Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([CH:11]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=3)=[C:16]([CH3:31])[CH:15]=2)[CH3:12])=[CH:9][CH:10]=1)=[O:5])C.[OH-].[Li+].Cl>C1COCC1>[C:27]([C:24]1[CH:23]=[CH:22][C:21]([C:17]2[C:18]([CH3:20])=[CH:19][C:14]([O:13][CH:11]([C:8]3[S:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][CH:9]=3)[CH3:12])=[CH:15][C:16]=2[CH3:31])=[CH:26][CH:25]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)c1ccc(C(C)Oc2cc(C)c(-c3ccc(C(C)(C)C)cc3)c(C)c2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(OC(C)c2ccc(C(=O)O)s2)cc(C)c1-c1ccc(C(C)(C)C)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To a mixture of (±)-5-[1-(4′-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carboxylic acid ethyl ester (0.603 g, 1.38 mmol) in THF (14 mL) is added lithium hydroxide (1N aqueous, 14 mL). The mixture is warmed to 70° C. and stirred overnight. The reaction mixture is acidified with 1N HCl (15 mL), extracted into ethyl acetate (3×25 mL), dried over MgSO4, and concentrated, to provide (±)-5-[1-(4′-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carboxylic acid (0.554 g, 98%) as a white foam. MS (ES): 407.3 [M−H]−.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[N:29]3[C:24]([C:25]([NH2:30])=[N:26][CH:27]=[N:28]3)=[C:23]([C:31]3[CH:32]=[CH:33][C:34]4[C:38]([CH:39]=3)=[N:37][N:36]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:35]=4)[CH:22]=2)[CH2:17][CH2:16]1)=[O:14])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:40]([N:36]1[CH:35]=[C:34]2[C:38]([CH:39]=[C:31]([C:23]3[CH:22]=[C:21]([CH:18]4[CH2:17][CH2:16][N:15]([C:13](=[O:14])[C@@H:9]5[CH2:10][CH2:11][CH2:12][NH:8]5)[CH2:20][CH2:19]4)[N:29]4[C:24]=3[C:25]([NH2:30])=[N:26][CH:27]=[N:28]4)[CH:32]=[CH:33]2)=[N:37]1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnn2c(C3CCN(C(=O)[C@@H]4CCCN4)CC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 17.7 %

Procedure:
To a solution of 2-{4-[4-Amino-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-piperidine-1-carbonyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (73.5 mg, 0.1 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.2 mL). The reaction was stirred at rt for 5 h. The sample was concentrated and the residue taken up in 1.5 mL of methanol, 0.5 mL of acetonitrile and 0.5 mL of water. The sample was then free-based using Phenomenex's Strata-X-C cation mixed mode polymer SPE plate (500 mg/6 mL/well) to give 9.20 mg (17%) of desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.80 (d, J=8.56 Hz, 1 H), 7.60 (s, 1 H), 7.29-7.39 (m, 5 H), 7.15 (d, J=8.56 Hz, 1 H), 6.63 (d, J=11.49 Hz, 1 H), 4.52 (d, J=12.59 Hz, 1 H), 4.05 (d, J=11.62 Hz, 1 H), 2.78 (t, J=12.47 Hz, 1 H), 2.56-2.66 (m, 1 H), 2.17 (s, 1 H), 1.99-2.10 (m, 5 H), 1.77-1.85 (m, 5 H), 1.63-1.69 (m, 2 H), 1.52-1.62 (m, 3 H), 1.17-1.27 (m, 2 H); MS LC-MS [M+H]+=521.5, RT=2.96 min.
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[C:9](Cl)(=[O:13])[CH:10]([CH3:12])[CH3:11]>O>[C:9]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:13])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)C(=O)OOC(C)(C)C

Procedure:
The reaction is effected in a reactor arrangement of a first reactor of type E with a downstream reactor of type C. Before the start of the reaction, the first reactor is filled with a solution of 24.4% by weight of tert-butyl hydroperoxide and 12.7% by weight of potassium hydroxide in water. 33.6 kg/h of a solution of 70% by weight of tert-butyl hydroperoxide in water, 27.2 kg/h of a solution of 45% by weight of potassium hydroxide in water, 38.0 kg/h of water and 18.4 kg/h of isobutyroyl chloride are then fed to the first reactor. Cooling with cooling water keeps the internal temperature in the first reactor at 11° C. and in the second reactor at 12° C. The reaction mixture withdrawn from the second reactor is mixed with 8.0 kg/h of isododecane and the organic phase is removed. The organic phase is washed successively with an 8% by weight solution of sodium hydroxide in water, with a solution of 10% by weight of sodium sulphite in water comprising acetic acid and with a 1% by weight solution of sodium hydrogencarbonate in water, and then dried by stripping in a packed column at 20° C. and 47 mbar. 33.4 kg/h of a 75% by weight solution of tert-butyl peroxyisobutyrate in isododecane are obtained (92.8% based on isobutyroyl chloride). The space-time yield is 2.69 kg/l·h.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH3:7][NH:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11]>C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:7][N:8]1[C:9]2[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:11][C:2](=[O:3])[C:1]1=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CNc1ccccc1N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cn1c(=O)c(=O)[nH]c2ccccc21

Procedure:
A mixture of 12 g of 98% oxalylchloride in 19.5 ml of triethylamine and 50 ml of toluene was added dropwise to a stirred solution of 8.5 g of o-N-methylamino aniline in 80 ml of toluene. The resulting mixture was heated at reflux for one hour. The precipitate was washed wih ether. The residue was stirred with water and filtered to give 1,2,3,4-tetrahydro-1-methyl-2,3-dioxo-quinoxaline.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](#[N:15])[CH3:14].[F:16][C:17]1[CH:18]=[C:19]([CH:25]=[C:26]([F:28])[CH:27]=1)[C:20](OCC)=[O:21].C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[F:16][C:17]1[CH:18]=[C:19]([C:20](=[O:21])[CH2:14][C:13]#[N:15])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: CCOC(=O)c1cc(F)cc(F)c1
Reactant: CC#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#CCC(=O)c1cc(F)cc(F)c1
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 43 %

Procedure:
Diisopropylamine (10.6 mL, 76 mmol) was dissolved in dry THF (10 mL) and the solution cooled to −20° C. A solution of n-butyllithium (2.5N in hexanes, 30.5 mL, 76 mmol) was added slowly at such a rate as to keep the internal temperature below 0° C. After stirring for 5 min, the solution was cooled to −20° C. and added to a solution of acetonitrile (2.37 mL, 45.3 mmol) and ethyl 3,5-difluorobenzoate (6.23 g, 36.2 mmol) in dry THF (18 mL) at such a rate as to keep the temperature below −40° C. A further 10 mL of dry THF was used to transfer the remaining lithium diisopropylamide to the reaction. The reaction was allowed to warm to ambient over 2 h before being quenched with saturated aqueous ammonium chloride solution. The reaction was extracted with ethyl acetate (×2) and the extracts discarded. The aqueous was acidified with 2N HCl and extracted with ethyl acetate. The organic extract was washed with 2N HCl and brine before being dried over MgSO4, filtered and evaporated. Purification using chromatography (silica gel, gradient 5 to 100% ethyl acetate/isohexane) gave 3-(3,5-difluorophenyl)-3-oxopropanenitrile as a yellow solid (2.82 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([N:21]1[CH2:24][C:23](=O)[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(O)(=O)C>CO.[Pd]>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:23]2[CH2:22][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:24]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(N2CCN(Cc3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1-benzylpiperazine (0.500 ml) in methanol (25 ml) were added 1-Boc-azetidin-3-one (495 mg), acetic acid (0.182 ml), followed by stirring at room temperature for 5 min. 10% palladium on carbon (308 mg) was added thereto, followed by stirring at room temperature under a hydrogen atmosphere for 15 hr. The catalyst was removed by filtration. The residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. This was concentrated to provide a crude product of 4-benzyl-1-(1-Boc-azetidin-3-yl)piperazine (ESI-MS (m/z): 332 [M+H]+). This was dissolved in tetrahydrofuran (10 ml). Lithium aluminum hydride (219 mg) was added thereto while stirring in an ice bath. The mixture was stirred under a nitrogen atmosphere in an ice bath for 15 min, at room temperature for 15 min, and was heated to reflux at 100° C. for 3.5 hr. The reaction mixture was cooled in an ice bath. Water (0.22 ml), a 5N aqueous solution of sodium hydroxide (0.22 ml) and water (1.1 ml) were added thereto, followed by stirring in an ice bath for 1 hr. Insoluble matter was removed by filtration. To the filtrate was added a 4N solution of hydrochloric acid in ethyl acetate (2.17 ml), which was concentrated to provide a crude product of 4-benzyl-1-(1-methylazetidin-3-yl)piperazine trihydrochloride (ESI-MS (m/z): 246[M+H]+). This was dissolved in water (25 ml) and 2-propanol (25 ml). 10% palladium on carbon (615 mg) was added thereto, followed by stirring under a hydrogen atmosphere at room temperature for 12 hr. The catalyst was removed by filtration. Concentration of the filtrate provided a crude product of the titled compound as a white solid (382 mg).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[N:19]=3)[N:14]=[CH:13][C:12]=2[F:23])[OH:10])[CH2:4]1.[O:24]=[C:25]1[CH2:30][S:29][C:28]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[N:34][C:27]=2[NH:26]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>C(Cl)Cl.CCO>[F:23][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:11]=1[C@@H:9]([OH:10])[CH2:8][N:5]1[CH2:6][CH2:7][C@@H:3]([CH2:2][NH:1][CH2:35][C:33]3[CH:32]=[CH:31][C:28]4[S:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=4[N:34]=3)[CH2:4]1)=[N:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2ncc(F)c([C@@H](O)CN3CC[C@@H](CN)C3)c2n1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2ncc(F)c([C@@H](O)CN3CC[C@@H](CNCc4ccc5c(n4)NC(=O)CS5)C3)c2n1
Reaction time: 18 h
Yield: 3.6 %

Procedure:
To a stirred solution of (1R)-2-[(3S)-3-(aminomethyl)-1-pyrrolidinyl]-1-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethanol (90 mg, 0.28 mmol) in dry CH2Cl2 (2 mL) and dry EtOH (2 mL) was added 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde (55 mg, 0.28 mmol) along with Na2SO4 (350 mg, 2.46 mmol). After 18 h at room temperature, NaBH4 (24 mg, 0.56 mmol) was added. After 2 h, the solution wa partitioned between ethyl acetate and the aqueous solution of sodium bicarbonate. The aqueous solution was extreacted several times with ethyl acetate. The organic fraction were pooled, concentrated and purified with column chromatography (silica, 0-8% MeOH in DCM (1% NH4OH)) affording a light yellow solid, which was completed with chiral purification. The title compound (5 mg, 3.6%) was provided as a white solid: LC/MS (ES) m/e 499 (M+H)+; 1H NMR (400 MHz, CD3OD): δ 8.56 (s, 1H), 8.14 (d, J=9.0 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.10 (d, J=9.2 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 5.82-5.84 (m, 1H), 4.03 (s, 3H), 3.64 (s, 2H), 3.39-3.41 (m, 1H), 3.09-3.12 (m, 1H), 2.87-3.07 (m, 2H), 2.59-2.67 (m, 2H), 2.48-2.52 (m, 2H), 2.28-2.36 (m, 2H), 1.86-1.97 (m, 1H), 1.37-1.46 (m, 1H), 1.16-1.18 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][N:4]=1.CN(C=O)C.C(Cl)(=O)C([Cl:22])=O>ClCCl>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:22])=[O:8])=[CH:5][N:4]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 1 L 3-neck flask equipped with an overhead stirrer, Claisen adaptor, nitrogen bubbler, 60 mL addition funnel, and thermocouple was added 6-(trifluoromethyl)nicotinic acid (45 g, 235.5 mmol), dichloromethane (540 mL) and DMF (0.910 mL, 11.77 mmol) via syringe. To this solution was added oxalyl chloride (24.51 mL, 282.56 mmol) and the reaction was allowed to stir at ambient temperature overnight. The reaction was then filtered and the clear filtrate was concentrated in vacuo to afford the title compound as a brownish semisolid.
Reaction SMILES: C(O[C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)C.ClC1C=CC(C2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=[CH:34][CH:33]=4)[N:26]=3)=[CH:23][NH:22][N:21]=2)=CC=1>>[Cl:11][C:7]1[CH:6]=[C:5]([C:4]2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][N:41]([CH2:42][CH3:43])[CH2:44][CH3:45])=[CH:34][CH:33]=4)[N:26]=3)=[CH:23][NH:22][N:21]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CCN(CC)CCOc1ccc(Nc2nccc(-c3c[nH]nc3-c3ccc(Cl)cc3)n2)cc1
Reactant: CCOC(=O)c1cccc(Cl)c1
Product: CCN(CC)CCOc1ccc(Nc2nccc(-c3c[nH]nc3-c3cccc(Cl)c3)n2)cc1

Procedure:
The title compound is prepared as described in Example 1 using 3-chloro-benzoic acid ethyl ester (see Example 5) and 4-(2-diethylamino-ethoxy)-phenylamine (see Example 3).
Reaction SMILES: [CH3:1][N:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[C:5]([NH:18][C:19](=[O:23])[CH:20]=NO)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[OH:24]S(O)(=O)=O.[OH-].[Na+]>>[CH3:1][N:2]1[CH2:11][CH:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:9]2=[CH:8][CH:7]=[C:6]3[C:5]([NH:18][C:19](=[O:23])[C:20]3=[O:24])=[C:4]2[CH2:3]1
Reactant: O=S(=O)(O)O
Reactant: CN1C=C(c2ccccc2)c2cccc(NC(=O)C=NO)c2C1
Agent: [Na+]
Agent: [OH-]
Product: CN1Cc2c(ccc3c2NC(=O)C3=O)C(c2ccccc2)C1
Temperature: 45 °C

Procedure:
17.5 g (0.0566 mol) of N-methyl-4-phenyl-8-(hydroxyiminoacetylamino)isoquinoline were added in small portions to 43.75 ml of concentrated H2SO4 at 45° C. and the mixture was warmed at 45° C. for 75 minutes. It was cooled to room temperature and poured onto 450 g of ice. A pH of 6.8 was then established with 2N NaOH. The precipitate which had separated out was filtered off with suction and washed with water. After drying, 15.3 g (92.5% of theory) of orange-colored crude product are obtained. (Melting point of the pure product=about 188° C., decomposition).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[N:21]3[C:16]([CH:17]=[N:18][C:19](O)=[N:20]3)=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[NH:27][C:28](=[O:30])[CH3:29]>>[C:1]([O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[N:21]3[C:16]([CH:17]=[N:18][C:19]([NH:23][C:24]4[CH:25]=[C:26]([NH:27][C:28](=[O:30])[CH3:29])[CH:31]=[CH:32][CH:33]=4)=[N:20]3)=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OCc1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: CC(=O)Nc1cccc(N)c1
Product: CC(=O)Nc1cccc(Nc2ncc3ccc(-c4cccc(COC(C)(C)C)c4)n3n2)c1
Yield: 39 %

Procedure:
Analogous to Example 1510b, 7-(3-tert-Butoxymethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (109 mg, 0.37 mmol) and 3′-aminoacetanilide (0.0689 g, 0.459 mmol) were reacted to afford N-{3-[7-(3-tert-Butoxymethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-acetamide as an orange foam (62 mg, 39%). LCMS: 430 (M+H); 1H-NMR (DMSO-d6): 9.84 (s, 1H), 9.46 (s, 1H), 8.98 (s, 1H), 8.12 (s, 1H), 8.06 (d, 1H, J=7.71 Hz), 7.72 (s, 1H), 7.63 (d, 1H, J=7.71 Hz), 7.44 (t, 1H, J=7.71 Hz), 7.35 (d, 1H, J=7.71 Hz), 7.22 (m, 2H), 7.19 (d, 1H, 4.65 Hz), 6.96 (d, 1H, J=4.65 Hz), 4.46 (s, 2H), 2.03 (s, 3H), 1.22 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[K+]>CCO.O.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH3:16])([CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)(C)c1ccc(N)cc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
A solution of ethyl 2-(4-nitrophenyl)-2-methylpropanoate (900 mg, 3.8 mmol) in EtOH (10 mL) was treated with 10% Pd—C (80 mg) and heated to 45° C. A solution of potassium formate (4.10 g, 48.8 mmol) in H2O (11 mL) was added over a period of 15 min. The reaction mixture was stirred at 65° C. for 2 h and then treated with additional 300 mg of Pd/C. The reaction was stirred for 1.5 h and then filtered through Celite. The solvent volume was reduced by approximately 50% under reduced pressure and extracted with EtOAc. The organic layers were dried over Na2SO4 and the solvent was removed under reduced pressure to yield ethyl 2-(4-aminophenyl)-2-methylpropanoate (G-1) (670 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 7.14 (d, J=8.5 Hz, 2H), 6.65 (d, J=8.6 Hz, 2H), 4.10 (q, J=7.1 Hz, 2H), 1.53 (s, 6H), 1.18 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[I-].[Na+].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29]Cl)[CH2:24][CH2:23]2)=[CH:17][CH:16]=1>O1CCCC1>[C:3]([CH:2]([CH2:29][CH2:28][N:25]1[CH2:24][CH2:23][C:22](=[C:21]([C:18]2[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=2)[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: Fc1ccc(C(=C2CCN(CCCl)CC2)c2ccc(F)cc2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)C(C)=O
Temperature: 20 °C

Procedure:
0.182 mol of ethyl acetoacetate is added at 0° C. to a suspension containing 0.182 mol of sodium hydride in 800 ml of tetrahydrofuran. The reaction medium is maintained for one hour at 20° C. and 0.182 mol of sodium iodide is then added. The mixture is cooled to 0° C. and 0.182 mol of 4-[bis(4-fluorophenyl)methylene]-1-(chloroethyl)piperidine is added. The mixture is brought to reflux for 12 hours and then concentrated under vacuum. The residue is taken up in water and the product is extracted with dichloromethane. The oil obtained is purified by chromatography on a column of 70-230 mesh silica, eluting with a mixture of dichloromethane and methanol (99:1 V/V).
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:9][CH2:8][N:7](C=O)[CH2:6][CH2:5]1)#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][CH2:25][CH2:26]N.[O-]CC.[Na+]>C(O)C>[NH:7]1[CH2:6][CH2:5][CH:4]([CH2:3][C:1]2[NH:2][CH2:26][CH2:25][CH2:24][N:23]=2)[CH2:9][CH2:8]1
Reactant: NCCCN
Reactant: N#CCC1CCN(C=O)CC1
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCO
Product: C1CN=C(CC2CCNCC2)NC1
Temperature: 200 °C
Yield: 56.7 %

Procedure:
A mixture of 4-cyanomethyl piperidine-1-carboxaldehyde (4. g, 0.026M) and 1,3-diaminopropane mono p-toluenesulfonate (7.3 g, 0.052M) was heated at 100° C. for 1/2 hrs and 200° C. for 2 hrs. The reaction mixture was dissolved in ethanol (50 ml) and sodium ethoxide (0.052M) was added. The mixture was filtered and the filtrate was stripped to dryness and distilled from about 170° to about 190° C./0.2 mmHg to yield 1,4,5,6-tetrahydro-2-[(4-piperidinyl)methyl]-pyrimidine (2.7 g, 56.7% yield). This compound was characterized as dihydrochloride salt, mp 279°-281° C. (EtOH).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH:4]([C:6](O)=[O:7])[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[F:54][C:55]([F:59])([F:58])[CH2:56][NH2:57]>CN(C=O)C>[F:54][C:55]([F:59])([F:58])[CH2:56][NH:57][C:6]([CH:4]1[CH2:5][C:2]([OH:1])([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=4)([C:20]([F:21])([F:22])[F:23])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:3]1)=[O:7]
Reactant: O=C(O)C1CC(O)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reactant: NCC(F)(F)F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(F)(F)F)C1CC(O)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.3 %

Procedure:
To a stirred solution of 3-hydroxy-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid (Preparation 4, 0.050 g, 0.098 mmol) in DMF (0.5 mL) was added HOBt (0.013 g, 0.096 mmol), DIPEA (0.025 g, 0.193 mmol) EDCl.HCl (0.019 g, 0.099 mmol) and 2,2,2-Trifluoro-ethylamine hydrochloride (0.013 g, 0.096 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 18 h under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (5 mL) and extracted with EtOAc (2×5 mL). Combined organic layer was washed with brine (5 mL), dried over sodium sulphate and evaporated in vacuo to get thick oil, 0.093 mg crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 2% methanol in DCM to afford thick yellow oil, which was re-purified by DCM in pentane (1:9) to afford white solid (0.020 g, 37.5%). 1H-NMR (400 MHz, CDCl3) δ: 2.55-2.57 (m, 2H), 2.87-2.91 (m, 3H), 3.67 (d, 1H, J=17.24), 3.96-4.01 (m, 2H), 4.08 (d, 1H, J=17.2 Hz), 4.71 (s, 1H), 5.97 (t, 1H, J=6.32 Hz), 7.55 (d, 2H, J=8.44 Hz), 7.64-7.6 (m, 4H). LC-MS (m/z): [M−H] 586.90.
Reaction SMILES: [NH4+].[Cl-].[Cl:3][C:4]1[CH:18]=[CH:17][C:7]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][C:5]=1[N+:19]([O-])=O>[Fe].CCO>[NH2:19][C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][C:4]=1[Cl:3])[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Sat. aq. NH4Cl (50 mL) followed by iron powder (5.51 g, 98.7 mmol) were added at rt to a mixture of tert-butyl 4-chloro-3-nitrobenzylcarbamate (5.66 g, 19.7 mmol) and EtOH (50 mL). After stirring for 4 h at 80° C., 4 h at 90° C. and at rt overnight the reaction mixture was filtered through celite and washed with EtOAc. The aq. layer was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and concentrated to give the sub-title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]([OH:20])[C:15](=[NH:19])OCC)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10].[C:21]1(N)[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]([C:15]2[NH:19][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:27]=2)[OH:20])[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=N)C(O)c1cc(OC)c(OC)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1N
Solvent: CCO
Product: COc1cc(C(O)c2nc3ccccc3[nH]2)cc([N+](=O)[O-])c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19.7 g of ethyl (3,4-dimethoxy-5-nitro-phenyl)hydroxyacetimidate are dissolved in 500 ml of ethanol, 6.73 g of o-phenylenediamine are added, the mixture is stirred at room temperature for 2 hours and subsequently held at the reflux temperature overnight. After distillation of the solvent, the residue is treated with 50 ml of water, made alkaline with sodium carbonate solution and extracted twice with 250 ml of methylene chloride each time. The organic phase is washed with water, dried over sodium sulfate and evaporated. The orange residue obtained is chromatographed on 400 g of silica gel with methylene chloride/ethyl acetate (1:1). From ether/hexane there is obtained α-(3,4-dimethoxy-5-nitrophenyl)-2-benzimidazolemethanol in the form of yellowish crystals of m.p. 50° (dec.).