Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:27]([C:30]1[CH:35]=[CH:34][C:33]([C@H:36]2[CH2:41][CH2:40][C@H:39]([OH:42])[CH2:38][CH2:37]2)=[CH:32][CH:31]=1)[CH2:28][CH3:29]>C1C=CC=CC=1.N1C=CC=CC=1>[CH2:27]([C:30]1[CH:35]=[CH:34][C:33]([C@H:36]2[CH2:37][CH2:38][C@H:39]([O:42][C:24]([C:21]3[CH:20]=[CH:19][C:18]([C:15]4[CH:14]=[CH:13][C:12]([C@H:9]5[CH2:8][CH2:7][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]5)=[CH:17][CH:16]=4)=[CH:23][CH:22]=3)=[O:25])[CH2:40][CH2:41]2)=[CH:32][CH:31]=1)[CH2:28][CH3:29]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(=O)Cl)cc3)cc2)CC1
Reactant: CCCc1ccc([C@H]2CC[C@H](O)CC2)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(=O)O[C@H]4CC[C@H](c5ccc(CCC)cc5)CC4)cc3)cc2)CC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
The crude 4'-(trans-4-pentylcyclohexyl)-4-biphenylcarboxylic acid chloride obtained was dissolved in 40 ml of benzene and then added dropwise to a solution of 0.90 g of trans-4-(p-propylphenyl)cyclohexanol in 20 ml of pyridine. The mixture was stirred at a bath temperature of 65° C. overnight, then poured into ice-water and extracted with diethyl ether. The extract was washed four times with 25 ml of 3N hydrochloric acid each time, then washed with 25 ml of 2N sodium carbonate solution and several times with water, dried over sodium sulphate and concentrated. The crude 4'-(trans-4-pentylcyclohexyl)-4-biphenylcarboxylic acid trans-4-(p-propylphenyl)cyclohexyl ester obtained was recrystallized once from ethanol containing a small amount of ethyl acetate and once from ethyl acetate. Yield 1.1 g; m.p. (C-S) 131.2° C.; phase transition S-N 143.3° C.; cl.p. (N-I) 337.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:17][CH2:16][CH:10]3[N:11]([CH3:15])[CH2:12][CH2:13][CH:14]=[C:9]3[C:7]=2[CH:8]=1.C([Li])CCC.[C:23]([N:27]=[C:28]=[O:29])([CH3:26])([CH3:25])[CH3:24]>C1COCC1.CCCCCC.O>[C:23]([NH:27][C:28]([C@H:13]1[CH2:12][N:11]([CH3:15])[C@@H:10]2[CH2:16][O:17][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=3[C:9]2=[CH:14]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1ccc2c(c1)C1=CCCN(C)C1CO2
Reactant: CC(C)(C)N=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C1=C[C@@H](C(=O)NC(C)(C)C)CN(C)[C@@H]1CO2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a well stirred solution of 1.16 g of 9-methoxy-4-methyl-2,3,4a,5-tetrahydro-4H-[1]-benzopyrano[3,4-b]pyridine in 15 ml of THF is added 3.4 ml of 1.5M butyl lithium in hexane at 0°. After 5 minutes at 0°, the reaction mixture is cooled to -70° and 0.6 ml of t-butyl isocyanate is added. After warming to room temperature the reaction mixture is diluted with water and the products extracted with ether. After drying over magnesium sulfate, the solvent is removed in vacuo and the residue is crystallized from ether/hexane to yield cis-2-(N-t-butylcarbamoyl)-9-methoxy-4-methyl-2,3,4a,5,-tetrahydro-4H-[1]-benzopyrano[3,4-b]pyridine, which is converted wiht ethanolic hydrogen chloride to cis-2-(N-t-butylcarbamoyl)-9-methoxy-4-methyl-2,3,4a,5-tetrahydro-4H-[1]-benzopyrano[3,4-b]pyridine hydrochloride, melting point 188°-189° (from ethanol/ether).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=2)[C:18]([O:20]CC)=[O:19])=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>C1COCC1>[CH2:1]([O:8][CH2:9][N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=2)[C:18]([OH:20])=[O:19])=[N:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc(-c2nnn(COCc3ccccc3)n2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2nnn(COCc3ccccc3)n2)c1
Reaction time: 8 h

Procedure:
A solution of ethyl 3-(2-(benzyloxymethyl)-2H-tetrazol-5-yl)benzoate (653 mg, 1.93 mmol) in THF (10 mL) was treated with a 0.5 M aqueous lithium hydroxide solution (5.8 mL, 2.9 mmol), and the reaction was stirred overnight. Analysis by LC/MS indicated that the reaction had not gone to completion, so the mixture was treated with a 0.5 M aqueous lithium hydroxide solution (1 mL, 0.5 mmol), and the reaction was stirred for an additional 6 hours. The THF was removed under reduced pressure, and the aqueous solution was treated with 1 N HCl (3.5 mL, 3.5 mmol). The mixture was extracted 3× with ethyl acetate, and the combined organic phases were dried over sodium sulfate and concentrated in-vacuo to yield the title compound as a colorless powder which was used as-is in the next step.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-:14].[Na+].[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.C(Cl)(=O)C1C=CC=CC=1>[C:10]([O:9][C:7]([NH:6][N:5]([C:22](=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:1]([CH3:4])([CH3:3])[CH3:2])=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)NNC(=O)OC(C)(C)C
Reactant: Cc1ccccc1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: O=C(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)NN(C(=O)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mechanically stirred solution of N'-t-butyl-N-t-butoxycarbonylhydrazine (61 g, 0.32 mol) in toluene (120 ml) cooled in an ice bath, was treated dropwise and simultaneously with 50% sodium hydroxide (31 g) in water (50 ml) and benzoyl chloride (45 g). The addition was complete in 20 minutes and the resulting mixture was warmed to room temperature and allowed to stir for one hour. The resulting white solid was filtered, washed with water and air dried to afford 94 g of N-t-butoxycarbonyl-N'-benzoyl-N'-t-butylhydrazine, m.p. 167°-170° C.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:20][O:21]C1C=CC(C=O)=CC=1>>[CH3:20][O:21][C:7]1[CH:8]=[CH:3][C:4]([C:9]2[NH:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:6]=1
Reactant: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(-c2nc3ccccc3c(=O)[nH]2)cc1
Yield: 96.4 %

Procedure:
According to the preparation of 42, 4-methoxybenzaldehyde (35) (1.0 g, 7.3 mmol) was used to afford 44 (1.8 g, 96.4%) as pale yellow needles.
Reaction SMILES: [CH2:1]([N:5]([CH3:24])[C:6]([C:8]1[CH:9]=[C:10]([C:21](O)=[O:22])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:13]=1)=[O:7])[CH:2]([CH3:4])[CH3:3].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH2:48][C@@H:49]([C:53]1[CH:54]=[N:55][C:56]([CH3:59])=[CH:57][CH:58]=1)[CH2:50][CH2:51][OH:52].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:52][CH2:51][CH2:50][C@@H:49]([NH:48][C:21]([C:10]1[CH:11]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH:13]=[C:8]([C:6]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH3:24])=[O:7])[CH:9]=1)=[O:22])[C:53]1[CH:54]=[N:55][C:56]([CH3:59])=[CH:57][CH:58]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N(C)CC(C)C)c2)cc1
Reactant: Cc1ccc([C@H](N)CCO)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](CCO)c3ccc(C)nc3)cc(C(=O)N(C)CC(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(isobutyl(methyl)carbamoyl)-4′-methylbiphenyl-3-carboxylic acid (15 mg, 0.046 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (18 mg, 0.092 mmol), 1-hydroxybenzotriazole hydrate (7.0 mg, 0.046 mmol), and CH2Cl2 (2 mL) were added (R)-3-amino-3-(6-methylpyridin-3-yl)propan-1-ol (11 mg, 0.069 mmol) (WO 2008/130481) and N,N-diisopropylethylamine (12 μL, 0.069 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 40-70% MeCN/water[10 mM Et2NH]) to afford a white foam.
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[B:9](OC(C)C)([O:14]C(C)C)[O:10]C(C)C.C([Li])CCC.Cl>COCCOC.CCO.O>[CH3:8][C:3]1[C:2]([B:9]([OH:14])[OH:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1ncccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: Cc1ncccc1B(O)O
Temperature: -70 °C
Yield: 66.7 %

Procedure:
To a solution of 3-bromo-2-methylpyridine (4.00 g, 23 mmol), triisopropyl borate (6.40 mL, 28 mmol) in 50 mL of 4/1 toluene/THF (4/1, 50 mL) at −78° C. was added was added butyllithium (17 mL, 28 mmol), dropwise. The mixture was allowed to warm up to 30 min at −70° C. LCMS and then to 20° C. HCl (2M) was added to bring the solution to pH1. Then water (20 mL) was added and the mixture was extracted with toluene. The aqueous layer was neutralized with 1 M NaOH and extracted with dichloromethane. The aqueous layer was concentrated to dryness and the white solid was washed with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give 2.10 g of 2-methylpyridin-3-ylboronic acid as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:9]1[CH:19]=[CH:18][C:12]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:11][C:10]=1[N+:20]([O-:22])=[O:21]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:9]1[CH:19]=[CH:18][C:12]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:11][C:10]=1[N+:20]([O-:22])=[O:21]
Reactant: CN(C)CCCN
Reactant: CN(C)C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: CN(C)CCCNc1ccc(C(=O)N(C)C)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
N,N-Dimethy-1,3-propanediamine (1.95 g) was added to 4-chloro-N,N-dimethyl-3-nitrobenzamide (2.18 g) and stirred for 2 hours at 90° C. The reaction mixture, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution, water and saturated brine successively, dried over sodium sulfate anhydride, and concentrated, thereby yielding the entitled compound (2.83 g) as yellowish orange oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.CCN(CC)CC.ClC(OCC)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>CC(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([N:23]=[N+:24]=[N-:25])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)c1ccc(Cl)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To a solution of 5-chloro-2-thiophene-carboxylic acid (5.00 g, 30.7 mmol) in 130 mL of acetone is added Et3N (4.29 mL, 30.7 mmol). The mixture is cooled to 0° C. and ethyl chloroformate (3.23 mL, 33.8 mmol) is added. The mixture is stirred at 0° C. for 1 h and sodium azide (3.40 g, 52.3 mmol) is added. The mixture is stirred at 0° C. for 2 h, then poured into 300 mL of ice water and the aqueous layer is extracted with CH2Cl2 (2×). The combined organics are washed with water (2×) and brine, then dried, filtered and concentrated. The crude residue is purified via flash column chromatography eluting with 10% EtOAc/hexanes to provide the title compound (3.00 g, 16.0 mmol) as a white solid. 1H NMR (CDCl3, 300 MHz) δ7.67 (d, 1H), 6.99 (d, 1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:21])[NH2:22]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: CC(C)C[C@H](NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (LC/MS): m/e=346.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[CH:8]=[C:7]2[S:11][CH2:12][CH2:13][N:6]2[C:5]1=[O:14])[CH2:2][CH3:3].S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21]>>[N+:20]([C:8]1[C:9](=[O:10])[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:14])[N:6]2[CH2:13][CH2:12][S:11][C:7]=12)([O-:22])=[O:21]
Reactant: CCCn1c(=O)cc2n(c1=O)CCS2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCCn1c(=O)c([N+](=O)[O-])c2n(c1=O)CCS2
Yield: 85 %

Procedure:
6-Propyl-2,3-dihydro-5H-thiazolo[3,2-c]pyrimidine-5,7-(6H)-dione (2.12 g) was added to concentrated sulfuric acid (5.2 ml) little by little under ice cooling, and then, fuming nitric acid (1.8 ml) was added dropwise thereto with stirring. The mixture was stirred under ice cooling for 1 hour. The reaction temperature was kept under 5° C. for this period. The reaction solution was poured on ice water, and the resulting crystals were collected by filtration and recrystallization from ethanol-ethyl acetate to give pale yellow needles (2.0 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17]([CH3:19])=O)[N:3]=1.SC[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccc(F)cc2)c1C#N
Reactant: SCCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1ccc(F)cc1

Procedure:
From 2-amino-4-(4-fluoro-phenyl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 352 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([NH:18][CH2:19][CH2:20][OH:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)(=O)C>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[N:18]([CH2:19][CH2:20][OH:21])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1nc2ccccc2s1
Reactant: OCCNCc1ccccc1
Solvent: CCOC(C)=O
Product: OCCN(Cc1ccccc1)c1nc2ccccc2s1

Procedure:
2-Chlorobenzothiazole (13g) and 2-(benzylamino)ethanol (29 g) were heated together in a sealed vessel at 120° C. for 20 h. After cooling, the reaction mixture was dissolved in ethyl acetate (200 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate (3×100 ml), water (3×100 ml) and brine (100 ml), dried over anhydrous magnesium sulphate and evaporated to give the title compound (m.p. 95°-96° C.; dichloromethane/hexane).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH:15]=[N:16][OH:17])[CH:13]=3)[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][C:19](=[CH2:22])[C:20]#[N:21].Cl[O-].[Na+]>O1CCCC1>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]4[CH2:18][C:19]([CH3:22])([C:20]#[N:21])[O:17][N:16]=4)[CH:13]=3)[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C=C(C)C#N
Reactant: ON=Cc1ccc2cnn(C3CCCC3)c2c1
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: CC1(C#N)CC(c2ccc3cnn(C4CCCC4)c3c2)=NO1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of compound obtained from step b above (50 mg, 0.218 mmol) and methylacrylonitrile (29.3 mg, 0.436 mmol) was added tetrahydrofuran (5 ml) and stirred the reaction mixture for 10 minutes at room temperature. To the resulting reaction mixture was added sodium hypochlorite (3 ml) with vigorous stirring, which was continued for 15 hours. The solvent was evaporated under reduced pressure and extracted the compound with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title compound. The residue thus obtained was purified by column chromatography using ethylacetate in hexane solvent mixture as eluent to furnish the title compound. Yield: 65 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=1)[CH3:20].O>CN(C)C=O>[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=3)[CH:8]=[CH:9]2)=[CH:25][CH:24]=1)[CH3:20]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2ccc3ccc([N+](=O)[O-])cc32)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
To a solution of 6-nitro-1H-indole (0.5 g) in N,N-dimethylformamide (10 mL) were added cesium carbonate (1.2 g) and 4-fluoro benzoic acid ethyl ester (0.62 g), and this mixture was stirred at 75° C. overnight. This reaction mixture was poured into water and the precipitated solid was collected by filtration, and washed with water and n-hexane, dried under reduced pressure to give the title compound (0.64 g).
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([Br:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[N:31]1([CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[Br:24][C:20]1[CH:21]=[C:22]([F:23])[C:17]([CH2:16][O:15][C:12]2[C:11]([C:27]([NH2:28])=[O:29])=[C:10]([NH:9][C:8]([NH:40][CH2:39][CH2:38][CH2:37][CH2:36][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:7])[S:14][N:13]=2)=[C:18]([F:26])[C:19]=1[F:25]
Reactant: NC(=O)c1c(OCc2c(F)cc(Br)c(F)c2F)nsc1NC(=O)Oc1ccccc1
Reactant: NCCCCN1CCCC1
Product: NC(=O)c1c(OCc2c(F)cc(Br)c(F)c2F)nsc1NC(=O)NCCCCN1CCCC1

Procedure:
The title compound was prepared from [3-(4-bromo-2,3,6-trifluoro-benzyloxy)-4-carbamoyl-isothiazol-5-yl]-carbamic acid phenyl ester and 4-pyrrolidin-1-yl-butylamine by the procedure analogous to Example 1. MS (APCl, m/z): 550 and 552 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:25])([CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)CCCCCCBr
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)(C)CCCCCCNS(=O)(=O)c1ccc(Cl)cc1
Yield: 22.8 %

Procedure:
A mixture of 4-chlorobenzenesulphonamide (4.5 g), ethyl 8-bromo-2,2-dimethyloctanoate (3.3 g) and potassium carbonate (9.3 g) in dry methylethylketone (140 ml) was refluxed for 9 hours. The inorganic residues were removed by filtration and the filtrate was evaporated to dryness to give an oil. Chromatography on silica gel eluted with chloroform-petroleum ether 15:1 gave the title compound (1.05 g) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([O:14][C:15]([C:17](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:18])=[O:16])[CH3:13]>O1CCCC1>[CH3:18]/[C:17](=[CH:8]\[C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)/[C:15]([O:14][CH2:12][CH3:13])=[O:16]
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C/c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 4-nitrobenzaldehyde (2 g, 13.2 mmol) and (1-ethoxy carbonylethylidene)triphenyl phosphorane (4.80 g, 13.2 mmol) in tetrahydrofuran (130 mL) was refluxed for 24 hours. The reaction was concentrated in vacuo and was purified by flash column chromatography on silica gel with hexanes and EtOAc to give (E)-ethyl 2-methyl-3-(4-nitrophenyl)acrylate (645).
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[NH:32]1[C:36]([CH2:37][C:38](O)=[O:39])=[N:35][N:34]=[N:33]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[NH:32]1[C:36]([CH2:37][C:38]([N:5]2[CH2:6][CH2:7][N:2]([C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]4[N:18]=[C:19]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[O:20][C:21]=4[C:22]([F:23])([F:25])[F:24])=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:4]2)=[O:39])=[N:35][N:34]=[N:33]1
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: O=C(O)Cc1nnn[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCN(C(=O)Cc3nnn[nH]3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl-phenyl)-amide, hydrochloride (53 mg, 0.117 mmol), (1H-tetrazol-5-yl)-acetic acid (15 mg, 0.117 mmol), and triethylamine (49 uL, 0.351 mmol) were dissolved in 1.5 mL of DMF and chilled in an ice bath. To this solution was added BOP (52 mg, 0.122 mmol) in one portion. The mixture was stirred at room temperature for 30 minutes and then diluted with 30 ml CH2Cl2. The organic phase was washed with 1N citric acid (1×8 mL), water (3×8 mL) and saturated sodium chloride (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to dryness under vacuum. The residue was crystallized from acetonitrile to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-(2-1H-tetrazol-5-yl-acetyl)-piperazin-1-yl]-phenyl}-amide as light yellow crystals (26 mg, 42%). ES-MS calcd for C24H21F3N8O3 (m/e) 526.48, obsd 527 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]3[C:12](=[C:13]([C:15]([OH:17])=O)[CH:14]=2)[CH2:11][CH2:10][CH2:9]3)[CH:2]=1.CN(C)C=O.[Cl:23]CCCl>S(Cl)(Cl)=O.C1CCCCC1>[ClH:23].[Cl:23][C:15]([C:13]1[CH:14]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]2[C:12]=1[CH2:11][CH2:10][CH2:9]2)=[O:17]
Reactant: ClCCCl
Reactant: O=C(O)c1cc(-c2cccnc2)n2c1CCC2
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cl
Product: O=C(Cl)c1cc(-c2cccnc2)n2c1CCC2
Temperature: 80 °C

Procedure:
A suspension of 5-(3-pyridyl)-2,3-dihydro-1H-pyrrolizine-7-carboxylic acid (11.4 g) in a mixture of thionyl chloride (17.4 cc), dimethylformamide (0.05 cc) and 1,2-dichloroethane (150 cc) is heated at a temperature of about 80° C. for 3 hours. The reaction mixture is cooled to a temperature of about 20° C. and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 60° C. The residue obtained is suspended in cyclohexane (250 cc) and the solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 60° C. The same operation is repeated twice. 7-Chloroformyl-5-(3-pyridyl)-2,3-dihydro-1H-pyrrolizine hydrochloride (14.1 g) is thus obtained in the form of yellow crystals melting at 230° C.