Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH:2]1(Br)[CH2:4][CH2:3]1.[CH:6]([O:9][CH2:10][CH2:11][C:12](=[O:14])[CH3:13])([CH3:8])[CH3:7].CC(=O)CC.[Cl-].[NH4+]>O1CCCC1>[CH:2]1([C:12]([OH:14])([CH2:11][CH2:10][O:9][CH:6]([CH3:8])[CH3:7])[CH3:13])[CH2:4][CH2:3]1
Reactant: BrC1CC1
Reactant: CC(=O)CCOC(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCC(C)=O
Solvent: C1CCOC1
Product: CC(C)OCCC(C)(O)C1CC1

Procedure:
To the Grignard reagent [production according to E. Renk et al. J. Am. Chem. Soc. 83, 1987 (1961)], from 9.06 g (0.37 mol) of magnesium and 42.8 g (0.35 mol) of cyclopropyl bromide in 460 cc of absolute tetrahydrofurane, is added dropwise at 5°C over the course of 10 minutes, in an atmosphere of nitrogen and while stirring, a solution of 46 g (0.35 mol) of 4-isopropoxy-2-butanone -butanone in 100 cc of absolute tetrahydrofurane. After stirring the reaction mixture at room temperature for 20 hours, saturated ammonium chloride solution and ice are added and the mixture is extracted with ether. The ether extract is washed with saturated salt solution, dried over sodium sulphate and the ether evaporated off. The resulting 2-cyclopropyl-4-isopropoxy-2-butanol is obtained after distillation at 75°-79°/12 mm as a colourless oil.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1.[O:28]1[CH2:33][CH2:32][CH:31]([CH2:34][C:35](O)=[O:36])[CH2:30][CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:35](=[O:36])[CH2:34][CH:31]5[CH2:32][CH2:33][O:28][CH2:29][CH2:30]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1
Reactant: O=C(O)CC1CCOCC1
Reactant: NC1CCC(CCN2CCN(c3nccc4ccoc34)CC2)CC1
Agent: Cl
Product: O=C(CC1CCOCC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4ccoc34)CC2)CC1

Procedure:
The title compound, white solid (43 mg, 47%), MS (ISP) m/z=455.4 [(M+H)+], mp 213° C., was prepared in accordance with the general method of example 6 from 4-[2-(4-furo[2,3-c]pyridin-7-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and tetrahydropyran-4-yl-acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:28])[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21]O)=[N:19][N:18]=[C:17]1[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26].[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:28])[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][N:33]2[C:32](=[O:34])[C:31]3=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]3[C:29]2=[O:39])=[N:19][N:18]=[C:17]1[CH2:23][CH2:24][N:25]([CH3:26])[CH3:27]
Reactant: CN(C)CCc1nnc(CO)n1-c1ccc(F)cc1C(=O)c1ccccc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(F)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 1B, 2'-chloro-5-fluoro-2-[3-[2-(dimethylamino)ethyl]-5-(hydroxymethyl)-4H-1,2,4-triazol-4-yl]benzophenone in tetrahydrofuran is treated with phthalimide, triphenylphosphine and diethyl azodicarboxylate to give 2'-chloro-5-fluoro-2-[3-[2-(dimethylamino)ethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol- 4-yl]benzophenone.
Reaction SMILES: [C:1]1([N:7]([CH2:14][CH2:15][CH2:16][N:17]2[C:21](=O)C3=CC=CC=C3C2=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=CC=CC=1.CSC1[NH:35][C:34](=[O:36])[C:33]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)=[CH:32][N:31]=1>N1C=CC=CC=1>[CH2:1]([N:7]([CH2:14][CH2:15][CH2:16][NH:17][C:21]1[NH:35][C:34](=[O:36])[C:33]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=2)=[CH:32][N:31]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:6]
Reactant: O=C1c2ccccc2C(=O)N1CCCN(c1ccccc1)c1ccccn1
Reactant: CSc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Solvent: c1ccncc1
Product: CCN(CCCNc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1)c1ccccn1

Procedure:
Substituting ethyl iodide (10.31 g) for n-propyl iodide and using the corresponding molar proportions of the other reagents in the method of example 15(i) gave 2-[N-(3-aminopropyl)-N-ethylamino]pyridine (2.32 g) as an oil. (ii) 2-[N-(3-aminopropyl)-N-ethylamino]pyridine (1.0 g) and 2-methylthio-5-(4-chlorobenzyl)pyrimid-4-one (0.99 g) were heated together under reflux in pyridine (2.5 ml) for 28 hr. After stripping the residue was crystallized from ethanol and recrystallized from ethanol/water to give 2-[3-(N-ethyl-N-pyrid-2-ylamino)propylamino]-5-(4-chlorobenzyl)pyrimid-4-one 0.9 H2O, 1.23 g (79%) m.p. 86°-89° C.
Reaction SMILES: C(OC1C=C(C=[CH:17][CH:18]=1)C(OC)=O)C1C=CC=CC=1.[S:19]([OH:23])(=[O:22])(=[O:21])[CH3:20].S(O)(=O)(=O)C.[NH2:29][NH:30][C:31]([NH2:33])=[NH:32].N>>[S:19]([OH:23])(=[O:22])(=[O:21])[CH3:20].[NH2:33][C:31]1[N:30]=[N:29][CH:17]=[CH:18][N:32]=1
Reactant: COC(=O)c1cccc(OCc2ccccc2)c1
Reactant: N=C(N)NN
Agent: CS(=O)(=O)O
Agent: N
Product: Nc1nccnn1

Procedure:
Prepared by reacting acenaphthenequinone (3) with aminoguanidine bismesylate for 24 hrs using the above procedure except that the basification step with ammonia was omitted. The title compound was obtained as bright yellow prisms in 83.2%, mpt=264-266° (froth)
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:17])[NH:15][NH2:16])=[N:6]1.[O:22]=[CH:23][C:24](OCC)=O>C(O)C>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][CH:24]=[C:23]([OH:22])[N:17]=2)=[N:6]1
Reactant: CCOC(=O)C=O
Reactant: N=C(NN)c1nn(Cc2ccccc2F)c2ncccc12
Solvent: CCO
Product: Oc1cnnc(-c2nn(Cc3ccccc3F)c3ncccc23)n1

Procedure:
22.000 g (purity 68%, approx. 52.621 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidohydrazide in 220 ml of ethanol were initially introduced, admixed dropwise with 18.265 (89.455 mmol) of ethyl oxoacetate (50% strength solution in toluene) and heated under reflux overnight. The resulting suspension was concentrated on a rotary evaporator and stirred with diethyl ether. The solid was filtered off with suction and dried under high vacuum. Further purification was effected by chromatography on silica gel (mobile phase: dichloromethane/methanol, gradient 30:1→10:1). This gave 12.07 g of the target compound (purity 69%; 49% of theory).
Reaction SMILES: Cl.Cl.Cl.[CH2:4]1[C:13]2[C:8](=[CH:9][CH:10]=[N:11][CH:12]=2)[CH2:7][CH2:6][N:5]1[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([CH3:21])[CH:15]=1.C(N(CC)C(C)C)(C)C.[C:31]1([CH3:40])[CH:36]=[CH:35][CH:34]=[C:33]([N:37]=[C:38]=[O:39])[CH:32]=1>C(Cl)Cl>[CH2:4]1[C:13]2[C:8](=[CH:9][CH:10]=[N:11][CH:12]=2)[CH2:7][CH2:6][N:5]1[C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:38]([NH:37][C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([CH3:40])[CH:32]=2)=[O:39])=[C:16]([CH3:21])[CH:15]=1
Reactant: Cc1cc(N2CCc3ccncc3C2)ccc1N
Reactant: Cc1cccc(N=C=O)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(NC(=O)Nc2ccc(N3CCc4ccncc4C3)cc2C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
To a mixture of 4-(3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2-methylaniline trihydrochloride (35 mg, 0.10 mmol) and N,N-diisopropylethylamine (0.061 mL, 0.35 mmol) in 1.5 mL CH2Cl2 at rt was added meta-tolyl isocyanate (0.019 mL, 0.15 mmol) and the reaction stirred at rt for 3 hours. The reaction was quenched into a brine/aqueous Na2CO3 solution, then extracted with EtOAc. The EtOAc layer was washed with brine/aqueous Na2CO3 solution, dried with anhydrous Na2SO4, and evaporated to a solid. The solid was triturated with EtOAc and then with 20% CHCl3/EtOAc to give the title compound as a beige solid (21 mg, 56%). 1H NMR (Acetone-d6) δ: 8.44 (s, 1H), 8.31 (d, J=5.0 Hz, 1H), 8.07 (s, 1H), 7.56-7.61 (m, 1H), 7.35-7.38 (m, 1H), 7.26-7.34 (m, 2H), 7.08-7.16 (m, 2H), 6.92-6.95 (m, 1H), 6.87-6.92 (m, 1H), 6.75-6.80 (m, 1H), 4.39 (s, 2H), 3.55 (t, J=5.9 Hz, 2H), 2.98 (td, J=5.9, 0.9 Hz, 2H), 2.27 (s, 3H), 2.26 (s, 3H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]2[O:9][C:10]3[C:15]([C:16]([O:18][CH2:19][C:4]=2[CH:3]=1)=[O:17])=[C:14]([O:20][CH3:21])[C:13]([C@@H:22]([OH:27])[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:12][CH:11]=3.F[B-](F)(F)F.[O:33]=[N+:34]=[O:35]>C(Cl)Cl>[OH:8][C:6]1[C:5]2[O:9][C:10]3[CH:11]=[CH:12][C:13]([CH:22]([OH:27])[CH2:23][CH:24]([CH3:25])[CH3:26])=[C:14]([O:20][CH3:21])[C:15]=3[C:16](=[O:17])[O:18][CH2:19][C:4]=2[C:3]([N+:34]([O-:35])=[O:33])=[C:2]([CH3:1])[CH:7]=1
Reactant: COc1c([C@@H](O)CC(C)C)ccc2c1C(=O)OCc1cc(C)cc(O)c1O2
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COc1c(C(O)CC(C)C)ccc2c1C(=O)OCc1c(c(O)cc(C)c1[N+](=O)[O-])O2
Temperature: -68 °C
Reaction time: 1 h

Procedure:
150 mg (0.4 mmol) of penicillide are dissolved in 15 ml of methylene chloride and stirred for 1 h under inert gas at a bath temperature of -68° C. after addition of 0.8 ml of a 0.5 molar solution of nitronium tetrafluoroborate. The reaction mixture is added to ice. After extraction with methylene chloride, washing with water and bicarbonate, drying and evaporating, the residue is chromatographed on silica gel in petroleum ether:ether=1:1. After evaporating, 86 mg (51% of theory) of yellowish solid are obtained.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:9]([CH2:10][CH2:11][C:12]3[C:13]4[C@:20]([CH3:28])([CH2:21][CH2:22][C:23]=32)[C@@H:16]([C@@H:17]([OH:19])[CH3:18])[CH2:15][CH:14]=4)[C:8]1([CH3:30])[CH3:29])[CH3:5])[CH3:2].CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:56][CH:57]=[C:58]([CH3:60])[CH3:59]>O.C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:9]([CH2:10][CH2:11][C:12]3[C:13]4[C@:20]([CH3:28])([CH2:21][CH2:22][C:23]=32)[C@@H:16]([C@H:17]([CH3:18])[O:19][CH2:56][CH:57]=[C:58]([CH3:60])[CH3:59])[CH2:15][CH:14]=4)[C:8]1([CH3:30])[CH3:29])[CH3:5])[CH3:2]
Reactant: CC(C)=CCBr
Reactant: CCOC(C)O[C@H]1CC[C@]2(C)C3=C(CC[C@H]2C1(C)C)C1=CC[C@H]([C@H](C)O)[C@@]1(C)CC3
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(C)O[C@H]1CC[C@]2(C)C3=C(CC[C@H]2C1(C)C)C1=CC[C@H]([C@H](C)OCC=C(C)C)[C@@]1(C)CC3
Temperature: 70 °C

Procedure:
xvii)—A mixture of (3β,5α,20S)-3-[(1-ethoxyethyl)oxy]-4,4-dimethylpregna-8,14-dien-20-ol (17; 1.65 g), dry toluene (115 ml), potassium t-butoxide (5.68 g), 18-crown-6 (0.99 g) and 4-bromo-2-methyl-2-butene (4.44 ml) was heated at 70° C. for 1 h. After cooling, the reaction mixture was poured into water and the product extracted into ethyl acetate. The combined organic phases were washed with water and with brine, dried over sodium sulfate, and concentrated under reduced pressure to give (3β,5α,20S)-3-[(1-ethoxyethyl)oxy]-4,4-dimethyl-22-oxacholesta-8,14,24-triene (compound 18; 2.30 g), which was used in the following step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9]O)[C:5]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])=[CH:4][N:3]=1.[Na].C(=S)=[S:18].[ClH:20]>C(O)C>[ClH:20].[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][SH:18])[C:5]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])=[CH:4][N:3]=1
Reactant: Cc1ncc(C=CC(=O)O)c(CO)c1O
Reactant: S=C=S
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1ncc(C=CC(=O)O)c(CS)c1O

Procedure:
A mixture of 1.23 g. of 2-methyl-3-hydroxy-4-hydroxymethylpyridine-5-acrylic acid, 1 g. of sodium metal, 5 ml. of carbon disulfide, and 75 ml. of absolute ethanol was refluxed for 26 hours. Concentrated hydrochloric acid (3 ml.) was added and the mixture was evaporated to dryness. The residue was extracted with 125 ml. of boiling ethanol and filtered hot. Evaporation of the extract gave a syrup which was crystallized from chloroform-ether to give 2-methyl-3-hydroxy-4-mercaptomethylpyridine-5-acrylic acid hydrochloride, m.p. 227°-228° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br>C(Cl)Cl>[OH:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:10][C:11]([OH:13])=[O:12])=[CH:3][C:2]=1[CH3:1]
Reactant: COc1ccc(CC(=O)O)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(CC(=O)O)ccc1O
Temperature: 25 °C
Yield: 74.3 %

Procedure:
To a solution of 3-methyl-4-methoxyphenylacetic acid (2.3 g., 12.8 mmol) in anh CH2Cl2, cooled to 0° C., was added 15 ml of a solution of BBr3 (1.0 M in CH2Cl2) via syringe. After addition was complete, the reaction was allowed to warm to room temperature and then quenched with 5 ml water. The CH2Cl2 was removed and the residue was extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated to yield the title compound (1.58 g, 75% yield): ES−MS (m/z) 167 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[O:14][C@:15]3([CH2:23][N:24]=2)[CH:20]2[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]2)[CH2:16]3)[N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[O:14][C@:15]3([CH2:23][N:24]=2)[CH:20]2[CH2:19][CH2:18][N+:17]([O-:33])([CH2:22][CH2:21]2)[CH2:16]3)[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1nc(NC2=NC[C@@]3(CN4CCC3CC4)O2)cc2ccccc12
Solvent: ClC(Cl)Cl
Product: [O-][N+]12CCC(CC1)[C@]1(CN=C(Nc3cc4ccccc4c(F)n3)O1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
To (R)—N-(1-Fluoroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.063 g, 0.193 mmol) in CHCl3 (15 mL) was added m-CPBA (0.034 g, 0.195 mmol) at room temperature. The reaction was stirred at room temperature for 3 hours. TLC showed lower spot and no starting material. The mixture was purified by chromatography (Biotage: 15-20% of 9:1 MeOH:NH4OH in CHCl3; ˜1.1 L) to yield the pure fractions. The fractions were combined and the solvent was removed to yield (S)-2-(1-fluoroisoquinolin-3-ylamino)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]1′-oxide (0.050 g, 0.146 mmol, 76% yield) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.12-8.42 (m, 1H), 8.01 (d, J=8.2 Hz, 1H), 7.86 (br. s., 1H), 7.73 (br. s., 1H), 7.43-7.60 (m, 1H), 6.93-7.35 (m, 1H), 3.69-4.05 (m, 1H), 3.58 (br. s., 1H), 3.00-3.33 (m, 6H), 2.19 (br. s., 2H), 1.94 (d, J=10.1 Hz, 3H). LC/MS: retention time 1.78 (M+1=343.1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:33]1([CH2:36]N)[CH2:35][CH2:34]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:36][CH:33]3[CH2:35][CH2:34]3)=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NCC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(=O)NCC2CC2)C1

Procedure:
Following general method 6, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and cyclopropanemethylamine, afforded the crude title compound as an orange foam (114 mg); LCMS (method B): RT=3.94 min, M+H+=500. This crude material was used in the next step without further purification.
Reaction SMILES: O[C:2]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:14]=2)[CH2:4][CH2:3]1>Cl>[C:22]1([C:2]2[CH2:7][CH2:6][N:5]([CH2:8][C:9]3[CH:10]=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=4)[CH:14]=3)[CH2:4][CH:3]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OC1(c2ccccc2)CCN(Cc2cncc(-c3ccc(F)cc3)c2)CC1
Agent: Cl
Product: Fc1ccc(-c2cncc(CN3CC=C(c4ccccc4)CC3)c2)cc1

Procedure:
3.62 g of 3-(4-hydroxy-4-phenyl-1-piperidyl-methyl)-5-p-fluorophenyl-pyridine (obtainable by reaction of 3-bromomethyl-5-p-fluorophenyl-pyridine with 4-piperidone, subsequent reaction with C6H5Li and hydrolysis) are heated at 50° with 40 ml of 1 N hydrochloric acid for 2 hours and the mixture is worked up in the customary manner to give 3-(4-phenyl-1,2,3, 6-tetrahydropyridyl-methyl)-5-p-fluorophenyl-pyridine, melting point: 128°-129°.
Reaction SMILES: [C-:1]#[N:2].[Na+].O.Br[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=1>C(O)C>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:1]#[N:2])=[CH:8][CH:9]=1)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: [C-]#N
Reactant: CC(C)(C)C(=O)c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)C(=O)c1ccc(CC#N)cc1
Temperature: 50 °C

Procedure:
A solution of 34.3 g. (0.700 mole) sodium cyanide in 40 ml. of water is warmed to 50°C. and a solution of α-bromo-4-pivaloyl toluene in 85 ml. ethanol is then added dropwise at such a rate as to maintain the temperature at 50°C. After the addition is complete, the mixture is refluxed for four hours. The excess ethanol is removed in vacuo and the resulting residue is treated with ether/water. The layers are separated and the ether is washed with cold 50% sulfuric acid, water and sodium bicarbonate; then the ether layer is dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is distilled in vacuo to give 4-pivaloylphenyl acetonitrile (b.p. 143°-148°C/0.75 mm n22 =1.5244.)
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[CH2:5][NH:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:25][C:26](OC(C)=O)=[O:27]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[CH2:5][N:4]([C:26](=[O:27])[CH3:25])[CH2:3]1
Reactant: CC1(C)CNCc2cc([N+](=O)[O-])ccc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1Cc2cc([N+](=O)[O-])ccc2C(C)(C)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-(dimethylamino)pyridine (0.125 g, 1.02 mmol), 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydro-isoquinoline (0.21 g, 1.02 mmol), DIEA (0.53 mL, 3.06 mmol), and Ac2O (0.19 mL, 2.04 mmol) in 7 mL of CH2Cl2 was stirred at RT under N2 for two days. The volatiles were removed under vacuum. The residue was partitioned between EtOAc and brine, and the organic portion was dried with Na2SO4, filtered, and concentrated. The crude material was purified by flash column chromatography (2-3% MeOH in CH2Cl2), to yield the desired compound as a light yellowish solid. MS (ES+): 249.3 (M+H)+. Calc'd for C13H16N2O3-248.28.
Reaction SMILES: FC(F)(F)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15](Cl)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C>ClCCl>[CH2:27]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:15]([C:10]2[C:9]([C:6]3[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH2:22][CH2:23]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3 g (0.014 mol) of 4′-trifluoromethyl-biphenyl-2-carboxylic acid chloride, dissolved in 30 ml of dichloromethane, are added dropwise at 15 to −20° C. to a solution of 2.65 ml (0.013 mol) of 4-amino-1-benzyl-piperidine and 6 ml (0.043 mol) of triethylamine in 100 ml of dichloromethane. The mixture is stirred for 14 hours at ambient temperature. The reaction solution is extracted with a mixture of I molar sodium hydrogen carbonate solution and 1N sodium hydroxide solution. The organic phase is dried over sodium sulphate and the solvent is eliminated. The residue is recrystallised from 650 ml of ethanol.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)[CH2:2][CH3:3].C(=O)([O-])O.[Na+].Br[CH2:23][C:24]1[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]>O>[CH2:1]([N:4]([CH2:23][C:24]1[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCOC(=O)c1ccccc1CBr
Reactant: CCCNc1ccc(CC(=O)OCC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCN(Cc1ccccc1C(=O)OCC)c1ccc(CC(=O)OCC)cc1
Yield: 85.8 %

Procedure:
N-n-propyl-4-ethoxycarbonylmethylaniline (11.1 g, b.p. 131°-135°C./0.5 mmHg), sodium hydrogencarbonate (6.3 g), water (10 ml), and ethyl 2-bromomethylbenzoate (14.6 g) were treated in the same manner as described in Example 1 to obtain N-n-propyl-N-(2-ethoxycarbonylbenzyl)-4-ethoxycarbonylmethylaniline (16.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[CH:25][C:26](=[O:30])[N:27]([CH3:29])[N:28]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:22][C:23]2[CH:24]=[CH:25][C:26](=[O:30])[N:27]([CH3:29])[N:28]=2)[C:9]2[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nn(C)c(C)c1C(O)c1ccc(Cl)cc1
Reactant: Cn1nc(N)ccc1=O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1nn(C)c(C)c1C(Nc1ccc(=O)n(C)n1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy with the procedure described in Step 1.4 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (Step 28.2) and 6-amino-2-methylpyridazin-3(2H)-one (Step 32.1). tR: 4.25 min (HPLC 1); tR: 0.94 min (LC-MS 2); ESI-MS: 416 [M+H]+ (LC-MS 2); Rf=0.43 (CH2Cl2/MeOH 9:1).
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[CH3:8].[Li]CCCC.CN([CH:17]=[O:18])C.C>C(OCC)C.CCCCCC>[CH3:8][C:3]1[S:4][CH:5]=[C:6]([CH3:7])[C:2]=1[CH:17]=[O:18]
Reactant: Cc1csc(C)c1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1csc(C)c1C=O
Temperature: -78 °C
Reaction time: 4 h

Procedure:
A solution of 3-bromo-2,4-dimethylthiophene, B8, (5.9 g, 0.031 mol) in 200 mL of diethyl ether was cooled to -78° C., and a solution of n-BuLi (25.0 mL, 1.6M) in hexanes was added dropwise. When the addition was complete, the reaction was stirred at -78° C. for 4 h. TLC analysis indicated very little conversion so reaction mixture was warmed slowly to -25° C. Then a solution of DMF (4.5 g, 0.062 mol) in 25 mL of ether was cannulated into the reaction mixture which was allowed to warm to ambient temperature and was stirred overnight. The reaction was quenched with water and extracted twice with diethyl ether. The organic extracts were combined, washed with twice with water and then brine and dried (MgSO4). The solution was filtered and concentrated to provide an amber oil which was dissolved in hexane. The solution was treated with charcoal, filtered through Dicalite, and concentrated to give 2,4-dimethylthiophene-3-carboxaldehyde, C,8, which was used directly in the next step. ##STR60##
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:21]C(=O)OC(C)(C)C)[CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCOCC1.Cl>C1COCC1>[NH2:21][C@@H:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:9][N:10]1[C:11](=[O:20])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]1=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Yield: 110.8 %

Procedure:
A solution of tert-butyl {(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (2.8 g, 7.25 mmol) in 4 M HCl dioxane (10 mL, 40 mmol) and THF (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure to afford 2.3 g (99% yield) of the desired product. LC-MS found: 287.1 (M+H)+.