Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:8][CH2:9][CH2:10][S:11][C:12]([O:14]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:36]1[CH2:43][CH2:42][CH2:41][C@H:37]1[C:38]([OH:40])=[O:39]>>[C:24]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:8][CH2:9][CH2:10][S:11][C:12]([N:36]2[CH2:43][CH2:42][CH2:41][C@H:37]2[C:38]([OH:40])=[O:39])=[O:14])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=C(O)[C@@H]1CCCN1C(=O)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 50 %

Procedure:
N-triphenylmethyl-2-paranitrophenoxycarbonylthioethylamine (1.0 g) and L-proline (713 mg) were subjected to a similar reaction described in Reference 2 to give N-triphenylmethyl-2-[(S)-2-carboxypyrrolidino)carbonylthioethylamine (475 mg) which was then dissolved in a mixture of anhydrous dimethylformamide (1.5 ml) and anhydrous acetonitrile (4 ml). After addition of dicyclohexylcarbodiimide (256 mg) and 4-aminohenol (256 mg), the reaction solution was stirred at room temperature for 5 hours and was then concentrated under reduced pressure. The concentrated solution was dissolved in chloroform (50 ml), followed by washing in turns with an aqueous solution of 10% citric acid, a saturated sodium bicarbonate solution, water and a saturated solution of sodium chloride. The chloroform layer was dried by use of anhydrous sodium sulfate and was then concentrated under reduced pressure. The residual substance was purified by silica gel column chromatography using a solvent system of chloroform/methanol (20:1 v/v) to obtain N-triphenylmethyl-2-[(S)-2-(4-hydroxyphenyl)aminocarbonylpyrrolidino]carbonylthioethylamine (0.45 g: yield 79.0%). From the product triphenylmethyl was removed in a similar manner to that described in Example 4 to produce 2-(S)-2-4-hydroxyphenyl)aminocarbonylpyrrolidino]carbonylthioethylamine (crude formate: 445 mg). This product was dissolved in anhydrous methanol (7 ml). To the reaction solution were added triethylamine (873 μl) and mitomycin A (380 mg: 0.87 molar equivalent). The mixture was treated in a similar manner to that described in Example 1 to obtain Compound 45 (160 mg) in the form of grayish blue powders with a yield of 39%.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][C@H:25]([C:33]([NH:35][NH:36][C:37]([CH3:39])=[O:38])=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23])=[O:19])[CH2:15][CH2:16][CH3:17])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.N(C(OCC1C=CC=CC=1)=O)[C@H](C(N[C@@H](C(NCC(O)=O)=O)[C@H](C)O)=O)CC1C=CC(O)=CC=1>>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][C@H:25]([C:33]([NH:35][NH:36][C:37]([CH3:39])=[O:38])=[O:34])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:23])=[O:19])[CH2:15][CH2:16][CH3:17])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NNC(C)=O
Agent: C[C@H](O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)NCC(=O)O
Product: CCC[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NNC(C)=O
Yield: 49.9 %

Procedure:
Using Z-Tyr-(D)-Nva-Gly-Phe-NH-NH-COCH3 (0.40 g), the desired compound(0.16 g) is obtained in a similar manner to (II) of Example 4. Rf2 =0.36, [α]D23 +22.6° (c=0.30, MeOH). Amino acid analysis (hydrolized with HCl): Gly 1.00, Nva 1.10, Tyr 0.99, Phe 1.07.
Reaction SMILES: [OH-].[Na+].Cl.Cl[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.Cl.[SH:13][CH2:14][CH2:15][NH2:16]>C(O)C>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH2:5][S:13][CH2:14][CH2:15][NH2:16])[CH:7]=1
Reactant: NCCS
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NCCSCc1cccnc1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
16.8 g of sodium hydroxide was dissolved in 350 ml of ethanol and 17.2 g of 3-chloromethylpyridine hydrochloride and 23.7 g of 2-mercaptoethanamine hydrochloride were added with ice bath cooling. The reaction mixture was allowed to warm to room temperature over 2 hours, was concentrated, diluted with water, and extracted with 3×100 ml of dichloromethane. The combined organic layers were washed with saturated brine, dried over potassium carbonate and concentrated. The residue was distilled to give 12.30 g (70%) of 2-[[(3-pyridyl)methyl]thio]ethanamine, bp 115°-125° C./0.1 mm.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]3[N:12]=[CH:13][NH:14][C:15]=3[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH:9]=[CH:10][C:5]=2[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:3]1=[O:29].[H-].[Na+].Cl[C:33]1[CH:38]=[N:37][CH:36]=[CH:35][N:34]=1>CN(C=O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]3[N:12]([C:33]4[CH:38]=[N:37][CH:36]=[CH:35][N:34]=4)[CH2:13][NH:14][C:15]=3[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH:9]=[CH:10][C:5]=2[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:3]1=[O:29]
Reactant: Cc1cccc(-c2[nH]cnc2-c2ccc3c(c2)n(C)c(=O)n3-c2ccccc2)c1
Reactant: Clc1cnccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(C2=C(c3ccc4c(c3)n(C)c(=O)n4-c3ccccc3)N(c3cnccn3)CN2)c1
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3-Methyl-1-phenyl-5-(5-m-tolyl-1H-imidazol-4-yl)-1,3-dihydro-benzoimidazol-2-one (prepared as described previously in Example 200, 33 mg, 0.087 mmol) in DMF (0.1 mL) was added NaH (4 mg, 0.095 mmol). After stirring for 20 min, 2-chloropyrazine (9.3 mL, 0.10 μmol) was added and the reaction mixture was heated to 120° C. for 14 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by LC (Waters Symmetry C8, formic acid/acetonitrile/water) to afford 2 mg of the title compound.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:14]([CH3:16])[CH3:15])=[N:5][S:6][C:7]=1[N:8]=[C:9](Cl)[N:10]([CH3:12])[CH3:11])#[N:2].[C-:17]#[N:18].[K+]>C(#N)C>[C:1]([C:3]1[C:4]([CH:14]([CH3:16])[CH3:15])=[N:5][S:6][C:7]=1[N:8]=[C:9]([C:17]#[N:18])[N:10]([CH3:12])[CH3:11])#[N:2]
Reactant: [C-]#N
Reactant: CC(C)c1nsc(N=C(Cl)N(C)C)c1C#N
Agent: [K+]
Solvent: CC#N
Product: CC(C)c1nsc(N=C(C#N)N(C)C)c1C#N
Yield: 63.8 %

Procedure:
In the manner of Example VII, 7 g of N'-(4-cyano- 3-isopropyl-5-isothiazolyl)-N,N-dimethylchloroformamidine, 3.6 g of anhydrous potassium cyanide, and a catalytic amount of 2,3,11,12-dibenzo-1,4,7,10,13,16-hexaoxacycloocta- 2,11-diene in 200 ml of dry aceto-nitrile were allowed to react for several days. After solvents were removed under reduced pressure, the residue was recrystallized from methylcyclohexane to yield 4.3 g of N'-(4-cyano-3-isopropyl-5-isothiazolyl)-N,N-dimethylcyanoformamidine, mp 78°-79°. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2](=O)[C:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:5])[CH3:4].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[C:2]([C:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:5])[CH3:4])#[N:1]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(N)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C#N)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of tert-butyl 1-amino-2-methyl-1-oxopropan-2-ylcarbamate (Example 12 a, 12.5 g) and triethylamine (CAN 121-44-8, 29 g) in methylene chloride (150 mL) was added trifluoroacetic acid anhydride (CAN 407-25-0, 27.2 g) dropwise at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 4 h. After that the mixture was washed with water, 5 N citric acid and brine, the organic phase was dried over anhydrous sodium sulfate and concentrated to give the title compound (11 g, 97%) as a yellow solid; MS: m/e=207.1 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)[CH:9]=[C:10]([C:12]#[CH:13])[CH:11]=1.[NH2:26][C@H:27]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:28][OH:29].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[F:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:14]([C:18]([NH:26][C@H:27]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:28][OH:29])=[O:20])=[C:15]([CH3:17])[N:16]=2)[CH:9]=[C:10]([C:12]#[CH:13])[CH:11]=1
Reactant: CCCC[C@@H](N)CO
Reactant: C#Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)O)n2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)N[C@@H](CO)CCCC)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 50 mg (0.15 mmol) of 8-[(2,6-difluorobenzyl)oxy]-6-ethynyl-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid were dissolved in 0.5 ml of dry dimethylformamide, 20.54 mg (0.18 mmol, 1.2 equivalents) of (R)-(−)-2-aminohexanol, 72 μl of diisopropylethylamine (0.44 mmol, 3 equivalents) and 72 mg of HATU (0.19 mmol, 1.3 equivalents) were added and the mixture was stirred at room temperature overnight. A little water was then added, and the mixture was purified directly by preparative HPLC (Method 8). This gave 37.5 mg of the target compound (58% of theory).
Reaction SMILES: [C:1]([C:3]1([CH2:13][O:14][C:15]2[C:23]([CH:24]3[CH2:26][CH2:25]3)=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([F:27])[CH:16]=2)[CH:10]2CC3C[CH:8]([CH2:12][CH:4]1C3)[CH2:9]2)#[N:2].C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)CCCCC1)#N.CS(N)(=O)=O.[N:56]1([S:60]([NH2:63])(=[O:62])=[O:61])[CH2:59][CH2:58][CH2:57]1>>[N:56]1([S:60]([NH:63][C:19](=[O:21])[C:18]2[CH:22]=[C:23]([CH:24]3[CH2:25][CH2:26]3)[C:15]([O:14][CH2:13][C:3]3([C:1]#[N:2])[CH2:4][CH2:12][CH2:8][CH2:9][CH2:10]3)=[CH:16][C:17]=2[F:27])(=[O:62])=[O:61])[CH2:59][CH2:58][CH2:57]1
Reactant: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Reactant: NS(=O)(=O)N1CCC1
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CCCCC1
Product: N#CC1(COc2cc(F)c(C(=O)NS(=O)(=O)N3CCC3)cc2C2CC2)CCCCC1

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-((1-cyanocyclohexyl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained as a colorless solid (0.061 g, 42%): 1H NMR (300 MHz, DMSO-d6) δ 11.65 (br s, 1H), 7.14 (d, J=8.1 Hz, 1H), 6.99 (d, J=12.6 Hz, 1H), 4.15 (s, 2H), 4.02 (t, J=7.6, 7.6 Hz, 4H), 2.18-2.08 (m, 2H), 2.03-1.97 (m, 3H), 1.73-1.66 (m, 3H), 1.51-1.39 (m, 4H), 1.20 (br s, 1H), 0.91-0.85 (m, 2H), 0.69-0.64 (m, 2H); 19F NMR (282 MHz, DMSO-d6) δ −112.6 (s, 1F); MS (ES−) m/z 434.1 (M−1).
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1.Cl.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37]N>>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:32]=1[NH:37][CH:2]=[C:6]2[CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:27])[CH:24]([CH3:25])[CH3:26])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC3OCCO3)CC2)c1
Reactant: COc1ccccc1NN
Agent: Cl
Product: COc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c[nH]c12

Procedure:
Prepared by Procedure H and Scheme S using N-(3-{1-[4-(1,3-dioxolan-2-yl)butyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methoxyphenyl)hydrazine hydrochloride: ESMS m/e: 434.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.Br[CH2:12][CH2:13][CH3:14]>>[CH3:10][C:4]1[CH:3]=[C:2]([O:1][CH2:12][CH2:13][CH3:14])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: CCCBr
Reactant: Cc1cc(O)ccc1C=O
Product: CCCOc1ccc(C=O)c(C)c1
Yield: 70.1 %

Procedure:
The compound was synthesized as in Example 87.1, using 4-hydroxy-2-methylbenzaldehyde (54.4 mg, 0.40 mmol) in place of 4-hydroxybenzaldehyde and 1-bromopropane (98 mg, 0.80 mmol) in place of 1-iodo-(3,3,3-trifluoro)propane to give 2-methyl-4-propoxybenzaldehyde (50 mg, 71%). Used without further characterization.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([CH:16]=[N:17]O)=[C:5]2[C@@H:4]2[CH2:19][CH2:20][CH2:21][N:3]12>C(OC(=O)C)(=O)C>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]#[N:17])=[C:5]2[C@@H:4]2[CH2:19][CH2:20][CH2:21][N:3]12
Reactant: O=C1c2ccccc2-n2cnc(C=NO)c2[C@@H]2CCCN12
Solvent: CC(=O)OC(C)=O
Product: N#Cc1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2

Procedure:
A solution of 5.24 g (18.5 mmol) of (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxaldehyde-1-oxime in 50 ml of acetic acid anhydride is heated to boiling under reflux for 3 hours and subsequently evaporated in vacuo. The residue is taken up in chloroform, the solution is washed once with ca 30 ml of saturated sodium hydrogen carbonate solution and once with ca 30 ml of water, dried over magnesium sulphate and evaporated. After column chromatography and recrystallisation from ethyl acetate, there is obtained (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carbonitrile of melting point 223°-225° C.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH2:4][CH2:3]1.[Br:13]Br>C(OCC)(=O)C>[Br:13][CH:4]1[CH2:3][CH:2]([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:12]
Reactant: BrBr
Reactant: CC1CCC(=O)c2ccccc21
Solvent: CCOC(C)=O
Product: CC1CC(Br)C(=O)c2ccccc21

Procedure:
4.8 g (0.03 mole) of 4-methyl-1-tetralone are reacted with 4.8 g (0.03 mole) of bromine in ethyl acetate, analogously to the instructions indicated in Example 29 (a), to give 2-bromo-4-methyl-1-tetralone. The oily product is further processed immediately without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1.[CH3:26][C:27](=[O:30])[CH:28]=[CH2:29]>O(CC)CC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:29][CH2:28][C:27](=[O:30])[CH3:26])=[CH:4][CH:3]=1
Reactant: C=CC(C)=O
Reactant: Oc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(=O)CCOc1ccc(F)cc1
Reaction time: 96 h
Yield: 39.7 %

Procedure:
To a stirred solution of 134 parts of 4-fluorophenol and 2 parts of 4-methylbenzenesulfonic acid in 1080 parts of benzene were added 42 parts of 3-butene-2-one. Stirring was continued for 4 days at room temperature. 700 Parts of 1,1'-oxybisethane were added and the whole was washed four times with 500 parts of a cold sodium hydroxide solution 1N and with water. The organic phase was dried, filtered and evaporated. The oily residue was purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue solidified upon cooling. The product was suspended in cold petroleum-ether. The product was filtered off and dried at room temperature, yielding 43.4 parts (39.7%) of 4-(4-fluorophenoxy)-2-butanone (intermediate 26).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[N+:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2)([O-:12])=[O:11].[H-].[Na+]>CN(C=O)C.O>[N+:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:17]=[CH:16]2)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(ccn2CCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
Dissolve 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (2.36 g, 13.9 mmol) and 5-nitro-1H-indole (1.50 g, 9.23 mmol) in DMF (25 mL) and carefully treat with sodium hydride (60% dispersion, 1.50 g, 37.5 mmol). Stir the mixture at room temperature overnight, then dilute with cold water (100 mL) and extract with EtOAc (3×50 mL). Was the combined organic portions with water (2×50 mL) and brine (50 mL). Dry, filter and concentrate under vacuum. Purify the crude material by flash chromatography, using 100% acetone as eluant, to give the title compound as a yellow oil (2.08 g, 87%). MS (ES+) 260.1 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 8.57 (d, 1H, J=2.2 Hz), 8.10 (dd, 1H, J=9.2, 2.2 Hz), 7.37 (d, 1H, J=9.2 Hz), 7.30 (d, 1H, J=3.1 Hz), 6.67 (d, 1H, J=3.1 Hz), 4.29 (t, 2H, J=7.3 Hz), 2.89 (t, 2H, J=7.0 Hz), 2.54 (m, 4H), 1.78 (m, 4H).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[Br:16][C:17]1[C:18](F)=[C:19]2[C:25]([NH:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=3)=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1>CCCCO>[Br:16][C:17]1[C:18]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7])[CH2:11]2)=[C:19]2[C:25]([NH:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=3)=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccnc1
Solvent: CCCCO
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Temperature: 160 °C
Reaction time: 24 h

Procedure:
(R)-tert-Butyl methyl(piperidin-3-yl)carbamate (384 mg, 1.79 mmol) was added to N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (200 mg, 0.597 mmol, Example 1, Step I) in n-BuOH (3 mL), and the reaction was stirred at 160° C. for 24 hours in a sealed tube. The reaction was concentrated to dryness. The residue was then purified by chromatography (Biotage SP4, C-18 25M+ column, 10-90% CH3CN/water gradient, 30 CV) to yield (R)-tert-butyl 1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:13]O>C[Re](=O)(=O)=O.ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N+:5]([O-:13])=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: OO
Agent: C[Re](=O)(=O)=O
Solvent: ClCCl
Product: [O-][n+]1ccc(Cl)c2ccc(Cl)cc21

Procedure:
A mixture of 4,7-dichloroquinoline (9.9 g, 50 mmol) and methyltrioxorhenium (80 mg, 0.32 mmol) was stirred in the mixture of hydrogenperoxide (40%, 20 mL) and dichloromethane at room temperature for 24 hours. Pale yellow solid was collected by filtration and dried under vacuum. MS (ESI(+)Q1MS m/z 215 (M+H)+.
Reaction SMILES: C(OC1C(NC(=O)C[NH:17][C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21](C(F)(F)F)[CH:20]=2)CN(C(OCC2C=CC=CC=2)=O)C1)C1C=CC=CC=1.[Si](I)(C)(C)C>ClCCl>[C:18]([NH2:17])(=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C(=O)OCc2ccccc2)CC1OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: NC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of benzyl rac-(3R,4R)-3-(benzyloxy)-4-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidine-1-carboxylate in dichloromethane was slowly added TMSI (˜3 equiv.). After 1 hour, all volatiles were removed and the slurry was taken up in acetonitrile (3 mL). 1-(4-methoxyphenyl)piperidin-4-one and sodium triacetoxyborohydride were added and the reaction mixture was stirred overnight. To the mixture was added NaHCO3 (sat. aq., 10 mL) and dichloromethane (10 mL). The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford N-[2-({(3R,4R)-4-benzyloxy)-1-[1-(4-methoxyphenyl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-trifluoromethyl)benzamide (55 mg overall) as a white solid. 1H-NMR (CDCl3) δ: 1.98-2.15 (m, 1H), 2.53-2.62 (m, 2H), 3.05-3.19 (m, 2H), 3.33-3.38 (m, 1H), 3.47-3.52 (d, J=12.3 Hz, 2H), 3.63-3.69 (m, 4M), 3.86-3.99 (m, 1H), 4.14-4.22 (m, 3H), 4.52-4.77 (m, 3H), 6.73-6.78 (m, 4H), 7.22-7.35 (m, 5H), 7.47-7.52 (t, J=7.6 Hz, 1H), 7.67-7.70 (d, J=7.5 Hz, 1H), 8.03-8.07 (m, 2H), 8.12 (s, 1H). MS m/z: 611 (M+1)
Reaction SMILES: C([NH+](CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O-:37])=[O:36])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.C(N(CC)CC)C.[CH:45]1[C:50]([F:51])=[C:49]([F:52])[C:48](OC(C(F)(F)F)=O)=[C:47]([F:60])[C:46]=1[F:61]>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][C:45]2[C:50]([F:51])=[C:49]([F:52])[CH:48]=[C:47]([F:60])[C:46]=2[F:61])=[O:36])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(C(NCCCCCC(=O)[O-])(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(Oc1c(F)c(F)cc(F)c1F)C(F)(F)F
Agent: CC[NH+](CC)CC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(NCCCCCC(=O)Oc2c(F)c(F)cc(F)c2F)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
The acid 6 obtained as described above (2.2 g, 4.4 mmol) was dissolved in anhydrous CH2Cl2 and treated with 1 ml of triethylamine followed by 0.8 ml of 2,3,5,6-tetrafluorophenyltrifluoroacetate. After being kept at room temperature for 30 min, the reaction was concentrated to an oil (crude 7), which then was re-suspended in 20% ethyl acetate/80%hexane and applied to a silica gel column. Elution with 15% ethyl acetate/85% hexane and concentration of the pure product fractions afforded 2.0 g (82%) of the TFP ester (7) as a colorless, viscous oil.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:27])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[CH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][CH:7]=1>C(O)(C)C>[CH3:3][C:4]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:27])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[CH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc(C=C(C)CCC=C(C)CCC=C(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)=CCCC(C)=CCCC(C)=Cc1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.7 %

Procedure:
20 g of potassium hydroxide was dissolved in 200 ml of isopropanol. 50 g of ethyl p-(2,6,10-trimethyl-1,5,9-undecatrienyl)benzoate was added to the solution under heating, reflux and stirring. After 10 min, the solution was poured into ice/water and extracted with 200 ml of n-hexane. The aqueous layer was made acidic with dilute hydrochloric acid, extracted with ethyl ether, washed with water and dried over magnesium sulfate. The product was concentrated to obtain 42 g of crude crystals. The crude crystals were recrystallized from 150 ml of n-hexane to obtain 32 g of intended p-(2,6,10-trimethyl-1,5,9-undecatrienyl)benzoic acid as white crystals.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)[CH3:2].Cl.[NH2:17][OH:18]>>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12](=[N:17][OH:18])[CH2:11][CH2:10]1)[CH3:2]
Reactant: NO
Reactant: CCOCCCCCN1CCC(=O)CC1
Agent: Cl
Product: CCOCCCCCN1CCC(=NO)CC1

Procedure:
1-(5-Ethoxypentyl)-4-piperidone oxime is prepared from 1-(5-ethoxypentyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.