Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:19][C:20]([O:22][CH2:23][C:24](=[CH2:27])[CH2:25][OH:26])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Br:28][CH2:29][CH2:30][CH2:31][CH2:32][N:33]=[C:34]=[O:35].CCOCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([NH:19][C:20]([O:22][CH2:23][C:24](=[CH2:27])[CH2:25][O:26][C:34]([NH:33][CH2:32][CH2:31][CH2:30][CH2:29][Br:28])=[O:35])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C=C(CO)COC(=O)NCCCCCCCCCCCCCCCCCC
Reactant: O=C=NCCCCBr
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: C=C(COC(=O)NCCCCBr)COC(=O)NCCCCCCCCCCCCCCCCCC
Temperature: 22 °C
Reaction time: 22 h

Procedure:
3-Octadecylaminocarbonyloxy-2-methylenepropan-1-ol (from Preparation 3) (2.0 g) was dissolved in methylene chloride (40 ml). 4-Dimethylaminopyridine (0.13 g) and 4-bromobutyl isocyanate (1.30 g) were added, and the mixture was stirred for 22 hours at 22° C. Ether (40 ml) was added, and the mixture was purified through a column of silica gel 60 (70-230 mesh, 20 g) eluting with ether/chloroform 1:1. Further purification was achieved by chromatography on a Waters PrepLC®/System 500A using a PrepPAK®-500/SILICA cartridge with ether/chloroform/pentane 1:1:2 as eluent.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].CS(O)(=O)=O.[CH:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18](Cl)=[O:19])=[CH:12][CH:11]=1.C(O[K])(C)=O>O.C(O)C.C(COC)OC>[NH2:3][CH2:2][CH2:1][NH:4][C:18](=[O:19])[O:17][CH2:16][C:13]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1
Reactant: NCCN
Reactant: O=C(Cl)OCc1ccccc1
Agent: CC(=O)O[K]
Agent: CS(=O)(=O)O
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: NCCNC(=O)OCc1ccccc1
Yield: 50.9 %

Procedure:
Ethylenediamine (1.0 g, 16.7 mmol) is dissolved in water (3.0 mL) containing bromoaresal green as an indicator. Methane sulfonic acid (2.8 g, 31 mmol) in water (3.0 ml) was added until a blue to pale yellow color transition is just achieved. The solution was diluted with ethanol (8.0 mL) and vigorously stirred. To the mixture was added the solution of Cbz-Cl (2.8 g, 16.7 mmol) in dimethoxyethane (4 mL) and 50% w/v aqueous AcOK (10 mL) at 20° C. simultaneously to maintain the pale yellow-green color of the indicator. After the additions are complete the mixture was stirred (RT, 1 h) and concentrated at low temperature under vacuum to removed the volatiles. The residue was shaken with water (20 mL) and filtered. The filtrate was then washed with toluene (3×50 mL), basified with excess 40% aqueous NaOH and extracted with toluene (3×50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4 and evaporated to give benzyl 2-aminoethylcarbamate as an oil (1.65 g, 51%). Mass calculated for C10H14N2O2=194.23. found: [M−H]+=193.3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:14]=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[C:18]1[S:19][CH:20]=[CH:21][N:22]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[C@@H:14]([C:18]1[S:19][CH:20]=[CH:21][N:22]=1)[OH:15])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[Si](C)(C)c1nccs1
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@H](O)c1nccs1
Reaction time: 48 h
Yield: 4.6 %

Procedure:
To a solution of 10.8 g of t-butoxycarbonyl-L-leucinal in 40 of dichloromethane was added 9.4 g of 2-trimethylsilyl thiazole in 10 ml of dichloromethane. The reaction was allowed to stand for 48 hours, then was cooled in an ice bath and treated cautiously with 30 ml of 1M tetra-n-butylammonium fluoride in tetrahydrofuran. This mixture was refluxed for 1.5 hours and then concentrated to an oil. The oil was dissolved in 100 ml of ethyl acetate, washed with 50 ml each of 2N citric acid, 1M sodium bicarbonate and brine and dried. The solution was treated with activated carbon, filtered through a pad of hydrous magnesium silicate and concentrated to an oil. This oil was dissolved in 50 ml of 10% ethyl acetate in dichloromethane and chromatographed on two columns in the same solvent. Refractive index was monitored at S 20, 250 ml/minute. The main peak in hold-back volumes 6-10 was cut into 1 liter portions which were separately evaporated. The first three of these all crystallized and the solids were recrystallized form isopropyl ether and hexane, giving 0.7 g of (S)2-(t-butoxycarbonyl)amino-4-methyl-(S)1-(2-thiazolyl)pentan-1-ol as crystals, mp 121°-122° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9].[NH3:12]>>[O:10]=[C:5]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][C:3]([NH2:12])=[O:2]
Reactant: N
Reactant: CCCCC(=O)CC(=O)OC
Product: CCCCC(=O)CC(N)=O
Temperature: 90 °C

Procedure:
0.4 mol (63.7 ml) 3-oxo-heptanoic acid methylester and 400 ml 7 N ammonia solution was stirred for three hours at 100° C. in a pressure reactor. After cooling off, the solvents were distilled off on a rotavap, the raw products were taken up in 200 ml water and 40 ml ethanol and set to about pH 3 with 40 ml 32% HCl. The reaction mixture was heated to 90° C. for 4 hours and then again concentrated to dryness in the rotavap, taken up in 600 ml dichloromethane and washed 3 times with 100 ml water. The organic phase was distilled off and the raw product recrystallized from 100 ml toluene. The product was filtrated off and dried in a vacuum drying cabinet at 50° C. 3.5 g of the title compound was obtained.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:21][C:22](=[O:37])[NH:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:25]=1[OH:36])[C:17]([O:19][CH3:20])=[O:18])=O)C1C=CC=CC=1.CO.[ClH:40]>[C].[Pd].CCCCCC>[ClH:40].[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:21][C:22](=[O:37])[NH:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([C:32]([CH3:33])([CH3:34])[CH3:35])[C:25]=1[OH:36])[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)Nc1cc(OC)cc(C(C)(C)C)c1O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)[C@H](CCCCN)NC(=O)Nc1cc(OC)cc(C(C)(C)C)c1O
Reaction time: 1 h
Yield: 85 %

Procedure:
To a mixed solution comprising 1 g of 2-[3-((1S)-5-benzyloxycarbonylamino-1-methoxycarbonylpentyl)ureido]-4-methoxy-6-tert-butylphenol and 30 ml of methanol were added 0.5 ml of conc. hydrochloric acid and 200 mg of 10% palladium-carbon (Pd-C). The mixture was subjected to catalytic reduction at normal temperature under normal pressure for one hour. After removing the catalyst, the filtrate was condensed. Hexane was added to the residue to give 685 mg of 2-[3-((1S)-5-amino-1-methoxycarbonylpentyl)ureido]-4-methoxy-6-tert-butylphenol hydrochloride (yield: 85%, state: yellow powder, IR: 3300 (br), 1725, 1650, 1560 cm-1).
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][CH3:6])[CH2:3]O.[OH-].[Na+].[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C1(C)C=CC=CC=1>[C:9]1([S:15]([N:1]2[CH2:3][C@H:2]2[CH2:5][CH3:6])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC[C@@H](N)CO
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC[C@@H]1CN1S(=O)(=O)c1ccccc1
Temperature: 62 °C
Yield: 70.7 %

Procedure:
Four grams of 2-(R)-aminobutanol and 7.2 grams of NaOH are suspended in toluene in a round bottom flask at ambient temperature. Benzenesulfonyl chloride (16.7 g) is added with agitation in one portion. The resulting white suspension is heated at 62° C. for 6 hours. Water (90 mL) is added and the layers are separated. The organic layer is washed with 70 ml of water, dried over magnesium sulfate and concentrated to provide 1-benzenesulfonyl-2(R)-ethylaziridine (6.7 g) as a colorless oil which is purified by flash chromatography over silica gel. MS: m/z (E1, 70EV) 212 (20%)
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([O:7][C:8]2[C:9]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:10][C:11]([C:18]([OH:20])=[O:19])=[CH:12][C:13]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[CH:5][CH:6]=1.Cl[CH2:27][C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29].C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O>[NH2:17][S:14]([C:13]1[CH:12]=[C:11]([CH:10]=[C:9]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:8]=1[O:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:18]([O:20][CH2:27][C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[O:19])(=[O:16])=[O:15]
Reactant: CCN(CC)C(=O)CCl
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)COC(=O)c1cc(N2CCCC2)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
In a similar manner to Example 6, piretanide can be reacted with 2-chloro-N,N-diethylacetamide, triethylamine and sodium iodide in dimethylformamide (DMF) to yield N,N-diethylaminocarbonylmethyl 3-aminosulfonyl-4-phenoxy-5-(1-pyrrolidinyl)benzoate.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.Br.[C:22]([NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][NH:31][CH2:30]2)(=[O:24])[CH3:23].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:22]([NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][N:31]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:30]2)(=[O:24])[CH3:23]
Reactant: CC(=O)NCc1ccc2c(c1)CNC2
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn4c3c1OCC4C)C2
Yield: 56.4 %

Procedure:
422 mg of 9,10-difluoro-2,3-dihydro-3methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 490 mg of 5-acetamidomethylisoindoline hydrobromide, 795 mg of DBU, and 3 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 382 mg of 10-(5-acetamidomethyl-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[CH:12]1(B(O)O)[CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:12]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[N:7][CH:6]=[CH:5]3)[CH2:14][CH2:13]1
Reactant: OB(O)C1CC1
Reactant: Brc1ccc2cnccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: c1cc2cc(C3CC3)ccc2cn1
Temperature: 110 °C
Reaction time: 10 h

Procedure:
To a degassed solution of 6-bromoisoquinoline (0.9 g, 0.004 mol) in 1,4-dioxane (15 mL) was added cyclopropylboronic acid (0.560 g, 0.007 mol) followed by the addition of degassed aqueous solution of K2CO3 (3.1 g, 0.02 mol) and PdCl2(dppf) (0.190 g, 0.002 mol). The resulting reaction mixture was stirred at 110° C. for 10 h. After completion, the reaction mixture was filtered over Celite® (diatomaceous earth) and the filtrate was concentrated at reduced pressure to obtain crude 6-cyclopropylisoquinoline. Purification was done by silica gel column chromatography eluting with EtOAc in hexanes (10-30%) to afford pure 6-cyclopropyl-isoquinoline (0.500 g, 68%) as yellow liquid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C:13]2[S:14][CH:15]=[CH:16][C:17]=2[NH:18][C:19](=O)OC(C)(C)C)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[CH3:19][NH:18][C:17]1[CH:16]=[CH:15][S:14][C:13]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ccsc1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1ccsc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of LAH in THF was added a solution of tert-butyl (2-phenyl-3-thienyl)carbamate in THF, followed by stirring at room temperature for 30 minutes and the stirring at 70° C. for 4 hours. After cooling at room temperature, Na2SO4.10H2O was added thereto, followed by stirring at room temperature for 30 minutes. The reaction mixture was filtered and concentrated under reduced pressure to obtain 3-methylamino-2-phenylthiophene as a colorless oily substance.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:24][CH3:25])=[CH:12][C:13]2[O:18][C:17](=[O:19])[CH:16]=[C:15]([CH2:20][CH2:21][CH3:22])[C:14]=2[CH:23]=1)(=O)=O.[C:26]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC(OC)(C)C.C([O-])(=O)/C=C/C([O-])=O>CO.CC(C)=O>[CH3:25][O:24][C:11]1[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:35]2[CH2:36][CH2:37][CH:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:33][CH2:34]2)=[CH:23][C:14]2[C:15]([CH2:20][CH2:21][CH3:22])=[CH:16][C:17](=[O:19])[O:18][C:13]=2[CH:12]=1
Reactant: CCCc1cc(=O)oc2cc(OC)c(OCCCOS(C)(=O)=O)cc12
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CO
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: CCCc1cc(=O)oc2cc(OC)c(OCCCN3CCC(c4ccccc4)CC3)cc12
Yield: 54 %

Procedure:
Method A (20 h at 60° C.); starting materials: 6-[3-(methanesulfonyloxy)propoxy]-7-methoxy-4-propyl-2H-1-benzopyran-2-one (example 76) and 4-phenylpiperidine; yield 54%; fusion point 101°-102° C. (from TBME and petroleum ether). Fumarate: method E; yield 62%; fusion point 191°-194° C. (from acetone and methanol).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[N+:9]([C:12]1[S:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1)([O-:11])=[O:10].C(O)(C(F)(F)F)=O>C(O)(C)C>[N+:9]([C:12]1[S:16][C:15]([CH:17]=[N:1][C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7]#[N:8])=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: N#Cc1ccsc1N
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: N#Cc1ccsc1N=Cc1ccc([N+](=O)[O-])s1
Yield: 70.7 %

Procedure:
2-Amino-thiophene-3-carbonitrile (30 mg) and 5-nitro-thiophene-2-carboxaldehyde (41 mg) were mixed in isopropanol with TFA and refluxed for 28 hours. The reaction was then purified by flash chromatography, resulting in 45 mg (71%) of the title compound as an orange powder. M.p.: 192°-194° C. 1H-NMR (300 MHz, [D]acetone): δ=8.98 (s, 1H), 8.12 (d, 1H, 3J=4.3 Hz), 7.85 (d, 1H, 3J=4.3 Hz), 7.61 (d, 1H, 3J=5.7 Hz), 7.38 (d, 1H, 3J=5.7 Hz). 13C-NMR (300 MHz, [D] acetone): δ=161.2, 154.3, 147.3, 133.7, 130.0, 128.6, 125.9, 125.1, 109.5, 108.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH:12]([O:16][CH3:17])[C:13]([OH:15])=O.[NH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>>[C:19]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:13](=[O:15])[CH:12]([C:3]2[CH:4]=[C:5]([O:10][CH3:11])[C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[O:16][CH3:17])=[CH:22][CH:21]=1)#[N:18]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COc1cc(F)c(C(OC)C(=O)O)cc1OC
Product: COc1cc(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2)cc1OC

Procedure:
(RS)-(2-Fluoro-4,5-dimethoxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-4,5-dimethoxy-phenyl)-2-methoxy-acetamide. Red foam. MS 359.2 ([M+H]+)
Reaction SMILES: [NH2:1]/[C:2](=[N:20]\[O:21][C:22]([C@H:24]([CH2:33][CH2:34][CH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=O)/[CH:3]1[CH2:6][N:5]([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4]1>C1(C)C=CC=CC=1>[CH:7]([N:5]1[CH2:6][CH:3]([C:2]2[N:1]=[C:22]([C@H:24]([CH2:33][CH2:34][CH2:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:25][C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[O:21][N:20]=2)[CH2:4]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O/N=C(\N)C1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C2CN(C(c3ccccc3)c3ccccc3)C2)no1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A solution of tert-butyl (3R)-3-[({[(Z)-amino(1-benzhydryl-3-azetidinyl)methylidene]amino}oxy)carbonyl]-6-cyclohexylhexanoate (preparation 35) (2.85 g, 5.07 mmol) in toluene (90 ml) was heated at 140° C. under Dean and Stark conditions for 18 hours. The reaction mixture was allowed to cool to room temperature. The solvent was removed under reduced pressure. The residue was purified on a silica column eluting with a solvent gradient of cyclohexane:Et2O (90:10) gradually changing to (60:40) to afford the title compound as a colourless oil (2.0 g, 73%).
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[C:4]([CH:6]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:15][C:14]=2[F:27])[CH2:9][CH2:8]1)=[O:5])[CH3:2].[H-].[Na+].[CH3:38]I>CN(C=O)C.O>[CH2:34]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[N:7]1[CH2:8][CH2:9][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:38])[C:20](=[O:26])[CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:15][C:14]=2[F:27])[CH2:11][CH2:12]1)=[O:5])[CH3:35]
Reactant: CI
Reactant: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)N(CC)CC)c3ccccc3)CC2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)C(=O)N(C)c1ccc(N2CCN(C(C(=O)N(CC)CC)c3ccccc3)CC2)c(F)c1
Reaction time: 0.17 h
Yield: 50.3 %

Procedure:
A solution of N-{4-[4-(diethylcarbamoyl-phenyl-methyl)-piperazin-1-yl]-3-fluoro-phenyl}-2-ethyl-butyramide (48 mg, 0.10 mmol) in DMF (2 mL) was treated with NaH (60% in mineral oil; 5 mg, 0.12 mmol). After 10 min, MeI (7 μL, 0.12 mmol) was added. After 3 h, the mixture was diluted with water and extracted with DCM. The organic layer was concentrated to give an oil, which was purified by PTLC to give an off white solid (25 mg, 50%). MS (ESI): mass calcd. for C29H41FN4O2, 496.96. m/z found, 497.5 [M+H]+. 1H NMR (CDCl3): 7.49-7.46 (m, 2H), 7.40-7.32 (m, 3H), 6.93-6.89 (m, 1H), 6.87-6.81 (m, 2H), 4.37 (s, 1H), 3.51-3.47 (m, 1H), 3.45-3.40 (m, 1H), 3.33-3.25 (m, 1H), 3.24 (s, 3H), 3.19-3.16 (m, 5H), 2.75-2.70 (m, 4H), 2.23-2.19 (m, 1H), 1.63-1.56 (m, 2H), 1.41-1.33 (m, 2H), 1.12-1.05 (m, 6H), 0.81 (t, J=7.4, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][C@H:14]1[CH2:19][C:18](OCC)([O:20]CC)[CH2:17][CH2:16][N:15]1[C@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27])[CH2:8]2.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][C@H:14]1[CH2:19][C:18](=[O:20])[CH2:17][CH2:16][N:15]1[C@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27])[CH2:8]2
Reactant: CCOC1(OCC)CCN([C@@H](C)c2ccccc2)[C@@H](CN2Cc3cccc(OC)c3C2=O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1C(=O)N(C[C@H]1CC(=O)CCN1[C@@H](C)c1ccccc1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
2-(R)-(7-Methoxy-2,3-dihydro-isoindol-1-one-2-ylmethyl)-4,4-diethoxy-1 (1-(S)-phenyl-ethyl)-piperidine (2.0 g, 4.4 mmol) was dissolved in a ice cold mixture of trifluoroacetic acid and water (10 ml, 9:1) and stirred or 0.5 hour on an ice bath. The reaction mixture was poured on aqueous sodium carbonate (100 ml) and extracted with dichloromethane (2×50 ml). The organic phase was dried (MgSO4), filtered and evaporated in vacuo, affording 1.67 g (100%) of 2-(R)-(7-methoxy-2,3-dihydro-isoindol-1-one-2-ylmethyl)-4-oxo-1 (1-(S)-phenyl-ethyl)-piperidine.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][CH2:4][N:3]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2]1.[H-].[Na+].Cl[CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27]>CN(C=O)C>[CH3:29][N:28]([CH3:30])[C:26](=[O:27])[CH2:25][N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH2:1][CH2:2][N:3]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4][CH2:5][C:6]1=2
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccccc3c2CC1
Reactant: CN(C)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
tert-Butyl 1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.100 g, 0.349 mmol) was dissolved in DMF (1.0 mL) under N2 at rt. NaH (0.0450 g, 1.13 mmol, 3.22 equiv., 60% dispersion) was added and the mixture was stirred at rt for 30 min. 2-Chloro-N,N-dimethylacetamide (86 μL, 0.102 g, 0.838 mmol, 2.4 equiv.) was added, and the reaction mixture was stirred at rt for 24 h. The reaction mixture was poured over ice, then extracted with EtOAc (2×). The organic extracts was washed first with water, then with brine and dried over MgSO4. The organic extracts was filtered and concentrated to yield a crude product (0.148 g). The crude product was chromatographed (SiO2 18 g, eluted with 3:1 toluene:acetone) to give tert-butyl 6-[2-(dimethylamino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.116 g) in 90% yield. 1H NMR (300 MHz, CDCl3) δ 1.50, 2.87-2.95, 3.01, 3.00-3.07, 3.13, 3.68-3.80, 4.85, 7.07-7.19, 7.47-7.51; MS (ESI+) for C21H29N3O3 m/z 372.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[NH:9][C:10](=[O:25])[C:11]([NH:14]C(OCC1C=CC=CC=1)=O)([CH3:13])[CH3:12]>CO.[Pd]>[CH3:1][C:2]1([CH3:26])[CH2:6][CH2:5][C:4]([CH3:7])([CH3:8])[CH:3]1[NH:9][C:10](=[O:25])[C:11]([NH2:14])([CH3:13])[CH3:12]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)NC1C(C)(C)CCC1(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(N)C(=O)NC1C(C)(C)CCC1(C)C

Procedure:
N-Cbz-2-aminoisobutyric acid 2,2,5,5-tetramethylcyclopentyl amide is dissolved in CH3OH and is hydrogenated over 5% Pd/C in a Parr hydrogenation apparatus. When the reaction is complete the mixture is filtered through Celite and concentrated to yield 2-aminoisobutyric acid 2,2,5,5-tetramethylcyclopentyl amide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].C[C:14]([N:16](C)C)=O>>[CH:5]([C:4]1[CH:3]=[C:2]([C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=1)[C:14]#[N:16])=[O:6]
Reactant: COc1cc(C=O)cc(Br)c1O
Reactant: CC(=O)N(C)C
Product: COc1cc(C=O)cc(C#N)c1O

Procedure:
A mixture of 23.1 g of 3-bromo-4-hydroxy-5-methoxy benzaldehyde, 9.3 g of cuprous cyanide and 140 ml of dimethyl acetamide (DMA) was refluxed for 2 hours with stirring. After cooling, the mixture was poured over ice and extracted with an ethyl acetate-methanol mixture (90-10). The organic phase was washed and dried and the solvents were eliminated to obtain 18 g of crude product, which was used as is for the following step. It melted at 180° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][C:11]([O:19][CH2:20][C:21]#[CH:22])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CO.O.[OH-].[Na+]>CCOCC>[Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([O:19][CH2:20][C:21]#[CH:22])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C#CCOc1cc(C(=O)OCC)n(-c2ncc(Cl)cc2Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: C#CCOc1cc(C(=O)O)n(-c2ncc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a 100 mL flask, ethyl 1-(3,5-dichloropyridin-2-yl)-3-(prop-2-ynyloxy)-1H-pyrazole-5-carboxylate (0.3 g, 0.88 mmol), methanol (10 mL), water (10 mL) and sodium hydroxide (0.04 g, 0.88 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. When reacted completely, water (40 mL) was added. The water (40 mL), ether (50 mL) were added and partitioned, acidified with concentrated hydrochloric acid to pH of 4, extracted with ethyl acetate (150 mL). The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and concentrated at reduced pressure to give the product (0.27 g) as slight yellow solid in 73% yield. Melting point: 151-157° C.