Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([NH:8]N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH:15]2[CH2:16][C:17]([CH2:19][CH:12]1[CH2:13][CH2:14]2)=O>C(O)C>[CH3:10][N:11]1[CH:12]2[C:19]3[C:7]4[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=4)[NH:8][C:17]=3[CH2:16][CH:15]1[CH2:14][CH2:13]2
Reactant: NNc1ccccc1
Reactant: CN1C2CCC1CC(=O)C2
Agent: Cl
Solvent: CCO
Product: CN1C2CCC1c1c([nH]c3ccccc13)C2
Temperature: 25 °C

Procedure:
A mixture of phenylhydrazine hydrochloride (2.89 g, 19.99 mmol; Aldrich) and tropinone (2.78 g, 19.99 mmol; Aldrich) in ethanol (15 mL) was heated at reflux for 3 hours. The resulting solution was cooled to room temperature and the volatiles were removed under vacuum. The residue was taken up in 7% (w/w) H2SO4/dioxane (42 g) and heated at 60° C. under nitrogen for 14 hours. The mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in water (25 mL) and the solution was made basic (pH >9) by addition of 25% NaOH (20 mL). The resulting mixture was extracted with CH2Cl2 (2×25 mL) and the extract was concentrated to residue which was purified by flash chromatography (120 g silica eluted with CH2Cl2—CH3OH-14.8 M aqueous, 90:10:1) followed by crystallization from ethyl acetate to provide the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.56-1.72 (m, 1H), 1.89 (t, J=9.3 Hz, 1H), 2.20-2.34 (m, 2H), 2.36 (s, 3H), 2.46 (d, J=16.7 Hz, 1H), 3.25 (dd, J=16.7, 4.8 Hz, 1H), 3.55 (t, J=5.4 Hz, 1H), 4.20 (d, J=5.2 Hz, 1H), 6.90-7.05 (m, 2H), 7.25 (d, J=7.1 Hz, 1H), 7.38 (d, J=7.1 Hz, 1H); MS (DCI) m/z 213 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:14]=3[O:13][CH2:12]2)=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].[Cl:25][C:26]1[N:31]=[C:30](Cl)[CH:29]=[CH:28][N:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][C:18]([O:20][C:28]4[CH:29]=[CH:30][N:31]=[C:26]([Cl:25])[N:27]=4)=[CH:19][C:14]=3[O:13][CH2:12]2)=[O:10])=[CH:4][C:3]=1[C:21]([F:22])([F:24])[F:23]
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N1COc2cc(O)ccc21
Reactant: Clc1ccnc(Cl)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N1COc2cc(Oc3ccnc(Cl)n3)ccc21

Procedure:
To a solution of 290 mg (0.81 mMol) 6-hydroxy-benzooxazole-3-carboxylic acid (4-chloro-3-trifluoromethyl-phenyl)-amide (Step 1.3) and 134 mg (0.90 mMol) 2,4-dichloropyrimidine in 15 ml NMP, 377 mg (1.78 mMol) K3PO4 are added. After 2 h at rt the reaction mixture is dissolved in EtOAc and water, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; CH2Cl2→CH2Cl2/EtOAc 9:1) gives the title compound: m.p.: 140-142° C.; MS: [M+1]+=471/473.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[CH3:8][N:7]1[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:3]=[CH:2]1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnc(-c2ccncc2)cc1=O
Yield: 160.5 %

Procedure:
A solution of 2S-(4-bromophenyl)-4-benzyloxycarbonyl-piperazine (788 mg, 2.10 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (444 mg, 2.00 mmol) and diisopropylethylamine (0.70 mL, 4.00 mmol) in dimethylformamide (20 mL) was stirred at 80° C. for 3 h. The reaction mixture was poured into water and the whole was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. Chromatographic purification of the residue provided 2-(2S-(4-bromophenyl)-4-benzyloxycarbonyl-piperazin-1-yl)}-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (601 mg, 54%). 1H NMR (300 MHz, CDCl3), δ 3.05(1H, m), 3.30-3.48(3H, m), 3.64(3H, s), 4.08-4.22(2H, m), 4.68(1H, m), 5.15(1H, d, J=12.3 Hz), 5.21(1H, d, J=12.6 Hz), 6.63(1H, s), 7.21(2H, d, J=8.4 Hz), 7.28-7.39(7H, m), 7.59(2H, d, J=6.3 Hz), 8.68(2H, d, J=6.3 Hz).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:17][C:16]2[C:15]3[C:10](=[C:11]([F:18])[CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH2:7][CH2:6]1)(=O)[CH3:2].C(NC1CCC(=O)CC1)(=O)C.Cl.FC1C=CC=CC=1NN.Cl>C(O)C>[CH2:1]([NH:4][CH:5]1[CH2:17][C:16]2[C:15]3[C:10](=[C:11]([F:18])[CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH2:7][CH2:6]1)[CH3:2]
Reactant: CC(=O)NC1CCc2[nH]c3c(F)cccc3c2C1
Agent: CC(=O)NC1CCC(=O)CC1
Agent: Cl
Agent: NNc1ccccc1F
Solvent: CCO
Product: CCNC1CCc2[nH]c3c(F)cccc3c2C1

Procedure:
3-Acetamido-8-fluoro-1,2,3,4-tetrahydrocarbazole -- A solution of 7.8 g. of 4-acetamidocyclohexanone and 8.1 g. of 2-fluorophenylhydrazine hydrochloride in 75 ml. of absolute ethyl alcohol and 25 ml. of 5-N hydrogen chloride in absolute ethyl alcohol was heated under reflux for two hours, cooled, filtered, and the filtrate was evaporated to dryness. The residue was dissolved in chloroform and adsorbed on a column of aluminum oxide. Dilution with ether yielded first a small amount of side-product followed by the desired product which was recrystallized by dissolving in methyl alcohol, adding toluene, and evaporation of the methyl alcohol, to give 10.5 g. of 3-acetamido-8-fluoro-1,2,3,4-tetrahydrocarbazole, m.p. 202°-204°C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[N:25]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[N:23]([CH3:29])[C:22]=2[CH:30]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC.N>[Cu](I)I.CS(C)=O>[CH:26]1([C:24]2[N:23]([CH3:29])[C:22]3[CH:30]=[C:18]([N:11]4[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]5[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=5)=[CH:9][C:10]4=[O:14])[CH:19]=[CH:20][C:21]=3[N:25]=2)[CH2:27][CH2:28]1
Reactant: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Reactant: Cn1c(C2CC2)nc2ccc(Br)cc21
Agent: I[Cu]I
Agent: CNCCNC
Agent: N
Solvent: CS(C)=O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Temperature: 150 °C
Reaction time: 2 h
Yield: 36.9 %

Procedure:
A mixture of 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (2.44 g), 6-bromo-2-cyclopropyl-1-methyl-1H-benzimidazole (2.8 g), potassium carbonate (4.62 g), N,N′-dimethylethylenediamine (1.20 ml), copper iodide (2.12 g) and DMSO (56 ml) was stirred at 150° C. under Ar atmosphere for 2 h. After cooling to 0° C., 28% NH3 solution (56.0 ml) was added. The mixture was stirred at 0° C. for 1 h and then at room temperature for 1 h. The precipitate was collected by filtration and washed with water and IPE. The collected material was dissolved in THF (500 ml), passed through a short NH silica gel column (EtOAc 100%) and concentrated in vacuo. The resulting solid was collected, washed with IPE (50 ml) and then EtOAc (50 ml), and dissolved in MeOH. To the solution was added activated carbon (ca. 200 mg), and the mixture was stirred at room temperature for 10 min. The insoluble material was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc), and recrystallized from EtOH/water to give the title compound (1.60 g) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)[N:9]=2)=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:46])OC2C=CC=CC=2)=[CH:33][CH:32]=1>>[CH3:30][NH:29][C:27]([NH:26][C:23]1[CH:22]=[CH:21][C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:38](=[O:46])[NH:37][C:34]4[CH:33]=[CH:32][N:31]=[CH:36][CH:35]=4)=[CH:7][CH:6]=3)[N:9]=2)=[CH:25][CH:24]=1)=[O:28]
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3CCOCC3)n2)cc1
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CCOCC3)n2)cc1
Yield: 3.9 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl pyridin-4-ylcarbamate. Yield 75 mg, 3.9% yield.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][N:13]([CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH3:29])[C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[ClH:37]>CO>[ClH:37].[ClH:37].[C:1]12([CH2:11][CH2:12][N:13]([CH2:26][CH2:27][NH:28][CH3:29])[C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[O:15])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CN(CCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCCc1ccncc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CNCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCCc1ccncc1
Temperature: 25 °C

Procedure:
Methanol (4.4 ml) was added to 1-[2-(1-adamantyl)ethyl]-1-[2-[N-(t-butoxycarbonyl)-N-methylamino]ethyl]-3-[3-(4-pyridyl)propyl]urea (Compound No. 1-26) (0.30 g, 0.6 mmol), a calcium chloride tube was attached to the vessel, and the mixture was stirred at room temperature. A 10% solution of hydrogen chloride in methanol (4.4 ml) was added to the mixture, the whole was stirred for one day, and the reaction mixture was concentrated under reduced pressure to give 0.30 g (quantitatively) of the titled compound as pale yellow noncrystalline powder.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](S(C)(=O)=O)[C:5]2[N:6]([C:8]([I:11])=[CH:9][N:10]=2)[CH:7]=1.[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18].O>CN1CCCC1=O>[Br:1][C:2]1[N:3]=[C:4]([NH:20][CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]2[N:6]([C:8]([I:11])=[CH:9][N:10]=2)[CH:7]=1
Reactant: CS(=O)(=O)c1nc(Br)cn2c(I)cnc12
Reactant: CC(C)CN
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)CNc1nc(Br)cn2c(I)cnc12
Temperature: 23 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a stirred solution of 5.08 g (12.64 mmol) 6-bromo-3-iodo-8-methanesulfonyl-imidazo[1,2-a]pyrazine which was prepared according to intermediate example 1c in 100 mL 1-methylpyrrolidin-2-one were added 3.77 mL isobutylamine. After stirring at 23° C. for 2 hours, 500 mL water were added and the mixture was extracted with ethyl acetate. The organic phase was filtered, evaporated and the residue was recrystallized from methanol/water to yield 3.87 g (78%) of the title compound.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][NH2:14])[C:5]=2[CH2:4][CH2:3]1.[Br:15]N1C(=O)CCC1=O>C(O)(=O)C>[Br:15][C:9]1[CH:8]=[CH:7][C:6]2[O:2][CH2:3][CH2:4][C:5]=2[C:10]=1[CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: NCCCc1cccc2c1CCO2
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: CC(=O)O
Product: NCCCc1c(Br)ccc2c1CCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the free base (200 mg) liberated from 3-(2,3-dihydro-benzofuran-4-yl)-propylamine hydrochloride and N-bromosuccinimide (215 mg) in acetic acid (5 ml) was stirred at room temperature overnight. The solution was evaporated to dryness and the residue taken up in water, basified to pH9-10 with 2N sodium hydroxide and extracted with ethyl acetate. The extracts were dried and evaporated to give the title compound (256 mg) as a pale yellow oil. Tic SiO2 (Dichloromethane/methanol/0.880 ammonia 75:8:1) Rf 0.53
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[C:15]3[CH2:21][CH2:20][N:19]([C:22]([CH2:24][S:25][CH:26]([CH3:28])[CH3:27])=O)[CH2:18][C:16]=3[S:17][C:13]=2[N:12]2[C:29]([CH3:32])=[N:30][N:31]=[C:11]2[CH2:10][N:9]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[C:15]3[CH2:21][CH2:20][N:19]([C:22]([CH2:24][S:25][CH:26]([CH3:28])[CH3:27])=[S:42])[CH2:18][C:16]=3[S:17][C:13]=2[N:12]2[C:29]([CH3:32])=[N:30][N:31]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1sc3c(c1C(c1ccccc1Cl)=NC2)CCN(C(=O)CSC(C)C)C3
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1nnc2n1-c1sc3c(c1C(c1ccccc1Cl)=NC2)CCN(C(=S)CSC(C)C)C3

Procedure:
Into the same reactor as in example 1, were poured, under nitrogen circulation, 300 ml of toluene, 12.2 g (0.025 mol) of the product of example 1 and 4.75 g (0.0117 mol) of Lawesson's reagent. The reaction mixture was slowly warmed over two hours to reflux temperature and reflux was maintained for two hours. After evaporation to dryness and treatment with dichloromethane, the solution was passed on a silica gel column, eluting with dichloromethane:methanol 95:5 by volume. After evaporation to dryness of the resulting solution, the residue was recrystallized from methanol. Yield 10.2 g (82%).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][S:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](OCC)=[O:25])=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.Cl>O1CCCC1>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][S:15][C:16]3[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:20][CH:21]=3)[N:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1ccc(SCc2coc(/C=C/c3ccccc3)n2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCCCc1ccc(SCc2coc(/C=C/c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a solution of ethyl 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethylthio]phenyl]propionate (205 mg) in tetrahydrofuran (10 ml) was added lithium aluminum hydride at 0° C. and then stirred for one hour at room temperature. To the reaction mixture were added water and 1N-hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure to give crystals of 3-[4-[2-[(E)-2-phenyl ethenyl]-4-oxazolylmethylthio]phenyl]propanol (135 mg, 77%). Recrystallization from ethyl acetate-hexane gave colorless needles, mp 91-92° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[NH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1>CC(O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[N:3]=1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: NCCc1ccc(O)cc1
Solvent: CC(C)O
Product: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(Cl)nc21
Reaction time: 8 h

Procedure:
2,6-dichloro-9-isopropyl-9H-purine (1.1 mmol) was mixed with tyramine (1.16 mmol) dissolved in i-PrOH (6 ml) and the mixture was stirred overnight. The reaction mixture was concentrated, and the residue purified by column chromatography on silica gel, eluting with hexane/EtOAc (5:1 to 1:2) to afford the title compound as a white solid. 1H NMR (500 MHz, CDCl3): δ 9.21 (br, 1H), 8.49 (s, 1H), 7.80 (s, 1H), 7.10 (d, 2H), 6.73 (d, 2H), 4.87 (m, 1H), 4.03 (t, 2H), 3.01 (t, 2H), 1.68 (d, 6H); HRMS (EI) calcd for C16H18ClN5O (M+H±) 332.1273, found 332.1278.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[O:6])[CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:13][C:14](Cl)([Cl:19])[C:15]([F:18])([F:17])[F:16].[Cl-].[NH4+]>CN(C=O)C.[Zn]>[CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]([OH:6])[C:14]([Cl:19])([Cl:13])[C:15]([F:18])([F:17])[F:16])[CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C1C(C=O)C1(C)C
Reactant: FC(F)(F)C(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CN(C)C=O
Product: CCOC(=O)C1C(C(O)C(Cl)(Cl)C(F)(F)F)C1(C)C
Temperature: 50 °C
Reaction time: 10 h
Yield: 57 %

Procedure:
To a solution of 174 mg (1.02 mmol) of ethyl 2,2-dimethyl-3-formylcyclopropanecarboxylate in 1 ml of DMF, 96 mg (1.47 mmol) of zinc powder and 0.356 ml (3.00 mmol) of 1,1,1-trichlorotrifluoroethane were added, and the mixture was stirred at 0° C. for 2 hours and at 50° C. for 10 hours. Then, 2 ml of a saturated ammonium chloride aqueous solution was added thereto, and the mixture was extracted with diethyl ether (2 ml×3 times). The ethereal extract was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin layer chromatography (silica gel, dichloromethane/hexane=1/1) to obtain 188 mg of ethyl 2,2-dimethyl-3-(1-hydroxy-2,2-dichloro-3,3,3trifluoropropyl)cyclopropanecarboxylate (a mixture of two stereoisomers in a ratio of 94:46).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21](C)[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH2:20][CH2:21][CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCNn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.073 g, 0.18 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 2% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.95 (t, J=7.35 Hz, 3 H) 1.54 (m, 2 H) 2.99 (t, J=6.99 Hz, 2 H) 6.66 (s, 1 H) 7.44 (d, J=5.15 Hz, 1 H) 7.55 (t, J=7.54 Hz, 1 H) 7.64 (d, J=8.09 Hz, 1 H) 7.78 (t, J=7.17 Hz, 1 H) 7.93 (d, J=7.72 Hz, 1 H) 8.35 (d, J=5.15 Hz, 1 H) 14.20 (s, 1 H) 14.81 (s, 1 H). MS (ESI−) m/z 403 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[C:14](C1C=CC=C(C(C)(C)C)C=1O)(C)(C)[CH3:15].CC([O-])=O.[Na+]>CN(C)C(=O)C>[CH:14]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1)=[CH2:15]
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C=Cc1ccc2cc(OC)ccc2c1

Procedure:
23.7 g of 2-bromo-6-methoxynaphthalene (100 mmol) are dissolved in 150 ml of N,N-dimethylacetamide. 1 mg of 2,6-di-tert-butylphenol, 10 g of NaOAc (1.2 eq) and 50 mg of palladacycle are added. The solution is transferred to a V4A stirred autoclave and is stirred at 140° C. under an ethylene pressure of 20 bar until conversion is complete. Time: from 10 to 16 hours
Reaction SMILES: [Br-:1].[OH:2][C@@H:3]1[CH:8]2[CH2:9][CH2:10][N+:5]([CH2:11][C:12](=[O:19])[NH:13][C:14]3[CH:18]=[CH:17][O:16][N:15]=3)([CH2:6][CH2:7]2)[CH2:4]1.[C:20]1(C2C(N)=NOC=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>NC1C=CON=1>[Br-:1].[OH:2][C@@H:3]1[CH:8]2[CH2:9][CH2:10][N+:5]([CH2:11][C:12](=[O:19])[NH:13][C:14]3[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:17][O:16][N:15]=3)([CH2:6][CH2:7]2)[CH2:4]1
Reactant: Nc1nocc1-c1ccccc1
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1ccon1
Agent: Nc1ccon1
Agent: [Br-]
Product: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1nocc1-c1ccccc1

Procedure:
This compound is prepared by an analogous method to (R)-3-hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate A) by replacing in 3-aminoisoxazol in step (Ai) with 4-phenylisoxazol-3-ylamine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([CH3:31])=[C:21]([NH:23][C:24]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)=[S:25])[CH:22]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[N:32]1C=CC(N)=[C:34](N)[CH:33]=1>CN(C=O)C>[NH2:32][C:33]1[CH:34]=[CH:27][N:28]=[CH:29][C:30]=1[NH:26][C:24]([NH:23][C:21]1[CH:22]=[C:17]([C:15]([N:12]2[CH2:13][CH2:14][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH2:10][CH2:11]2)=[O:16])[CH:18]=[CH:19][C:20]=1[CH3:31])=[S:25]
Reactant: Nc1ccncc1N
Reactant: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1NC(=S)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1NC(=S)Nc1cnccc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)-1H-imidazole-1-carbothioamide (281.1) in DMF continued from the prior step was added pyridine-3,4-diamine (0.034, 0.32 mmol). The mixture was stirred at room temperature for 3 hours. LCMS showed the reaction was complete. The reaction was carried to the next step without workup or purification. m/z (ES+) 471 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11](O)[CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)[CH2:16][CH2:15]3)=[CH:10][C:5]=2[O:4][C:3]1=[O:31]>Br>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=[CH:12][CH2:13][N:14]3[CH2:15][CH2:16][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)[CH2:18][CH2:19]3)=[CH:10][C:5]=2[O:4][C:3]1=[O:31]
Reactant: Cn1c(=O)oc2cc(C(O)CCN3CCN(c4cccc(C(F)(F)F)c4)CC3)ccc21
Agent: Br
Product: Cn1c(=O)oc2cc(C=CCN3CCN(c4cccc(C(F)(F)F)c4)CC3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.015 mole of 3-methyl-6-{3-[4-(3-trifluoromethylphenyl)-1-piperazinyl]-1-hydroxypropyl}benzoxazolinone is dissolved in 47% strength hydrobromic acid in a 250-cm3 flask, and the solution is stirred at room temperature for 2 hours. The precipitate obtained is drained, washed with acetone, suspended in water and alkalinized with sodium hydroxide. The mixture is extracted several times with chloroform, the organic phases are combined and dried over calcium chloride, filtered and evaporated to dryness on a water bath under vacuum and the base is recrystallized in cyclohexane.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[C:18]([N:25]1[CH2:32][CH2:31][CH2:30][C@H:26]1[C:27](O)=[O:28])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:11]([O:10][C:8]([C@H:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][C:27]([CH:26]2[CH2:30][CH2:31][CH2:32][N:25]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:28])[CH2:3][CH2:4]1)=[O:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NC1CCC(C(=O)OCc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)N[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.7 %

Procedure:
To a stirred solution of benzyl 4-aminocyclohexanecarboxylate (900 mg, 3.9 mmol), boc-proline (830 mg, 3.9 mmol), HOBt (521 mg, 3.9 mmol), and triethylamine (1.6 ml, 11.6 mmol) in CH2Cl2 (30.0 ml) was added EDC.HCl (1.1 g, 5.8 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc. The extract was washed with sat. NaHCO3, 2-M citric acid, and sat. NaHCO3, then dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (6:1, v/v) as eluent to give benzylcis-4-[(1-tert-butoxycarbonyl-2-pyrrolidinyl)carbonylamino]cyclohexanecarboxylate (600 mg, 36%) as an amorphous solid. 1H-NMR (CDCl3) δ 1.44 (s, 9H), 1.50–1.90 (m, 12H), 2.20–2.26 (m, 1H), 3.25–3.50 (m, 2H), 3.80–3.90 (m, 1H), 4.10–4.25 (m, 1H), 5.12 (s, 2H), 7.35–7.36 (m, 5H).