (dd, J=5.2 Hz, 1.4 Hz, 1H), 6.02-6.05 (m, 1H), 5.82-5.98 (m, 1H), 4.94-5.16 (m, 2H), 2.53-2.60 (m, 2H), 2.33-2.43 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 148.59, 147.67, 143.18, 140.86, 140.78, 137.85, 133.48, 131.38, 131.36, 127.85, 127.82, 127.18, 127.13, 124.75, 118.35, 114.29, 33.36, 30.20.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1)[CH:9]=2)=[O:4]
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Product: COC(=O)c1c(O)c2ccc(-c3ccc(F)cc3)cc2sc1=O

Procedure:
7-(4-Fluoro-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) and 4-fluorophenylboronic acid under conditions analogous to Example 7(a). 1H NMR (200 MHz, CDCl3): δ (ppm)=15.27 (s, 1H), 8.39 (d, J=8.5 Hz, 1H), 7.60-7.50 (m, 4H), 7.21-7.17 (m, 2H), 4.02 (s, 3H).