Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH3:12])([CH3:11])[CH:8](Cl)[CH3:9])=[CH:3][CH:2]=1.[K].[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1.CO>CN(C)C=O.O.ClCCl>[C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH3:12])([CH3:11])[CH:8]([N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH3:9])=[CH:3][CH:2]=1
Reactant: CC(Cl)[Si](C)(C)c1ccc(-c2ccccc2)cc1
Reactant: c1nc[nH]n1
Agent: [K]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CC(n1cncn1)[Si](C)(C)c1ccc(-c2ccccc2)cc1
Reaction time: 64 h
Yield: 13.1 %

Procedure:
A mixture of 2.50 g (7.46 mmol) of 82% pure (1,1'-biphenyl-4-yl)dimethyl-1-chloroethylsilane and 1.60 g (15 mmol) of 1H-1,2,4-triazole potassium salt in 15 ml of dimethylformamide was stirred at 50° for 64 hours, cooled, diluted with water, and extracted with ether. The ether extracts were washed with water and brine, dried over magnesium sulfate, and evaporated to leave a viscous oil. Chromatography over silica gel eluting with 2% methanol in dichloromethane gave 0.30 g (13%) of the title compound as a pale yellow oil: nmr (CDCl3) 0.38 and 0.42 (total 6H, two equal s), 1.6 (3H, d, J=7 Hz), 4.2 (1H, q, J=7 Hz), 7.3-7.8 (9H, m), 7.9 (1H, s) and 8.0 (1H, s).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([CH2:40][C:41](O)=O)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17]2[N:18]=[C:41]([CH2:40][N:37]3[CH2:38][CH2:39][N:34]([C:32]([O:31][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:33])[CH2:35][CH2:36]3)[O:20][N:19]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)O)CC1
Product: CON=C1C[C@@H](c2noc(CN3CCN(C(=O)OC(C)(C)C)CC3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 75 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and [4-(tert-butoxycarbonyl)-1-piperazinyl]acetic acid, the title compound, tert-butyl 4-({3-[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]-1,2,4-oxadiazol-5-yl}methyl)-1-piperazinecarboxylate, was obtained in 75% yield (88% purity by HPLC).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>>[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[O:1][CH2:2][CH2:3][CH2:4]2)=[O:17]
Reactant: c1ccc2c(c1)CCCO2
Reactant: O=C(Cl)CCCCCl
Product: O=C(CCCCCl)c1ccc2c(c1)CCCO2

Procedure:
Using chroman (5.40 g) and 5-chlorovaleryl chloride (6.82 g) according to the same method as that of Reference Example 1, the title compound was obtained as a fine yellow oil (7.9 g).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([OH:14])(=[O:13])[CH:11]=[CH2:12]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([CH:12]=[CH:11][C:10]([OH:14])=[O:13])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Br)cc1
Reactant: C=CC(=O)O
Product: N#Cc1ccc(C=CC(=O)O)cc1
Yield: 78.6 %

Procedure:
A Heck reaction of 4-bromobenzonitrile and acrylic acid gave 4-cyanocinnamic acid. The acid was reduced to the corresponding alcohol with ethyl chloroformate and then sodium borohydride. Yield 78.6%
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[N:4]([CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[N:3]=1.[Cl-].[NH4+]>C(O)C.[Fe]>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[N:4]([CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)c(Cl)nn2CCN1CCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccc2c(c1)c(Cl)nn2CCN1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.9 %

Procedure:
A mixture of 3-Chloro-5-nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole (0.40 g, 1.4 mmol), iron powder (0.76 g, 14 mmol), and ammonium chloride (37 mg, 0.68 mmol) in 80% ethanol was heated to reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was stirred in triethylamine/ethyl acetate (1/4, 20 mL) for 15 minutes, filtered through a plug of silica gel, which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure to provide the title compound (0.30 g, 84%). 1H NMR (300 MHz, DMSO-d6) ppm 1.62 (m, 4H), 2.44 (m, 4H), 2.81 (t, J=6.44, 2H), 4.34 (t, J=6.44, 2H), 5.05 (s, 2H), 6.58 (m, 1H), 6.88 (m, 1H), 7.12 (m, 1H); MS (DCI/NH3) m/z 265 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][CH2:8][CH:9]1[O:15][CH:14]2[N:11]([C:12](=[O:16])[CH2:13]2)[CH2:10]1)=[O:6])=[N+:2]=[N-:3].[CH3:17][C:18](C)=O>>[N:1]1([CH2:4][C:5]([NH:7][CH2:8][CH:9]2[O:15][CH:14]3[N:11]([C:12](=[O:16])[CH2:13]3)[CH2:10]2)=[O:6])[CH:18]=[CH:17][N:3]=[N:2]1
Reactant: [N-]=[N+]=NCC(=O)NCC1CN2C(=O)CC2O1
Reactant: CC(C)=O
Product: O=C(Cn1ccnn1)NCC1CN2C(=O)CC2O1
Temperature: 65 °C
Yield: 69 %

Procedure:
150 mg of (3RS,5RS)-3-[N-(Azidoacetyl)aminomethyl]-4-oxa-1-azabicyclo[3.2.0]heptan-7-one was dissolved in 10 ml of Acetone and Acetylene was bubbled at -78° C. for 5 minutes. The reaction mixture was heated at 60-70° C. in seal tube for 17 hrs. After reaction completed, solvent was removed in vacuo and the residue was purified by silicagel column chromatography (Ethyl acetate+Acetone 3:1). The title compound was obtained as oil.
Reaction SMILES: Cl.[S:2]1[C:6]([C:7]2([N:17]([CH3:19])[CH3:18])[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)=[CH:5][C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]1=2.Cl.CNC.Cl>O>[S:2]1[C:6]([C:7]2([N:17]([CH3:18])[CH3:19])[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]2)=[CH:5][C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]1=2
Reactant: CN(C)C1(c2cc3ccccc3s2)CCC2(CC1)OCCO2
Agent: CNC
Agent: Cl
Solvent: O
Product: CN(C)C1(c2cc3ccccc3s2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The 8-benzo[b]thiophen-2-yl-1,4-dioxa-spiro[4.5]dec-8-yl)-dimethylamine hydrochloride (0.60 g, 1.7 mmole) was dissolved in water (0.8 ml), conc. hydrochloric acid (1.04 ml, 151 mmole) was added, and the mixture was stirred for 3 days at room temperature. After completion of the hydrolysis the reaction mixture was extracted with diethyl ether (2×25 ml) and the aqueous phase was made alkaline with 5N sodium hydroxide solution, extracted with dichloromethane (3×25 ml), dried over sodium sulfate and concentrated by evaporation in vacuo.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:16])[C:4]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([OH:9])=O.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[Cl:1][C:2]1[N:3]([CH3:16])[C:4]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])=[O:9]
Reactant: Cn1nccc1-c1cc(C(=O)O)c(Cl)n1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c(Cl)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of 2-chloro-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxylic acid (0.116 g, 0.48 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (0.186 g, 0.48 mmol)[prepared according to Preparation 5] and N,N-diisopropylethylamine (0.42 ml, 2.42 mmol) in dichloromethane (2.49 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (0.25 g, 0.53 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 2-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxamide (250 mg, 0.38 mmol, 78% yield) as a clear oil: LCMS (ES) m/e 570, 572 (M, M+2)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([NH2:34])=[CH:31][CH:32]=2)[CH:27]=[N:26]1>CCCCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:34][C:30]4[CH:29]=[C:28]5[C:33](=[CH:32][CH:31]=4)[N:25]([CH3:24])[N:26]=[CH:27]5)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ncc2cc(N)ccc21
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Solvent: CCCCO
Product: Cn1ncc2cc(Nc3ncnc4[nH]c(C5=CCN(C(=O)OC(C)(C)C)CC5)cc34)ccc21
Temperature: 120 °C
Reaction time: 15 h

Procedure:
A suspension of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (638.1 mg, 1.906 mmol, 1 eq) and 1-methyl-1H-indazol-5-ylamine (567.4 mg, 3.855 mmol, 2 eq) in n-BuOH (26 mL) was stirred at 120° C. for 15 h. A white precipitate was filtered off, washed several times with MeOH, and dried under high vacuum, giving the title compound, as a white solid. The filtrate was adsorbed onto Hydromatrix, dry loaded, and purified by chromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with MeOH:DCM 2%→4%→6%]. Fractions containing product were combined and concentrated in vacuo, affording a second batch of the title compound, as a brown solid. 1H NMR (400 MHz, DMSOd6): δ=1.44 (s, 9H), 2.43-2.53 (m, 2H), 3.57 (t, J=5.6 Hz, 2H), 4.03 (s, 5H), 6.38 (s, br, 1H), 6.76 (s, br, 1H), 8.60 (d, J=8.8 Hz, 1H), 7.69 (dd, J=8.8, 2.0 Hz, 1H), 8.01 (d, J=0.8 Hz, 1H), 8.26 (s, 1H), 8.39 (d, J=1.6 Hz, 1H), 9.34 (s, —NH), 11.91 (d, J=2.0 Hz, —NH). MS (ES+): m/z 446.07 (100) [MH+]. HPLC: tR=2.59 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>CO.[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][C:2]([CH3:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)ccc1C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-methyl-5-nitrobenzoate (60 g, 307 mmol) in MeOH (600 mL) was added Pd (10 wt % on carbon) (1.6 g). The reaction was shaken under hydrogen (30-50 psi) for 1 h, filtered through a celite pad and concentrated to afford the desired product as a red paste, which was used in the next step without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH:24]4[CH2:26][CH2:25]4)=[CH:22][C:21]([CH:27]4[CH2:29][CH2:28]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:30][N:31]1[CH2:35][CH2:34][NH:33][C:32]1=[O:36]>>[CH:24]1([C:23]2[C:18]([N:15]3[CH2:16][CH2:17][N:12]([C:10]([C:5]4[CH:4]=[CH:3][C:2]([N:33]5[CH2:34][CH2:35][N:31]([CH3:30])[C:32]5=[O:36])=[CH:9][C:6]=4[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]3)=[N:19][CH:20]=[C:21]([CH:27]3[CH2:29][CH2:28]3)[CH:22]=2)[CH2:26][CH2:25]1
Reactant: N#Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: CN1CCNC1=O
Product: CN1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C4CC4)CC3)c(C#N)c2)C1=O
Yield: 80.2 %

Procedure:
Using 5-bromo-2-[4-(3,5-dicyclopropylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (451 mg) described in Preparation Example 245 and 1-methylimidazolidin-2-one (120 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (377 mg) was obtained.
Reaction SMILES: [ClH:1].[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[NH:12][CH:13]=[CH:14][N:15]=1.[CH2:16](Br)[CH3:17]>>[ClH:1].[CH2:16]([N:15]1[CH:14]=[CH:13][N:12]=[C:11]1[C:3]1[O:2][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=1)[CH3:17]
Reactant: c1ccc2oc(-c3ncc[nH]3)cc2c1
Reactant: CCBr
Agent: Cl
Product: CCn1ccnc1-c1cc2ccccc2o1

Procedure:
This was prepared from 2-(benzofuran-2-yl)imidazole hydrochloride and ethyl bromide according to the procedure of example 2; m.p.=183°-185° C.
Reaction SMILES: [CH:1]([C@H:14]1[CH2:20][C@H:19]2[C@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>C(O)C>[CH:1]([C@H:14]1[CH2:20][C@H:19]([OH:18])[C@@H:17]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)[C@H]2C[C@@H]3O[C@@H]3CO2)cc1
Reactant: NCc1ccc(F)cc1
Solvent: CCO
Product: O[C@H]1C[C@H](C(c2ccccc2)c2ccccc2)OC[C@@H]1NCc1ccc(F)cc1

Procedure:
(1R, 4R, 6S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane, 28c, (0.02 g, 0.075 mmol) was reacted with para-fluoro-benzylamine (0.19 g, 1.50 mmol) in ethanol (Procedure E) to yield (2R, 4S, 5S)-2-benzhydryl-5-(4-fluoro-benzylamino)-tetrahydropyran-4-ol, (+)-29b, 0.028 g (94%, [α]D-(+)77.6, c=1, MeOH).
Reaction SMILES: NC1C([Cl:12])=CC=CC=1C(OC)=O.[CH:13]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][CH:22]([N:26]([C:42](=[O:44])[CH3:43])[CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[C:21]2[CH:45]=[CH:46][CH:47]=[CH:48][C:20]1=2)=[O:18])([CH3:15])[CH3:14]>>[C:42]([N:26]([CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[C:30]([C:38]([F:39])([F:40])[F:41])[CH:29]=1)[CH:22]1[CH2:23][CH2:24][CH2:25][N:19]([C:17]([O:16][CH:13]([CH3:15])[CH3:14])=[O:18])[C:20]2[C:48]([Cl:12])=[CH:47][CH:46]=[CH:45][C:21]1=2)(=[O:44])[CH3:43]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccccc21
Reactant: COC(=O)c1cccc(Cl)c1N
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(Cl)cccc21

Procedure:
This compound was prepared utilizing the same methodology described in Example 1 wherein replacement of 2-amino-benzoic acid methyl ester with methyl 2-amino-3-chlorobenzoate following the procedure of Example 1, Steps 1-8 for the synthesis of 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid isopropyl ester. CI MS 551 (M+H).
Reaction SMILES: [C:1]([N:8]1[C@@H:13]([C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:20])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C(O)C.[Pd]>[C:1]([N:8]1[C@@H:13]([C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:20])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C=CCCC(=O)[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCCCC(=O)[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Yield: 94.8 %

Procedure:
A solution of trans-N-Boc-2-methyl-6-(ethenyl propionyl)piperidine (2.0 g, 6.70 mmol) in 3 mL of ethanol was shaken under 58 psi of H2 pressure over 0.65 g Pd/C catalyst overnight, and then the mixture was filtered through Celite and concentrated to give 1.8 g (90%) of the product which was homogeneous by TLC analysis. 1H NMR (250 MHz) δ4.16-4.08 (q, 2 H), 3.93-3.83 (m, 2 H), 2.36-2.28 (t, 2 H), 2.04-1.08 (m, 20 H); 13C NMR (62.7 MHz) 155.4 (s), 79.1 (s), 60.3 (s), 51.0 (s), 47.2 (s), 31.9 (s), 29.6 (s), 28.5 (s), 26.9 (s), 25.8 (s), 24.2 (s), 20.5 (s), 14.2 (s), ppm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:9]=1)[C:7]#[N:8].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[Sn](CCCC)(CCCC)CCCC>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: N#Cc1cc(O)ccc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1cc(O)ccc1-c1ccco1
Temperature: 100 °C

Procedure:
5-Hydroxy-2-iodo-benzonitrile (200 mg, 0.82 mmol) and PdCl2(PPh3)2 (20 mg, 0.028 mmol) and 2-furyltributyltin (400 g, 1.12 mmol) in N,N-dimethylformamide (5 mL) is degassed and heated at 100° C. for 15 min. After the mixture cooled to room temperature, an aqueous work up is performed and the product is isolated from chromatography (100 mg, 66%). MS (ESI): 184 (M−1)−1.
Reaction SMILES: [I:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([I:10])[CH:5]=[C:4]([I:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18](O)=[O:19])=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=1.S(Cl)([Cl:26])=O>>[I:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([I:10])[CH:5]=[C:4]([I:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([Cl:26])=[O:19])=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: CCc1c(I)cc(I)c(-c2ccc(C(=O)O)c([N+](=O)[O-])c2)c1I
Product: CCc1c(I)cc(I)c(-c2ccc(C(=O)Cl)c([N+](=O)[O-])c2)c1I

Procedure:
2′,4′,6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carboxylic acid (13) is reacted with thionyl chloride to yield 2′,4′,6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carbonyl chloride (14).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](OCC)=O)=[CH:5][CH:4]=1.[Br:15][C:16]1[CH:21]=C[C:19]([C:22]#[N:23])=[C:18](F)[CH:17]=1.CC(C)([O-])C.[K+].[OH-].[Na+]>CN1CCCC1=O.CO>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[C:10]([CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH:21]=1
Reactant: CCOC(=O)Cc1ccc(OC)cc1
Reactant: N#Cc1ccc(Br)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CN1CCCC1=O
Product: COc1ccc(Cc2cc(Br)ccc2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 25 g of ethyl (4-methoxy-phenyl)-acetate, 27.4 g of 1-bromo-4-cyano-3-fluoro-benzene and 20 mL of N-methyl-pyrrolidin-2-one is slowly added to 31.4 g of potassium tert butoxide in 130 mL of N-methyl-pyrrolidin-2-one keeping the temperature below 10° C. After stirring for 1 hour at room temperature, 100 mL of methanol and 137 mL of 1 M aqueous sodium hydroxide are added and the mixture is stirred overnight at room temperature. The methanol fraction is evaporated, the residue is basified with 1 M aqueous sodium hydroxide and extracted with tert butyl-methyl ether. The aqueous phase is acidified with 4 M hydrochloric acid and extracted with ethyl acetate several times. The combined ethyl acetate extracts are evaporated and the residue together with 120 mL of N,N-dimethyl formamide and 24.9 g of potassium carbonate heated at 100° C. for 1 hour. The reaction mixture is diluted with aqueous sodium bicarbonate and extracted several times with ethyl acetate. The combined extracts are evaporated and the residue crystallized from methanol.
Reaction SMILES: [OH:1][CH:2]([CH2:26][CH3:27])[C:3](=[N:19][NH:20][C:21](OCC)=[O:22])[N:4]1[CH2:9][CH2:8][C:7]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:12][C:6]=2[CH2:5]1.[Na].Cl>CCO>[CH2:26]([CH:2]1[O:1][C:21](=[O:22])[NH:20][N:19]=[C:3]1[N:4]1[CH2:9][CH2:8][C:7]2[N:10]=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:12][C:6]=2[CH2:5]1)[CH3:27]
Reactant: CCOC(=O)NN=C(C(O)CC)N1CCc2nc(-c3ccccc3)oc2C1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCC1OC(=O)NN=C1N1CCc2nc(-c3ccccc3)oc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
330.00 mg (576 μmol) ethyl N′-[2-hydroxy-1-(2-phenyl-6,7-dihydro-4H-oxazolo[5,4-c]pyridin-5-yl) butylidene]-hydrazinecarboxylate are placed in 10 mL EtOH, a solution of 280.00 mg (12.17 mmol) sodium in 10 mL EtOH is added and the mixture is stirred overnight at RT. The reaction mixture is adjusted to pH 5-6 with ethanolic HCl and the solvent is eliminated in vacuo. The residue is extracted with EA and H2O, the organic phase is dried and the solvent is eliminated in vacuo. The residue is purified on silica gel. (Eluant: cyclohexane/EA).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:18][CH2:17][CH:16]([CH:19]3OCC(C)(C)C[O:20]3)[CH2:15][CH2:14]2)[CH2:9][CH2:8]1)[CH3:2]>C1(C)C=CC=CC=1.C(O)=O>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:14][CH2:15][CH:16]([CH:19]=[O:20])[CH2:17][CH2:18]2)[CH2:9][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)CCC1CCC(C2CCC(C3OCC(C)(C)CO3)CC2)CC1
Solvent: O=CO
Solvent: Cc1ccccc1
Product: CCOC(=O)CCC1CCC(C2CCC(C=O)CC2)CC1

Procedure:
A solution of 3-[4′-(5,5-Dimethyl-[1,3]dioxan-2-yl)-bicyclohexyl-4-yl]-propionic acid ethyl ester (17 g, 45 mmol) in toluene (200 ml) and formic acid (70 ml) is stirred overnight at 80° C. The solution is washed with water, dried (Na2SO4), concentrated and recrystallised to give 3-(4′-formyl-bicyclohexyl-4-yl)-propionic acid ethyl ester as colourless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[OH:17])=[O:5])[CH3:2].S(Cl)([Cl:21])(=O)=O.O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:17])[C:8]2[C:13]([C:14](=[O:16])[C:15]=1[Cl:21])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(O)c2ccccc2c1O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C1=C(Cl)C(=O)c2ccccc2C1=O
Reaction time: 1.5 h

Procedure:
23 g of compound (6) prepared above was suspended in 300 ml of chloroform and, while keeping the solution at 5°-10° C., 27.4 g of sulfuryl chloride was slowly dropwise added thereto. After reacting for 1.5 hours, water was added to the reaction solution to conduct separation and extraction. The organic phase was dried with anhydrous sodium sulfate, and chloroform was distilled off under reduced pressure. Rapid purification of the residue through silica gel column chromatography gave compound (7) as crystals. Yield: 8.8 g (33%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][CH3:11].[CH2:12]([O:14][C:15]1[C:16](=O)[C:17](=[O:22])[C:18]=1[O:19]CC)[CH3:13]>C(#N)C.C(OCC)(=O)C>[O:19]=[C:18]1[C:17](=[O:22])[C:16]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH2:10][CH3:11])=[C:15]1[O:14][CH2:12][CH3:13]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CCc1cc(C#N)ccc1N
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOc1c(Nc2ccc(C#N)cc2CC)c(=O)c1=O
Temperature: 150 °C
Yield: 34 %

Procedure:
4-Amino-3-ethylbenzonitrile (0.86 g, 5.88 mmol) and 3,4-diethoxy-3-cyclobutene-1,2-dione (1.0 g, 5.88 mmol) in acetonitrile (2 mL) was heated in an oil bath at 110° C. for 21 hours. 3,4-Diethoxy-3-cyclobutene-1,2-dione (0.5 g, 2.9 mmol) was added to the reaction mixture and the temperature of the oil bath increased to 150° C. After 48 hours the reaction mixture was cooled to room temperature, then diluted with ethyl acetate and filtered. The filtrate was concentrated and the resulting solid was taken up in ethyl acetate (5 mL) and sonicated. Filtration gave 0.54 g (34%) of 4-(3,4-dioxo-2-ethoxy-cyclobut-1-enylamino)-3-ethylbenzonitrile as a light brown solid: 1H NMR (DMSO-d6): δ 10.56 (br s, 1H), 7.70 (br s overlapping a doublet at δ 7.69, 2H), 7.30 (d, 1H), 4.71 (q, 2H), 2.74 (q, 2H), 1.37 (t, 3H), 1.15 (t, 3H).