Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:17])[C@@H:7]([NH:9][C:10]([C:12]1[NH:13][CH:14]=[CH:15][N:16]=1)=[O:11])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[NH:13]1[CH:14]=[CH:15][N:16]=[C:12]1[C:10]([NH:9][C@@H:7]([CH3:8])[C:6]([OH:17])=[O:5])=[O:11]
Reactant: C[C@H](NC(=O)c1ncc[nH]1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: C[C@H](NC(=O)c1ncc[nH]1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (2S)-2-[(1H-imidazole-2-carbonyl)-amino]-propionic acid tert-butyl ester (0.257 g) in dichloromethane (2 ml) was cooled to 0° C. before dropwise addition of trifluoroacetic acid and the reaction mixture was warmed to room temperature and stirred for 2 hr before evaporation under reduced pressure. The residue was co-evaporated with dichloromethane (twice) and toluene (twice) to leave the required (2S)-2-[(1H-imidazole-2-carbonyl)-amino]-propionic acid that was used without further purification (0.40 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH:5]([CH:8]=[N:9][OH:10])[CH2:4][CH2:3]1.[Cl:12]N1C(=O)CCC1=O>>[OH:10][N:9]=[C:8]([Cl:12])[CH:5]1[CH2:4][CH2:3][C:2]([CH3:11])([CH3:1])[CH2:7][CH2:6]1
Reactant: CC1(C)CCC(C=NO)CC1
Reactant: O=C1CCC(=O)N1Cl
Product: CC1(C)CCC(C(Cl)=NO)CC1

Procedure:
N-Hydroxy-4,4-dimethylcyclohexanecarbimidoyl chloride (I-9D) was prepared by reaction of 4,4-dimethylcyclohexanecarbaldehyde oxime and N-chloro succinimide following the same protocol as described for I-6B. MS m/z 190.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([CH3:29])=[N:11][N:12]([C:19]3[C:20]([O:27][CH3:28])=[N:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=3)[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[C:34]([CH3:40])[C:35](=[O:39])[N:36]([CH3:38])[CH:37]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:31][C:32]2[CH:33]=[C:34]([CH3:40])[C:35](=[O:39])[N:36]([CH3:38])[CH:37]=2)[C:9]2[C:10]([CH3:29])=[N:11][N:12]([C:19]3[C:20]([O:27][CH3:28])=[N:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=3)[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: Cc1cc(N)cn(C)c1=O
Reactant: CCOC(=O)c1c(C(O)c2ccc(Cl)cc2)c(C)nn1-c1cnc(OC)nc1OC
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1c(C(Nc2cc(C)c(=O)n(C)c2)c2ccc(Cl)cc2)c(C)nn1-c1cnc(OC)nc1OC

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-1H-pyrazole-5-carboxylate (Step 52.3) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). tR: 4.74 min (HPLC 1); tR: 1.09 min (LC-MS 2); ESI-MS: 553 [M+H]+ (LC-MS 2); Rf=0.55 (CH2Cl2/MeOH 9:1).
Reaction SMILES: ClCCl.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][NH:12][C:13](=[O:15])[CH3:14].[C:16](Cl)(=[O:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>O>[C:16]([C:8]1[CH:9]=[CH:10][C:5]([Cl:4])=[C:6]([CH2:11][NH:12][C:13](=[O:15])[CH3:14])[CH:7]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)NCc1ccccc1Cl
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)NCc1cc(C(C)=O)ccc1Cl
Reaction time: 2 h

Procedure:
To 169.9 kg of the dichloromethane solution of N-[(2-chlorophenyl)methyl]acetamide obtained in Example 3-(A), 47.1 kg (0.6 moles) of acetyl chloride was added and 108.0 kg (0.81 kmoles) of aluminum chloride was added at 15 to 30° C. over 1.5 hours. After dichloromethane was distilled off was distilled off under normal pressure until the temperature reaches 50° C. over 2 hours, the mixture was aged for 6 hours (objective product: other position isomers=76.75%:1.65%; GC area %). After the completion of the reaction, the resulting solution was added dropwise to 450 kg of water at 15 to 35° C. over 2 hours. The solution was extracted twice with 90 kg of dichloromethane and 40 kg of dichloromethane to obtain 199.8 kg of a dichloromethane solution of N-[(5-acetyl-2-chlorophenyl)methyl]acetamide.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[CH2:7]([N:14]1[CH2:19][CH2:18][C:17]([OH:22])([C:20]#[N:21])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-:23].[Na+]>O>[CH2:7]([N:14]1[CH2:15][CH2:16][C:17]([OH:22])([C:20]([NH2:21])=[O:23])[CH2:18][CH2:19]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: [OH-]
Reactant: N#CC1(O)CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)C1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A mixed solution of 18 ml conc. sulfuric acid and 1.8 ml water was cooled to 0° C., and 5 g of 1-benzyl-4-hydroxy-4-piperidinecarbonitrile hydrochloride was added thereto little by little. A mixed solution of 25 ml conc. sulfuric acid and 2.5 ml water was added thereto, and stirred at room temperature for 2 hr. It was left overnight in a freezer. The reaction solution was poured onto ice, and 47 g of sodium hydroxide was added thereto little by little. It was extracted 3 times with a mixed solvent of tetrahydrofuran and ethyl acetate (1:1). The extract was washed with brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was evaporated and subjected to silica gel column chromatography to give 3.19 g of 1-benzyl-4-hydroxy-4-piperidine carboxamide.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:14][CH2:15][CH2:16][CH2:17]I.O>CN(C=O)C.C(OCC)(=O)C>[Cl:14][CH2:15][CH2:16][CH2:17][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: ClCCCI
Reactant: COC(=O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(CCCCl)c1ccccc1
Reaction time: 0.17 h

Procedure:
A solution of methyl phenylacetate (2.0 g) in DMF (5 mL) was added to a solution of sodium hydride (containing mineral oil at 40%, 590 mg) in DMF (20 mL) under ice-cooling. The reaction solution was stirred for 10 minutes, further stirred at room temperature for 30 minutes and then ice-cooled again. A solution of 1-chloro-3-iodopropane (2.99 g) in DMF (5 mL) was added to the reaction mixture, and the reaction solution was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain a crude product of methyl 5-chloro-2-phenylpentanoate. Hydrazine monohydrate (8 mL) was added to a solution of the resulting crude methyl 5-chloro-2-phenylpentanoate (3.279 g) in ethanol (20 mL), and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. Saturated sodium bicarbonate water and ethyl acetate and were added to the residue, and the organic layer was separated. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 730 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:22])[CH2:19][CH2:20][NH2:21])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.CCN=C=NCCCN(C)C.[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[O:43][C:44]([C:50]([F:53])([F:52])[F:51])=[C:45]([C:47](O)=[O:48])[N:46]=2)=[CH:38][CH:37]=1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C>ClCCl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:22])[CH2:19][CH2:20][NH:21][C:47]([C:45]3[N:46]=[C:42]([C:39]4[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=4)[O:43][C:44]=3[C:50]([F:53])([F:52])[F:51])=[O:48])=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)oc1C(F)(F)F
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCN)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccc(F)cc4)oc3C(F)(F)F)cc2)CC1
Reaction time: 24 h

Procedure:
A mixture of trans-{4-[4-(3-aminopropionylamino)phenyl]cyclohexyl}acetic acid methyl ester (60 mg, 0.16 mmol), EDCI (90.3 mg, 0.47 mmol), 2-(4-fluorophenyl)-5-trifluoromethyloxazole-4-carboxylic acid (62.2 mg, 0.23 mmol), HOBt (38.2 mg, 0.28 mmol) and ethyldiisopropylamine (85.4 mg, 0.7 mmol) dissolved in dichloromethane solvent (10 mL) was stirred for 24 hours. The reaction mixture was diluted with aqueous NaHCO3 and extracted with dichloromethane. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column chromatography to obtain trans-{4-[4-(3-{[2-(4-fluorophenyl)-5-trifluoromethyloxazole-4-carbonyl]amino}propionylamino)phenyl]cyclohexyl}acetic acid methyl ester (89 mg, 82%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:37])[CH:13](OS(C3C=CC(C)=CC=3)(=O)=O)[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:8]=2)[O:3]1.[F-:39].[K+]>C(#N)C.O>[CH3:1][C:2]1([CH3:38])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:37])[CH:13]([F:39])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:8]=2)[O:3]1
Reactant: [F-]
Reactant: COc1cc(C(OS(=O)(=O)c2ccc(C)cc2)C(=O)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(F)C(=O)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To a solution of toluene-4-sulfonic acid 2-(2,2-dimethyl-chroman-6-yl)-2-oxo-1-(3,4,5-trimethoxy-phenyl)-ethyl ester (21.6 mg, 0.04 mmol) in anhydrous ACN (0.5 mL) is added KF (4.72 mg, 0.08 mmol) and Kryptofix (30.6 mg, 0.08 mmol). After completion of addition the reaction mixture is heated to 90° C. After 15 minutes, the reaction mixture is cooled down to room temperature and diluted with water. The aqueous layer is separated and extracted with ethyl acetate (3×). All combined organic layers are dried over Na2SO4, filtered, and concentrated to yield an oil. The crude material is purified using reverse phase to yield the desired compound.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)[CH3:2].[CH2:22]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:29]([N:28]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:12](=[O:14])[CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([O:3][CH2:1][CH3:2])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][CH:15]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CCCCCCNCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCN(Cc1ccccc1)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.110 g, 0.37 mmol) in methylene chloride (3.7 mL) were added N-hexyl-benzylamine (0.079 g, 0.41 mmol) and DMAP (0.045 g, 0.37 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.071 g, 0.37 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with methylene chloride (25 mL), and the organic phase was washed with 5% HCl (3×25 mL), aqueous NaHCO3 (25 mL), and brine (25 mL), dried over Na2SO4, and concentrated in, vacuo.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[O:19][C:20]5[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:21]=5[N:22]=4)=[CH:13][CH:12]=3)[C:3]=12.[ClH:42]>CC(C)=O>[ClH:42].[ClH:42].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18]4[O:19][C:20]5[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:21]=5[N:22]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCN(C(=O)OC(C)(C)C)CC5)c5ncnc(N)c45)cc3)nc2c1
Agent: Cl
Solvent: CC(C)=O
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCNCC5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 45 °C
Reaction time: 2.5 h

Procedure:
tert-Butyl 4-(4-amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (142 mg, 0.256 mmol) was dissolved in acetone (7 mL) and 6N aqueous hydrochloric acid (1.4 mL). The reaction was then heated at 45° C. which yielded a precipitate. After 2.5 hours, the precipitate was collected by vacuum filtration, washed with a minimal amount of acetone and dried on the lyophilizer to N2-{4-[4-amino-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl}-5,7-dimethyl-1,3-benzoxazol-2-amine dihydrochloride as an orange solid (130 mg, 96%); -HPLC 10.436 min, 96% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z (MH+)=455.3.
Reaction SMILES: [NH2:1][N:2]1[C:6]([CH2:7][CH3:8])=[CH:5][CH:4]=[C:3]1[C:9]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15])=O.[CH3:19][C:20](=O)[CH2:21][C:22](=[O:24])[CH3:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:22]([C:21]1[C:20]([CH3:19])=[N:1][N:2]2[C:6]([CH2:7][CH3:8])=[CH:5][CH:4]=[C:3]2[C:9]=1[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15])(=[O:24])[CH3:23]
Reactant: CCc1ccc(C(=O)c2cccc(C#N)c2)n1N
Reactant: CC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1ccc2c(-c3cccc(C#N)c3)c(C(C)=O)c(C)nn12
Yield: 24.8 %

Procedure:
To a solution of 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (200 mg) in toluene (6 mL) was added 2,4-pentanedione (837 mg) and p-toluenesulfonic acid monohydrate (32 mg) at ambient temperature. The reaction mixture was refluxed for 1 hour. The residue was purified by flash silica gel chromatography (silica gel, 80 mL) eluted with hexane-ethyl acetate=10-1 to give 3-(3-acetyl-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl)benzonitrile (63 mg, 24.8%) as an yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C.IC>C(#N)C>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(I)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CI
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccc(I)c([N+](=O)[O-])c1
Temperature: 2.5 °C

Procedure:
55 g (0.19 mol) 4-Iodo-3-nitrobenzoic acid (Compound V), 16.5 g (0.12 mol) potassium carbonate and 550 ml acetonitrile were added into a reaction flask, and started to stir. The mixture was cooled to 0 to 5° C., and 52.9 ml (0.38 mol) triethylamine was added. The temperature was controlled below 10° C., and 71 ml (1.12 mol) iodomethane was added. The mixture was heated to about 40° C. for 8 hours, and concentrated under reduced pressure after completing the reaction until most of the acetonitrile was evaporated. The mixture was then extracted with 500 ml ethyl acetate, washed with water for three times, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to the least amount, and then 300 ml petroleum ether was added, stirred for 30 min, and then filtered. The filter cake was washed with petroleum ether, and dried to obtain methyl 4-iodo-3-nitrobenzoate (Compound IV), about 41.2 g (0.13 mol), yield 71.5%.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[N:8]=1.CCOC(C)=O.[Cl-].[NH4+]>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[CH:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]3[O:14][CH2:15][CH2:16][O:17]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: Brc1cccc(C2OCCO2)n1
Reactant: Br[Mg]C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1cc(C2CC2)nc(C2OCCO2)c1
Temperature: 25 °C
Yield: 61 %

Procedure:
To a solution of ZnCl2 in THF (0.5 M, 25 mL) was added dropwise a solution of cyclopropylmagnesium bromide (0.5 M, 25 mL) at −78° C. under nitrogen. The reaction mixture was then allowed to warm up to room temperature and stirred for an hour. The above mixture was then transferred to a sealed tube with 2-bromo-6-[1,3]dioxolan-2-yl-pyridine (1.9 g, 8.25 mmole, see subpart (a) above) and Pd(PPh3)4 (0.4 g, 0.35 mmole). TLC showed major formation of the product and some starting material. The mixture was then heated to 120° C. for 2 hours and cooled down to room temperature and then worked up with EtOAc and saturated ammonium chloride and dried over MgSO4. The residue from concentration was purified on silica gel column with 5% EtOAc in CH2Cl2 to yield 2-cyclopropyl-6-[1,3]dioxolan-2-yl-pyridine as a bright yellow liquid (0.96 g, 61%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:14]=[CH:13][C:12]=2[NH:22]C(=O)OC(C)(C)C)=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH2:37]1[C:40]2([CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:39][N:38]1C(OC(C)(C)C)=O>CS(C)=O>[NH2:22][C:12]1[CH:13]=[CH:14][C:15]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[CH:16][C:11]=1[NH:10][C:8](=[O:9])[C:5]1[CH:4]=[CH:3][C:2]([N:43]2[CH2:44][CH2:45][C:40]3([CH2:37][NH:38][CH2:39]3)[CH2:41][CH2:42]2)=[N:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(N2CCC3(CC2)CNC3)nc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
tert-Butyl [2-{[(6-chloropyridin-3-yl)carbonyl]amino}-4-(2-thienyl)phenyl]carbamate F (20 mg, 0.088 mmol) was dissolved in 1 mL of DMSO and treated with Et3N(0.010 mL) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (20 mg, 0.047 mmol). The mixture was stirred at 90° C. for 18 h, partitioned between EtOAc and saturated NaHCO3, dried (MgSO4), filtered and concentrated), concentrated and the residue was purified by chromatography on SiO2 (EtOAc/CH2Cl2, 0% to 100%). The residue was dissolved in 1 mL of 1:1 TFA/CH2Cl2, stirred for 1 h and concentrated. Neutralization with EtOAc/sat'd NaHCO3 extraction and drying (MgSO4) gave desired product, N-[2-amino-5-(2-thienyl)phenyl]-6-(2,7-diazaspiro[3.5]non-7-yl)nicotinamide, which was confirmed by MS (ESI+): cal'd [M+H]+ 420.2, obs'd 420.1.
Reaction SMILES: N[CH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.C(Cl)CCl.ON1C2C=CC=CC=2N=N1.C[N:23]([CH:25]=[O:26])C>ClCCl>[NH:7]1[C:3]([CH2:2][C:25]([NH2:23])=[O:26])=[N:4][N:5]=[N:6]1
Reactant: CN(C)C=O
Reactant: NCc1nnn[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: NC(=O)Cc1nnn[nH]1

Procedure:
Carboxylic acid 14.4 can be coupled with 5-aminomethyltetrazole 19.1 (available commercially from Dynamit Nobel GmbH, Leverkusen, Germany) using any of a variety of peptide coupling reagents, including EDC and 1-hydroxybenzotriazole in dichloromethane or DMF, to give 1H-tetraazol-5-ylmethyl carboxamide 19.2. Under similar reaction conditions, 14.4 can be coupled with 5-aminotetrazole 19.3 to afford 1H-tetraazol-5-yl carboxamide 19.4.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=[C:4]2[CH:3]=1.[C:17](=[O:24])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[NH2:18].C(=O)([O-])[O-].[Cs+].[Cs+]>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:20]([O:19][C:17](=[O:24])[NH:18][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=[C:4]2[CH:3]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Brc1ccn2nc(-c3ccccc3)nc2c1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 100 °C
Reaction time: 22 h
Yield: 69.6 %

Procedure:
To an nitrogen purged suspension of 7-bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (9 g, 32.8 mmol) in dioxane (180 ml) is added successively tert-butyl carbamate (4.71 g, 39.4 mmol), tris(dibenzylidene-acetone)dipalladium(0) (601 mg, 657 umol), 4,5-bis(diphenylphos-phino)-9,9-dimethylxanthene (760 mg, 1.31 mmol) and cesium carbonate (15 g, 46 mmol). The brown mixture is then stirred for 22 hours at 100° C. under nitrogen atmosphere. The solvent is removed in vacuo and the brown residue partitioned between ethyl acetate and water. The aqueous layer is extracted twice with ethyl acetate and the combined organic layers are washed with water (3×120 ml) and with brine and dried with magnesium sulfate. The solution is concentrated in vacuo to ca 80 ml: crystallization. The suspension is stirred for 10 min in an ice bath and the solid is collected by filtration, washed with little cold ethyl acetate and dried affording (2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-carbamic acid tert-butyl ester (7.09 g) as an off-white solid. The mother liquor is evaporated and the residue (4.79 g) is loaded on silica (16 g). The product is isolated by chromatography on a 120 g silica cartridge (eluent heptane/ethyl acetate 10-50%, 45 min) yielding a second crop of 1.748 g of a white solid. mp.: 200-201° C. dec. MS: m/z=311.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:14]([OH:15])[C:13](=[O:16])[NH:12][C:11]3[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:10]=3[S:9]2)=[CH:4][CH:3]=1.[CH2:22]([O:29][C:30]([N:32]([CH2:34][CH2:35]Cl)[CH3:33])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[K+]>CS(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:14]([OH:15])[C:13](=[O:16])[N:12]([CH2:35][CH2:34][N:32]([C:30]([O:29][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:31])[CH3:33])[C:11]3[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:10]=3[S:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc([C@@H]2Sc3cc(C)ccc3NC(=O)[C@@H]2O)cc1
Reactant: CN(CCCl)C(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2O)cc1
Yield: 42 %

Procedure:
A mixture of 0.90 g of (-)-cis-2-(4-methylphenyl)-3-hydroxy-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 1.03 g of 2-(N-benzyloxycarbonyl-N-methylamino)ethyl chloride, 0.20 g of potassium hydroxide and 10 ml of dimethylsulfoxide is treated in the same manner as described in Example 1-(1), whereby 0.62 g of (-)-cis-2-(4-methylphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained as an oil.