Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:33][CH2:32][C:5]2[N:6]([CH2:14][CH2:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20][CH2:19]3)=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.FC(F)(F)C(O)=O.FC(F)(F)C([O-])=O>ClCCl>[NH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:33][CH2:32][C:5]2=3)[CH2:19][CH2:20]1
Reactant: Cc1ccc2c(c1)c1c(n2CCC(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)CCN(C)C1
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCC(=O)N2CCC(N)CC2)CCN(C)C1
Yield: 25.6 %

Procedure:
Tert-butyl 1-(3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoyl)piperidin-4-ylcarbamate (See Example 54) (50 mg) was stirred with trifluoroacetic acid (2 ml) in dichloromethane (2 ml) for 16 h at 25° C. to obtain 10 mg of 1-(4-aminopiperidin-1-yl)-3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propan-1-one as a trifluoroacetate salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][C:5]=12.[N+:12]([CH2:15][CH3:16])([O-:14])=[O:13].C(N)C>C(O)C.C(N)CCC>[N+:12]([C:15]([CH3:16])=[CH:10][C:8]1[CH:7]=[CH:6][C:5]2[N:4]([CH:3]=[CH:2][N:1]=2)[CH:9]=1)([O-:14])=[O:13]
Reactant: O=Cc1ccc2nccn2c1
Reactant: CC[N+](=O)[O-]
Agent: CCN
Solvent: CCO
Solvent: CCCCN
Product: CC(=Cc1ccc2nccn2c1)[N+](=O)[O-]
Yield: 11.9 %

Procedure:
In 40 ml of ethanol, 6.9 g of 6-imidazo[1,2-a]pyridinecarbaldehyde was stirred under reflux for 14 hours, together with 10.6 g of nitroethane and 30 drops of n-butyl amine. Then, a small quantity of ethyl amine was added thereto and the mixture was stirred under reflux for further 18 hours. After insoluble matters were removed by filtration upon heating, 50 ml of ethanol and 150 ml of ether were further added to remove insoluble matters by filtration. The solvent was removed by distillation under reduced pressure and the residue was recrystallized twice from ethanol to obtain 1.14 g of 6-(2-nitro-1-propenyl)imidazo[1,2-a]pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([OH:23])=[O:22])[C:15]=3[N:14]=[C:13]2[C:24](=[O:35])[NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]3[CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[O:10])=[N:6][CH:7]=1.[CH:36]1([CH2:39]O)[CH2:38][CH2:37]1>>[CH:36]1([CH2:39][O:22][C:21]([C:20]2[C:15]3[N:14]=[C:13]([C:24](=[O:35])[NH:25][CH:26]4[CH2:31][CH2:30][N:29]([CH:32]5[CH2:34][CH2:33]5)[CH2:28][CH2:27]4)[N:12]([CH2:11][C:9](=[O:10])[NH:8][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=4)[C:16]=3[CH:17]=[CH:18][CH:19]=2)=[O:23])[CH2:38][CH2:37]1
Reactant: O=C(Cn1c(C(=O)NC2CCN(C3CC3)CC2)nc2c(C(=O)O)cccc21)Nc1ccc(Cl)cn1
Reactant: OCC1CC1
Product: O=C(Cn1c(C(=O)NC2CCN(C3CC3)CC2)nc2c(C(=O)OCC3CC3)cccc21)Nc1ccc(Cl)cn1

Procedure:
1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid cyclopropylmethyl ester was prepared by a procedure according to example 69 starting from 589.0 mg (1.19 mmol) 1-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid and 1.92 mL (23.8 mmol) cyclopropyl-methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].[CH3:9][O:10][C:11]([C:13]#[C:14][C:15]([O:17][CH3:18])=[O:16])=[O:12]>C(Cl)(Cl)Cl>[O-:8][N+:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1]/[C:13](=[CH:14]\[C:15]([O:17][CH3:18])=[O:16])/[C:11]([O:10][CH3:9])=[O:12]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1cccc[n+]1[O-]
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C(\Nc1cccc[n+]1[O-])C(=O)OC
Reaction time: 1 h

Procedure:
To a stirred solution of 2-aminopyridine-N-oxide in chloroform at 0° C. was added dropwise a solution of DMAD (1 eq.) in chloroform. After addition the cooling bath was removed and stirring was continued for 1 hour. A further 0.2 eq. of DMAD was added and stirring continued for 1 hour. The solution was filtered over a silica gel plug. After elution with EtOAc/PE (4:6), the product was eluted with MeOH/EtOAc. The combined MeOH/EtOAc-phases were concentrated to dryness. The title compound was obtained as a brown oil, which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10])#[N:2].C([Sn]([N:24]=[N+:25]=[N-:26])(CCCC)CCCC)CCC>C1(C)C(C)=CC=CC=1.C(OCC)C>[CH3:10][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]1[N:24]=[N:25][NH:26][N:2]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: COc1ccccc1C#N
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: COc1ccccc1-c1nn[nH]n1
Yield: 98.1 %

Procedure:
A mixture of 1-cyano-2-methoxybenzene (1.02 g, 7.7 mmol) and tributyltin azide (3.4 g, 10.0 mmol) in 3.0 mL of xylene was heated under reflux for 5hours. The reaction mixture then was cooled and diluted with diethyl ether.Anhydrous hydrochloric acid was bubbled into the mixture and a white precipitate formed. The precipitate was collected by suction filtration and washed repeatedly with diethyl ether. Drying gave 5-(2-methoxyphenyl)-2H-tetrazole (1.33 g, 7.55 mmol).
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH3:4].[NH2:7][C:8]1[C:13]([NH2:14])=[C:12]([CH3:15])[CH:11]=[CH:10][N:9]=1.[NH4+].[OH-]>>[CH3:15][C:12]1[CH:11]=[CH:10][N:9]=[C:8]2[N:7]=[C:1]([CH2:2][CH2:3][CH3:4])[NH:14][C:13]=12
Reactant: CCCC(=O)O
Reactant: Cc1ccnc(N)c1N
Agent: [NH4+]
Agent: [OH-]
Product: CCCc1nc2nccc(C)c2[nH]1
Temperature: 100 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
A mixture of butyric acid (6.57 mL, 71.9 mmol), 2,3-diamino-4-picoline (8.05 g, 65.4 mmol) (Lappin, G. R., Slezak, F. B. J. Am. Chem. Soc. (1950) 72, 7806-7) and polyphosphoric acid (50 g) was heated to 100° C. with stirring for 3 hours. The reaction was monitored by tlc of NH4OH neutralized aliquots. Basification (NH4OH), extraction (CH2Cl2, 4×50 mL), drying (K2CO3), purification (by filtering through 100 g SiO2, EtOAc elution), and concentration gave 10.0 g (95%) of the title compound as an amorphous tan solid which was judged pure by 1H NMR and tlc: mp 110°-112° C. (without recrystallization).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][N:20]=[C:19]2[NH:28][C:29]1[S:30][C:31]2[CH:37]=[C:36]([NH2:38])[CH:35]=[CH:34][C:32]=2[N:33]=1>O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][N:20]=[C:19]2[NH:28][C:29]1[S:30][C:31]2[CH:37]=[C:36]([NH:38][C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=3)=[O:11])[CH:35]=[CH:34][C:32]=2[N:33]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Solvent: O
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)Nc5cccc(C(F)(F)F)c5)cc4s3)c2cc1OC

Procedure:
1-[2-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl]-3-(3-trifluoromethylphenyl)urea was prepared from 3-trifluoromethylphenyl isocyanate (16 μL, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 3. The mixture was poured into water (20 mL) and the resulting precipitate was purified by pTLC (dichloromethane:methanol=9:1) to obtain a yellow solid (44 mg, 81 μmol, 72%). LC/ESI-MS: m/z=541 [M+H]+; m/z=539 [M−H]−; Rt=3.59 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]=[C:12]=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:14]([NH2:18])(=[O:17])[CH2:15][CH3:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([NH:18][C:14](=[O:17])[CH2:15][CH3:16])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCC(N)=O
Reactant: COc1ccc(N=C=O)cc1OC
Product: CCC(=O)NC(=O)Nc1ccc(OC)c(OC)c1
Reaction time: 0.25 h

Procedure:
A mixture of 3,4-dimethoxyphenylisocyanate (26.0 g, 145 mM) and propionamide (10.61 g, 145 mM) is heated at 160°-165° C. for 11/2 hours. A homogeneous pale yellow solution forms which after 15 minutes solidifies. The heating is discontinued and the flask is allowed to cool slowly. The mixture is triturated with acetone and this resulting white solid is filtered and dried. Yield: 32.45 g, mp 193°-197° C.
Reaction SMILES: C([O:8][C@H:9]1[C@@H:15]([C@@H:16]([CH2:25][O:26]CC2C=CC=CC=2)[O:17]CC2C=CC=CC=2)[O:14][CH:11]([O:12][CH3:13])[C@@H:10]1[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])C1C=CC=CC=1.N.[Na]>CCOCC>[CH2:35]([O:34][C@@H:10]1[C@@H:9]([OH:8])[C@@H:15]([C@@H:16]([CH2:25][OH:26])[OH:17])[O:14][CH:11]1[O:12][CH3:13])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCO[C@H]1C(OC)O[C@H]([C@@H](COCc2ccccc2)OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: N
Agent: [Na]
Solvent: CCOCC
Product: CCCCCCCO[C@H]1C(OC)O[C@H]([C@H](O)CO)[C@@H]1O
Temperature: 25 °C
Yield: 89.3 %

Procedure:
Methyl 3,5,6-tri-O-benzyl-2-O-heptyl-D-glucofuranoside (10.5 g, 0.019 mol) was dissolved in 25 ml of anhydrous ether and placed in a flask maintained at -40 to -50 C. in an acetone-dry ice bath. Ammonia (100 ml) was condensed into the flask, and 2.05 g (1.6 eq.) of sodium metal was added in small portions, until a deep blue color persisted. The excess sodium metal was quenched by the careful addition of solid ammonium chloride, and the mixture was allowed to warm up to room temperature with nitrogen sparging. The mixture was filtered, the residue was washed with acetone, and the combined filtrate and washings were evaporated to give a syrup which was purified by flash chromatography (70:30 ethyl acetate in hexane, then neat ethyl acetate) to afford 4.96 g (91.3%) of the title compound methyl-2-O-heptyl-D-glucofuranoside, roughly 4:5 as a mixture of alpha and beta anomers. NMR: 4.94 (d, H-1, alpha); 4.88 (s, H-1, beta); 3.41 (S, ome); 3.38 (s, ome) 1.28 (m, 8H, 4 CH2); 0.89 (t, 3H, CH3)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[N:10]=[N:11][NH:12][N:13]=2)=[CH:4][CH:3]=1.[C:14](O)([CH3:17])([CH3:16])[CH3:15].FC(F)(F)C(O)=O.S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[N:10]=[N:11][N:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[N:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)O
Reactant: Brc1ccc(Cc2nn[nH]n2)cc1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)n1nnc(Cc2ccc(Br)cc2)n1
Yield: 54 %

Procedure:
A mixture of 5-[(4-bromophenyl)methyl]-2H-tetrazole (18.5 g. 77 mmol). t-butanol (11.4 g. 150 mmol), trifluoroacetic acid (76 mL. 1.0 mol) and concentrated sulfuric acid (3.8 g. 39 mmol) was stirred for 24 h and then partitioned between ethyl acetate (250 mL) and water (100 mL). The organic layer was washed with water (4×100 mL) and 1M NAOH (2×100 mL) and was dried over sodium sulfate. Filtration and removal of the solvent in vacuo produced a solid that was recrystallized from hexane to give 5-[(4-bromophenyl)methyl]-2-(1,1-dimethylethyl)-2H-tetrazole. (12.3 g, 47 mmol) in 54% yield, mp. 69°-70° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:19])=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[C:7](=[O:12])[N:6]([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[C:5]2=[O:18].[Cl:20][C:21]1[C:26]([CH:27]=O)=[C:25]([O:29][CH3:30])[N:24]=[CH:23][CH:22]=1>CO.C(O)(=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][N:24]=[C:25]([O:29][CH3:30])[C:26]=1[C:27]1[NH:11][C:10]2=[CH:9][C:8]3[C:7](=[O:12])[N:6]([CH2:13][CH2:14][N:15]([CH3:16])[CH3:17])[C:5](=[O:18])[C:4]=3[C:3]([CH3:19])=[C:2]2[N:1]=1
Reactant: COc1nccc(Cl)c1C=O
Reactant: Cc1c(N)c(N)cc2c1C(=O)N(CCN(C)C)C2=O
Solvent: CO
Solvent: CC(=O)O
Product: COc1nccc(Cl)c1-c1nc2c(C)c3c(cc2[nH]1)C(=O)N(CCN(C)C)C3=O
Temperature: 50 °C

Procedure:
A mixture of 5,6-diamino-2-(2-(dimethylamino)ethyl)-4-methylisoindoline-1,3-dione (0.36 g, 1.37 mmol) and 4-chloro-2-methoxynicotinaldehyde (0.26 g, 1.51 mmol) in a mixture of methanol (8 mL) and acetic acid (0.4 mL) was heated at 50° C. for 14 h. After the end of reaction was established by TLC, the reaction mixture was concentrated under vacuum to dryness, and the crude product was subjected to the next step without further purification. Mass (ESI, positive) m/z 414.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25](O)=[O:26])[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[CH3:35][N:36]([CH3:42])[CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[CH3:35][N:36]([CH3:42])[CH:37]1[CH2:41][CH2:40][N:39]([C:25]([C:21]2[CH:20]=[C:19]([C:12]3[CH:11]=[C:10]4[C:15]([CH2:16][CH:17]([CH3:18])[N:8]([C:6]5[CH:5]=[C:4]([N:28]6[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]6)[N:3]=[C:2]([NH2:1])[N:7]=5)[CH2:9]4)=[CH:14][CH:13]=3)[CH:24]=[CH:23][N:22]=2)=[O:26])[CH2:38]1
Reactant: CN(C)C1CCNC1
Reactant: CC1Cc2ccc(-c3ccnc(C(=O)O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CC1Cc2ccc(-c3ccnc(C(=O)N4CCC(N(C)C)C4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 61B starting from 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 61B, Step 2) and 3-(dimethylamino)pyrrolidine (TCI, Cat. No. D1859). LCMS (M+H)+: m/z=556.3.
Reaction SMILES: [NH2:1][CH2:2][C:3]#[C:4][CH2:5][NH:6][C:7](=[O:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([NH:6][CH2:5][C:4]#[C:3][CH2:2][NH:1][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=2)=[O:27])=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: NCC#CCNC(=O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(CCCCC(c1ccc(F)cc1)c1ccc(F)cc1)NCC#CCNC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6,6-bis-(4-fluoro-phenyl)-hexanoic acid (4-amino-but-2-ynyl)-amide (0.69 g, 1.86 mmol) in dry CH2Cl2 (40 ml) was added 4-chlorobenzoic acid (0.29 g, 1.86 mmol) under nitrogen. To the reaction was added EDC (0.71 g, 3.72 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (30 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (20:1) to give a desired product in good yield.
Reaction SMILES: C([N:4]1[CH2:8][CH:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:5]1)C=C.CC#N>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH:6]3[CH:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:8][NH:4][CH2:5]3)[CH2:15][CH2:16]2)=[CH:25][CH:24]=1
Reactant: C=CCN1CC(CN2CCC(c3ccc(F)cc3)CC2)C(C(C)(C)C)C1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)C1CNCC1CN1CCC(c2ccc(F)cc2)CC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
A mixture of 1 g (2.7 mmol) of 1-allyl-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-t-butylpyrrolidine and 0.13 g (0.14 mmol) of Wilkinson's catalyst [Rh(PPh3)3Cl] in 40 mL of an 85% solution of CH3CN and water was heated to 90° C. and stirred for 3 h. The reaction mixture was cooled to rt and concentrated. The residue was partitioned between EtOAc and water. The organic fraction was washed with sat. NaHCO3, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chomatography (silica, CHCl3: MeOH:NH3, 90:10:1) to give 0.75 g of the title compound.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[C:14](=[O:22])[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][N:7]3[C:8]=2[C:3]=1[CH:4](C(O)=O)[CH2:5][N:6]3[CH3:23].O>CN1CCCC1=O>[F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[C:14](=[O:22])[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:23]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c(F)c3c1=O)C(C(=O)O)CN2C
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c(F)c3c1=O)CCN2C
Temperature: 160 °C
Yield: 48.4 %

Procedure:
300 mg of the compound (197) obtained in Example 68 was dissolved in 6 ml of N-methylpyrrolidone, and the solution was heated at 160° C. for 3 hours. After air-cooling, the water was added to the reaction solution, and the solution was extracted with chloroform three times. After drying over magnesium sulfate, the solvent was removed by distillation. The residue was separated by column chromatography (silica gel, eluent solvent; chloroform) to obtain 128 mg of the subject compound (198) in a 49% yield.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16](=O)[CH2:17][CH2:18][C:19]2[S:20][C:21]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:22]=3[C:23]=2[CH2:24][CH2:25][CH3:26])=[CH:4][C:5]([CH3:15])=[C:6]([CH:14]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl.[NH2:37][OH:38].C([O-])(=O)C.[Na+]>CCO.O>[OH:1][C:2]1[C:3]([C:16](=[N:37][OH:38])[CH2:17][CH2:18][C:19]2[S:20][C:21]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:22]=3[C:23]=2[CH2:24][CH2:25][CH3:26])=[CH:4][C:5]([CH3:15])=[C:6]([CH:14]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCCc1c(CCC(=O)c2cc(C)c(OCC(=O)OCC)cc2O)sc2cc(C(F)(F)F)ccc12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCc1c(CCC(=NO)c2cc(C)c(OCC(=O)OCC)cc2O)sc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Yield: 37.6 %

Procedure:
To a solution of Ethyl 5-hydroxy-2-methyl-4-[3-[3-propyl-6-(trifluoromethyl)benzothiophen-2-yl]propionyl]-phenoxyacetate (obtained in Example 22-(4), 19 mg, 0.0381 mmol) in EtOH (0.4 mL) was added hydroxylamine hydrochloride (2.9 mg, 0.0419 mmol) and sodium acetate (3.8 mg, 0.0457 mmol) in water (0.3 mL). The mixture was heated for 10 hours under reflux and cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was recrystallized from chloroform-hexane, to give the titled compound as a white crystal (7.5 mg, yield 38%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH:17]=[O:18])[CH:14]=[CH:13][C:12]=1[N+:19]([O-])=O)[CH3:2].O>C(O)C.Cl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH:17]=[O:18])[CH:14]=[CH:13][C:12]=1[NH2:19])[CH3:2]
Reactant: CCOC(=O)CCCCCOc1cc(C=O)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCCCOc1cc(C=O)ccc1N
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-(5-formyl-2-nitro-phenoxy)-hexanoic acid ethyl ester (1.0 g, 3.23 mmol) in ethanol (20 ml) and concentrated HCl (5 ml) was added stannous chloride (2.17 g, 11.63 mmol). The mixture was stirred at 70° C. for 90 minutes while being monitored by thin layer chromatography. After cooling to room temperature, the mixture was poured into water (100 ml) and neutralized with a saturated solution of sodium bicarbonate resulting in the precipitation of tin salts and a dark brown oil. The salts were washed with ethyl acetate and the washings were combined with the original filtrate, the aqueous phase was separated and the remaining ethyl acetate phase was dried with magnesium sulfate, filtered and concentrated by rotary evaporation to a brown oil which was purified by column chromatography (45% CH2Cl2, 45% hexane, 10% Et3N). The product, 6-(2-amino-5-formyl-phenoxy)-hexanoic acid ethyl ester, was obtained as a red oil (0.33 g, 35%). An additional 0.32 g of red oil was obtained from the column but found to be a mixture of unidentified byproducts. 1H NMR (400 MHz, CDCl3) δ: 9.72 (s, 1H), 7.30 (m, 2H), 613 (d, 1H, J=8.4 Hz), 4.50 (s, 2H), 4.15 (q, 2H, J=7.2 Hz), 4.08 (t, 2H, J=6.8 Hz), 2.35 (t, 2H, J=8.8 Hz), 1.88 (m, 2H), 1.74 (m, 2H), 1.55 (m, 2H) 1.30 (t, 3H, J=6.8 Hz). 13C NMR (400 MHz, CDCl3) δ: 109.59, 173.60, 146.08, 143.31, 127.78, 127.55, 112.72, 109.11, 68.18, 60.35, 34.20, 28.83, 25.69, 24.61, 14.18. IR (neat): 3481, 3362, 2936, 2868, 2722, 2360, 2341, 2229, 2156, 1964, 1727, 1671, 1612, 1587, 1572, 1517, 1444, 1394, 1368, 1313, 1243, 1164, 1140, 1095, 1029, 864, 817, 789, 748.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][NH:5][CH2:6][C@@H:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:8]([CH3:11])[CH2:9][CH3:10].[C:21]1([CH:31]=O)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([CH2:6][C@@H:7]([NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[C@@H:8]([CH3:11])[CH2:9][CH3:10])[CH2:31][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC[C@H](C)[C@@H](CNCC(=O)OC)NC(=O)OC(C)(C)C
Reactant: O=Cc1cccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC[C@H](C)[C@@H](CN(CC(=O)OC)Cc1cccc2ccccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-[2 (S)-(t-Butoxycarbonylamino)-3 (S)-methylpentyl] glycine methyl ester (2.00 g, 6.97 mmol) was dissolved in 1,2dichloroethane (56 ml) and 3A molecular sieves were added followed by 1-naphthaldehyde (1.89 ml, 13.9 mmol) and sodium triacetoxyborohydride (6.65 g, 31.4 mmol). The mixture was stirred at ambient temperature for 16 h, filtered and evaporated in vacuo. The residue was partitioned between EtOAc (100 ml) and sat. aq. NaHCO3 (25 ml). The aqueous layer was extracted with EtOAc (3×50 ml). The organic extracts were combined, dried (Na2 SO4), filtered, and evaporated in vacuo to afford a residue which was purified by chromatography (SiO2, 15-33% ethyl acetate in hexanes) to afford the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[S:16][C:5]2=[N:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9](=[O:10])[N:4]2[CH:3]=1.C1C(=O)N([Br:24])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:24][CH2:1][C:2]1[S:16][C:5]2=[N:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9](=[O:10])[N:4]2[CH:3]=1
Reactant: CCOC(=O)c1cnc2sc(C)cn2c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2sc(CBr)cn2c1=O
Temperature: 25 °C
Yield: 63.1 %

Procedure:
A mixture of ethyl 2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxylate (Preparation 8, 1.19 g), NBS (1.07 g) and benzoyl peroxide (25 mg) is heated to reflux in carbon tetrachloride (50 mL) for 6 h. After the mixture is cooled to rt, the precipitate is filtered. The precipitate is re-dissolved in methylene chloride (100 mL) and washed with water. The organic layer is separated, dried (MgSO4), and concentrated to afford 1.0 g (60%) of the title compound as a pale yellow solid. Physical characteristics: MS (ESI+) m/z 317, 319 (M+H)+. 1H NMR (CDCl3) δ9.80, 8.15, 4.42, 1.40.