Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:27])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.I[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[O:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:27])[CH:16]([C:17]1[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:21][CH:22]=1)[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[O:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1
Reactant: COC(=O)Cc1ccc(S(C)(=O)=O)cc1
Reactant: ICC1CCCC1OC1CCCCO1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1OC1CCCCO1)c1ccc(S(C)(=O)=O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.1 %

Procedure:
A solution of diisopropylamine (846 μL, 6.04 mmol) in dry tetrahydrofuran (4.4 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.4 mL) was cooled to −78° C. and then treated with a 2.5M solution of n-butyllithium in hexanes (2.4 mL, 6.04 mmol). The reaction mixture was stirred at −78° C. for 30 min and then was treated with a solution of (4-methanesulfonyl-phenyl)-acetic acid methyl ester (prepared as in Example 8, 1.06 g, 4.64 mmol) in dry tetrahydrofuran (4.4 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.4 mL). The resulting reaction mixture was allowed to stir at −78° C. for 45 min and then the reaction mixture was treated with a solution of 2-(2-iodomethyl-cyclopentyloxy)-tetrahydropyran (prepared as in Example 24, 1.87 g, 6.04 mmol) in a small amount of dry tetrahydrofuran. The reaction mixture was stirred at −78° C. and then allowed to warm to 25° C., where it was stirred for 68 h. The reaction mixture was quenched with water (100 mL) and then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 7/3 hexanes/ethyl acetate) afforded the 2-(4-methanesulfonyl-phenyl)-3-[2-(tetrahydropyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester (859.2 mg, 45%) as a light yellow oil: FAB-HRMS m/e calcd for C21H30O6S (M+H)+ 411.1841, found 411.1831.
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][O:5][C:6]1[C:11]([CH:12]=CC)=[CH:10][CH:9]=[CH:8][C:7]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22]>C(OCC)(=O)C.C(O)(=O)C>[CH3:4][O:5][C:6]1[C:7]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:8][CH:9]=[CH:10][C:11]=1[CH:12]=[O:1]
Reactant: CC=Cc1cccc(Oc2ccccc2Cl)c1OC
Reactant: O=[O+][O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1c(C=O)cccc1Oc1ccccc1Cl

Procedure:
Ozone gas was introduced into a solution of 2-chlorophenyl 2-methoxy-3-(1-propenyl)phenyl ether (17.60 g) in a mixture of ethyl acetate (120 ml) and acetic acid (5 ml) at 5° C. for an hour. Thereafter, nitrogen gas was introduced to the reaction mixture to remove the excess of ozone gas, and then dimethyl thioether was added thereto. The mixture was washed with aqueous solution of sodium bicarbonate and water successively, dried over magnesium sulfate and then evaporated. The oily residue was dissolved in diethyl ether, washed with an aqueous solution of sodium bicarbonate, dried and then evaporated to give oily 2-methoxy-3-(2-chlorophenoxy)benzaldehyde (7.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C:20]2[N:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.CCOCC>C1COCC1.[Ni]>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[N:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:13][CH2:14]1
Reactant: O=C1CCc2ccc(C=CCCCN3CCN(c4ccc(F)cc4Cl)CC3)nc2N1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1CCc2ccc(CCCCCN3CCN(c4ccc(F)cc4Cl)CC3)nc2N1
Yield: 79.7 %

Procedure:
7-{5-[4-(2-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.268 g, 0.623 mmol) was hydrogenated using Ra—Ni (0.2 g) in THF for 13 hours. The reaction was filtered and concentrated to give an oil. Et2O was added and the product crashed out. The mixture was filtered and dried to give the title compound as a white solid (0.214 g, 80%). MS: APCI: M+1: 431.3 (Exact Mass: 430.19).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:17]=2)[N:12]([CH2:30][CH2:31][CH2:32][O:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)[C:11]=1[C:44]([O:46]CC)=[O:45])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1.CO>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH:17]=2)[N:12]([CH2:30][CH2:31][CH2:32][O:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)[C:11]=1[C:44]([OH:46])=[O:45])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccccc2C(C)C)c2cc(OCCCCN3CCOCC3)ccc2n1CCCOc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1ccccc1-c1c(C(=O)O)n(CCCOc2cccc3ccccc23)c2ccc(OCCCCN3CCOCC3)cc12

Procedure:
A mixture of EXAMPLE 149A (36 mg), 1-chloro-4-iodobutane (0.043 ml) and cesium carbonate (116 mg) in N,N-dimethylformamide (2 ml) was stirred at room temperature overnight. The inorganic salt was filtered off. To the N,N-dimethylformamide solution was added morpholine (0.2 ml) and the resulting mixture was heated at 60° C. for 5 hours. The reaction mixture was concentrated and the residue was purified by RPHPLC (mobile phase: 10%-100% acetonitrile in 0.1% TFA aqueous solution during 60 min) on a C18 column to give ethyl 3-(2-isopropylphenyl)-5-(4-morpholinobutoxy)-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate. This ester was hydrolyzed with aqueous NaOH in a mixture of tetrahydrofuran and methanol to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 9.52 (s, 1H), 8.20 (d, J=8.29 Hz, 1H), 7.87 (d, J=7.98 Hz, 1H), 7.59 (d, J=8.90 Hz, 1H), 7.43-7.57 (m, 3H), 7.30-7.43 (m, 3H), 7.14-7.23 (m, 1H), 7.06 (d, J=7.36 Hz, 1H), 6.89 (dd, J=9.05, 2.30 Hz, 1H), 6.85 (d, J=7.67 Hz, 1H), 6.43 (d, J=2.45 Hz, 1H), 4.88 (t, J=7.21 Hz, 2H), 4.15 (t, J=5.83 Hz, 2H), 3.89-4.03 (m, J=11.97 Hz, 2H), 3.75-3.89 (m, 2H), 3.55-3.70 (m, 2H), 3.07-3.17 (m, 2H), 3.02 (s, br, 2H), 2.61-2.78 (m, 2H), 2.23-2.45 (m, 2H), 1.60-1.85 (m, 4H).
Reaction SMILES: [CH2:1]([N:5]1[CH2:11][CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].Br.Br.[NH2:24][CH2:25][C:26]([NH2:28])=[NH:27]>>[NH2:28][C:26]1[CH:25]=[N:24][C:9]2[CH2:10][CH2:11][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][C:8]=2[N:27]=1
Reactant: CCCCN1CCC(O[Si](C)(C)C)=C(O[Si](C)(C)C)CC1
Reactant: N=C(N)CN
Agent: Br
Product: CCCCN1CCc2ncc(N)nc2CC1

Procedure:
This compound was prepared analogous to Example 3 from 1-butyl-2,3,6,7-tetrahydro-4,5-bis(trimethylsilyloxy)azepine and 2-amino-acetamidine dihydrobromide.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.O.[NH2:15][NH2:16]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:15][NH2:16])=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Clc1cc(N2CCCC2)c(Cl)nn1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: NNc1cc(N2CCCC2)c(Cl)nn1

Procedure:
3,6-Dichloro-4-(pyrrolidin-1-yl)pyridazine (7.2 g, 33 mmol) and hydrazine hydrate (9.96 g, 0.2 mol) were heated at reflux in dioxan (130 ml) for 6 h. Upon cooling the desired isomer crystallized from the reaction and was collected by filtration (4.1 g, 58%). 1H NMR (250 MHz, d6-DMSO) 1.79-1.84 (4H, m), 3.25-3.40 (4H, m), 4.12 (2H, br), 6.09 (1H, s), 7.47 (1H, s). MS (ES+) 214 [MH]+, 216 [MH]+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:12]([CH3:15])([O-])=O>>[NH2:12][CH2:15][CH:8]([OH:9])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: C[N+](=O)[O-]
Product: NCC(O)c1ccc([N+](=O)[O-])cc1

Procedure:
The method of Schoenenberger, Archiv. der Pharmazie, 1975, 308(9), 717-719 can be employed. 4-Nitrobenzaldehyde can be reacted with nitromethane and base, followed by selective reduction of the aliphatic nitro group to yield 1-amino-2-hydroxy-2-(4-nitrophenyl) ethane. This substance can be reacted with 2,6-dichlorobenzaldehyde to yield a mixture of cis-(±) and trans-(±)-2-(2,6-dichlorophenyl)-5-(4-nitrophenyl)-1,3-oxazolidines. The nitrophenyl group can be reduced with tin (II) dichloride or iron powder and ammonium chloride to yield the corresponding aniline. This aniline can be reacted with 2,2-dichloroacetyl chloride and triethylamine to yield a mixture of cis-(±) and trans-(±)-2,2-dichloro-N-[4-[2-(2,6-dichlorophenyl)-5-(1,3-oxazolidinyl)]phenyl]acetamides.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:10][C@H:9]1[CH2:22]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:10][C@H:9]1[CH2:22][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1COS(C)(=O)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1CN1CCCC1
Temperature: 25 °C

Procedure:
17.3 To a stirred solution of 200 mg (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester at r.t. in 5 ml THF under an argon atmosphere were added 0.38 ml pyrrolidine. The mixture was heated to reflux for 6 h, then cooled to r.t. and concentrated. The crude product was purified by column chromatography (silica gel, gradient CH2Cl2->CH2Cl2/MeOH 9:1) to give 138 mg (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid tert-butyl ester as off-white amorphous solid. MS 414.4 ([M+H]+)
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:27][N:28]1C(=O)CCC1.C([Cu])#N.CN(C=O)C>O>[CH3:26][N:24]1[CH:25]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]3[N:16]([C:12]([CH2:11][C:8]4[CH:9]=[CH:10][C:5]5[N:6]([C:2]([C:27]#[N:28])=[CH:3][N:4]=5)[CH:7]=4)=[CH:13][N:14]=3)[N:17]=2)[CH:22]=[N:23]1
Reactant: CN1CCCC1=O
Reactant: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(Br)n5c4)n3n2)cn1
Agent: N#C[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(C#N)n5c4)n3n2)cn1
Temperature: 200 °C

Procedure:
3-(3-Bromo-imidazo[1,2-a]pyridin-6-ylmethyl)-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 296, 55 mg, 0.135 mmol) was introduced in a microwave reactor with NMP (150 μL) and CuCN (15.7 mg, 0.175 mmol). The RM was heated at 200° C. for 10+15 min. The black solid obtained was taken up with DMF. Water was added to the mixture and it was extracted with EtOAc/MeOH (9:1) twice. Combined organic layers was washed with 10% ammonia solution. The organic layer was dried over Na2SO4 filtered and concentrated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, 0 to 20% MeOH in DCM). Combined fractions were concentrated. The white solid obtained was a repurified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and were lyophilized. The residue was dissolved in MeOH and it was passed through an SPE cartridge of HCO3− to remove the TFA salt. The filtrate was evaporated to give the free salt of the title compound as a white solid (tR 0.8 min (conditions 2), MH+=355).
Reaction SMILES: C1(CCC(O)C[N:11]2C=CC=[N:12]2)C=CC=CC=1.Cl[CH2:18][CH:19](O)[CH2:20][CH2:21][C:22]1C=CC=CC=1.Cl[CH2:30][CH:31]([OH:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:33]1([CH2:32][CH:31]([OH:39])[CH2:30][N:11]2[C:19]([CH3:18])=[CH:20][C:21]([CH3:22])=[N:12]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: OC(CCc1ccccc1)Cn1cccn1
Reactant: OC(CCl)CCc1ccccc1
Reactant: OC(CCl)Cc1ccccc1
Product: Cc1cc(C)n(CC(O)Cc2ccccc2)n1

Procedure:
(Phdmpzp)H 4-Phenyl-1-pyrazol-1-yl-butan-2-ol [(Phdmpzb)H] (formula 17). This compound was prepared as described above except 1-chloro-4-phenylbutan-2-ol was utilized in place of 1-chloro-3-phenylpropan-2-ol.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=[C:10](N(C)C)[O:11][N:12]1[C:16]2N=CC=CC=2N=N1.[Cl:25][C:26]1[C:27]2[N:28]([N:42]=[CH:43][CH:44]=2)[C:29]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[C:30]([C:32](O)=[O:33])[CH:31]=1.C(N(CC)C(C)C)(C)C.Cl.CNOC>CN(C)C=O.C(OCC)(=O)C>[Cl:25][C:26]1[C:27]2[N:28]([N:42]=[CH:43][CH:44]=2)[C:29]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[C:30]([C:32]([N:12]([O:11][CH3:10])[CH3:16])=[O:33])[CH:31]=1
Reactant: O=C(O)c1cc(Cl)c2ccnn2c1-c1cccc(F)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc(Cl)c2ccnn2c1-c1cccc(F)c1
Reaction time: 2 h
Yield: 86.9 %

Procedure:
The N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.46 g, 1.2 mmol) was added to a solution of 4-chloro-7-(3-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carboxylic acid (0.29 g, 1.0 mmol) in N,N-dimethylformamide (3.0 mL) containing N,N-diisopropylethylamine (0.35 mL, 2.0 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.14 g, 1.5 mmol) at room temperature. The reaction was complete after stirring for 2 hours. This was taken up in ethyl acetate, washed with water, brine, dried over magnesium sulfate and concentrated to give the crude amide. The product was purified on silica gel eluting hexane:ethyl acetate gradient to give 4-chloro-7-(3-fluorophenyl)-N-methoxy-N-methylpyrazolo[1,5-a]pyridine-6-carboxamide (0.29 g, 88%) as a glass. LCMS calculated for C16H14ClFN3O2 (M+H)+: m/z=334.1. found: 333.9.
Reaction SMILES: [N:1]([C@:4]1([CH2:36][O:37]C(=O)C2C=CC=CC=2)[O:8][C@@:7]([CH3:17])([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[C@:6](C(=O)C2C=CC=CC=2)([OH:18])[C@:5]1(C(=O)C1C=CC=CC=1)[OH:27])=[N+:2]=[N-:3]>N>[N:1]([C@:4]1([CH2:36][OH:37])[O:8][C@@:7]([CH3:17])([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[C@H:6]([OH:18])[C@@H:5]1[OH:27])=[N+:2]=[N-:3]
Reactant: C[C@@]1(n2ccc(=O)[nH]c2=O)O[C@@](COC(=O)c2ccccc2)(N=[N+]=[N-])[C@](O)(C(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1
Agent: N
Product: C[C@@]1(n2ccc(=O)[nH]c2=O)O[C@@](CO)(N=[N+]=[N-])[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 14 h
Yield: 46.2 %

Procedure:
4′-Azido-1′-methyl-2′,3′,5′-O-tribenzoyluridine (37-7) (0.20 g, 0.34 mmol) was dissolved in saturated methanolic ammonia (50 mL), and the mixture was stirred at R.T. for 14 hours. The solvent was removed, and the residue was purified on a silica gel column (DCM/MeOH=50:1 to 30:1) to give (54) as a white solid (47 mg, 46.0%). 1H NMR (CD3OD, 400 MHz) δ 8.15 (d, J=8.4 Hz, 1H), 5.63 (d, J=8.4 Hz, 1H), 4.73 (d, J=5.6 Hz, 1H), 4.17 (d, J=5.2 Hz, 1H), 3.67 (d, J=12.0 Hz, 1H), 3.55 (d, J=12.0 Hz, 1H), 1.76 (s, 3H); ESI-negative-MS: m/z=298.1 [M−H]+, 597.2 [2M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.CO[C:15]1[C:19](OC)=[N:18][S:17](=[O:22])[N:16]=1.[NH3:23]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:15]2[C:19]([NH2:23])=[N:18][S:17](=[O:22])[N:16]=2)=[N:6][CH:7]=1
Reactant: N
Reactant: COC1=NS(=O)N=C1OC
Reactant: NCCCNc1ccc(Br)cn1
Solvent: CO
Product: NC1=NS(=O)N=C1NCCCNc1ccc(Br)cn1
Reaction time: 18 h

Procedure:
A solution of 3-(5-bromopyrid-2-ylamino)propylamine (1 g) and 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (0.71 g) was stirred in methanol for 3 hours. Methanol saturated with ammonia (10 ml) was added and the solution was stirred for 18 hours, concentrated in vacuo and the residue was chromatographed on silica eluted with 10% v:v methanol in chloroform followed by recrystallisation from methanol to give 3-[3-(5-bromopyrid-2-ylamino)propylamino]-4-amino-1,2,5-thiadiazole-1-oxide (0.63 g), m.p. 215°-216° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([NH:5][CH2:6][C:7](=O)[CH3:8])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1C=CC=CC=1>[CH3:8][C:7]1[S:21][C:3]([C:2]([F:11])([F:10])[F:1])=[N:5][CH:6]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)CNC(=O)C(F)(F)F
Solvent: c1ccccc1
Product: Cc1cnc(C(F)(F)F)s1
Reaction time: 4.5 h

Procedure:
Trifluoroacetamidoacetone (8.45 g, 50 mmol) and 20.2 g (50 mmol) of Lawesson's reagent were slurried in 100 mL of benzene and the mixture heated at reflux with stirring for 4-5 hr to obtain a clear solution. This was allowed to cool and was washed with 50 mL of 10 percent aqueous sodium hydroxide solution, dried over magnesium sulfate, and filtered. The resulting solution was kugelrohr distilled at 160° C. and the distillate was distilled through a 40 cm column packed with glass helices (to remove the benzene) until the head temperature began to drop. It was then distilled through a 20 cm Vigreauz column to obtain 5.1 g (61 percent of theory) of the title compound as a pale oil boiling at 138°-141° C.
Reaction SMILES: C[O:2][C:3]([CH:5]1[N:10]([C:11](=[O:25])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][C:8]2[N:26]=[CH:27][N:28]([CH2:29][CH2:30][C:31]34[CH2:40][CH:35]5[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]5)[CH2:32]3)[CH2:38]4)[C:7]=2[CH2:6]1)=[O:4].[OH-].[Na+]>O1CCCC1CO>[C:31]12([CH2:30][CH2:29][N:28]3[C:7]4[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[N:10]([C:11](=[O:25])[CH:12]([C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:9][C:8]=4[N:26]=[CH:27]3)[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH2:32]1)[CH2:38]2
Reactant: COC(=O)C1Cc2c(ncn2CCC23CC4CC(CC(C4)C2)C3)CN1C(=O)C(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: O=C(O)C1Cc2c(ncn2CCC23CC4CC(CC(C4)C2)C3)CN1C(=O)C(c1ccccc1)c1ccccc1

Procedure:
A solution of 2.0 g methyl-1-(2-(1-adamantyl)ethyl)-5-diphenylacetyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]-pyridine-6-carboxylate in tetrahydrofuranmethanol (3:1, 20 mL) is treated at 25° C. with 4.1 mL 1N NaOH. After 6 hr the solution is evaporated, the residue is suspended in 10 mL water and treated with 4.1 mL 1N HCl. The resulting precipitate is collected by filtration and dried to afford a white solid, 1(2-(1-adamantyl)ethyl)-5-diphenylacetyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid. MS (FAB) 524 (M+1). mp 168°-175° C. or 187° to 200° C. dec.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][C:18]3([OH:32])[CH2:23][CH:22]4[CH2:24][CH2:25][CH:19]3[CH:20]=[C:21]4[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[C:41](Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]>C(Cl)Cl.C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][C@:18]3([O:32][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:23][C@H:22]4[CH2:24][CH2:25][C@@H:19]3[CH:20]=[C:21]4[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1cccc2[nH]c(CCCN(C)CCC3(O)CC4CCC3C=C4c3ccccc3)nc12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cccc2[nH]c(CCCN(C)CC[C@]3(OC(=O)C(C)(C)C)C[C@H]4CC[C@@H]3C=C4c3ccccc3)nc12
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of 150 mg of rac-(1R*,2R*,4R*)-2-(2-{[3-(4-methoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol in 2 mL DCM and 2 mL THF were added 0.21 mL of NEt3 and 41 mg of DMAP. The reaction mixture was cooled to 0° C., 0.17 mL of pivaloyl chloride were added and it was then stirred at 65° C. for 24 h. During the next 4 days further 0.52 mL of NEt3 and 0.41 mL of pivaloyl chloride were added in small aliquots. The reaction was quenched with sat. aq. NaHCO3, extracted with DCM, dried and concentrated in vacuo. Purification by CC using DCM-MeOH (10:1) yielded 40 mg of rac-2,2-dimethyl propionic acid (1R*,2R*,4R*)-2-(2-{[3-(4-methoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester as brownish foam.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[OH:6][C:7]1[CH:12]=[CH:11][C:10](NCC(O)=O)=CC=1.[CH2:18]([OH:20])[CH3:19]>>[C:1]([OH:4])(=[O:3])[CH2:2][CH3:7].[CH2:18]([O:20][C:7](=[O:6])[CH2:12][C:11]([CH3:10])=[O:3])[CH3:19]
Reactant: CCO
Reactant: CC(=O)[O-]
Reactant: O=C(O)CNc1ccc(O)cc1
Agent: [Na+]
Product: CCC(=O)O
Product: CCOC(=O)CC(C)=O

Procedure:
40 g of sodium acetate and 75 g of p-hydroxyphenylglycine are refluxed in 500 ml of ethanol for 2 hours. To the suspension obtained 0.5 ml of propionic acid and 75 g of acetoacetic acid ethylester are added and the mixture is refluxed for additional 90 minutes under distillation. A fraction of 330 ml is distilled off. The suspension obtained is cooled to -5° C., then filtered and the crystals are washed with ethylacetate and dried in vacuo at 60° C. 126.1 g of sodium-D-N-(2-ethoxycarbonyl-1-methyl-vinyl)-α-amino-(p-hydroxy-phenyl)-acetate are obtained.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)[C:12]2N=CC=CC=2N=[N:9]1.[CH2:25]([N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]3NN=C[C:38]3=2)[CH2:33][CH:32]([CH2:43][C:44]([OH:46])=O)[C:31]1=[O:47])[C:26]([CH3:29])([CH3:28])[CH3:27].C(N(CC)C(C)C)(C)C.[O:57]=[C:58]1[N:67]([CH:68]2[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]2)[CH2:66][C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[NH:59]1>ClCCl>[CH2:25]([N:30]1[C:39]2[CH:38]=[C:37]3[CH:12]=[N:8][NH:9][C:36]3=[CH:35][C:34]=2[CH2:33][CH:32]([CH2:43][C:44](=[O:46])[N:71]2[CH2:72][CH2:73][CH:68]([N:67]3[CH2:66][C:65]4[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=4)[NH:59][C:58]3=[O:57])[CH2:69][CH2:70]2)[C:31]1=[O:47])[C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)CN1C(=O)C(CC(=O)O)Cc2ccc3[nH]ncc3c21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CN1C(=O)C(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)Cc2cc3[nH]ncc3cc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (116 mg, 0.3 mmol) was added to a solution of 2-(1-neopentyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[3,4-h]quinolin-3-yl)acetic acid (95 mg, 0.3 mmol) and N,N-diisopropylethylamine (158 μL, 0.9 mmol) in dichloromethane (5.0 mL). Mixture was stirred at room temperature for 45 minutes. 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine (70 mg, 0.3 mmol) was then added to the mixture. After 3 h stirring at room temperature, the crude reaction mixture was purified by prep HPLC starting from 30% methanol in water to 90% methanol in water over a period of 8 min and at a flow rate of 40 ml/min. Removal of solvent furnished the desired. MS (ESI) 529 (M+H); Rf=1.57.