Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[OH:18][C:19]([CH3:34])([C:23]([NH:25][CH2:26][C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[O:24])[C:20](O)=[O:21].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.Cl>O1CCCC1>[OH:18][C:19]([CH3:34])([C:23]([NH:25][CH2:26][C:27]([F:32])([F:33])[C:28]([F:29])([F:30])[F:31])=[O:24])[C:20]([NH:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2)=[O:21]
Reactant: CC(O)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Reactant: N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(O)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 40.6 %

Procedure:
A solution of 101 mg (0.45 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one and 119 mg (0.45 mmol) (RS)-2-hydroxy-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid in 15 ml tetrahydrofuran were cooled to 0° C. and 61.8 mg (0.45 mmol) 1-hydroxy-benzotriazole hydrate, 157 μl (0.90 mmol) diisopropylethylamine and 87.6 mg (0.45 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued overnight at room temperature. The mixture was poured on ice/water and 1 N aqueous hydrochloric acid was added until pH=1 was reached. Extraction with diethylether, washing with saturated aqueous sodium hydrogen carbonate solution and brine and chromatography on silicagel with ethylacetate/cyclohexane 1/1 yielded 86.1 mg (41%) (R/S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide as a white solid, MS (m/e): 472.1 (M+H)+.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22].[CH3:23][O:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=O>>[Br:21][C:18]1[CH:19]=[CH:20][N:15]2[N:14]=[C:27]([C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[O:24][CH3:23])[N:22]=[C:16]2[CH:17]=1
Reactant: Nc1cc(Br)cc[n+]1N
Reactant: COc1ccccc1C(=O)Cl
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: COc1ccccc1-c1nc2cc(Br)ccn2n1
Yield: 28.4 %

Procedure:
The product was prepared in the same manner as described in example 1b using 1,2-diamino-4-bromopyridinium 2,4,6-trimethylbenzenesulfonate (2.2 g, 5.67 mmol) and 2-methoxybenzoyl chloride (1.52 ml, 11.3 mmol) as starting materials. The reaction affords 7-bromo-2-(2-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (490 mg, 28.4%) as a white solid. MS: m/z=306.0 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:29](=[S:31])=[S:30].[CH3:32]I>CO>[C:18]([O:17][C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:29](=[S:31])[S:30][CH3:32])=[CH:4][CH:5]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CI
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CN)cc1
Reactant: S=C=S
Solvent: CCN(CC)CC
Solvent: CO
Product: CSC(=S)NCc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 1.415 g (5 mmol) of 4-aminomethyl-2'-(t-butoxycarbonyl)biphenyl and 751 μl (545 mg, 5.4 mmol) of triethylamine in 5 ml of methanol was stirred under N2 at room temperature as a solution of 342 μl (434 mg, 5.7 mmole) of carbon disulfide in 2 ml of methanol was added dropwise over about 10 minutes. After 2.5 hours, the solution was cooled in an ice-methanol bath, and a solution of 311 μl (710 mg, 5 mmole) of methyl iodide in 2 ml of methanol was added dropwise over about 10 minutes. The cooling bath was removed, and the solution was allowed to warm to room temperature. After two hours, the solution was concentrated at 25° C. The residue was partitioned between 50 ml of ether plus 10 ml of CH2Cl2 and 50 ml of 0.2 N HCl. The organic phase was washed with 25 ml of saturated NaCl solution (aqueous), dried over MgSO4, filtered, and concentrated. Crystallization of the residual oil from ether yielded 1.57 g (84%) of nearly colorless crystals, mp 127.5°-128.5° C., satisfactory purity by TLC in 4:1 hexane-EtOAc; mass spectrum (FAB) m/e 374 (M+1)+.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:7]([C:8]([NH2:10])=[NH:9])[N:6]=[C:5]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=1>CO.[H][H].[C].[Pd]>[ClH:1].[NH2:2][C:3]1[N:7]([C:8]([NH2:10])=[NH:9])[N:6]=[C:5]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=1
Reactant: N=C(N)n1nc(C=Cc2ccccc2)cc1N
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N=C(N)n1nc(CCc2ccccc2)cc1N
Yield: 62.9 %

Procedure:
0.1 g of 10% palladium-carbon were added to a solution of 0.6 g of 5-amino-3-(2-phenylethenyl)-1H-pyrazole-1-carboxamidine hydrochloride in 40 ml of methanol and stirred for 30 minutes in hydrogen atmosphere of normal pressure at room temperature. The reaction solution was filtered to remove the insoluble solids therefrom, and the solvent was removed by distillation under reduced pressure. The resulting residue was recrystallized from ethanol-ether to obtain 0.38 g of 5-amino-3-(2-phenylethyl)-1H-pyrazole-1-carboxamidine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]=[CH:9]N(C)C)=[CH:4][CH:3]=1.[Na+].[I-].Cl[CH2:16][C:17](=[O:19])[CH3:18]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:16]([C:17](=[O:19])[CH3:18])=[CH:9][N:8]=2)[N:7]=1
Reactant: CN(C)C=Nc1ccc(Cl)nn1
Reactant: CC(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1cnc2ccc(Cl)nn12
Temperature: 80 °C
Yield: 51.1 %

Procedure:
To a solution of N′-(6-chloro-pyridazin-3-yl)-N,N-dimethyl-formamidine (1.3 g, 7 mmol) in DMF (60 mL) was added NaI (1 g, 6.7 mmol) and chloroacetone (1 mL, 12.6 mmol). The mixture was heated at 80° C. overnight and then concentrated under reduced pressure. The residue was purified by column chromatography to afford 1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethanone (0.7 g) in 51% yield. 1H-NMR (400 MHz, CDCl3) δ ppm 8.42 (s, 1H), 8.05 (d, 1H), 7.31 (d, 1H), 2.77 (s, 3H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5]C(S(O)(=O)=O)=CC=1.[NH2:12][CH:13]([C:16]#[N:17])[C:14]#[N:15].C(N(CC)CC)C.C(OC)(OC)(OC)CCC.[NH2:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45]>C1COCC1>[NH2:15][C:14]1[N:35]([CH2:36][CH2:37][O:38][CH2:39][CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[C:5]([CH2:6][CH2:1][CH3:11])=[N:12][C:13]=1[C:16]#[N:17]
Reactant: CC(C)(C)OC(=O)NCCOCCN
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: N#CC(N)C#N
Agent: CCCC(OC)(OC)OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1nc(C#N)c(N)n1CCOCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 91.5 %

Procedure:
Under a nitrogen atmosphere, aminomalononitrile p-toluenesulfonate (55.0 g, 0.217 mol) and anhydrous THF (1.1 L) were combined, and triethylamine (23.1 g, 0.228 mol) was added with stirring to the resulting suspension. After the suspension was stirred for 25 minutes; the reaction became homogeneous, and trimethyl orthobutyrate (36.5 mL, 0.228 mol) was added. The solution was heated at reflux for 75 minutes. An analysis by TLC indicated the presence of starting material, and additional trimethyl orthobutyrate (3.5 mL) was added. The solution was heated at reflux for another 15 minutes and allowed to cool to 25° C. Triethylamine (32 mL, 0.29 mol) and tert-butyl 2-(2-aminoethoxy)ethylcarbamate (48.8 g, 0.239 mol) were added, and the reaction was stirred for 18 hours at room temperature. The volatiles were removed under reduced pressure, and the residue was partitioned between dichloromethane (1 L) and saturated aqueous sodium bicarbonate (250 mL). The organic layer was separated and washed sequentially with saturated aqueous sodium carbonate (250 mL) and brine (250 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was combined with material from another run and purified by column chromatography on silica gel (eluting with 20% ethyl acetate in hexane) to provide 67 g (77%) of tert-butyl 2-[2-(5-amino-4-cyano-2-propyl-1H-imidazol-1-yl)ethoxy]ethylcarbamate as an orange semi-solid.
Reaction SMILES: [H-].[Na+].[O:3]([C:10]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[OH:26])=[CH:14][CH:13]=[CH:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CI.[C:29](OCC)(=O)C>CN(C=O)C>[O:3]([C:10]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[O:26][CH3:29])=[CH:14][CH:13]=[CH:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(C)=O
Reactant: Oc1cnccc1CCCOc1cccnc1Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cnccc1CCCOc1cccnc1Oc1ccccc1
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 0.04 g, 1.0 mmol) is suspended in DMF (10 ml), and thereto is added 2-phenoxy-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine (0.20 g, 0.62 mmo) obtained in Example 30 at room temperature, and the mixture is stirred for 30 minutes. To the mixture is added methyl iodide (0.06 ml, 1.0 mmol) under ice-cooling, and the mixture is stirred for 1 0 minutes. To the reaction solution is added ethyl acetate (50 ml), and the mixture is washed with a saturated brine (30 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform/methanol), and recrystallized from isopropyl ether to give the title compound (0.09 g) as colorless crystals, m.p. 101-102° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:24](OS(OCC)=O)[CH3:25].O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[N:12]([CH2:24][CH3:25])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Reactant: CCOS(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
2.8 g of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was dissolved in 30 ml of dry dimethylformamide. To the solution was added 0.6 g of about 50 % sodium hydride, and stirring was performed for 30 minutes. To the mixture was further added 3.5 g of diethylsulfite and the whole was reacted for 2 hours at room temperature. After the reaction was finished, the solvent was distilled off from the mixture under reduced pressure. To the residue thus obtained was added water to precipitate a crude product. This product was recrystallized from methanol to yield 2.7 g of 1-(m-nitrophenyl)-3-ethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione as pale yellow prisms, melting at 210°-211°C.
Reaction SMILES: [OH:1][C:2]([CH3:18])([CH3:17])[CH:3]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]#N)[N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.S(=O)(=O)(O)[OH:20].C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[N:4]1([CH:3]2[C:9]3[C:10](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:20])[O:1][C:2]2([CH3:18])[CH3:17])[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: O=S(=O)(O)O
Reactant: CC(C)(O)C(c1ccccc1C#N)n1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)OC(=O)c2ccccc2C1n1ccnc1

Procedure:
Crude 2-(2-hydroxy-1-imidazol-1-yl-2-methyl-propyl)-benzonitrile (1.75 g) is dissolved in dioxane (15 mL) and water (15 mL). Sulfuric acid (1.5 mL, 29.0 mmol) is added and the mixture is stirred at reflux for 2 h. After cooling down, the pH is adjusted with solid sodium bicarbonate. The mixture is extracted with ethyl acetate and the combined organic phase is washed with water, dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (dichloromethane-methanol, 19:1) to give 4-(imidazol-1-yl)-3,3-dimethyl-isochroman-1-one; MS (ESI) m/z 242.9 (M+H); 1H NMR (400 MHz, MeOD) δ ppm. 1.30 (s, 3 H), 1.53 (s, 3 H), 5.76 (s, 1 H), 6.98 (s, 1 H), 7.09 (s, 1 H), 7.52 (d, J=7.6 Hz, 1 H), 7.64-7.73 (m, 1 H), 7.76-7.85 (m, 1 H), 7.89 (s, 1 H), 8.25 (dd, J=7.7, 1.4 Hz, 1 H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[C:10]1(C)[CH:15]=CC=C[CH:11]=1.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C(=O)CC>CCCCCCC>[N:1]1([CH:11]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([C:18]([F:26])([F:27])[F:17])=[CH:20][CH:21]=2)[CH2:10][CH3:15])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: Cc1ccccc1
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CCC=O
Solvent: CCCCCCC
Product: CCC(Nc1ccc(C(F)(F)F)cc1)n1nnc2ccccc21
Reaction time: 24 h

Procedure:
A two liter, four neck flask under nitrogen atmosphere was charged with benzotriazole (36.96 g, 310 mmol, 1.0 equiv) and dry toluene (400 mL). A room temperature solution of 4-(trifluoromethyl)aniline (39.1 mL, 310 mmol, 1.0 equiv) and 50 mL toluene was added over one minute. A room temperature solution of propionaldehyde (24.6 mL, 341 mmol, 1.1 equiv) and 50 mL toluene was then added over 20 minutes. There was an exotherm from 23° C. to 30° C. during this addition. After stirring 24 h, n-heptane (500 mL) was added, and the slurry stirred an additional 1 h. The suspension was filtered, the solids were washed with n-heptane (1×100 mL, then 1×200 mL, and dried. (1-Benzotriazol-1-yl-propyl)-(4-trifluoromethyl-phenyl)-amine was isolated as shiny white needles (81.3 g, 82%). After 24 h, a second crop was isolated from the filtrate (8.7 g, 9%). mp 130-132° C.; 1H NMR (DMSO-d6, 400 MHz) δ0.82 (t, 3H, J=7.5 Hz), 2.25 (m, 2H), 6.49 (m, 1H), 6.80 (d, 2H, J=8.7 Hz), 7.35 (m, 3H), 7.50 (m, 1H), 7.88 (d, 1H, J=8.3 Hz), 7.99 (m, 1H), 8.09 (d, 1H, J=8.5 Hz); 13C NMR (DMSO-d6, 100 MHz) δ149.32, 146.19, 131.46, 127.73, 126.8, 125.33 (q, J=270 Hz), 124.44, 119.88, 118.27 (q, J=31.7 Hz), 112.91, 111.56, 71.03, 28.08, 10.29; DEPT spectrum: quaternary carbons δ149.32, 146.19, 131.46, 125.33, 118.27; CH carbons δ127.73, 126.8, 124.44, 119.88, 112.91, 111.56, 71.03; CH2 carbon δ28.08; CH3 carbon δ10.29; IR (drifts) 3292 (s), 3038 (m), 2975 (m), 1621 (s), 1331 (s), 1320 (s), 1114 (vs); Anal. Calcd for C16H15N4F3: C, 59.99; H, 4.72; N, 17.49. Found (first crop): C, 60.16; H, 4.74; N, 17.86. Found (second crop): C, 59.97; H, 4.66; N, 17.63.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=O)=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:13][C:12]2=[O:18])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)cc2C(=O)NCCN2CCCC2)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.5 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (90 mg, 77%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]1[CH:20]=[CH:19][C:16]([C:17]#N)=[CH:15][CH:14]=1)[NH:6][C:7]2=[O:12].[OH-:21].[Na+].Cl.[OH2:24]>>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]1[CH:20]=[CH:19][C:16]([C:17]([OH:24])=[O:21])=[CH:15][CH:14]=1)[NH:6][C:7]2=[O:12]
Reactant: Cc1cccc2c(=O)[nH]c(-c3ccc(C#N)cc3)cc12
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(C(=O)O)cc3)cc12
Yield: 63 %

Procedure:
To 4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzonitrile (100 mg, 0.38 mmol) was added 2M NaOH (1.5 mL) and the reaction mixture irradiated using a microwave (300 W, 130° C., 20 min). The reaction mixtures was diluted with water and adjusted to pH2 with 2M HCl whereupon a pale yellow solid precipitated out of solution. The solid was filtered, washed with water and dried. The solid was dissolved in DMF and passed through a Si-thiol cartridge to remove any residual palladium, eluting with DMF. The eluent was removed in vacuo to give 4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzoic acid as a pale yellow solid (120 mg, 63%).
Reaction SMILES: ClC[C:3]([NH:5][CH2:6][C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](OC(C)(C)C)=O)=[O:4].C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH2:6]1[NH:5][C:3](=[O:4])[CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@H:7]12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CNC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CN2CCC[C@@H]2CN1
Temperature: 60 °C

Procedure:
1,1-Dimethylethyl (2R)-2-{[(chloroacetyl)amino]methyl}-1-pyrrolidinecarboxylate (D13; 1.24 g, 4.5 mmol), was dissolved in 20 ml of DCM and treated with TFA (5 ml) at room temperature. After 1 h complete conversion into the desired material was observed and the reaction mixture was loaded onto a SCX cartridge. The product obtained after elution with 2M NH3 in MeOH was then dissolved in acetonitrile (30 ml) and treated with sodium carbonate (1.43 g, 10.34 mmol). The reaction mixture was heated at 60° C. for 6 hours; the crude obtained after removal is purified by flash-chromatography eluting with dichloromethane/MeOH 95/5 affording 250 mg of the desired compound.
Reaction SMILES: [C:1]([S:5]([CH2:8][C@@H:9]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:10]([NH:12][C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][NH:36][CH:37]=1)[C:14]([NH:16][C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C(C)C)=[O:15])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)(C)C=O.C(Cl)Cl.CCOCC>[C:1]([S:5]([CH2:8][C@@H:9]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:10]([NH:12][CH:13]([CH2:32][C:33]1[N:34]=[CH:35][NH:36][CH:37]=1)[C:14]([NH2:16])=[O:15])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)C
Agent: CC(C)(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)NC(Cc1c[nH]cn1)C(N)=O
Reaction time: 24 h

Procedure:
130 mg of (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S, 2R, 3S )-1-(cyclohexylmethyl)-2,3-dihydroxy-4-methylpentyl]imidazole-4-propionamide and 130 mg of p-toluenesulphonic acid in 1 ml of trimethylacetaldehyde and 10 ml of methylene chloride are left to stand at room temperature for 24 hours. Thereafter, the reaction mixture is taken up in ether and the organic phase is washed in succession with 2N sodium bicarbonate solution and water, dried and evaporated. Chromatography of the residue on 30 g of silica gel using a 200:10:1 mixture of methylene chloride, methanol and ammonia yields (S)-N-[(S)-1-[(2R or S,4R,5S)-2-t-butyl-5-isopropyl-1,3-dioxolan-4-yl]-2-cyclohexylethyl]-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]imidazole-4-propionamide as a foam, MS: 701 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5])#[N:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[NH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:4](=[O:5])[C:3]([C:1]#[N:2])=[CH:17][N:18]([CH3:19])[CH3:20])=[CH:7]1
Reactant: N#CCC(=O)c1c[nH]c2ccccc12
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C#N)C(=O)c1c[nH]c2ccccc12

Procedure:
1-indol-3-yl-2-cyano-3-dimethylaminopropen-1-one was prepared from 3-(cyanoacetyl) indole (4.0 g, mmol) and dimethylformamide dimethylacetal (4.1 mL, 23.9 mmol) as a yellow solid (2.4 g), m.p. 187-188°. δH (d6 DMSO) 11.73 (1H, bs), 8.26 (1H, s), 8.12 (1H, dd, J 6.8, 1.3 Hz), 7.98 (1H, s), 7.47-7.44 (1H, m), 7.20-7.09 (2H, m), 3.35 (3H, s) and 3.26 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[N+:13]2[O-])=[CH:8][CH:7]=1)=[O:5])[CH3:2].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:32][NH2:33].O1CCCC1>ClCCl>[CH3:32][NH:33][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[N:13]=1
Reactant: CCOC(=O)c1ccc2ccc[n+]([O-])c2c1
Reactant: CN
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2ccc(NC)nc2c1
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 41 %

Procedure:
To a −70° C. solution of 7-(ethoxycarbonyl)quinoline 1-oxide (1.67 g, 7.70 mmol) in dichloromethane (80 mL) was added trifluoromethanesulfonic anhydride (1.43 mL, 8.47 mmol) dropwise, under a nitrogen atmosphere. The mixture was stirred at −70° C. for 5 minutes. Then a solution of methylamine in tetrahydrofuran (21 mL, 42 mmol, 2.0 M) was added dropwise at −70° C. The mixture was stirred for 5 minutes and then the reaction was quenched with water (20 mL). The layers were separated and the aqueous was extracted with dichloromethane (3×30 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave the title compound (720 mg, 41%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.42 (s, 1 H), 7.84-7.82 (m, 2 H), 7.63-7.61 (m, 1 H), 6.72-6.70 (m, 1 H), 4.92 (br. s., 1 H), 4.44-4.38 (m, 2 H), 3.12-3.11 (m, 3 H), 1.44-1.40 (m, 3 H).
Reaction SMILES: [N:1]1([C:6]2[CH:27]=[CH:26][C:9]([CH2:10][C:11]3[C:12](OC)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][C:15]=4C)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>CN(C=O)C.CCOC(C)=O>[N:1]1([C:6]2[CH:27]=[CH:26][C:9]([CH2:10][C:11]3[C:12]([N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCNCC
Reactant: COc1nc2c(C)cc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)c1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 115 °C

Procedure:
A mixture of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline (1.44 g, 3.33 mmol, Intermediate 6, step c) and diethylamine (6.91 mL, 66.5 mmol) in DMF (10 mL) in a sealed tube was heated in a 115° C. oil bath for 23 hours. The mixture was diluted with EtOAc and extracted with water (5×, saturated aqueous NaCl added as needed to achieve phase separation). The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, dry loading, 2-10% EtOAc-Heptane first column, 0-4% EtOAc-Heptane second column) to afford the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.Cl.[CH3:16]O>>[CH3:16][O:13][C:12]([C:3]1[C:2]([OH:1])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1)=[O:14]
Reactant: CO
Reactant: O=C(O)c1cc2c(cc1O)CCCC2
Agent: Cl
Product: COC(=O)c1cc2c(cc1O)CCCC2
Reaction time: 2 h

Procedure:
A 281 g sample of 3-hydroxy-5,6,7,8-tetrahydro-2-naphthoic acid was dissolved in 1.4 l of methanol, and while hydrogen chloride gas was supplied, the solution was first exposed to room temperature for 2 hours, and then heated at 60° to 70° C. for 4 hours. Methanol was distilled off under vacuum, water was added to the residue, which was then extracted with ethyl acetate. The ethyl acetate layer was washed with sodium bicarbonate until it became neutral, and then it was dehydrated and concentrated. The residual oily product was distilled under vacuum to provide 279 g of the title compound (1) having the following physical properties.