Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][N:12]([CH2:14][CH2:15][C:16]([NH2:19])([CH3:18])[CH3:17])[CH:13]=2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.[OH-].[Na+]>C(OCC)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[CH:11][N:12]([CH2:14][CH2:15][C:16]([NH2:19])([CH3:17])[CH3:18])[CH:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cn(CCC(C)(C)N)cn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(N)CCn1cnc(-c2ccc(O)cc2)c1
Temperature: 0 °C
Yield: 54 %

Procedure:
1.0 g (4.00 mmol) 3-[4-(4-methoxy-phenyl)-imidazol-1-yl]-1,1-dimethyl-propylamine and 4.00 g pyridine hydrochloride were stirred for 2 h at 200° C. in a sealed reaction vessel in a microwave. The reaction mixture was poured into 40 mL ice water and 40 mL ethyl acetate, the pH of the aqueous phase was adjusted to over 9 with sodium hydroxide solution (2M) and the phases were separated. The aqueous phase was extracted five times with 50 mL ethyl acetate. The combined organic phases were dried over magnesium sulphate and the solvent was eliminated using the rotary evaporator. 0.530 g (2.16 mmol, 54%) 3-[4-(4-hydroxy-phenyl)-imidazol-1-yl]-1,1-dimethyl-propylamine were obtained as a colourless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](Br)[CH:20]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:19]2[CH:18]=[N:17][CH:16]=[C:15]([Br:14])[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(Br)c2)CC1
Yield: 53.8 %

Procedure:
A mixture of piperazine-1-carboxylic acid tert-butyl ester (1.86 g, 10 mmol), 3,5-dibromopyridine (2.37 g, 10 mmol), palladium(II) acetate (0.11 g, 0.5 mmol), anphos (0.35 g, 0.6 mmol), and sodium tert-butoxide (1.68 g, 15 mmol) in dioxane (10 mL) was heated at 130° C. in a microwave reactor for 2 hours. The mixture was then diluted with water, and extracted with EtOAc. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluent with ethyl acetate:hexane=1:5) to afford the title compound as a white solid (1.84 g, 54%). MS: 342.2 (M+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][C@H:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][NH2:37])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]([N:28]1[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][CH2:36][NH:37][C:12]([C@@H:10]2[CH2:9][S:8][CH:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[NH:11]2)=[O:14])[CH2:32][CH2:33]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCCN1CCN(C(c2ccccc2)c2ccccn2)CC1
Reactant: O=C(O)[C@@H]1CSC(c2cccnc2)N1
Product: O=C(NCCCN1CCN(C(c2ccccc2)c2ccccn2)CC1)[C@@H]1CSC(c2cccnc2)N1
Yield: 16 %

Procedure:
The title compound was prepared in a yield of 16% in a similar manner to that described in Example 17 by reacting 2-(3-pyridyl) thiazolidine-4(R)-carboxylic acid and 4-[α-(2-pyridyl)benzyl]-1-(3-aminopropyl)piperazine (prepared as described in Preparation 41').
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.Cl[C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1.C([Li])CCC.C1COCC1>[Cl-].[Cl-].[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([C:25]4[CH:30]=[N:29][CH:28]=[CH:27][N:26]=4)=[CH:3][C:4]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Reactant: Clc1cnccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cnccn4)cc3C)c(C)nc12
Yield: 48 %

Procedure:
Using a procedure similar to Example 31, 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.40 g, 1.02 mmol) (example Rupp-2), 2-chloropyrazine (0.11 mL, 1.22 mmol), 1.42 M n-Bu-Li (1.52 mL, 1.07 mmol), 0.5 M ZnCl2 in THF (2.14 mL, 1.07 mmol), and PdCl2(dppf) (0.037 g, 0.051 mmol) furnish the title compound (0.19 g, 0.49 mmol, 48%). 1H NMR (CDCl3), δ 0.90 (t, J=7.5 Hz, 6H), 1.75-1.94 (m, 4H), 2.20 (s, 3H), 2.52 (s, 3H), 2.53 (s, 3H), 3.31-3.40 (m, 1H), 6.69 (s, 1H), 7.63 (s, 1H), 8.40 (d, J=2.6 Hz, 1H), 8.51 (t, J=1.9 Hz, 1H), 8.96 (d, J=0.9 Hz, 1H). LC/MS (m/z): calcd. for C22H25N5S (M+H)+: 392.3; found: 392.2.
Reaction SMILES: B.CSC.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([NH2:21])=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1>O1CCCC1>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][NH2:21])[CH2:15][CH2:14]2)=[CH:11][CH:12]=1
Reactant: COc1ccc(N2CCC(C(N)=O)CC2)cc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: COc1ccc(N2CCC(CN)CC2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 5.3 %

Procedure:
Borane-dimethyl sulphide complex (15 ml; 10M in dimethyl sulphide) was added dropwise at 15°-20° C., under nitrogen, to a stirred suspension of 1-(4-methoxyphenyl) piperidine-4-carboxamide (10 g) in tetrahydrofuran (95 ml). The mixture was heated under reflux for 4 hours then allowed to stand at ambient temperature for 16 hours. Ice water was added to destroy excess reducing agent then the mixture was acidified by the addition of hydrochloric acid (5M) and washed with ether (200 ml). The aqueous layer was basified by the addition of concentrated aqueous sodium hydroxide solution then the product was extracted into ether (3×250 ml). The combined extracts were dried over magnesium sulphate and the solvent removed in vacuo. The residue was purified by flash chromatography over silica using a 9:1 mixture of dichloromethane and industrial methylated spirit as eluant. The solvents were removed in vacuo from the appropriate fractions to give 1-[1-(4-methoxyphenyl)-piperid-4-yl]methylamine as an oil (0.5 g).
Reaction SMILES: [H-].[Na+].[OH:3]/[N:4]=[C:5](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)\[CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].Cl[CH2:19][C:20]1[CH:40]=[CH:39][C:23]([O:24][CH2:25][CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30][C:31]=2[CH3:32])=[CH:22][CH:21]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:32][C:31]1[O:30][C:29]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[N:28][C:27]=1[CH2:26][CH2:25][O:24][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][O:3]/[N:4]=[C:5](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)\[CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:40][CH:39]=1
Reactant: COC(=O)CC/C(=N\O)c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: COC(=O)CC/C(=N\OCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Reaction time: 1 h
Yield: 42.7 %

Procedure:
Sodium hydride (60% in oil, 134 mg) was added to a solution of methyl E-4-(hydroxyimino)-4-phenylbutyrate (632 mg) and 4-[2-(4-chloromethylphenoxy)ethyl]-5-methyl-2-phenyloxazole (1.00 g) in N,N-dimethylformamide (10 ml) at room temperature under nitrogen atmosphere and stirred for 1 hour. 1N hydrochloric acid (5 ml) was added, an aqueous saturated solution of sodium bicarbonate was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain crystals from an ethyl acetate-hexane (1:3, v/v)-eluted fraction. The crystals were recrystallized from ethyl acetate-hexane to obtain methyl E-4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyloxyimino]-4-phenylbutyrate (650 mg, yield 43%) as colorless crystals. m.p. 73-74° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][N:21]=[C:22]=[O:23]>O1CCCC1>[CH3:1][N:2]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)[C:22](=[O:23])[NH:21][CH2:20][CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1
Reactant: CNc1cccc2ccccc12
Reactant: O=C=NCCc1ccccn1
Solvent: C1CCOC1
Product: CN(C(=O)NCCc1ccccn1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3.14 gm. (0.02 mole) of N-methyl-1-naphthylamine in 75 ml. of tetrahydrofuran there is added 2.96 gm. (0.02 mole) of 2-pyridylethylisocyanate with stirring. After 30 minutes of stirring at ambient temperature, the mixture is refluxed for 1 hour. The solvent is then removed in vacuo and the residue crystallized from alcohol-water (4:1 v/v) to furnish 3-methyl-3-(1-naphthyl)-1-(2-pyridylethyl)urea.
Reaction SMILES: I[C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:3]=1.CCN(C(C)C)C(C)C.[CH2:33]([SH:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.N>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O>[CH2:33]([S:40][C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:3]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: SCc1ccccc1
Reactant: CN1CCC(OC2c3ccccc3CCn3cc(I)nc32)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: N
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(OC2c3ccccc3CCn3cc(SCc4ccccc4)nc32)CC1
Temperature: 120 °C

Procedure:
To a solution of compound 2-iodo-4-(1-methyl piperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 2A) (50 mg, 0.12 mmoles) in 1,4-dioxane (0.5 mL) in a screw-capped vial under argon are added DIEA (31 μL, 0.18 mmole), benzylmercaptan (21 μL, 0.18 mmole), bis(dibenzilideneacetone)Palladium(0) (3.5 mg, 6 μmole), Xantphos (3.5 mg, 6 μmole). The reaction mixture is heated at 120° C. overnight. As the reaction is not complete, bis(dibenzilideneacetone)Palladium(0) (3.5 mg, 6 μmole), Xantphos (3.5 mg, 6 μmole) are added to the reaction mixture. After one overnight at 120° C., water is added to the reaction mixture and pH adjusted to 9-10 by adding concentrated ammonia solution. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) as eluent with a gradient from (98:2:0.1) to (96.5:3.5:0.35) to afford 2-benzylsulfanyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene.
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]([Br:9])=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[CH3:10][Mg]Br.C1(C)C=CC=CC=1.C1COCC1>C1COCC1>[Br:9][C:6]1[S:5][C:4]([C:1]([OH:3])([CH3:10])[CH3:2])=[CH:8][CH:7]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(Br)s1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(Br)s1
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-acetyl-5-bromothiophene in THF (2.5 mL/mmol) at −30° C. was added 1.4M methylmagnesium bromide in 3:1 toluene-THF (1.5 eq) and the resulting mixture was warmed to −10° C. and stirred for 1.5 hours. After quenching with saturated aqueous ammonium chloride solution, the mixture was partitioned between ether and water. The organic fraction was dried and evaporated, and the crude material was chromatographed on silica gel eluting with a 1:4 mixture of ether and hexane to afford the 2-bromo-5-(1-hydroxy-1-methylethyl)thiophene compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:23])[CH:3]=1.[CH3:24][O:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[C:26]([O:25][CH3:24])=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:3]=[C:4]([CH3:23])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: Cc1cc(Cl)nc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)c1
Reactant: COc1ncccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ncccc1-c1cc(C)cc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)n1
Yield: 37.4 %

Procedure:
To N-(6-chloro-4-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (150 mg, 0.46 mmol) in 1,2-dimethoxyethane (4 mL) was added 2-methoxypyridin-3-ylboronic acid (84 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium (0) (53 mg, 0.046 mmol), and 2 M Na2CO3 (680 μL, 1.4 mmol). The reaction mixture was irradiated in the microwave at 120° C. for 20 minutes. The reaction mixture was evaporated to dryness and the residue was purified by silica gel chromatography eluting with (0-20% ethyl acetate/hexanes) to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-4-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (69 mg, 38%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(O)=O.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: Cc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CC1CCc2ccccc2N1
Temperature: -20 °C
Reaction time: 20 h
Yield: 102.1 %

Procedure:
In 60 ml of methylene chloride, 1.00 g of 2-methylquinoline was dissolved, and 66.5 mg (2.0 mol %) of crystalline (S)-chloro[(1,2,3,4,5-η)-pentamethyl-2,4-cyclopentadien-1-yl](2-pyrrolidinecarboxamidato-κN1, κN2)iridium(III) (Cp*Ir(Cl−)(S-PA-H+)) was added. After cooling to −20° C., 8.4 ml of a mixed solvent of formic acid/triethylamine (molar ratio: 5/2) was added dropwise, and the mixture was continuously stirred at the same temperature for 20 hours. Then, the reaction was completed. The reaction mixture was basified with an aqueous potassium carbonate solution and then the resulting layers were separated. The organic layer was washed with water and concentrated to give 1.05 g of 2-methyl-1,2,3,4-tetrahydroquinoline as an oil.
Reaction SMILES: [NH2:1][C@H:2]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].[C:34]([N:41]1[CH2:44][CH:43]([C:45](O)=[O:46])[CH2:42]1)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C@@H:2]([NH:1][C:45]([CH:43]2[CH2:44][N:41]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:42]2)=[O:46])[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]([CH2:22][CH:23]3[CH2:24][CH2:25]3)[S:18]([CH3:21])(=[O:19])=[O:20])[CH2:9][CH2:10]2)=[O:4])=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)(C)OC(=O)N1CC(C(=O)N[C@H](Cc2ccc(Cl)cc2)C(=O)N2CCN(c3ccccc3N(CC3CC3)S(C)(=O)=O)CC2)C1

Procedure:
tert-Butyl 3-{N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl)(methylsulfonyl)amino]phenyl}-piperazinyl)-2-oxoethyl]carbamoyl}-azetidine-carboxylate was prepared from (2R)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)amino]phenyl}piperazinyl)propan-1-one (Step 3) (220 mg, 0.46 mmol), according to the procedure for Preparation XIX using Boc-azetidine-3-carboxylic acid (100 mg, 0.50 mmol) (Peptech), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (275 mg, 0.925 mmol), HOAT (64 mg, 0.470 mmol), and DMF (7 mL). The compound was isolated (294 mg). MS (ESI, pos. ion) m/z: 674 (M+H), (ESI, neg. ion) m/z: 672 (M−H). Calc'd for C33H44ClN5O6S: 674.25.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]Br)[CH:5]=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18].[CH2:19]([S-:21])[CH3:20].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])[CH2:8][S:21][CH2:19][CH3:20]
Reactant: CC[S-]
Reactant: Fc1ccc(Oc2ccc(CBr)cc2Br)c(F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSCc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Yield: 99.5 %

Procedure:
A mixture of Example 52C (1.10 g, 2.91 mmol) and sodium ethanethiolate (0.245 g, 2.91 mmol) in dimethylformamide (10 mL) was stirred at ambient temperature for 4 hours. The reaction mixture was partitioned with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride twice, dried with anhydrous sodium sulfate, filtered, and concentrated to provide the title compound (1.04 g, 99%).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([NH2:12])=[O:11].[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([CH2:22]Br)=[N:19][C:18]=2[CH:24]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([CH2:22][O:8][C:7]3[C:2]([F:1])=[C:3]([C:10]([NH2:12])=[O:11])[C:4]([F:9])=[CH:5][CH:6]=3)=[N:19][C:18]=2[CH:24]=1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: BrCc1nc2cc(Br)ccc2s1
Product: NC(=O)c1c(F)ccc(OCc2nc3cc(Br)ccc3s2)c1F
Yield: 81 %

Procedure:
Synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide and 5-bromo-2-(bromomethyl)-1,3-benzothiazole, according to Method B, scheme 2. Yield 81%, mp 244-246° C., HPLC-MS (method 1): m/z 399, 401 [M+H]+, Rt=3.98 min.
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=2)[N:3]=1.C([N:19]([CH2:22][CH3:23])[CH2:20]C)C.Cl.N1CCC1>CC#N>[N:19]1([C:2]2[O:6][N:5]=[C:4]([C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=3)[N:3]=2)[CH2:20][CH2:23][CH2:22]1
Reactant: Cc1ccc(-c2noc(Cl)n2)cc1[N+](=O)[O-]
Reactant: CCN(CC)CC
Agent: C1CNC1
Agent: Cl
Solvent: CC#N
Product: Cc1ccc(-c2noc(N3CCC3)n2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazole (107) (3.6 g, 15.02 mmol, 1.00 equiv) in CH3CN (40 mL) was added triethylamine (3.03 g, 29.94 mmol) and azetidine hydrochloride (1.68 g, 17.96 mmol). The resulting solution was stirred for 1 hour at room temperature, concentrated under vacuum and purified by prep-HPLC to afford 5-(azetidin-1-yl)-3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazole (108) as a white solid. MS m/z 261.1 (M+1)+.
Reaction SMILES: [ClH:1].O1[C:6]2([CH2:11][CH2:10][CH:9]([C:12]([O:14]C(C)(C)C)=O)CC2)[CH2:5][NH:4][CH2:3]1.[CH3:19]O>>[ClH:1].[O:14]1[C:11]2([CH2:19][CH2:3][NH:4][CH2:5][CH2:6]2)[CH2:10][CH2:9][CH2:12]1
Reactant: CC(C)(C)OC(=O)C1CCC2(CC1)CNCO2
Reactant: CO
Agent: Cl
Product: C1COC2(C1)CCNCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
Methanolic hydrogen chloride (3M, 20 ml) was added over 10 minutes to a stirred, cooled (0° C.) solution of 1,1-dimethylethyl 1-oxa-8-azaspiro[4.5]decane-8-carboxylate (from step (iv) above, 3.18 g, 13.2 mmol) in methanol (10 ml) and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure to give the title compound (2.29 g, 98%).
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[Cl:14][S:15](O)(=[O:17])=[O:16]>>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccccc2C1
Reactant: O=S(=O)(O)Cl
Product: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-Acetyl-1,2,3,4-tetrahydroisoquinoline (180 gm., 1.03 m.) was added slowly to 800 gms. (6.9 m.) of chlorosulfonic acid and stirred at -50° C. The solution was stirred at 25° C. for two days, poured onto crushed ice and extracted with ethyl acetate. The extract was washed, dried over anhydrous sodium sulfate and evaporated to yield crude N-acetyl-7-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2.Br[CH2:21][C:22]([NH2:24])=[O:23]>>[C:17]([C:9]1[C:10]([C:13]([F:16])([F:14])[F:15])=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH2:21][C:22]([NH2:24])=[O:23])[C:4]([CH2:3][CH:2]([CH3:19])[CH3:1])=[CH:12]2)#[N:18]
Reactant: CC(C)Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: NC(=O)CBr
Product: CC(C)Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(N)=O

Procedure:
Synthesized as described in Example 4 using 2-(2-methylpropyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 2-bromoacetamide: 1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J=8.5 Hz, 1H), 7.71 (bs, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.34 (bs, 1H), 6.51 (d, J=2.2 Hz, 1H), 4.91 (s, 2H), 2.61 (d, J=7.0 Hz, 2H), 1.95 (m, 1H), 0.92 (d, J=6.6 Hz, 6H); MS (ES) m/z 324 (M+1).
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([CH2:10][C:11]2[CH:19]=[C:18]3[C:14]([C:15]([CH2:32][CH2:33][C:34](OC)=[O:35])=[CH:16][N:17]3[CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=3[O:30][CH3:31])=[CH:13][CH:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN(C)C1C=CN=CC=1.O>[CH:1]1([CH2:6][NH:7][C:8]([CH2:10][C:11]2[CH:19]=[C:18]3[C:14]([C:15]([CH2:32][CH2:33][C:34]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[O:35])=[CH:16][N:17]3[CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=3[O:30][CH3:31])=[CH:13][CH:12]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)CCc1cn(Cc2ccc(C(=O)O)cc2OC)c2cc(CC(=O)NCC3CCCC3)ccc12
Reactant: C1COCCN1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Product: COc1cc(C(=O)O)ccc1Cn1cc(CCC(=O)N2CCOCC2)c2ccc(CC(=O)NCC3CCCC3)cc21
Yield: 75 %

Procedure:
A solution of 4-[6-(cyclopentylmethylcarbamoyl)methyl-3-(2-methoxycarbonylethyl)indol-1-ylmethyl]-3-methoxybenzoic acid (0.40 g) and 4-dimethylaminopyridine (0.10 g) in morpholine (3 ml) was heated at 80° for 52 hr. The reaction was diluted with water and acidified to pH 1 with 10% (v/v) hydrochloric acid to form a precipitate which was collected by filtration to give 4-[6-(cyclopentylmethylcarbamoyl)methyl-3-(2-morpholinocarbonylethyl)indol-1-ylmethyl]-3-methoxybenzoic acid (0.34 g, 75%) as an ivory solid; partial NMR (250 MHz, CDCl3): 2.72(t, 2H, COCH2), 3.35-3.60(8H, morpholino), 3.66(s, 2H, COCH2Ar), 3.95(s, 3H, OCH3), 5.29(s, 2H, NCH2Ar). (It will be recognized that this compound is also an example of the invention.)
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:24][CH2:25][CH:26]=[CH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[C:31]([O:30][C:28]([CH2:27][CH2:26][CH2:25][CH2:24][C@@H:12]1[CH2:13][C@@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])[CH2:15][NH:11]1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)C=CCC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CCCC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1
Reaction time: 3 h

Procedure:
(2R,4R)-1-Benzyloxycarbonyl-2-(3-t-butoxycarbonylmethylidenepropyl)-4-t-butyldimethylsilyloxypyrrolidine (1.17 g) was dissolved in 24 ml of ethanol, and 350 mg of 5% palladium carbon was added thereto, followed by hydrogenation at room temperature under 1 atm for 3 hours. The catalyst was removed by filtration, and the filtrate was distilled to obtain (2R,4R)-2-(4-t-butoxycarbonylbutyl)-4-t-butyldimethylsilyloxypyrrolidine.