Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][C@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@@H:7]1[OH:20])#[N:2].[CH3:23][NH:24][CH3:25]>>[C:1]([N:3]=[C:4]([N:24]([CH3:25])[CH3:23])[NH:5][C@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@@H:7]1[OH:20])#[N:2]
Reactant: CNC
Reactant: CSC(=NC#N)N[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O
Product: CN(C)C(=NC#N)N[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O

Procedure:
A mixture of (3R,4S)-4-(3-cyano-2-methyl-1-isothioureido)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (2.12 g) and 50% aqueous dimethylamine solution (10.6 ml) was stirred under reflux for 1.5 hours to form white precipitates. These precipitates were collected by filtration, washed with water, and recrystallized from ethanol to give (3R, 4S)-4 -(2-cyano-3,3-dimethylguanidino)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (1.03 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9]Br)([CH3:4])([CH3:3])[CH3:2].[CH2:12]([O:14][C:15](=[O:28])[CH2:16][CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=2)[CH2:18]1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:28])[CH2:16][CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:11])[CH:23]=2)[CH2:18]1)[CH3:13]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CCOC(=O)CC1CCc2cc(O)ccc2C1
Product: CCOC(=O)CC1CCc2cc(OCCNC(=O)OC(C)(C)C)ccc2C1

Procedure:
The title compound is prepared according to the procedure of Example 19 except that (2-bromo-ethyl)-carbamic acid tert-butyl ester is used in place of (3-bromo-propyl)-carbamic acid tert-butyl ester and (6-hydroxy-1,2,3,4-tetrahydro-napthalen-2-yl)-acetic acid ethyl ester is used in place of (7-hydroxy-1,2,3,4-tetrahydro-napthalen-2-yl)-acetic acid ethyl ester.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[N+:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32])([O-:23])=[O:22]>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:31]([NH:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N+:21]([O-:23])=[O:22])=[O:32])[C:3]1=[O:20]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)Nc2ccccc2[N+](=O)[O-])N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-nitrophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 260°-261° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[O:5][C:4](=O)[CH:3]=1.C([O-])(=O)C.[NH4+:17]>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[NH:17][C:4](=[O:5])[CH:3]=1
Reactant: Cc1cc(C(F)(F)F)oc(=O)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1cc(C(F)(F)F)[nH]c(=O)c1
Temperature: 120 °C

Procedure:
To a solution of crude 4-methyl-6-(trifluoromethyl)-2H-pyran-2-one (28.8 g, 162 mmol) in acetic acid (330 mL) was added ammonium acetate (25.0 g, 324 mmol). The reaction solution was heated at 120° C. over weekend. The solvent was removed in vacuo. The residue was diluted with ethyl acetate and washed with saturated NaHCO3 and brine, dried over Na2SC4, filtered and concentrated. The crude was purified with pad silica gel. The solvent was removed. The solid was washed with 10:1 hexanes/ethyl acetate to give the desired product as white solid. LCMS (M+H)+: 178.0.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:15]([CH3:16])=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2)(=O)=O.O.[I-:23].[Li+]>CN(C)C=O>[I:23][C:7]1[C:15]([CH3:16])=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2
Reactant: [I-]
Reactant: Cc1cc([N+](=O)[O-])c2c(c1OS(=O)(=O)C(F)(F)F)CCC2
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c2c(c1I)CCC2
Temperature: 150 °C
Reaction time: 7 h
Yield: 77.8 %

Procedure:
To a solution of 5-methyl-7-nitroindan-4-yl trifluoromethanesulfonate (3.02 g) in N,N-dimethylformamide (10 mL) was added lithium iodide mono hydrate (6.10 g). The mixture was stirred under an argon atmosphere at 150° C. for 7 hours. Adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a 1 mol/L aqueous solution of sodium hydroxide, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (2.19 g).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[O:4].Cl.[C:7]([OH:12])(=[O:11])[C:8]([CH3:10])=O>O>[C:3]([NH:2][N:1]=[C:8]([CH3:10])[C:7]([OH:12])=[O:11])(=[O:4])[NH2:5]
Reactant: NNC(N)=O
Reactant: CC(=O)C(=O)O
Agent: Cl
Solvent: O
Product: CC(=NNC(N)=O)C(=O)O

Procedure:
22.3 g of hydrochloric acid semicarbazide was dissolved in 100 ml of water, and 13.9 ml of pyruvic acid was added to the solution while stirring. Precipitated crystals were filtered out, washed, and dried to obtain 21 g of 2-carbamoylhydrazonopropionic acid having a melting point of 201° C. (decomposed).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:13][CH3:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:13]([C:4]1[S:3][C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)=[N:6][C:5]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1sc(Br)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1sc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1ccccc1
Yield: 42.2 %

Procedure:
A solution of 2-bromo-5-ethyl-4-phenyl-1,3-thiazole (4.00 g, 14.9 mmol), tert-butyl piperazine-1-carboxylate (8.33 g, 44.7 mmol) and potassium carbonate (2.06 g, 14.9 mmol) in dimethylformamide (50 ml) was stirred at 120° C. for 13 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the desired product (2.35 g, 42.2%) as an oil.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([NH:11][CH:12]1[C:34](=[O:35])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:16]([CH3:20])([CH3:19])[S:17](=[O:18])[C@H:13]12)(=[O:10])[CH3:9].[Cl:36]N1C(=O)CCC1=O>O>[CH3:19][C:16](=[CH2:20])[CH:15]([N:14]1[C:34](=[O:35])[CH:12]([NH:11][C:8](=[O:10])[CH3:9])[CH:13]1[S:17]([Cl:36])=[O:18])[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(C)(C)S(=O)[C@H]12
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(C)=O)C1S(=O)Cl

Procedure:
Toluene (500 ml.) was heated in equipment containing a Dean-Stark water trap to azeotropically remove any moisture which may be present. To the resulting dried toluene was added 1.0 gms. (2.4 mmol.) of p-nitrobenzyl 6-acetamido-2,2-dimethylpenam-3-carboxylate-1-oxide. The resulting mixture was refluxed again using a Dean-Stark water trap to remove any additional amounts of water which may be present. The mixture then was cooled, and 400 mg. (2.9 mmol) of N-chlorosuccinimide were added. The mixture then was refluxed for 1 hour. A sample of the reaction mixture was withdrawn, and the solvent was removed. The product which was obtain was consistent by nmr analysis with the structure of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][N:8]([C:17](=[O:25])[C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1.C(N(CC)CC)C.[CH3:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][N:8]([C:17]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:36](=[O:37])[C:35]4[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=4[CH3:33])=[CH:22][CH:23]=3)=[O:25])[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1
Reactant: Cc1ncc2c(n1)-c1ccccc1N(C(=O)c1ccc(N)cc1)CC2
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncc2c(n1)-c1ccccc1N(C(=O)c1ccc(NC(=O)c3ccccc3C)cc1)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 0.216 mg of 6,7-dihydro-2-methyl-7-(4-aminobenzoyl)-5H-pyrimido[5,4-d][1]benzazepine in 6 ml of methylene chloride under argon is added 100 μl of triethylamine followed by a solution of 94 μl of 2-methylbenzoyl chloride in 1.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours, washed with water, saturated NaHCO3 and the separated organic layer treated with activated carbon and filtered through MgSO4. The filtrate is evaporated to a residue which is dissolved in ethyl acetate and evaporated in vacuo to give 300 mg of the desired product as a pale yellow foam.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[S:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:25])([F:37])[F:38])[CH:28]=1)(=[O:35])=[O:34])=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCCN1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)[C@@H]1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To 4.0 g (15.64 mmol or millimoles) of (S)-piperidine-2-carboxylic acid benzyl ester hydrochloride and 3.15 g (31.28 mmol) of triethylamine in (200 ml) was added 4.21 g (17.20 mmol) of 3-trifluoromethylbenzenesulfonyl chloride. The mixture was stirred at room temperature for 1 hour. The reaction mixture was then washed with water, brine and dried (sodium sulfate). Chromatography on silica gel, eluting with dichloromethane provided 6.7 g (15.64 mmol) of (S)-1-(3-Trifluoromethyl-benzenesulfonyl)-piperidine-2-carboxylic acid benzyl ester. LCMS (M+H): m/z 428, retention time 3.9 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:10])=[C:4]([NH2:9])[C:5]([Br:8])=[CH:6][CH:7]=1.C(O)(=O)C.[C:15]1([C:21]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[C:4]2[C:3]=1[N:10]=[C:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[N:9]2
Reactant: Nc1c(Br)ccc(Br)c1N
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc(Br)c2nc(-c3ccccc3)c(-c3ccccc3)nc12
Yield: 86 %

Procedure:
Preparation procedure: 3,6-dibromo-o-phenylene diamine (1.0 g, 3.7 mmol) is added to an acetic acid (20 mL) solution of benzil (0.39 g, 1.84 mmol) at 120° C. The resulting solution is mixed homogeneously and reflux for 12 hours. The reaction solution is poured into water, neutralized with sodium bicarbonate, extracted with chloroform, washed with saturated brine water, and dried over anhydrous sodium sulfate. The solvents are removed using a rotary evaporator. The crude product is subjected to column chromatography to give a white solid, which is then recrystallized in chloroform/n-hexane to afford a white solid powder (yield 86%), MALDI-TOF-MS (m/z): 440.1 (M+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.Cl.[CH2:23]([NH2:26])[CH2:24][CH3:25]>CO.C(Cl)Cl>[C:16]1([S:15][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([CH2:1][NH:26][CH2:23][CH2:24][CH3:25])[CH:4]=3)[NH:8][C:7]=2[C:12]([NH2:14])=[O:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCN
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCNCc1ccc2[nH]c(C(N)=O)c(Sc3ccccc3)c2c1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (80 mg, 0.27 mmol) with propylamine hydrochloride (28 mg, 0.30 mmol) as described in General Procedure X to afford Iae (41.0 mg, 44.8%) as an ivory colored solid, tlc Rf=0.1 (10% MeOH/CH2Cl2-0.2% Et3N), m/z obs=340 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][N:16]([C:17]4[N:22]=[C:21]([N:23]5[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29]C(=O)OC(C)(C)C)[C:24]5=[O:37])[CH:20]=[CH:19][CH:18]=4)[C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:29][C@H:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([N:16]3[C:10]4[CH:9]=[C:8]([C:6]5[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=5)[N:13]=[CH:12][C:11]=4[CH:14]=[N:15]3)[N:22]=2)[C:24]1=[O:37]
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCC[C@H](NC(=O)OC(C)(C)C)C3=O)n2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCC[C@H](N)C3=O)n2)n1
Yield: 39.2 %

Procedure:
A solution of tert-butyl N-[(3S)-1-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-2-oxo-3-piperidyl]carbamate (140 mg, 0.280 mmol) in dichloromethane 4.0 ml and trifluoroacetic acid (0.80 ml, 10 mmol) was stirred at RT 3 h. The reaction was concentrated and diluted with water then extracted with EtOAc. The aqueous layer was basified with 1M NaOH to pH 10 then extracted with EtOAc. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum. The crude product was submitted for reverse phase HPLC to give 225 (44 mg, 39% yield). MS (ESI) m/z: 401.1. 1H NMR (400 MHz, DMSO) δ 9.60 (s, 1H), 9.47 (s, 1H), 9.33 (s, 1H), 8.72 (s, 1H), 8.64 (s, 1H), 8.05 (t, J=8.1 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.1 Hz, 1H), 4.46-4.33 (m, 1H), 4.14-4.02 (m, 1H), 3.58 (dd, J=10.8, 6.4 Hz, 1H), 2.65 (s, 3H), 2.24 (dt, J=11.4, 5.3 Hz, 1H), 2.19-2.00 (m, 2H), 1.77 (ddd, J=23.0, 10.6, 5.1 Hz, 1H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][C@H:26]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO.Cl>O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C@H:26]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: N[C@H](CCc1ccccc1)CC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1nc(C(=O)N[C@H](CCc2ccccc2)CC(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 130 °C
Yield: 43 %

Procedure:
1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (75 mg, 0.234 mmol) and 3-(R)-Amino-5-phenyl-pentanoic acid (193 mg, 1.0 mmol) were placed in a CEM 10 mL Microwave vessel and sodium methoxide-methanol solution (0.5 M; 2.0 mL, 1.0 mmol) was added via syringe. The vessel was sealed and heated to 130° C. in a CEM microwave apparatus for 4.5 hours. The reaction mixture was diluted with water and treated with 1N hydrochloric acid and extracted three times with ethyl acetate then dried over sodium sulfate. The crude product was purified by MPLC (methylene chloride-methanol) to provide the title compound as an off-white solid in 43% yield. MS ESI(−) m/e: 480.1305 (M−1).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH:13]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17].O.NN>C(O)C>[NH2:3][CH2:12][CH:13]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: CC(C)(C)OC(=O)NC(CCS(C)(=O)=O)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(CN)CCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl [1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-(methylsulfonyl)butan-2-yl]carbamate (25 g, 63 mmol) in ethanol (500 mL) was added dropwise hydrazine hydrate (32 g, 0.63 mol) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes and then heated to reflux. After 2 hours, the reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel to give tert-butyl [1-amino-4-(methylsulfonyl)butan-2-yl]carbamate. MS ESI calc'd. for C10H23N2O4S [M+H]+ 267. found 267. 1H NMR (300 MHz, CD3OD) δ 3.59-3.54 (m, 1H), 3.29-3.09 (m, 2H), 2.96 (s, 3H), 2.71-2.56 (m, 2H), 2.08-1.76 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:10][C:9]2=[O:23])=[CH:4][C:3]=1[NH:24][CH3:25].[Cl:26][C:27]([Cl:33])([Cl:32])[C:28](=[NH:31])OC.O>CC(O)=O>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:31]=[C:28]([C:27]([Cl:26])([Cl:32])[Cl:33])[N:24]([CH3:25])[C:3]=4[CH:4]=3)[C:9](=[O:23])[CH:10]=2)=[CH:21][CH:20]=1
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: CNc1cc(-n2ccc(OCc3ccc(F)cc3)cc2=O)ccc1N
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(C(Cl)(Cl)Cl)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (270 mg) in AcOH (3 ml) was added methyl 2,2,2-trichloroacetimidate (0.196 ml) dropwise at 0° C. The mixture was stirred at room temperature for 2 h. Water was added to the mixture. The resulting precipitate was collected by filtration and dried to give the title compound (220 mg) as an ivory solid.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2.S(=O)(=O)(O)O.[C-:17]#[N:18].[Na+].CCOCC>CO>[C:17]([C:2]1([OH:11])[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)#[N:18]
Reactant: [C-]#N
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: N#CC1(O)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a well stirred solution of 2-adamantanone (45.0 grams, 0.3 mol) in 200 ml methanol were added 50 ml concentrated sulfuric acid at a rate that caused the solution to reflux. Then a saturated aqueous solution of sodium cyanide (88.2 grams, 0.6 mol) was added, and the mixture was first refluxed for 1 hour and then stirred at room temperature for 3 additional hours. Ether was added, and the organic solution was decanted from the precipitated salts. The ether solution was washed with an aqueous solution of sodium chloride and water and then dried and evaporated to leave 43.0 grams (81%) of compound 4 as a beige crystalline solid, melting point >240° C. (decomposition).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([CH:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]3)=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:24][CH2:25][N:26]([C:29]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[O:30])[CH2:27][CH2:28]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCC(C(=O)NC(CCCc3ccccc3)CCCc3ccccc3)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C(=O)C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 108 %

Procedure:
1-(1-tert-butoxycarbonylpiperidine-4-carbonyl)-piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (70) (1.84 g; 3.12 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. Trifluoroacetic acid (15 mL) is added in a slow stream, and the solution is stirred for 1.25 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (1.65 g) as a white solid. ESMS:MH+ 490.4
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([Cl:20])[N:3]=1.[CH:21]([Mg]Cl)([CH3:23])[CH3:22]>C1COCC1>[Cl:20][C:4]1[N:3]=[C:2]([CH:21]([CH3:23])[CH3:22])[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=1
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)NCc1ccc(Cl)cc1
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1cc(Cl)nc(C(C)C)c1C(=O)NCc1ccc(Cl)cc1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
A solution of 6.0 g (18.3 mmol) 2,6-dichloro-N-(4-chlorobenzyl)-4-methyl-pyridine-3-carboxylic acid amide (synthesized according to the method described in section a) of example 2) in THF (180 ml) and NMP (60 ml) was degassed for 30 min followed by the addition of 1.3 g (3.7 mmol) Fe(acac)3. This mixture was degassed again for 20 min. At −40° C. 137 ml (2M in THF, 274 mmol) isopropylmagnesiumchloride was added dropwise over 1 h. The reaction mixture was allowed to reach 0° C. and was quenched at this temperature with a sat. aq. NH4Cl sol. followed by stirring at 10° C. for 30 min. Then the mixture was diluted with EtOAc and the organic layer was separated, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 9:1) provided 2.45 g (7.3 mmol, 40%) 6-chloro-N-(4-chlorobenzyl)-2-isopropyl-4-methyl-pyridine-3-carboxylic amide.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[Br:14]Br>ClCCl>[Br:14][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[F:1])[CH:6]=[O:7]
Reactant: O=Cc1ccc(F)cc1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=Cc1ccc(F)c(Br)c1
Yield: 56.3 %

Procedure:
A solution of 4-fluorobenzaldehyde (49.6 g) in dry dichloromethane (20 cm3) was added to a cooled (0° C.) suspension of powdered aluminium trichloride (90.4 g) in dry dichloromethane (100 cm3). Bromine (70.4 g) was added, and the mixture heated at the reflux temperature of 16 hours. After cooling, the reaction mixture was carefully poured onto ice and extracted with dichloromethane. The combined organic layers were washed with saturated sodium metabisulphite solution, water and brine, then dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave a dark red oil, which was purified by distillation under reduced pressure, using a 4" Vigreux column to give 3-bromo-4-fluorobenzaldehyde (45.7 g) as an oil, boiling point 85°-108° C. at 8 mmHg.