Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][NH2:14])[CH3:8].[C:16]([C@H:19](OS(C)(=O)=O)[CH2:20][CH3:21])(=[O:18])[NH2:17]>C(#N)C>[CH2:7]([O:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][NH:14][C@H:19]([C:16](=[O:18])[NH2:17])[CH2:20][CH3:21])[CH3:8]
Reactant: CCOC(=O)CCCN
Reactant: CC[C@@H](OS(C)(=O)=O)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCN[C@@H](CC)C(N)=O
Temperature: 80 °C

Procedure:
A mixture of powdered potassium carbonate (14.0 g, 96.2 mmol, 5 equiv.), ethyl-4-aminobutyrate (IVb) (6.5 g, 38.6 mmol, 2 equiv.) and methanesulfonic acid (R)-1-carbamoyl-propyl ester (IIi) (3.5 g, 19.3 mmol, 1 equiv.) in acetonitrile (40 ml, 11 vol.) is heated to 80° C. for 17 hours. The mixture is then filtered and the cake rinsed with acetonitrile (30 ml). Combined filtrates are concentrated to dryness under reduced pressure. The crude methyl-(S)-4-(1-carbamoylpropylamino)butyrate (VIg) obtained as a yellow oil is used directly in the next step.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][N:12]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([C:8]2([NH2:7])[CH2:10][CH2:9]2)=[N:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(S(C)(=O)=O)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(C2(N)CC2)nc1
Reaction time: 4 h
Yield: 250.6 %

Procedure:
[1-(5-Methanesulfonyl-pyridin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester (148 mg, 0.47 mmol) was dissolved in DCM (4 mL). TFA (2 mL) was added dropwise. After 4 h, the reaction was concentrated in-vacuo to yield 250 mg of crude 1-(5-methanesulfonyl-pyridin-2-yl)-cyclopropylamine as a TFA salt (dark oil), m/z=213.3 [M+1]+. The product was used in subsequent reactions without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.CS(Cl)(=O)=O.[CH3:31][N:32]1[CH2:38][C:36](=[O:37])[NH:35][C:33]1=[O:34].[H-].[Na+]>CCN(CC)CC>[CH3:31][N:32]1[CH2:38][C:36](=[O:37])[N:35]([CH2:24][C:21]2[CH:22]=[CH:23][C:18]([C:16]([C:3]3[C:2]([CH3:1])=[CH:11][C:10]4[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=4[CH:4]=3)=[CH2:17])=[CH:19][CH:20]=2)[C:33]1=[O:34]
Reactant: C=C(c1ccc(CO)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: CN1CC(=O)NC1=O
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: C=C(c1ccc(CN2C(=O)CN(C)C2=O)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Yield: 42.6 %

Procedure:
Adopting the procedure outlined for example 9 using 40.0 mg (0.12 mmol) of {4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-phenyl}-methanol, 0.05 mL of methanesulfonyl chloride, 0.10 mL of NEt3, 300 mg of 1-methyl-hydantoin, and 63 mg of NaH, 22.0 mg of the product was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](OCCCCCCC)=[C:6]([CH:38]=1)[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2OC2C=CC(C(F)(F)F)=CC=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[F:47][C:48]([F:59])([F:58])[C:49]1[CH:54]=[CH:53][C:52](B(O)O)=[CH:51][CH:50]=1>>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=[CH:20][C:15]([CH2:14][C@H:10]([NH:9][C:7]([C:6]2[CH:5]=[CH:4][C:3]([C:52]3[CH:53]=[CH:54][C:49]([C:48]([F:59])([F:58])[F:47])=[CH:50][CH:51]=3)=[CH:2][CH:38]=2)=[O:8])[C:11]([OH:13])=[O:12])=[CH:16][CH:17]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCOc1ccc(Br)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Product: O=C(N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 87 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(5-bromo-benzoylamino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-trifluoromethyl phenyl boronic acid (0.133 mg, 0.69 mmol) by following general procedure D yielding the title compound (98 mg, 85%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(O)CO>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[N:13]=[CH:12][CH:11]=[CH:10][C:3]=2[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5])=[CH:17][CH:16]=1
Reactant: Nc1ccc(Br)cc1
Reactant: C#CCNC(=O)c1cccnc1Cl
Solvent: OCCO
Product: C#CCNC(=O)c1cccnc1Nc1ccc(Br)cc1
Temperature: 140 °C

Procedure:
Compound 8 (194 mg, 1 mmol) and 4-bromoaniline (9d, 172 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-bromophenylamino)-N-(prop-2-ynyl)nicotinamide 10d as pure product. To a solution of 2-(4-bromophenylamino)-N-(prop-2-ynyl)nicotinamide (10d, 150 mg, 0.45 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 112 mg, 0.5 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1d (220 mg 80%); mp: 160-162° C.; 1H NMR (300 MHz, CDCl3) δ 10.36 (s, 1H), 8.25 (dd, J=3.0, 1.5 Hz, 1H), 7.59 (m, 2H), 7.54 (s, 1H), 7.35-7.28 (m, 3H), 7.22 (brs, 1H), 7.11 (t, J=7.5 Hz, 1H), 7.03-6.94 (m, 7H), 6.67-6.63 (m, 1H), 5.45 (s, 2H), 4.64 ppm (d, J=6.0 Hz, 1H); MS (ESI m/z): 555 [M+H]+. Yield: 80%
Reaction SMILES: Cl[NH:2][C:3](=[NH:8])[C:4]([Cl:7])([Cl:6])[Cl:5].[S-:9][C:10]#[N:11].[K+]>CO>[Cl:5][C:4]([Cl:7])([Cl:6])[C:3]1[N:8]=[C:10]([NH2:11])[S:9][N:2]=1
Reactant: N=C(NCl)C(Cl)(Cl)Cl
Reactant: N#C[S-]
Agent: [K+]
Solvent: CO
Product: Nc1nc(C(Cl)(Cl)Cl)ns1
Reaction time: 1 h

Procedure:
11.8 parts (0.06 mol) of N-chloro-trichloroacetamidine are dissolved in 35 parts by volume of 50% strength methanol. A solution of 6.5 parts (0.066 mol) of potassium thiocyanate is added dropwise to the above solution at 0 to 5° C. After standing for one hour at 0° to 5° C, a precipitate forms, which is filtered off after 4 hours and is recrystallised from aqueous alcohol with addition of active charcoal. 8.4 parts of 3-trichloromethyl-5-amino-1,2,4-thiadiazole are isolated. Melting point 192° to 194° C (with decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](O)([CH3:12])[C:7](=O)[NH:8]2)=[CH:4][CH:3]=1>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(O)C(=O)Nc2cc(Br)ccc21
Solvent: C1CCOC1
Product: Cc1c[nH]c2cc(Br)ccc12
Temperature: 60 °C

Procedure:
A mixture of 6-bromo-3-hydroxy-3-methyl-1,3-dihydro-2H-indol-2-one (0.25 g, 1.0 mmol) and BH3—S(CH3)2 (5.16 mL. 1.0 M, 5.16 mmol) in THF (20 mL) was heated at 60° C. The reaction was quenched with MeOH. Volatiles were removed. Chromatography over silica eluting with 4:1 hexane:EtOAc afforded the title compound. LC-MS: calculated for C9H8BrN: 210.07; observed m/e 211.0 (M+H)+ (Rt 1.14 min).
Reaction SMILES: Br[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Br:10])[C:3]=1[C:4]#[N:5].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:2]2[CH:9]=[N:8][CH:7]=[C:6]([Br:10])[C:3]=2[C:4]#[N:5])[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: N#Cc1c(Br)cncc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cncc(Br)c2C#N)CC1
Temperature: 100 °C
Yield: 42.6 %

Procedure:
3,5-Dibromo-isonicotinonitrile (500 mg, 1.9 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (710 mg, 2.3 mmol) and 2.0 M Na2CO3 aqueous solution (1.9 mL, 3.8 mmol) are added into the 1,4-dioxane (20 mL). Argon gas is bubbled through the solution for 5 min. Then PdCl2dppf (140 mg, 0.19 mmol) is added and the mixture is heated at 100° C. for 3.5 hrs. The reaction mixture is filtered and the filtrate is concentrated to give the crude product. Purification by flash column chromatography affords 295 mg of 5-bromo-4-cyano-3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([C@@H:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15]2)=[O:13])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[O:30]=[S:31]1(=[O:40])[CH2:36][CH2:35][N:34]([C:37](Cl)=[O:38])[CH2:33][CH2:32]1>CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([C@@H:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]2[C:37]([N:34]2[CH2:35][CH2:36][S:31](=[O:40])(=[O:30])[CH2:32][CH2:33]2)=[O:38])=[O:13])[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2)no1
Reactant: O=C(Cl)N1CCS(=O)(=O)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2C(=O)N2CCS(=O)(=O)CC2)no1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of (S)-perhydro-azepine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide hydrochloride (0.30 g, 1.13 mmol), DIPEA (0.32 g, 2.48 mmol) and DMAP (16.0 mg, 0.13 mmol) is stirred at room temperature for 15 minutes. 1,1-Dioxo-1λ6-thiomorpholine-4-carbonyl chloride (0.27 g, 1.35 mmol) (prepared according to method M step 1) is added drop wise at 0° C. to the reaction mixture that is slowly warmed up to room temperature and stirred for 14 hours. The reaction mixture is diluted with EtOAc, washed with water and brine. After drying the organic phase over anhydrous Na2SO4, removal of the solvent under reduced pressured affords the crude product that is purified by prep TLC to afford the title product; m/z 427 [M+H+].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]([CH3:15])[CH3:14])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[C:16]([Mg]Br)#[CH:17]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]([OH:9])[C:16]#[CH:17])[CH:10]=[CH:11][C:12]=1[N:13]([CH3:15])[CH3:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1ccc(C=O)cc1C(C)(C)C
Reactant: C#C[Mg]Br
Product: C#CC(O)c1ccc(N(C)C)c(C(C)(C)C)c1

Procedure:
In a manner analogous to example 1 e, the process is carried out by a reaction of 1 g (4.9 mmol) of 3-tert-butyl-4-dimethylaminobenzaldehyde with 12 ml (6 mmol) of a 0.5M solution of ethynylmagnesium bromide. 900 mg of 1-(3-tert-butyl-4-dimethylaminophenyl)prop-2-yn-1-ol are obtained in the form of a colourless oil (yield=79%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.[Br:9]Br.O>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[Br:9]
Reactant: Nc1cccc(O)n1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(O)ccc1Br
Reaction time: 0.33 h
Yield: 52.8 %

Procedure:
To a solution of 6-amino-pyridin-2-ol (5 g, 45.4 mmol) in glacial acetic acid (60 mL) was added bromine (2.33 mL, 45.4 mmol) under Ar atmosphere. The mixture was stirred for 20 minutes, then water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to dryness to obtain crude 6-amino-5-bromo-pyridin-2-ol (4.53 g).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][NH:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[NH2:18])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C(N(CC)CC)C.[Cl-].C([O:29][C:30](=O)[C:31](O)=[O:32])C>O1CCCC1>[CH2:1]([O:3][P:4]([CH2:9][N:10]1[C:11]2[C:12](=[CH:13][CH:14]=[C:15]([F:17])[CH:16]=2)[NH:18][C:30](=[O:29])[C:31]1=[O:32])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOC(=O)C(=O)O
Reactant: CCOP(=O)(CNc1cc(F)ccc1N)OCC
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2ccc(F)cc21)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
660 mg of N(-2-amino-5-fluorophenyl)-aminomethanephosphonic acid diethyl ester is introduced in 70 ml of absolute tetrahydrofuran with 509 mg of triethylamine. A solution of 685 mg of oxalic acid ethyl ester chloride in 30 ml of tetrahydrofuran is slowly instilled into this solution. The batch is stirred for 4 hours at room temperature. After suctioning-off of the precipitated salts, the filtrate is concentrated by evaporation, boiled in a mixture of 23 ml of ethanol and 23 ml of 1 N hydrochloric acid for 2 hours at 110° C. bath temperature. It is evaporated to dryness and the residue is chromatographed on silica gel with methylene chloride:ethanol=10:1. 561 mg of (7-fluoro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl)-methanephosphonic acid diethyl ester is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[C:3]=1F.Br.[Na].[CH2:13]([OH:16])[CH2:14][OH:15].Cl>O>[F:9][C:4]1[C:5]([F:8])=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[O:15][CH2:14][CH2:13][OH:16]
Reactant: OCCO
Reactant: Fc1ccc(F)c(F)c1F
Agent: Br
Agent: Cl
Agent: [Na]
Solvent: O
Product: OCCOc1c(F)ccc(F)c1F
Reaction time: 3 h

Procedure:
1,2,3,4-Tetrafluorobenzene (67.7 g), sodium hydrobromide (20.8 g), and 200 ml of ethyleneglycol are refluxed with good stirring for 3 hours. The reaction mixture is poured into water (800 ml), acidified with 10% hydrochloric acid and then extracted with ether. The ether is washed with dilute sodium hydroxide and water, and then distilled under vacuum to give 2-(2,3,6-trifluorophenoxy) ethanol), b.p. about 100° at 15 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([CH3:17])([CH3:16])[CH2:10][C:9]2([CH3:19])[CH3:18])=[O:5])[CH3:2].Cl[CH:21]([O:23]C(Cl)Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([CH:21]=[O:23])[CH:15]=1)[O:12][C:11]([CH3:17])([CH3:16])[CH2:10][C:9]2([CH3:18])[CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Reactant: ClC(Cl)OC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc(C=O)c2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 25 °C
Yield: 19.7 %

Procedure:
A stirred, cooled (ice bath) solution of of 2,2,4,4-tetramethyl-chroman-6-carboxylic acid ethyl ester (Intermediate 36, 0.5 g, 1.92 mmol) in anhydrous dichloromethane (10 mL) was treated with titanium tetrachloride (0.4 mL, 3.26 mmol) followed by . . . ,-dichloromethyl ether (0.17 mL, 1.92 mmol). The reaction was allowed to warm to ambient temperature over 2 days, quenched cautiously with ice and water and extracted with dichloromethane. The organic extract was washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography to afford the title compound (0.11 g, 20%).
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:26])[O:6][CH2:7][C:8]1([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH:10]=[C:9]1[O:19]C)([CH3:3])[CH3:2].I[Si](C)(C)C>C(#N)C>[CH:1]([NH:4][C:5](=[O:26])[O:6][CH2:7][C:8]1([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][C:9]1=[O:19])([CH3:3])[CH3:2]
Reactant: COC1=CC(=O)c2ccccc2C1(CCC(C)C)COC(=O)NC(C)C
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CC(C)CCC1(COC(=O)NC(C)C)C(=O)CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
To a solution of Example 180B (32 mg, 0.09 mmol) in acetonitrile (1 mL) was added iodotrimethylsilane (TMSI) (19 μL, 0.13 mmol). The reaction solution was stirred at room temperature for 3 h. After which, additional 1.5 equivalents of TMSI (19 μL) were added and stirring was continued for 2 h. The solution was quenched with water (2 mL) and extracted with ethyl acetate (2×1 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica (70% ethyl acetate/hexane) afforded product as a white foam (24 mg, 77%). MS m/z 346.0 (M+H)+.
Reaction SMILES: CC(O)=O.C([N:12]1[CH2:17][CH2:16][C:15]([OH:21])([C:18]([NH2:20])=[O:19])[CH2:14][CH2:13]1)C1C=CC=CC=1>CO.[Pd]>[OH:21][C:15]1([C:18]([NH2:20])=[O:19])[CH2:16][CH2:17][NH:12][CH2:13][CH2:14]1
Reactant: NC(=O)C1(O)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)C1(O)CCNCC1
Reaction time: 14 h

Procedure:
Pd/C (150 mg) and HOAc (2 mL) are added to a solution of 1-benzyl-4-hydroxy-piperidine-4-carboxylic acid amide (2 g, 8.5 mmol) in MeOH. The mixture is shaken under H2 (40 psi) for 14 hours. The catalyst is removed by filtration and the solvent is removed in vacuo to give the title product. 1H NMR (CD3OD) 2-96 (m, 4H), 2.05 (m, 2H), 1.49 (m, 2H).
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH:15]=[O:16])=[CH:9]2)[CH2:2][CH:3]([CH3:5])[CH3:4].CI.[C:19](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:19])[C:10]([CH:15]=[O:16])=[CH:9]2)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CC(C)CCc1ccc2[nH]c(C=O)cc2c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)CCc1ccc2c(c1)cc(C=O)n2C
Temperature: 150 °C
Reaction time: 1 h
Yield: 15.2 %

Procedure:
To a solution of 5-isopentyl-1H-indole-2-carbaldehyde (100 mg, 0.46 mmol) and methyl iodide (71 mg, 0.50 mmol) in 0.93 mL dimethylformamide was added potassium carbonate (71 mg, 0.51 mmol). The resulting suspension was stirred vigorously at 150° C. in a sealed vial under argon for 1 h. Solids were filtered and the liquor concentrated before being subjected to chromatography on silica gel (40% ethyl acetate in hexanes) to give 5-isopentyl-1-methyl-1H-indole-2-carbaldehyde (16 mg, 15%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].F[C:12]1[CH:20]=[N:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:17]1[CH:18]=[N:19][CH:20]=[CH:12][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1ccncc1F
Reactant: NCc1ccc(Cl)cc1Cl
Product: O=C(O)c1ccncc1NCc1ccc(Cl)cc1Cl
Yield: 42 %

Procedure:
The title compound was prepared in 42% yield from 2,4-dichlorobenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.49 (br s, 1H), 8.04 (s, 1H), 7.87 (d, 1H, J=5.0 Hz), 7.66 (s, 1H), 7.59 (d, 1H, J=5.0 Hz), 7.38-7.42 (m, 2H), 4.63 (s, 2H). [M+H] calc'd for C13H10Cl2N2O2, 297, 299; found 297, 299.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH2:15][CH2:14][N:13]([C:16]([O:18]C(C)(C)C)=O)[CH2:12][CH2:11][C:5]=3[NH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1.[CH2:23]([CH2:26][O:27][CH3:28])OC.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.CCCCCC>[C:16]([N:13]1[CH2:14][CH2:15][C:4]2[C:3]3[C:2]([C:23]4[CH:11]=[CH:5][CH:4]=[CH:15][C:26]=4[O:27][CH3:28])=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:11][CH2:12]1)(=[O:18])[C:2]1[CH:3]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COCCOC
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cccc(Br)c3c2CC1
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: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccccc1-c1cccc2[nH]c3c(c12)CCN(C(=O)c1ccccc1)CC3
Temperature: 25 °C

Procedure:
tert-Butyl 10-bromo-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (4.40g, 11.9 mmol), Pd(PPh3)4 (1.40 g, 1.21 mmol), and dimethoxyethane (60 mL) were stirred at room temperature for 15 minutes then treated with 2-methoxyboronic acid (2.18 g, 14.3 mmol) and a 2 M solution of Na2CO3 (36 mL). The reaction was heated to reflux for 17.0 hours then cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×) and the organic layers were combined, washed with brine, dried over MgSO4 and concentrated in vacuo to give a brown foam which was passed through a column of silica gel with 40% ethyl acetate/hexane to give 3.87 g (82%) of a white solid as the title compound: mp 218.9-221.6° C. 1H NMR (400 MHz, DMSO-d6) δ 10.95-10.85 (m, 1 H), 7.43-7.38 (m, 4 H), 7.27-7.23 (m, 2 H), 7.17-6.97 (m, 4 H), 6.67-6.61 (m, 3.82 (m, 1 H), 3.66-3.53 (m, 5 H), 3.27 (m, 1 H), 3.09-3.06 (m, 1 H), 2.85 (m, 1 H), 2.39-2.32 (m, 1 H), 2.17-2.13 (m, 1 H); 13C NMR (100 MHz, DMSO-d6) δ 170.1, 169.8, 156.8, 156.7, 137.1, 135.7, 134.8, 134.6, 130.8, 130.5, 130.4, 130.2, 130.0, 128.9, 128.5, 128.3, 128.2, 126.1, 126.0, 120.5, 119.9, 119.8, 119.7, 111.2, 110.5, 110.2, 109.7, 109.5, 54.9, 54.7, 49.6, 48.3, 46.1, 44.2, 29.4, 27.5, 25.7, 24.6; IR (diffuse reflectance) 3202, 3181 (b), 1602 (s), 1500, 1489, 1466, 1434, 1299, 1266, 1249, 1241, 786, 759 (s), 748, 707 cm−1; HRMS (FAB) calcd for C26H24N2O2+H1 397.1916, found 397.1910. Anal. Calcd for C26H24N2O2: C, 78.76; H, 6.10; N, 7.07. Found: C, 78.40; H, 6.22; N, 6.97.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40])[CH:31]=[CH:32][C:33](O)=[O:34]>>[CH3:42][O:41][C:37]1[CH:36]=[C:30]([CH:29]=[C:28]([O:27][CH3:26])[C:38]=1[O:39][CH3:40])[CH:31]=[CH:32][C:33]([N:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=2)[CH2:21][CH2:22]1)=[O:34]
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Product: COc1cc(C=CC(=O)N2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (103 mg) and 3,4,5-trimethoxycinnamic acid (65 mg) were reacted in the same manner as in Example 56 to obtain the title compound as a free base.
Reaction SMILES: Cl[C:2]([CH3:21])([CH3:20])[CH:3]([N:18]=[O:19])[CH2:4][O:5][CH2:6][CH:7]([OH:17])[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[N+:14]([O-:16])=[O:15].[NH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([CH3:34])([CH3:33])[C:28](=[N:31][OH:32])[CH2:29]C.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:20][C:2]([CH3:21])([NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([CH3:34])([CH3:33])[C:28](=[N:31][OH:32])[CH3:29])[C:3](=[N:18][OH:19])[CH2:4][O:5][CH2:6][CH:7]([OH:17])[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[N+:14]([O-:16])=[O:15]
Reactant: CC(C)(Cl)C(COCC(O)Cn1ccnc1[N+](=O)[O-])N=O
Reactant: CCC(=NO)C(C)(C)NCCCN
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=NO)C(C)(C)NCCCNC(C)(C)C(COCC(O)Cn1ccnc1[N+](=O)[O-])=NO
Temperature: 40 °C

Procedure:
A slurry of 3-chloro-1-[2-hydroxy-3-(2-nitro-1H-imidazol-1-yl)propoxy]-3-methyl-2-nitrosobutane (3.2 g, 0.01 mol) in acetonitrile (35 mL) was maintained at 40° C. for 30 minutes. To this slurry was added a solution of N-(3-aminopropyl)-1-amino-1,1-dimethyl-2-butanoneoxime (1.73 g, 0.01 mol) in acetonitrile (10 mL) and diisopropylethylamine (1.5 g, 0.012 mol) and the mixture was maintained at 40° C. for 48 hrs. The solid which formed was filtered and the acetonitrile solution was evaporated on a rotary evaporator to give a green viscous oil which was dried under vacuum. The foamy solid obtained was triturated with acetonitrile to afford a thick oil which solidified on standing. This was purified by column chromatography (CH2Cl2 :CH3OH, 7:3, 50:50)). The fractions containing the product were collected and evaporated to give an oil which was dried under vacuum and triturated with acetonitrile to give a white solid. It was recrystallized from ethyl acetate to yield the title product. Yield: 1.2 g (26%). mp: 134°-35° C. MS: (M+H)+ =458+. 1H NMR (DMSO) δ 1.05 and 1.16 [s, 12H, C(CH3)2 ], 1.38 (m, 2H, NHCH2CH2CH2NH), 1.72 (s, 3H, CH3), 2.2 (m, 2H, NHCH2CH2CH2NH), 3.38 (m, 4H, CH2OCH2CHOH), 3.8 (m, 2H, OCH2CHOH), 4.28 and 4.6 (m, 3H, CHOHCH2N<), 7.12 and 7.58 (s, 2H, imi H), 10.4 and 10.85 (s, 2H, NOH). Anal. Calcd for C19H35N7O6 : C, 49.88; H, 7.71; N, 21.43. Found: C, 49.80; H, 7.79; N, 21.47.