Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][CH2:3]1.[Cl:18][C:19]1[N:20]=[C:21]([C:26](O)=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C(=O)C.ClCCl.O.C(O)(C(F)(F)F)=O.C(OCC)(=O)C>[Cl:18][C:19]1[N:20]=[C:21]([C:26]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][CH2:3]2)=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25]
Reactant: COC(=O)c1cccc(N2CCC(N)CC2)c1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)NC2CCN(c3cccc(C(=O)OC)c3)CC2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
10% palladium-carbon (wet, 200 mg) was added to a mixed solution of methyl 3-(4-benzyloxycarbonylaminopiperidin-1-yl)benzoate obtained in Example (192c) (120 mg, 0.345 mmol) in tetrahydrofuran/methanol=1/1 (10 mL), and the mixture was catalytically hydrogenated at room temperature for three hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to obtain methyl 3-(4-aminopiperidin-1-yl)benzoate as a colorless oily substance. The resulting amine was dissolved in a mixed solution of N,N-dimethylacetamide/dichloromethane=1/1 (8 mL). 4-Chloro-5-ethyl-1H-imidazole-2-carboxylic acid (described in Example 1d, 190 mg, 1.1 mmol), 1-hydroxybenzotriazole (220 mg, 1.63 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (312 mg, 1.63 mmol) and triethylamine (227 μL, 1.63 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with brine, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=1/1) to obtain 88 mg of the title compound as a colorless solid (41%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][C:27]=1[CH:32]=O)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][C:27]=1[CH:32]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[NH:12][C:11]1=[O:17])=[O:25])[CH3:35]
Reactant: O=C1Cc2c(cccc2-c2ccccc2F)N1
Reactant: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=C1C(=O)Nc2cccc(-c3ccccc3F)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 49.9 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)amide as a yellow solid (57.5 mg, 50%).
Reaction SMILES: Cl.Cl.[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([NH:26][CH2:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[C:16]([NH:21][C:22](=O)[CH2:23][CH3:24])[CH:17]=[N:18]2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[N:26]([CH2:27][CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[C:22]([CH2:23][CH3:24])=[N:21][C:16]=3[CH:17]=[N:18][C:19]=2[CH:20]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCC(=O)Nc1cnc2cc(OCc3ccccc3)ccc2c1NCC1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC1CCOCC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
N-{7-(Benzyloxy)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]quinolin-3-yl}propanamide dihydrochloride (14.2 g, 31.1 mmol) was slurried in ethanol (150 mL) and diluted with water (50 mL). Potassium carbonate (12.3 g, 89 mmol) in water (15 mL) was added and the reaction was stirred until dissolution (˜30 minutes). The reaction was then heated to 60° C. for 16 hours. The ethanol was evaporated under reduced pressure and the remaining water was extracted with dichloromethane. The organic fraction was sequentially washed with water, followed by saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated. Recrystallization from acetonitrile afforded 8.4 g of 7-(benzyloxy)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline as a tan powder.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([CH3:20])[CH2:13][C:14]1([CH2:17][C:18]#[N:19])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[O:11]=[C:12]([CH3:20])[CH2:13][C:14]1([CH2:17][C:18]#[N:19])[CH2:16][CH2:15]1
Reactant: CC(O)CC1(CC#N)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)CC1(CC#N)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.2 %

Procedure:
To a -78° C. solution of oxalyl chloride (0.70 mL, 8.0 mmol) in 40 mL of CH2Cl2 was added DMSO (0.62 mL, 8.7 mmol) and the resulting solution was stirred for 10 min. A solution of the alcohol from Step 3 (2.46 g, 17.7 mmol) in 5 mL CH2Cl2 was then added, and the mixture stirred 1 h at -78° C. Triethylamine (4.2 mL, 30 mmol) was then added, and the solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was then partitioned between 1M HCl and CH2Cl2, and the organic layer was washed with saturated NaHCO3 and brine, dried over MgSO4 and evaporated. Purification of the residue by flash chromatography (25% ethyl acetate/hexanes) provided 927 mg of the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][CH:26]([CH:31]([CH3:33])[CH3:32])[CH2:27][C:28](O)=[O:29].Cl.[CH3:35][O:36][C:37]([C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[CH2:44][CH2:43][C@H:42]2[NH2:48])=[O:38]>C1COCC1.C(OCC)(=O)C>[CH3:25][CH:26]([CH:31]([CH3:33])[CH3:32])[CH2:27][C:28]([NH:48][C@H:42]1[C:41]2[C:45](=[CH:46][CH:47]=[C:39]([C:37]([O:36][CH3:35])=[O:38])[CH:40]=2)[CH2:44][CH2:43]1)=[O:29]
Reactant: CC(C)C(C)CC(=O)O
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)CC(C)C(C)C)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
HATU (0.872 g, 2.3 mmol, 1 eq) and TEA (0.647 ml, 4.6 mmol, 2 eq) were added to an ice-cooled solution of 3,4-dimethylpentanoic acid (300 mg, 2.3 mmol, 1 eq) in THF (26 ml), and stirring was carried out for 15 min. (3R)-3-Amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester hydrochloride (A-01) (0.786 g, 3.5 mmol, 1.5 eq) was added to the reaction solution, and the mixture was then stirred overnight at RT. The reaction solution was diluted with ethyl acetate, washed with sat. sodium hydrogen carbonate solution and sat. NaCl solution, dried over magnesium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, cyclohexane:ethyl acetate 2:1), the desired product was obtained. Yield: 87% (0.61 g)
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]1([CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][C:29](OCC)=O)[CH2:22][CH2:21]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1>>[C:10]1([CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][C:29]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:22][CH2:21]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: ON=C1CCCCCC1
Reactant: CCOC(=O)CCCN1CCC(c2cccc3ccccc23)CC1
Product: c1ccc2c(C3CCN(CCCc4onc5c4CCCCC5)CC3)cccc2c1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(1-naphthyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(1-naphthyl)piperidin-1-yl)propyl-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[C:3]([C:10](Cl)=[O:11])[CH:2]=1.[Si:13]([O:20][C:21]([CH3:39])([CH3:38])[CH2:22][C:23]1[S:24][C:25]([NH2:37])=[C:26]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])[N:27]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CC=CC=1>C(Cl)Cl>[Si:13]([O:20][C:21]([CH3:39])([CH3:38])[CH2:22][C:23]1[S:24][C:25]([NH:37][C:10]([C:3]2[CH:2]=[N:1][N:5]3[CH:6]=[CH:7][CH:8]=[N:9][C:4]=23)=[O:11])=[C:26]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])[N:27]=1)([C:16]([CH3:18])([CH3:19])[CH3:17])([CH3:15])[CH3:14]
Reactant: COc1ccc(Cl)cc1-c1nc(CC(C)(C)O[Si](C)(C)C(C)(C)C)sc1N
Reactant: O=C(Cl)c1cnn2cccnc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1-c1nc(CC(C)(C)O[Si](C)(C)C(C)(C)C)sc1NC(=O)c1cnn2cccnc12
Reaction time: 72 h
Yield: 66 %

Procedure:
A solution of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (52.0 mg, 0.29 mmol), 2-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(5-chloro-2-methoxyphenyl)thiazol-5-amine (103 mg, 0.24 mmol) and pyridine (2 mL) was stirred at 60° C. for 2 hours, then at room temperature for an additional 72 hours. DCM was added, the organics washed with water, sodium hydrogen carbonate (sat. aq.) and brine, then evaporated to dryness. The residues were purified by flash chromatography on silica gel (0 to 20% ethyl acetate in dichloromethane) to yield 90.6 mg (66%) of N-(2-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(5-chloro-2-methoxyphenyl)thiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow solid. LCMS (ESI) m+H=572.1; 1H NMR (400 MHz, DMSO-d6): δ 10.45 (s, br, 1H); 9.38 (dd, 1H); 8.76 (s, 1H); 8.73-8.72 (m, 1H); 7.51 (dd, 1H); 7.45 (d, 1H); 7.35 (d, 1H); 7.31 (d, 1H); 3.79 (s, 3H); 3.06 (s, 2H); 1.32 (s, 6H); 0.90 (s, 9H); 0.11 (s, 6H).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([OH:11])=O)=[CH:4]1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][CH:45]=1)[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[CH:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:25]=[C:24]([NH:23][C:9]([C:5]5[C:6]([CH3:8])=[CH:7][N:3]([CH2:1][CH3:2])[CH:4]=5)=[O:11])[CH:45]=[CH:44][CH:43]=4)=[CH:33][N:32]3[N:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: CCn1cc(C)c(C(=O)O)c1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CCn1cc(C)c(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c1
Yield: 23.3 %

Procedure:
In the same manner as in Example 18-4 and using 1-ethyl-4-methyl-1H-pyrrole-3-carboxylic acid (198 mg, 1.29 mmol), tetrahydrofuran (7 mL), oxalyl chloride (169 μL, 1.94 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (67.0 mg, 23%) was obtained as a white solid.
Reaction SMILES: [C:1]([C:4]1[S:8][N:7]=[N:6][C:5]=1[CH3:9])(=[O:3])[CH3:2].[Br:10]Br.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:10][CH2:2][C:1]([C:4]1[S:8][N:7]=[N:6][C:5]=1[CH3:9])=[O:3]
Reactant: CC(=O)c1snnc1C
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nnsc1C(=O)CBr
Temperature: 25 °C
Yield: 99.7 %

Procedure:
To a solution of 5-acetyl-4-methyl-1,2,3-thiadiazole (1.00 g, 7.03 mmol) in chloroform (20 ml) was added dropwise a solution of bromine (1.24 g, 7.73 mmol) in chloroform (10 ml) over 0.5 h at room temperature. The mixture was heated at reflux temperature for 2 h. After cooling to room temperature, the mixture was made basic with saturated aqueous sodium bicarbonate and extracted with dichloromethane (100 ml×2). The extracts were dried (Na2SO4) and concentrated to give 1.55 g (100%) of the title compound as a brown oil.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:21][C@@H:22]([CH3:27])[C:23]([F:26])([F:25])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14]([OH:16])=O)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH:28]1[C:31]2([CH2:34][O:33][CH2:32]2)[CH2:30][CH2:29]1.C([O-])(=O)C([O-])=O>>[CH:1]1([C:4]2[C:5]([O:21][C@@H:22]([CH3:27])[C:23]([F:24])([F:26])[F:25])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:18])([CH3:20])[CH3:19])[C:14]([N:28]3[C:31]4([CH2:34][O:33][CH2:32]4)[CH2:30][CH2:29]3)=[O:16])=[O:11])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: C1CC2(COC2)N1
Reactant: C[C@H](Oc1cc(C(=O)NC(C(=O)O)C(C)(C)C)ncc1C1CC1)C(F)(F)F
Agent: O=C([O-])C(=O)[O-]
Product: C[C@H](Oc1cc(C(=O)NC(C(=O)N2CCC23COC3)C(C)(C)C)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoic acid (Example 199b) and 6-Oxa-1-azaspiro[3.3]heptane, ethanedioate (1:2) (CAN 1380571-72-1) as starting materials and isolated (23 mg, 38%); MS (ESI, m/z): 470.6 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:20][C@H:19]([N:21]([CH:32]3[CH2:34][CH2:33]3)[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C@@H:18]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:22](=[O:23])[N:21]([C@@H:19]2[C@@H:18]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[CH2:17][N:16]([C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:15])[CH2:20]2)[CH:32]2[CH2:34][CH2:33]2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2C[C@H](c3ccc(Cl)cc3)[C@@H](N(C(=O)Oc3ccc(F)cc3)C3CC3)C2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1CCNCC1)N1C[C@H](c2ccc(Cl)cc2)[C@@H](N(C(=O)Oc2ccc(F)cc2)C2CC2)C1

Procedure:
In analogy to the procedure described for the synthesis of [(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester the title compound was prepared from 4-{(3S,4R)-3-(4-Chloro-phenyl)-4-[cyclopropyl-(4-fluoro-phenoxycarbonyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester through cleavage of the protecting group with TFA. The title compound was obtained as light yellow foam. MS m/e: 486.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+]>ClCCl.O.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.C(O)C.C1(C)C=CC=CC=1.O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:4]2[N:3]=[C:2]([NH2:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=2)=[CH:15][CH:14]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(Cl)cc1
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: [Cl-]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: Nc1nc(-c2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 18 h
Yield: 27.5 %

Procedure:
Under a nitrogen atmosphere, 1 g (5.76 mmol) of 2-amino-6-chloro-3-nitropyridine is mixed with 1.26 g (8.07 mmol) of 4-chlorobenzeneboronic acid, 7.2 ml (14.4 mmol) of a 2M aqueous solution of sodium carbonate and 0.7 g (16.36 mmol) of lithium chloride in 44 ml of a pre-degassed mixture of ethanol/toluene/water (v/v: 1/1/0.4). 0.34 g (0.29 mmol) of tetrakis(triphenylphosphine)palladium(0) is added. The mixture is heated at 90° C. with stirring for 18 hours. The resulting mixture is cooled to ambient temperature and then diluted with 50 ml of dichloromethane and 25 ml of water. The organic phase is separated by settling out and washed with 25 ml of water and 25 ml of a saturated solution of sodium chloride. The resulting product is dried over sodium sulfate and evaporated to dryness. The product is purified by silica gel chromatography, elution being carried out with a 50:50 then 80:20 mixture of dichloromethane and cyclohexane. 0.395 g (yield: 27%) of 6-(4-chlorophenyl)-3-nitropyridin-2-ylamine is obtained in the form of a white powder.
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[N+:16]([O-])=O)([CH3:6])[C:3]([OH:5])=[O:4].[H][H]>O1CCCC1.[Ni]>[CH3:6][C:2]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[NH2:16])([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: [H][H]
Reactant: COc1ccc(NC(C)(C)C(=O)O)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1ccc(NC(C)(C)C(=O)O)c(N)c1

Procedure:
32.6 g (mol/7.8) of 2-methyl-(2'-nitro-4'-methoxyanilino)-propionic acid, in solution in 330 ml of tetrahydrofuran, are hydrogenated in the presence of 20 g of Raney nickel in an autoclave with a capacity of 500 ml. Hydrogen pressure in the cold: 150 kg/cm2. Temperature = 70°-90° C.; Duration: 3 hours
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19](B(O)O)=[C:18]([F:25])[CH:17]=2)=[CH:12][CH:11]=1)[CH2:8][CH3:9].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:2]3[S:3][CH:4]=[CH:5][CH:6]=3)=[C:18]([F:25])[CH:17]=2)=[CH:12][CH:11]=1)[CH2:8][CH3:9]
Reactant: CCCc1ccc(-c2ccc(B(O)O)c(F)c2)cc1
Reactant: Brc1cccs1
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: CCO
Solvent: Cc1ccccc1
Product: CCCc1ccc(-c2ccc(-c3cccs3)c(F)c2)cc1

Procedure:
A mixture of 25.3 g (0.16 mol) of 2-bromothiophene, 40.0 g (0.16 mol) of 4′-propyl-3-fluoro-4-biphenylboronic acid, 8.5 g (7.4 mmol) of tetrakis(triphenylphosphine)palladium(0) and 170 ml of 2 N sodium carbonate solution in 420 ml of toluene/ethanol (1:2) is refluxed for 18 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted a number of times with toluene. The combined organic phases are washed with water and sat. sodium chloride solution. The solution is dried using sodium sulfate and evaporated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:toluene=9:1). The further purification is carried out by recrystallisation from ethanol and n-heptane, giving 2-(4′-propyl-3-fluorobiphenyl-4-yl)thiophene as a colourless solid (m.p. 88° C.).
Reaction SMILES: C([O:4][CH2:5][C@@:6]([NH:27]C(=O)C)([CH3:26])[CH2:7][CH2:8][C:9]1[N:10]([CH3:25])[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:13]=1)(=O)C.O1CCCC1.CO.O.[OH-].[Li+]>O>[NH2:27][C@:6]([CH3:26])([CH2:7][CH2:8][C:9]1[N:10]([CH3:25])[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][CH:13]=1)[CH2:5][OH:4]
Reactant: CC(=O)N[C@](C)(CCc1ccc(CCCCCc2ccccc2)n1C)COC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cn1c(CCCCCc2ccccc2)ccc1CC[C@@](C)(N)CO
Yield: 90.7 %

Procedure:
To a solution of (2R)-1-acetoxy-2-acetylamino-2-methyl-4-[1-methyl-5-(5-phenylpentyl)pyrrol-2-yl]butane (75.0 mg, 0.18 mmol) obtained in Example (31b) in a mixed solvent of tetrahydrofuran (1 ml) and methanol (1 ml) were added successively water (1 ml) and lithium hydroxide monohydrate (76 mg, 1.81 mmol) with stirring, and the resulting mixture was stirred at 50° C. for 6 hours. After cooling, water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a basic silica gel column (NH type) using a mixed solvent of dichloromethane and methanol (1:0-50:1) as the eluent to afford (2R)-2-amino-2-methyl-4-[1-methyl-5-(5-phenylpentyl)pyrrol-2-yl]butan-1-ol (53.6 mg, yield: 90%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:16][NH2:17]>O1CCCC1.O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([NH:17][CH3:16])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CC(Oc2ccc(Br)cc2)C1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Oc2ccc(Br)cc2)C1
Reaction time: 18 h
Yield: 85.9 %

Procedure:
A stirred solution of 5.8 g (0.02 mole) of 3-(4-bromophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 4.7 g (0.06 mole) of 40% aqueous monomethylamine and stirring continued for 18 hr. The reaction mixture was diluted with 200 ml of water and the solid which separated was collected by filtration, 5.7 g. Recrystallization from ethanol-water yielded 4.9 g (85.9%) of fine white crystals, m.p. 135°-137° C.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH3:12])=[C:6]([N:26]2[CH:30]=[CH:29][CH:28]=[CH:27]2)[CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH3:12])=[C:6]([N:26]2[CH:30]=[CH:29][CH:28]=[CH:27]2)[CH:5]=1
Reactant: [H][H]
Reactant: CN(CCOc1ccc([N+](=O)[O-])cc1-n1cccc1)CCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(CCOc1ccc(N)cc1-n1cccc1)CCc1ccc(N)cc1
Yield: 99 %

Procedure:
1-[4-Nitro-2-(1H-pyrrol-1-yl)phenoxy]-2-[N-(4-nitrophenethyl)-N-methylamino]ethane (0.71 g, 1.73 mmol) was dissolved in 80 ml of a 1:1 solvent system of ethyl acetate and methanol and, after slowly adding 10% Pd/C (0.2 g), the solution was stirred at an ordinary temperature for 3 h as hydrogen gas was injected. Thereafter, the reaction mixture was filtered through Celite and the filtrate was evaporated to yield the compound 1-[4-amino-2-(1H-pyrrol-1-yl)phenoxy]-2-[N-(4-aminophenethyl)-N-methylamino]ethane (0.6 g) as a dark brown oil. The compound was dissolved in pyridine (30 ml) and, thereafter, the solution was cooled at 0° C. and methanesulfonyl chloride (0.344 ml, 4.45 mmol) was slowly added. Thereafter, the mixture was stirred at an ordinary temperature for 20 h and ethanol was added; the solvent pyridine was evaporated under vacuum and the resulting residue was added to an aqueous solution of 10% sodium hydroxide, followed by extraction with ethyl acetate. The organic layer was washed with water twice, dried with magnesium sulfate, and the solvent was evaporated. The residue was purified by being subjected to column chromatography on silica gel using, as an eluent, ethyl acetate containing 5% methanol. The fractions containing the product were collected and the solvent was evaporated to yield the titled compound 1-[4-methanesulfonamido-2-(1H-pyrrol-1-yl)phenoxy]-2-[N-(4-methanesulfonamidophenethyl)-N-methylamino]ethane (0.43 g) as a pale yellow substance.