Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:12]1([C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=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>CN(C=O)C.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:24][C:21]2[CH:20]=[CH:19][C:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:23][N:22]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(I)cc1
Reactant: Nc1ccc(-c2ccccc2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(I)cc1)Nc1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-iodophenyl)acetic acid 53-1 (816 mg, 3.14 mmol), 5-phenylpyridin-2-amine 53-2 (534 mg, 3.14 mmol) and HATU (1.19 g, 3.14 mmol) in DMF (1 mL) was added DIEA (1.57 mL, 9.42 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (50 mL), washed with saturated NaHCO3 aqueous solution, water and brine, dried over Na2SO4, and concentrated by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 40% ethyl acetate in hexane to give 2-(4-Iodophenyl)-N-(5-phenylpyridin-2-yl)acetamide 53-3 as pale yellow solid. MS m/z 415.2 (M+1)
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.[CH3:17][O:18][C:19](=[O:45])/[CH:20]=[CH:21]/[C:22]1[CH:23]=[C:24]2[C:41](=[CH:42][CH:43]=1)[O:40][C:27]1([CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]1)[CH2:26][C:25]2=[O:44]>CC(C)=O>[CH3:17][O:18][C:19](=[O:45])/[CH:20]=[CH:21]/[C:22]1[CH:23]=[C:24]2[C:41](=[CH:42][CH:43]=1)[O:40][C:27]1([CH2:28][CH2:29][N:30]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH2:31][CH2:32]1)[CH2:26][C:25]2=[O:44]
Reactant: Fc1ccc(CCBr)cc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(F)cc3)CC1)O2
Temperature: 50 °C
Reaction time: 54 h
Yield: 94.2 %

Procedure:
K2CO3 (414 mg, 3 mmol) and 1-(2-bromo-ethyl)-4-fluoro-benzene (0.21 ml, 1.5 mmol) were added to a suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (254 mg, 0.752 mmol, Intermediate 1, hydrochloride salt) in acetone (10 ml). The mixture was stirred at 50° C. for 54 h, then the solvent was evaporated and the residue was partitioned between water and DCM. The organic phase was dried, then evaporated and the crude residue was purified by column chromatography (eluent: DCM/MeOH 99:1 to 98:2) to give (E)-3-{1′-[2-(4-fluoro-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (300 mg) as a light yellow solid.
Reaction SMILES: OCN1[C:7](=O)[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=O.[C:14](OC(=O)C)(=O)C.[CH2:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]=[CH2:38])=[CH2:30]>ClC(Cl)C>[CH2:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]=[CH2:38])=[CH2:30].[CH3:21][CH2:22][CH2:23][CH2:7][CH2:6][CH2:9][CH2:10][CH2:11][CH2:12][CH:5]([CH3:4])[CH3:14]
Reactant: O=C1c2ccccc2C(=O)N1CO
Reactant: CC(=O)OC(C)=O
Agent: C=Cc1ccccc1C=C
Solvent: C=Cc1ccccc1
Solvent: CC(Cl)Cl
Product: CCCCCCCCCC(C)C
Temperature: 60 °C

Procedure:
354 g of N-hydroxymethyl phthalimide, dissolved in 1200 g of dichlorethane, are heated for 5 hours to reflux temperature with 227 g of acetic acid anhydride. After cooling to 60° C, 150 g of a macroporous styrene polymer crosslinked with 8 % of divinyl benzene (obtained by the bead polymerisation of styrene and divinyl benzene in the presence of 60 % by weight of isododecane, based on the sum total of monomers) are swollen in this solution over a period of 30 minutes. The mixture is then heated to reflux temperature, followed by the dropwise addition with stirring over a period of 4 hours of 240 g of concentrated sulphuric acid. After stirring for another 20 hours at the same temperature, the reaction product is separated off and freed from the dichlorethane adhering to it by suspension in aqueous ammonia solution, followed by azeotropic distillation, in the same way as described in Example 1. The polymer is then heated for 10 hours to 180° C with 40 % sodium hydroxide solution in an autoclave. After the sodium hydroxide has been washed out, 540 ml of a weakly basic anion exchanger are obtained with an acid-binding capacaty for N/10 hydrochloric acid of 2.4 Val/1 and a nitrogen content of 10.6 % in the dry material.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl[C:12]1[N:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][N:13]=1.C(N(C(C)C)C(C)C)C>O1CCCC1.ClCCl>[CH2:18]([C:15]1[CH:14]=[N:13][C:12]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[N:17][CH:16]=1)[CH3:19]
Reactant: C1CC2(CCN1)OCCO2
Reactant: CCc1cnc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1cnc(N2CCC3(CC2)OCCO3)nc1
Temperature: 25 °C

Procedure:
A mixture of 1,4-dioxa-8-aza-spiro[4.5]decane (11.08 mL), 2-chloro-5-ethylpyrimidine (7.50 mL), and ethyldiisopropylamine (15.50 mL) in tetrahydrofuran (60 mL) is heated under reflux for 30 min. After cooling to room temperature, the reaction mixture is diluted with dichloromethane and washed with 0.1 M citric acid and brine. The aqueous phase is basified with 1 M aqueous NaOH solution and extracted with dichloromethane. The combined organic phases are dried over MgSO4 and the solvent is evaporated in vacuo to give the title compound. LC (method 11): tR=1.10 min; Mass spectrum (ESI+): m/z=250 [M+H]+.
Reaction SMILES: O[CH:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[C:12]2[CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[O:26][CH3:27])=[CH:7][CH:6]=1)[CH:3]=[CH2:4].CO[C:30]([O:35]C)([N:32]([CH3:34])[CH3:33])[CH3:31]>C1(C)C=CC=CC=1>[CH3:34][N:32]([CH3:33])[C:30]([CH2:31][CH2:4][CH:3]=[CH:2][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[C:12]2[CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[O:26][CH3:27])=[CH:7][CH:6]=1)=[O:35]
Reactant: C=CC(O)c1ccc2cccc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Reactant: COC(C)(OC)N(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cc2cccc3ccc(C=CCCC(=O)N(C)C)cc23)c(OC)c1
Yield: 90 %

Procedure:
A mixture of methyl 4-[7-(1-hydroxyallyl)naphth-1-ylmethyl]-3-methoxybenzoate (2.4 g), N,N-dimethylacetamide dimethyl acetal (1.62 ml) and toluene (50 ml) was refluxed for 12 hours. Evaporation and flash chromatgraphy, eluting with a gradient of 1) 3:3:2 petroleum ether:methylene chloride:ethyl acetate, 2) 1:1:1 petroleum ether:methylene chloride:ethyl acetate, and 3) 6:6:7 petroleum ether:methylene chloride:ethyl acetate, afforded methyl 4-[7-[4-(dimethylcarbamoyl)but-1-enyl]naphth-1-ylmethyl]-3-methoxybenzoate (90%) as a light yellow syrup; MS(CI), m/e=432(M+H).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].CC(C)([O-])C.[K+:19]>CO>[C:1]([O-:13])(=[O:12])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[K+:19]
Reactant: C=CCCCCCCCCC(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: CCCCCCCCC=CC(=O)[O-]
Temperature: 0 °C

Procedure:
10-Undecenic acid (150 g, 0.814 mol) and potassium tert-butoxide (91.3 g, 0.814 mol) were added to methanol (250 mL), and the mixture was stirred at 0° C. The volatile matter was distilled off by heating under reduced pressure to give potassium undecenoate represented by the following formula:
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][C:12]([CH3:22])([CH3:21])[C:13](=[O:20])[CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:6][CH:5]=1.BrCC(=O)C(C)(C)CSC1C=CC(Cl)=CC=1>O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][C:12]([CH3:22])([CH3:21])[CH:13]([OH:20])[CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:6][CH:5]=1
Reactant: CC(C)(CSc1ccc(Cl)cc1)C(=O)Cn1ccnc1
Agent: CC(C)(CSc1ccc(Cl)cc1)C(=O)CBr
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(C)(CSc1ccc(Cl)cc1)C(O)Cn1ccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
0.3 g (0.0079 mol) of sodium borohydride in 8 ml of water was added dropwise to 7 g (0.024 mol) of 4-(4-chlorophenylmercapto)-3,3-dimethyl-1-(imidazol-1-yl)-butan-2-one, compound 6 of Example 6 hereinabove, at room temperature. The reaction mixture was subsequently stirred at room temperature for 1 hour and was poured onto water. The crystals which had precipitated were filtered off, and dried at 50° C. in vacuo. 6.5 g (91% of theory) of 4-(4-chlorophenylmercapto)-3,3-dimethyl-1-(imidazol-1-yl)-butan-2-ol of melting point 109°-110° C. were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.O[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:55][CH2:56][CH2:57][C:58]([OH:60])=[O:59].[OH-].[Na+].Cl>CO.O.C(OCC)(=O)C>[C:58]([CH2:57][CH2:56][CH2:55][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=1[O:33][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:12][CH:13]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19]1)([OH:60])=[O:59]
Reactant: O=C(O)CCCc1ccccc1O
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCCC(=O)O)cc1
Temperature: 25 °C

Procedure:
Analogously to Method G, 0.549 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.075 g of 4-(2-hydroxyphenyl)butyric acid are reacted. The yellow oil obtained after chromatography is dissolved in 9.5 ml of methanol and 3.2 ml of water, admixed with 1.5 ml of 1N NaOH and stirred at reflux over 2 hours. The reaction mixture is cooled to room temperature, diluted with ethyl acetate and water and acidified with 2N HCl. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with water, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless resin from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (95:5 dichloromethane-methanol); Rt=5.86.
Reaction SMILES: Cl.[O:2]=[C:3]1[O:7][C@H:6]([C:8]([OH:10])=O)[CH2:5][CH2:4]1.[CH2:11]([C@H:18]1[CH2:22][NH:21][C@H:20]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[O:24])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:22][N:21]([C:8]([C@@H:6]2[CH2:5][CH2:4][C:3](=[O:2])[O:7]2)=[O:10])[C@H:20]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:28][CH:27]=2)=[O:24])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C1CC[C@@H](C(=O)O)O1
Agent: Cl
Product: O=C1CC[C@@H](C(=O)N2C[C@H](Cc3ccccc3)C[C@H]2C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)O1
Yield: 29.2 %

Procedure:
Proceeding as in Example 1, but substituting (S)-5-oxotetrahydrofuran-2-carboxylic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 39, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-((S)-5-oxotetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxamide (8.8 mg, 29.2%). 1H-NMR (400 MHz, DMSO-D6): σ 10.04 (s, 1H), 7.53 (m, 2H), 7.27 (m, 2H), 7.18 (m, 5H), 6.94 (m, 4H), 5.28 (m, 1H), 4.52 (dd, 1H), 3.65 (m, 1H), 2.39 (m, 3H), 2.46 (m, 3H), 2.15 (m, 2H), 2.89 (m, 2H). MS (EI) for C29H27FN2O5: 503.5 (MH+).
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([CH:13]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:15].CO>[Ni]>[CH2:1]([C:8]1[O:12][C:11]([CH2:13][NH2:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cc2ccccc2)o1
Reactant: N
Agent: [Ni]
Solvent: CO
Product: NCc1ccc(Cc2ccccc2)o1
Temperature: 25 °C
Reaction time: 22 h
Yield: 65.8 %

Procedure:
7N Ammonia/methanol(40 mL) and Raney nickel(3 g) were added to 5-benzyl-furan-2-carbaldehyde described in Preparation Example 39 (2.5 g, 13 mmol), and the solution was stirred for 22 hours under hydrogen atmosphere at room temperature. After removing the catalyst by filtering through Celite pad, the solvent was evaporated in vacuo and C-(5-benzyl-furan-2-yl)methylamine (1.6 g, 8.6 mmol, 65.8%) was obtained.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[CH:31][N:32]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:33]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:41]=[N+:42]=[N-:43].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:43][N:42]=[N:41][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[CH:31][N:32]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:33]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc2c(C)cc(-c3cn(Cc4ccccc4)cn3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(-c3cn(Cc4ccccc4)cn3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[(2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: C[O:2][C:3]1[CH2:7][CH:6]([CH2:8][C:9]2[CH:13]=[C:12]([CH3:14])[O:11][N:10]=2)[C:5](=[O:15])[C:4]=1[C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=1[CH3:24].Cl>CC(C)=O>[CH3:14][C:12]1[O:11][N:10]=[C:9]([CH2:8][CH:6]2[CH2:7][C:3](=[O:2])[CH:4]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=3[CH3:24])[C:5]2=[O:15])[CH:13]=1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(Cc2cc(C)on2)C1
Agent: Cl
Solvent: CC(C)=O
Product: Cc1cc(C)c(C2C(=O)CC(Cc3cc(C)on3)C2=O)c(C)c1
Reaction time: 0.5 h

Procedure:
To a solution of 3-methoxy-5-(5-methyl-isoxazol-3-ylmethyl)-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (120 mg) in acetone (1 ml) in a microwave vial is added 2N HCl (0.6 ml) and the resultant solution is heated to 130° C. by microwave irradiation, with stirring, for 30 minutes. The solvent is removed under reduced pressure, and the residue triturated with hexane to give a white solid, which is filtered and washed well with hexane to give 4-(5-methyl-isoxazol-3-ylmethyl)-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:34]=[CH:33][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[O:24])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:52][C:53]1[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH:61]2[CH2:63][O:62]2)=[CH:55][CH:54]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:32][C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:23]([CH2:22][CH2:21][NH:20][C:18]([N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:63][C@H:61]([OH:62])[CH2:60][O:59][C:56]4[CH:57]=[CH:58][C:53]([OH:52])=[CH:54][CH:55]=4)=[CH:34][CH:33]=3)[CH2:17][CH2:16]2)=[O:19])=[O:24])=[CH:31][CH:30]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(NC2CCN(C(=O)NCCC(=O)Nc3ccc(F)cc3)CC2)cc1
Solvent: O=CO
Product: O=C(CCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1)Nc1ccc(F)cc1

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-[3-(4-fluoroanilino)-3-oxopropyl]-1-piperidinecarboxamide formate (0.28 g, 0.6 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane according to Procedure G to give the title compound (0.11 g, 0.13 mmol).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11].[H-].[Na+].Br[CH2:17][CH2:18][CH3:19].Cl>CS(C)=O>[CH2:17]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11])[CH2:18][CH3:19]
Reactant: COC(=O)c1cc2ccccc2[nH]1
Reactant: CCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCn1c(C(=O)OC)cc2ccccc21
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A suspension of methyl 1H-indole-2-carboxylate (5.0 g) and sodium hydride (60% dispersion in oil, 1.3 g) in dry dimethylsulphoxide was stirred at 60° C. for 30 minutes. The reaction mixture was cooled to room temperature before adding 1-bromopropane (2.85 ml) and then heated at 60°-80° C. for 3 hours. The cooled reaction mixture was poured into dilute hydrochloric acid and extracted with diethyl ether. The combined organic extracts were washed with water, dried (MgSO4) and the solvent removed in vacuo. The crude product was purified by chromatography on silica, and elution with 10% v/v diethyl ether in petroleum ether (bp 40°-60° C.) gave methyl 1-propyl-1H-indole-2-carboxylate (5.23 g) as a clear oil; NMR (CDCl3) δ0.93 (3H,t,J=7 Hz, C--CH3), 1.82 (2H, sext,J=7 Hz,C--CH2 --C), 3.89 (3H,s,OCH3), 4.52 (2H,t,J=7 Hz, N--CH2), 7.15 (4H,m,Ar--H), 7.67 (1H,m,Ar--H). The ester was converted to 2-(2-imidazolin-2-yl)-1-propyl-1H-indole hydrochloride using trimethylaluminium and ethylenediamine as described in Example 1(a); mp 186.5°-187° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[CH:4][C:3]=1[NH:11][C:12](=O)[CH3:13].C(N(C)C)C.[AlH3].C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(Cl)Cl>[CH2:12]([NH:11][C:3]1[CH:4]=[N:5][C:6]([CH2:8][CH2:9][CH3:10])=[CH:7][C:2]=1[NH2:1])[CH3:13]
Reactant: CCCc1cc(N)c(NC(C)=O)cn1
Agent: CCN(C)C
Agent: O=C([O-])[O-]
Agent: [AlH3]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCc1cc(N)c(NCC)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of the crude N-(4-amino-6-propyl-pyridin-3-yl)-acetamide (114 mg, 0.59 mmol) in THF (2.5 mL) at 0° C. under N2 is treated with 0.5 M EtNMe2.AlH3 in toluene (2.4 mL, 1.18 mmol). The reaction mixture is stirred for 4 h while slowly warming to rt, whereupon it is treated with additional 0.5 M EtNMe2.AlH3 in toluene (2.4 mL, 1.18 mmol). After stirring at room temperature overnight, the reaction mixture is cooled to 0° C. and treated with moist Na2CO3. The mixture is diluted with CH2Cl2 and stirred vigorously for 15 min. It is then filtered through a pad of Celite, and the filtrate concentrated. The crude material is partially purified by preparative thin layer chromatography, developing with 15:1 CHCl3—MeOH (+1% Et3N). The band containing the desired N3-ethyl-6-propyl-pyridine-3,4-diamine does not separate well from the approximately 10% of the slightly more polar, unreacted N-(4-amino-6-propyl-pyridin-3-yl)-acetamide. Both bands are collected, and the mixture is carried into the next reaction. 1H NMR (CDCl3, 300 MHz) δ 7.74 (s, 1H), 6.42 (s, 1H), 4.10 (br, 1H), 3.67 (m, 1H), 3.10 (q, J=7.2 Hz, 2H), 2.56 (m, 2H), 1.67 (sextet, J=7.2 Hz, 2H), 1.25 (t, J=7.2 Hz, 3H), 0.91 (t, J=7.2 Hz, 3H) ppm. Electrospray MS: m/z 180 [M+1].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:5](N(OC)C)=[O:6].[CH3:17][CH:18](C[AlH]CC(C)C)C>C1COCC1.Cl.CCOC(C)=O>[CH2:17]([C:3]1[C:2]([F:1])=[C:13]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:11][C:4]=1[CH:5]=[O:6])[CH3:18]
Reactant: CC(C)C[AlH]CC(C)C
Reactant: CON(C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1c(C=O)ccc([N+](=O)[O-])c1F
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of THF (800 mL) cooled in an ice-salt/water bath was added 3-fluoro-N-methoxy-N-methyl-4-nitrobenzamide followed by addition of 1 M DIBAL in THF by addition funnel over 30 min. The solution was allowed to stir under N2 for 1 h. The reaction mixture was then carefully diluted with 1N HCl (500 mL) and EtOAc (500 mL), transferred to separatory funnel, and separated. The organic phase was washed with 1N HCl (3×250 mL), 1N NaOH (2×250 mL), and water (250 mL). All aqueous layers were back extracted with EtOAc (2×250 mL). The organic layers were combined, dried (MgSO4), filtered, and concentrated in vacuo to afford 67 g of the above compound (396 mmol, yield 88%). 1H-NMR (DMSO-d6) δ 10.06 (s, 1H), 8.36 to 8.32 (t, J=7.8 Hz, 1H), 8.06 to 8.03(d, J=11.2 Hz, 1H), 7.95 to 7.93 (d, J=9.1 Hz, 1H).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[C:3]([S:14]([NH:17][C:18]2([C:24]([OH:26])=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:16])=[O:15])[CH:2]=1.C(Cl)(=O)C(Cl)=O.C(=O)(O)[O-].[Na+].Cl.[NH2:39][OH:40]>ClCCl.CN(C)C=O.O1CCCC1.O>[OH:40][NH:39][C:24]([C:18]1([NH:17][S:14]([C:3]2[CH:2]=[CH:1][C:9]3[C:8]4[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=4[O:6][C:5]=3[CH:4]=2)(=[O:16])=[O:15])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:26]
Reactant: O=C(O)C1(NS(=O)(=O)c2ccc3c(c2)oc2ccccc23)CCCCC1
Reactant: NO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(NO)C1(NS(=O)(=O)c2ccc3c(c2)oc2ccccc23)CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
1-(Dibenzofuran-3-sulfonylamino)-cyclohexanecarboxylic acid (0.18 g, 0.5 mmol) was dissolved in 50 mL dichloromethane with 2 drops of dimethylformamide. Oxalyl chloride (0.08 mL, 1.0 mmol) was added, and the resulting solution was stirred for 2 hours, then concentrated in vacuo. The resulting residue was dissolved in 10 mL tetrahydrofuran, and this solution was added dropwise to a mixture of sodium bicarbonate (0.61 g, 7.2 mmol) and hydroxylamine hydrochloride (0.33 g, 4.8 mmol) in 50 mL of a tetrahydrofuran/water mixture (1:1 ratio) that had been stirring for 10 minutes at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 64 hours. The reaction was concentrated in vacuo and partitioned between 1 M HCl and dichloromethane. The aqueous layer was extracted with additional dichloromethane, followed by drying the combined organic layers over magnesium sulfate, filtration, and concentration to give 0.07 g of an off-white solid, the structure of which is shown below. The compound had a melting point of about 184-186° C. 1HNMR (CDCl3): δ7.97 (d, 1H), 7.97 (s, 1H), 7.90 (dd, 2H), 7.75 (d, 1H), 7.48 (d, 1H), 7.41 (t, 1H), 7.27 (t, 1H), 6.65 (s, 1H), 1.79 (m, 4H), 1.14 (m, 6H) ppm. Analysis showed the compound to have an empirical formula of (C19H20N2O5S.0.25H2O).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([I:9])[CH:5]=[CH:4][N:3]=1.C(O)(=[O:12])C.O>>[F:8][C:7]1[C:2](=[O:12])[NH:3][CH:4]=[CH:5][C:6]=1[I:9]
Reactant: CC(=O)O
Reactant: Fc1nccc(I)c1F
Solvent: O
Product: O=c1[nH]ccc(I)c1F
Reaction time: 8 h
Yield: 71.4 %

Procedure:
2,3-Difluoro-4-iodopyridine (300 mg, 1.24 mmol) was suspended in acetic acid:water (2:1, 15 mL). The mixture was heated to reflux and stirred at this temperature overnight. Reaction was concentrated to dryness, and triturated in water (10 mL) for 30 min. The solid was collected via filtration, washed with water (2×10 mL), and pentane (2×20 mL) and dried under vacuum to afford the title compound as a white solid (354 mg, 71.4%). LC-MS m/z 342.0 (M+1). 1H NMR (400 MHz, METHANOL-d4) δ ppm 6.56-6.82 (m, 1H) 6.83-7.18 (m, 1H).