Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C([O-])=O.[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](O)=O.[OH-].[Na+]>O>[N:11]1([CH2:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][N:23]=3)=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NCCCCC(=O)O
Reactant: c1ccc(OCCCN2CCCCC2)cc1
Agent: O=C([O-])C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1cc(C2=NCCCC2)ccc1OCCCN1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of 1-(3-phenoxypropyl)piperidine, oxalate (0.2 g), 5-aminopentanoic acid (0.076 g) and polyphosphoric acid (2 g) is stirred at a temperature close to 100° C. for one hour. The mixture is cooled to room temperature, diluted with water (25 mL), made alkaline through addition of concentrated aqueous sodium hydroxide solution with external cooling and extracted twice with ethyl acetate (25 mL). The organic layers are pooled, washed with a saturated aqueous solution of sodium chloride (25 mL), dried over magnesium sulphate and purified by chromatography over silica gel. Fractions containing the expected product are pooled, concentrated under reduced pressure to give 0.172 g of 6-[4-(3-piperidinopropoxy)phenyl]-2,3,4,5-tetrahydropyridine which is dissolved in ethanol (2 mL). A solution of oxalic acid (0.104 g) in ethanol (0.5 mL) is added. The precipitate that appears on standing is filtered, rinsed with ethanol and dried to afford 200 mg of 6-[4-(3-piperidinopropoxy)phenyl]-2,3,4,5-tetrahydropyridine, oxalate as a white powder melting at 104° C.
Reaction SMILES: [O-][CH2:2][CH3:3].[Na+].[NH3:5].Cl.Cl[CH2:8][CH2:9][N:10]([C:14]([CH3:17])(C)C)[CH2:11][CH2:12]Cl.C(=O)=O>C(O)C.C(OCC)C>[CH2:14]([N:10]1[CH2:9][CH2:8][NH:5][CH2:12][CH2:11]1)[CH2:17][CH2:2][CH3:3]
Reactant: CC[O-]
Reactant: CC(C)(C)N(CCCl)CCCl
Reactant: N
Agent: Cl
Agent: O=C=O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCCCN1CCNCC1
Temperature: 60 °C

Procedure:
A solution (447 cc.) of sodium ethoxide in ethanol of concentration 1.34 moles per liter, followed by a solution (1,305 cc.) of ammonia in ethanol of concentration 4.6 moles per liter, are added to a suspension of N,N-bis(2-chloroethyl)-t-butylamine hydrochloride (140.7 g.) in ethanol (750 cc.). The reaction mixture is then heated at a temperature of about 60° C. for 1 hour, whilst keeping the ammonia refluxing by means of a condenser containing solid carbon dioxide. The ammonia is then allowed to dissipate, and the reaction mixture is cooled to a temperature of about 20° C. under a stream of nitrogen. A solution (894 cc.) of sodium ethoxide in ethanol of concentration 1.34 moles per liter is then added. The sodium chloride which precipitates is filtered off and then washed with ethanol (150 cc.). The filtrate is concentrated to dryness under reduced pressure and the residue obtained is taken up in diethyl ether (300 cc.). The insoluble product is filtered off and washed with diethyl ether (60 cc.). The filtrate is concentrated to dryness and then distilled under reduced pressure. 1-t.-butylpiperazine (8.8 g.), which boils at 85°-86° C. under a pressure of 28 mm.Hg, is thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[CH:47][N:46]([CH3:49])[C:45](=[O:50])[CH:44]=2)=[CH:38][C:37]=1[CH3:51].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:42][C:41]1[CH:40]=[C:39]([C:43]2[CH:48]=[CH:47][N:46]([CH3:49])[C:45](=[O:50])[CH:44]=2)[CH:38]=[C:37]([CH3:51])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2ccn(C)c(=O)c2)cc(C)c1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ccn(C)c(=O)c6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydro-benzofuran-3-yl)acetate and 4-(4-bromo-3,5-dimethylphenyl)-1-methylpyridin-2(1H)-one following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 11): tR=1.19 min; Mass spectrum (ESI+): m/z=554 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH:12]2[CH2:14][CH2:13]2)[CH2:9][C:10]#N)=[CH:4][CH:3]=1.[OH-:15].[Na+].C[OH:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH:12]2[CH2:14][CH2:13]2)[CH2:9][C:10]([OH:18])=[O:15])=[CH:4][CH:3]=1
Reactant: N#CC[C@@H](c1ccc(Cl)cc1)C1CC1
Reactant: [OH-]
Reactant: CO
Agent: [Na+]
Product: O=C(O)C[C@@H](c1ccc(Cl)cc1)C1CC1
Temperature: 0 °C
Yield: 100 %

Procedure:
(3R)-3-(4-Chlorophenyl)-3-cyclopropylpropanenitrile (5.30 g, 25.8 mmol) is refluxed for 18 hours in a mixture of methanol (100 ml) and a 10% aqueous sodium hydroxide (100 ml). Methanol is removed in vacuo, the residual solution is cooled to 0° C. and acidified to pH 4 with concentrated hydrochloric acid. The aqueous layer is extracted with ethyl acetate (100 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound as a colorless liquid (5.79 g, 100%) which is characterized by 1HNMR, IR and mass spectral analysis and used without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:3]=[O:4].[CH3:13][CH:14](O)[CH:15]=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][C:2]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH2:13]/[CH:14]=[CH:15]/[CH3:16])[CH:3]=[O:4]
Reactant: C=CC(C)O
Reactant: CC(C=O)CSc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C/C=C/CC(C)(C=O)CSc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Methyl-3-phenylthiopropanal (9.07 g, 0.05 mole), 3-buten-2-ol (18.04 g, 0.25 mole), and p-toluenesulfonic acid (0.24 g, 0.0013 mole) are added to 90 ml of xylenes. The reaction mixture is heated to reflux using a Dean-Stark trap to collect water. After 3 hours, the mixture is cooled to room temperature and quenched with 30 ml of saturated NaHCO3 solution. The two phases are separated and the aqueous phase is extracted with 30 ml of ethyl acetate. The combined organic extracts is washed with 20 ml of brine and dried with Na2SO4. After removing solvents, the crude product is purified by chromatography. The product is obtained in 74.3% as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][CH:6]([NH:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38]Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][CH:6]([NH:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=2)=[CH:10][CH:9]=1
Reactant: ClCc1ccccn1
Reactant: COC(=O)CCC(Cc1ccc(O)cc1)NC(=O)CCCCCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCC(Cc1ccc(OCc2ccccn2)cc1)NC(=O)CCCCCCc1ccccc1
Yield: 68.8 %

Procedure:
(RS)-5-(4-Hydroxy-phenyl)-4-(7-phenyl-heptanoylamino)-pentanoic acid methyl ester 92 (889 mg, 2.16 mmol), 2-picolylchloride hydrochloride (570 mg, 3.47 mmol) and finely powdered anhydrous K2CO3 (1.45 g, 10.5 mmol) was stirred in dry DMF (7 mL) for 48 hr. The mixture was poured onto water (40 mL) and extracted into EtOAc. The extract was successively washed with HCl solution (1 M, 30 mL), saturated NaHCO3 solution, brine, and then dried with MgSO4. Concentration of the solvent in vacuo afforded 93 (747 mg, 69 %): 1H NMR (CDCl3) δ 1.15-1.40 (m, 4H); 1.40-1.70 (m, 5H); 1.73-1.85 (m, 1H); 2.08 (t, J=7.6 Hz, 2H); 2.34 (m, 2H); 2.58 (t, J=7.6 Hz, 2H); 2.69 (dd, J=15, 6.9 Hz, 1H); 2.77 (dd, J=15, 6.2 Hz, 1H); 3.64 (s, 3H); 4.06-4.21 (m, 1H); 5.17 (s, 2H); 5.37 (d, J=9.3 Hz, 1H); 6.91 (d, J=8.4 Hz, 2H); 7.10 (d, J=8.4 Hz, 2H); 7.12-7.31 (m, 6H); 7.51 (d, J=7.5 Hz, 1H); 7.71 (dt, J=7.5, 1.6 Hz, 1H); 8.60 (m, J=6.0 Hz, 1H). 13C NMR (CDCl3) δ 174.4, 173.0, 157.5, 157.3, 149.4, 142.8, 137.0, 130.3, 125.8, 122.8, 121.5, 130.6, 128.5, 128.4, 115.0, 70.8, 51.9, 50.2, 40.6, 37.0, 36.0, 31.4, 31.1, 29.2, 29.1, 29.0, 25.8. ESMS 503 (M+H)+.
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)[CH:3]=1.C(S[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:22]=[C:23]2[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:27]([CH3:34])[C:24]2=[N:25][CH:26]=1)C.[S:35]([O-:39])([O-])(=[O:37])=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:35]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:22]=[C:23]2[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:27]([CH3:34])[C:24]2=[N:25][CH:26]=1)(=[O:39])=[O:37])[CH3:3]
Reactant: O=S([O-])([O-])=S
Reactant: CCSc1ccccc1-c1cnc2c(c1)nc(C(F)(F)F)n2C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1ccccc1-c1cnc2c(c1)nc(C(F)(F)F)n2C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.70 g of 3-chloroperbenzoic acid (purity of 65% or more) was added to a mixture of 0.35 g of 6-(2-ethylsulfanylphenyl)-3-methyl-2-trifluoromethyl-3H-imidazo[4,5-b]pyridine and 10 ml of chloroform under ice cooling, and then the mixture was stirred at room temperature for 4 hours. A 10% aqueous sodium thiosulfate solution and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate and then dried with anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.31 g of 6-(2-ethylsulfonylphenyl)-3-methyl-2-trifluoromethyl-3H-imidazo[4,5-b]pyridine (Compound of Present Invention 25).
Reaction SMILES: CN1CCOCC1.ClC(OCC(C)C)=O.[C:16]([O:20][C:21]([NH:23][C@H:24]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:25][C:26]([OH:28])=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].Cl.[F:40][C:41]([F:59])([F:58])[O:42][C:43]1[CH:57]=[CH:56][C:46]([CH2:47][CH:48]2[NH:54][CH2:53][CH2:52][CH2:51][NH:50][C:49]2=[O:55])=[CH:45][CH:44]=1>ClCCl>[C:16]([O:20][C:21]([NH:23][C@H:24]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:25][C:26]([N:54]1[CH2:53][CH2:52][CH2:51][NH:50][C:49](=[O:55])[C@H:48]1[CH2:47][C:46]1[CH:45]=[CH:44][C:43]([O:42][C:41]([F:58])([F:59])[F:40])=[CH:57][CH:56]=1)=[O:28])=[O:22])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: O=C1NCCCNC1Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCCNC(=O)[C@H]1Cc1ccc(OC(F)(F)F)cc1)Cc1cc(F)c(F)cc1F
Temperature: -20 °C
Reaction time: 2 h

Procedure:
N-Methylmorpholine (0.072 mL) and isobutyl chloroformate (0.039 mL) were added to a stirred solution of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (95 mg) in dichloromethane (5 mL) at −20° C. and the resultant mixture was stirred for 30 min. Hexahydro-3-[4-(trifluoromethoxy)benzyl]-2H-1,4-diazepin-2-one hydrochloride obtained in Step D (91 mg) and IV-methylmorpholine (0.036 mL) were added. The reaction mixture was stirred for 30 min at −20° C. and 2 h at ambient temperature and then evaporated. The residue was purified by preparative TLC (silica gel, methanol/saturated aqueous ammonium hydroxide/dichloromethane 4.4:0.1:95.5), and the isomers were subsequently resolved by HPLC (ChiralPAK OD, 7% ethanol/hexane) to provide the slower eluting (R,R)-isomer.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C@@H:3]([OH:7])[CH2:4][C:5]#[CH:6].C(N(CC)CC)C.FC(F)(F)S(O[Si:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25])(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][C:2]([CH3:9])([CH3:8])[C@@H:3]([O:7][Si:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:4][C:5]#[CH:6]
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Reactant: C#CC[C@H](O)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CC[C@H](O[Si](CC)(CC)CC)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 92.3 %

Procedure:
A mixture of (S)-5,5-dimethyl-1-hexyn-4-ol (1.96 g 16 mmol), triethylamine (4.5 ml, 32 mmol) and dry dichloromethane (30 ml) was cooled to 0° C. under a nitrogen atmosphere. Triethylsilyl trifluoromethanesulphonate (5.4 ml, 24 mmol) was slowly added and the mixture stirred at 0° C. for a further 40 min. The mixture was treated with saturated sodium bicarbonate solution (60 ml) and the organic layer separated. The aqueous layer was extracted with dichloromethane (3×20 ml) and the combined dichloromethane extracts dried (MgSO4) and evaporated. The residue was purified by column chromatorgaphy (silica eluted with Petroleum ether 40-60°) to yield the title compound 3.55 g (95%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(O)C.[OH-].[Na+].[CH2:17](Br)[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(OCC(=O)c2ccccc2)cc1[N+](=O)[O-]

Procedure:
3.0 G. 1-amino-4-hydroxy-2-nitrobenzene in 80 ml. aqueous ethanol, containing 0.80 g. sodium hydroxide, is reacted with 4.0 g. phenacyl bromide on a steam bath under nitrogen atmosphere for 2 hours, water is added and the product collected by filtration to afford 1-amino-2-nitro-4-phenacyloxybenzene. This latter compound is hydrogenated at one atmosphere pressure in 150 ml. methanol in the presence of hydrochloric acid and 2.0 g. palladized charcoal until the theoretical uptake of hydrogen has occurred. The catalyst is filtered off and the solution stripped uner vacuum to afford 1,2-diamino-4-[1-(2-hydroxy-2-phenyl)ethoxy]benzene. This latter compound is treated overnight at room temperature with 12 g. methoxy carbonyl isothiocyanate in 120 ml. acetone. The solution is evaporated and the residue triturated with water. Recrystallization from methanol yields 1,2-bis(3-methoxycarbonyl-2-thioureido)-4-[1-(2-hydroxy-2-phenyl)ethoxy]benzene.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])=[CH:10][CH:9]=2)[C:5]([CH2:22][CH2:23][CH2:24][CH3:25])=[N:4][N:3]=1.[Cl:26][CH2:27][C:28](=[O:30])[CH3:29]>>[Cl-:26].[CH2:27]([N+:3]1[N:4]=[C:5]([CH2:22][CH2:23][CH2:24][CH3:25])[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])=[CH:12][CH:13]=2)[C:2]=1[NH2:1])[C:28]([CH3:29])=[O:30]
Reactant: CCCCc1nnc(N)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(=O)CCl
Product: CCCCc1n[n+](CC(C)=O)c(N)n1Cc1ccc(-c2ccccc2C#N)cc1
Product: [Cl-]
Yield: 97 %

Procedure:
Reaction of 3-amino-5-butyl-4-[(2'-cyanobiphenyl-4-yl)methyl]-4H-1,2,4-triazole (from Example 1, Step D) with chloroacetone according to the procedure of Example 1, Step E, gave a 97% yield of the title compound as a yellow-brown solid, mp 221.5°-223° C.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:30])[C:5]2[S:10][C:9](=[S:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26]C(=O)C)[C@@H:18]([O:19]C(=O)C)[C@H:13]3[O:14]C(=O)C)[C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].CC(O)=O>CO>[NH2:1][C:2]1[NH:3][C:4](=[O:30])[C:5]2[S:10][C:9](=[S:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][OH:26])[C@@H:18]([OH:19])[C@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(=S)sc3c(=O)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nc2c(sc(=S)n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.3 %

Procedure:
Nucleoside triester 32 (100 mg, 0.21 mmol) and K2CO3 (42.7 mg, 0.31 mmol) were dissolved in MeOH (5 mL) and stirred for 16 h at ambient temperature. To this mixture was added HOAc (37 mg, 0.62 mmol) and the solvent was removed via rotary evaporation. The residue were then submitted to HPLC purification (MeCN—H2O) yielding 47 mg (66%) of a solid: 1H NMR (400 MHz, d6-DMSO) δ 11.66 (s, 1H), 6.91 (br s, 2H), 6.47 (s, 1H), 5.31 (d, J=5.2, 1H), 4.94 (s, 1H), 4.78 (s, 2H), 4.27 (d, J=8.0, 1H), 3.78 (m, 1H), 3.69 (m, 1H), 3.52 (m, 1H); [M+H]+ m/z 333. Analysis calc'd for C10H12N4O5S2.0.5TFA•0.75H2O.0.25MeCN: C, 33.43; H, 3.60; N, 14.41. Found: C, 33.11; H, 3.73; N, 14.80.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[NH2:12][CH:13]1[CH2:20][C:16]2([CH2:19][O:18][CH2:17]2)[N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:14]1.CCN(CC)CC>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:12][CH:13]2[CH2:20][C:16]3([CH2:17][O:18][CH2:19]3)[N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:14]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(N)CC12COC2
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(Nc2ccc(Cl)cc2[N+](=O)[O-])CC12COC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A mixture of 4-chloro-1-fluoro-2-nitrobenzene (264 mg, 1.50 mmol), tert-butyl 7-amino-2-oxa-5-azaspiro[3.4]octane-5-carboxylate (343 mg, 1.50 mmol) and NEt3 (0.44 mL, 3.12 mmol) in 10 mL of tetrahydrofuran was stirred at room temperature overnight and then heated under reflux for 5 hours. The resulting mixture was concentrated in vacuo and the residue was purified by flash column (eluting with 0-5% MeOH in DCM) to afford tert-butyl 7-[(4-chloro-2-nitrophenyl)amino]-2-oxa-5-azaspiro[3.4]octane-5-carboxylate (438 mg, yield: 76.1%) as an orange solid.
Reaction SMILES: C(C1C=CC(C2N(C(Cl)=O)[C@H](C3C=CC(Cl)=CC=3)[C@H](C3C=CC([Cl:22])=CC=3)N=2)=C(OCC(F)(F)F)C=1)(C)(C)C.[N:39]1([C:45](=[O:53])[CH2:46]N2CCNCC2)[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[ClH:22].[N:39]1([C:45](=[O:53])[CH3:46])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: CC(C)(C)c1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)Cl)c(OCC(F)(F)F)c1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Product: CC(=O)N1CCOCC1
Product: Cl

Procedure:
(4S,5R)-2-[4-tert-butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone hydrochloride was prepared from (4S,5R)-2-[4-tert-butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12l) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 760.5 [(M+H)+]
Reaction SMILES: [N:1]1[NH:2][CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][C:6]([CH:10]=[O:11])=[CH:5]2.C1(C(N)C2CCCCC2)CCCCC1.Cl[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32].CCOC(C)=O>C1COCC1>[CH3:32][Si:31]([CH3:34])([CH3:33])[CH2:30][CH2:29][O:28][CH2:27][N:2]1[CH:3]=[C:4]2[C:9]([CH:8]=[CH:7][C:6]([CH:10]=[O:11])=[CH:5]2)=[N:1]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=Cc1ccc2n[nH]cc2c1
Agent: NC(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc2cc(C=O)ccc2n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2H-Indazole-5-carbaldehyde (Stage 150.5, 770 mg, 5.27 mmol) was dissolved in THF (54 mL) and dicyclohexylmethylamine (1.37 mL, 6.32 mmol) was added. After dropwise addition of (2-chloromethoxy-ethyl)-trimethyl-silane (1.21 mL, 6.32 mmol), the RM was stirred for 48 h at rt. It was then taken into EtOAc and washed successively with 0.5 M aqueous NaOH solution and brine. The organic layer was dried on Na2SO4 and evaporated and the residue purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, n-hexane/EtOAc=100:0->70:30) to afford white crystals of the title compound (tR 7.14 min (conditions 3), MH+=277).
Reaction SMILES: [F:1][C:2]1[C:14]2[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:21]([O-:23])=[O:22])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:31])C(=O)C1.O>C(Cl)Cl.C(#N)C>[Br:31][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])[C:14]1[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]2=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1ccccc1-n1c2ccccc2c2cccc(F)c21
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccccc1-n1c2ccc(Br)cc2c2cccc(F)c21
Reaction time: 4 h

Procedure:
6.7 g (22.2 mmol) of fluoro-9-(2-nitrophenyl]-9H-carbazole are initially introduced in 150 ml of CH2Cl2. A solution of 3.9 g (22.3 mmol) of NBS in 100 ml of acetonitrile is subsequently added dropwise at −15° C. with exclusion of light, and the mixture is allowed to come to room temperature and is stirred at this temperature for a further 4 h. 150 ml of water are subsequently added to the mixture, which is then extracted with CH2Cl2. The organic phase is dried over MgSO4, and the solvents are removed in vacuo. The product is washed by stirring with hot hexane, and the solid is isolated.
Reaction SMILES: [CH3:1][C:2]([CH3:19])=[CH:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:6]1.[CH:20]([NH:23][NH:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH:20]([N:23]([C:16](=[O:18])/[CH:15]=[CH:14]/[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:4][CH:3]=[C:2]([CH3:1])[CH3:19])[CH:6]=1)[NH:24][C:25](=[O:33])[C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)([CH3:22])[CH3:21]
Reactant: Cc1ccc(C(=O)NNC(C)C)cc1
Reactant: CC(C)=CCn1cc(/C=C/C(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)=CCn1cc(/C=C/C(=O)N(NC(=O)c2ccc(C)cc2)C(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(3-methylbut-2-enyl)-1H-indol-3-yl)acrylic acid (100.0 mg, 0.39 mmol), N′-isopropyl-4-methylbenzohydrazide (113.4 mg, 0.59 mmol) and HATU (224.3 mg, 0.59 mmol) dissolved in DMF (3.0 ml), N,N-diisopropylethylamine (DIPEA)(0.10 ml, 0.59 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (35% EtOAc) for refinement and dried so that white (E)-N′-isopropyl-4-methyl-N′-(3-(1-(3-methylbut-2-enyl)-1H-indol-3-yl)acryloyl)benzohydrazide was obtained (74.0 mg, 44.1%).