Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([Cu])#[N:11].CCOC(C)=O.Cl>CN(C=O)C>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([C:10]#[N:11])=[CH:8][C:2]=1[F:1]
Reactant: Nc1ccc(I)cc1F
Reactant: N#C[Cu]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N)c(F)c1
Yield: 99.1 %

Procedure:
A mixture of 2-fluoro-4-iodoaniline (10.0 g, 42.2 mmol) and CuCN (7.56 g, 84.4 mmol) in DMF (40 mL) was heated at reflux for 5 h. After being cooled down, EtOAc and 1N HCl were added. The mixture was filtered through celite. The organic phase was separated, washed sequentially with 1N HCl and brine. It was then dried over MgSO4, concentrated in vacuo to give a brown solid (5.69 g), which was pure enough for the next step. MS 137.1 (M+H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:35](=[O:36])[N:6]2[C:7]([C:22]([O:24]CC3C=CC([N+]([O-])=O)=CC=3)=[O:23])=[C:8]([C:10]3[CH:14]=[C:13]([CH3:15])[N:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:11]=3)[CH2:9][C@H:5]12)[CH3:3].C(=O)([O-])O.[Na+:41]>O1CCCC1.O.[Pd]>[OH:1][C@@H:2]([C@H:4]1[C:35](=[O:36])[N:6]2[C:7]([C:22]([O-:24])=[O:23])=[C:8]([C:10]3[CH:14]=[C:13]([CH3:15])[N:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:11]=3)[CH2:9][C@H:5]12)[CH3:3].[Na+:41]
Reactant: Cc1cc(C2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)nn1-c1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)nn1-c1ccccc1
Reaction time: 0.12 h
Yield: 85.3 %

Procedure:
p-Nitrobenzyl (5R,6S)-6[(1R)-1-hydroxyethyl]-2-(5-methyl-1-phenylpyrazol-3-yl)carbapen-2-em-3-carboxylate (122 mg) in tetrahydrofuran (THF) (10 ml) and water (10 ml) was treated with sodium hydrogen carbonate (42 mg) (10 ml) and 3% Pd-C catalyst (50 mg) and the mixture was hydrogenareal at atmospheric pressure for 5-10 min. The mixture was filtered through Kieselguhr, washing the filter cake with water and ethyl acetate. Combined filtrate and washings were reduced in volume using a rotary evaporator, a little NaCl was added and the mixture was chromatographed on a Diaion HP20SS column (2×10 cm), eluting with water (200 ml), followed by water/THF mixtures:--2% THF (100 ml); followed by 3% THF (100 ml), followed by 4% THF, followed by 6% THF. Fractions were monitored by uv and hplc. Fractions containing the product were combined and evaporated to lower volume and then freeze-dried to give sodium (5R,6S)-6[(1R)-1-hydroxyethyl]-2-(5-methyl-1-phenylpyrazol-3-yl)carbapen-2-em-3-carboxylate (80 mg) νmax (KBr)/cm-1 1786, 1756, 1588, 1501, 1412, 1383, 1359, 1288 1246, 1223, and 1145; λmax (H2O)/nm 300.0 (ε/dm3 mol-1 cm-1 13,232), 236.5 (ε7,027); δ (D2O) 1.26 (3H, d, J 6.4 Hz), 2.20 (3H,s), 3.1-3.29 (2H, m), 3.46 (1H, dd, J 2.9 & 5.9 Hz), 4.16-4.28 (2H, m), 6.61 (1H,s), 7.39-7.57 (5H,m);
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9](C)[C:10](=O)C(F)(F)F)#[N:2]>C(=O)(O)[O-].[Na+].O.C(O)C>[CH3:10][NH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CN(C(=O)C(F)(F)F)c1ccccc1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CNc1ccccc1C#N
Yield: 189.2 %

Procedure:
N-(2-Cyanophenyl)-2,2,2-trifluoro-N-methylacetamide (3 g, 0.01 mol) was dissolved in a sodium bicarbonate/water/ethanol mixture, refluxed for 5 h and evaporated. Water was added and the mixture extracted with ethyl acetate, dried over sodium sulphate and evaporated to give the product (2.5 g). MS (+EI) 132 (M+), 1H NMR (CDCl3) 7.45 (2H, t), 6.69 (1H, d), 6.62 (1H, t), 6.19 (1H, s), 2.76 (3H, d).
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[F:17][C:18]1[CH:19]=[C:20]([C:25]2[O:29][C:28]([CH3:30])=[N:27][C:26]=2[C:31](O)=[O:32])[CH:21]=[C:22]([F:24])[CH:23]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:31]([C:26]3[N:27]=[C:28]([CH3:30])[O:29][C:25]=3[C:20]3[CH:21]=[C:22]([F:24])[CH:23]=[C:18]([F:17])[CH:19]=3)=[O:32])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Reactant: Cc1nc(C(=O)O)c(-c2cc(F)cc(F)c2)o1
Product: Cc1nc(C(=O)Nc2cnn(Cc3nc(C(C)(F)F)cs3)n2)c(-c2cc(F)cc(F)c2)o1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3,5-difluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:22]2[C:9](=[CH:10][C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][C:20]=3[CH:21]=2)[CH:17]=[CH:16][CH:15]=[CH:14]4)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[Br:24]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:24][C:19]1[C:20]2[CH:21]=[C:22]3[C:2]([CH3:23])([CH3:1])[C:3]4[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=4)[C:9]3=[CH:10][C:11]=2[CH:12]=[C:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]2
Reactant: CC1(C)c2ccccc2-c2cc3cc4ccccc4cc3cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)c2ccccc2-c2cc3cc4ccccc4c(Br)c3cc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
13,13-dimethyl-13H-indeno[1,2-b]anthracene (10 g, 0.034 mol) and N-bromosuccinimide (7.68 g, 0.034 mol) were dissolved in carbon tetrachloride (200 ml), and the reaction mixture was stirred for 8 hours at 60° C. After the reaction was terminated, the reaction solution was extracted with distilled water, and purified by column chromatography to give 11-bromo-13,13-dimethyl-13H-indeno[1,2-b]anthracene (9 g, yield=71%).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)([O-:5])=[O:4].[Cl:15][CH2:16][CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O>O1CCCC1>[Cl:15][CH2:16][CH2:17][N:10]1[C:11]2[C:7](=[C:6]([N+:3]([O-:5])=[O:4])[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc2c1ccn2CCCl
Yield: 31.6 %

Procedure:
Into a flask of 500 ml capacity fitted with a stirrer and cooling tube, there were introduced 7.2 g (corresponding to 0.21 mol) of an NaH oil dispersion, and 50 ml of tetrahydrofuran. The mixture was stirred on an ice-water bath. To this mixture was added, dropwise, little by little, a solution of 34.02 g of 4-nitroindole (0.21 mol) dissolved in 100 ml of tetrahydrofuran. After completion of the dropwise addition, the ice-water bath was removed and the mixture was stirred for one hour at room temperature. Then, 49.29 g (0.21 mol) of 2-chloroethyl-p-toluenesulfonate were added, and was reacted for 10 hours while stirring, heating under reflux. After completion of the reaction, the insoluble material was removed by filtration, and concentration was performed under reduced pressure. Further, this reaction mixture was purified by column chromatography using silica gel, to obtain 14.9 g of 1-(2-chloroethyl)-4-nitroindole.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][O:12][C:13](=[O:30])[CH:14]([O:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[CH:25]1[O:29][CH2:28][CH2:27][O:26]1)[CH2:15][CH3:16].I[CH2:32][CH3:33]>C1COCC1.C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:30])[C:14]([O:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[CH:25]1[O:29][CH2:28][CH2:27][O:26]1)([CH2:32][CH3:33])[CH2:15][CH3:16]
Reactant: CCI
Reactant: CCC(Oc1ccc(Cl)cc1C1OCCO1)C(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)(Oc1ccc(Cl)cc1C1OCCO1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
Lithium bis(trimethylsilyl)amide (60 mL, 60 mmol, 1 M in THF) was slowly added to a solution of 2-(4-chloro-2-[1,3]dioxolan-2-yl-phenoxy)-butyric acid methyl ester (15 g, 50 mmol) in anhydrous THF (150 mL) at −78° C. After the mixture was stirred for 15 min, iodoethane (9.3 g, 60 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 2 h. Then the mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of NH4Cl, dried over anhydrous Na2SO4 and concentrated to give the crude product as a oil (16 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH2:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:18]([NH:26][C:15]([C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:17])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCCCC[C@H]1C(=O)O
Reactant: CCCCCCCCN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCNC(=O)[C@@H]1CCCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(S)-(−)-1-(tert-Butoxycarbonyl)-2-azepanecarboxylic acid (prepared as described in Tetrahedron Letters (1994), 35(2), 237–240) (1.00 g; 4.11 mmol) is dissolved in methylene chloride (20 mL) at ambient temperature. n-Octylamine (0.584 g; 4.52 mmol), N,N-diisopropylethylamine (1.17 g; 9.04 mmol) and PyBOP (2.35 g; 4.52 mmol) are added sequentially. The reaction is stirred for 24 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silca gel chromatography affording the desired product (2).
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](O)=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].CN(C)C=O.C(Cl)(=O)C([Cl:33])=O>C(Cl)Cl>[CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([Cl:33])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1cccc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1cccc(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a suspension of 5.0 g of product from Example 23, 0.055 g of dimethylformamide and 70 ml of methylene chloride is added 1.96 ml of oxalyl chloride. The reaction is stirred at room temperature for 22 hours and concentrated. The residue is dissolved in diethyl ether, filtered and concentrated to give 5.28 g of the desired product as cream crystals.
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[O:4][C:5]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:20])[C:2]=1[S:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Sc1ccccc1
Reactant: CC(C)CCC1(c2ccccc2)CC(O)=C(Br)C(=O)O1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)CCC1(c2ccccc2)CC(O)=C(Sc2ccccc2)C(=O)O1

Procedure:
The title compound was prepared as described in General Method 6 from 1.5 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one (prepared in example CCC), 1.6 mmol of benzenethiol, and 1.6 mmol of piperidine in 20 mL of dichloromethane. The crude product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound, (m.p. 154°-155° C.). 1H NMR (DMSO-d6) δ0.80 (m, 6H), 0.97 (m, 1H), 1.16 (m, 2H), 1.42 (m, 1H), 1.91 (m, 2H), 3.40 (2H+H2O), 6.45 (m, 2H), 6.93 (m, 3H), 7.37 (m, 5H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:19](O)=[O:20])=[N:8][C:9]=2[O:10][C@H:11]([C:15]([F:18])([F:17])[F:16])[CH2:12][CH2:13][OH:14])[CH2:3][CH2:2]1.[NH2:22][C:23]([CH2:30][CH3:31])([CH2:28][CH3:29])[C:24]([NH:26][CH3:27])=[O:25]>>[CH2:28]([C:23]([NH:22][C:19]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:3][CH2:2]2)=[C:9]([O:10][C@H:11]([C:15]([F:16])([F:18])[F:17])[CH2:12][CH2:13][OH:14])[N:8]=1)=[O:20])([C:24](=[O:25])[NH:26][CH3:27])[CH2:30][CH3:31])[CH3:29]
Reactant: O=C(O)c1ccc(C2CC2)c(O[C@@H](CCO)C(F)(F)F)n1
Reactant: CCC(N)(CC)C(=O)NC
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(O[C@@H](CCO)C(F)(F)F)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-((S)-3-hydroxy-1-trifluoromethyl-propoxy)-pyridine-2-carboxylic acid (Example 319a) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials; MS (EI) 432.4 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:25]O)[CH:19]=[CH:20][C:21]=1[CH:22]1[CH2:24][CH2:23]1>>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:25][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH:19]=[CH:20][C:21]=1[CH:22]1[CH2:24][CH2:23]1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(C2CC2)c(Cl)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(C3CC3)c(Cl)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3-chloro-4-cyclopropylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 0.68-0.71 (2H, m), 1.01-1.06 (2H, m), 2.16-2.23 (1H, m), 5.17 (2H, s), 5.73 (1H, d, J=2.0 Hz), 6.94 (1H, d, J=8.0 Hz), 7.20 (1H, dd, J=1.6 Hz, 8.0 Hz), 7.40 (1H, dd, J=1.2 Hz, 5.2 Hz), 7.45 (1H, d, J=1.6 Hz), 7.56 (1H, d, J=1.6 Hz), 8.03 (1H, s), 8.71 (1H, d, J=4.8 Hz). [M+H] Calc'd for C19H15ClN4O, 351; Found, 351.
Reaction SMILES: C([N:3](CC)CC)C.ClC(OCC(C)C)=O.[S:16]1[CH:20]=[CH:19][C:18]2[C:21]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][O:34][C:35]4[C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=[C:37]([C:45](O)=[O:46])[CH:36]=4)[CH2:27][CH2:26]3)=[CH:22][CH:23]=[CH:24][C:17]1=2.N>C(#N)C.C(OCC)(=O)C>[S:16]1[CH:20]=[CH:19][C:18]2[C:21]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][O:34][C:35]4[C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=[C:37]([C:45]([NH2:3])=[O:46])[CH:36]=4)[CH2:27][CH2:26]3)=[CH:22][CH:23]=[CH:24][C:17]1=2
Reactant: O=C(O)c1cc(OCCCN2CCN(c3cccc4sccc34)CC2)c2ccccc2n1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(OCCCN2CCN(c3cccc4sccc34)CC2)c2ccccc2n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 14.7 %

Procedure:
Triethylamine (0.25 ml, 1.8 mmol) and isobutyl chloroformate (0.19 ml, 1.4 mmol) were added to a solution (10 ml) of 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]quinolin-2-carboxylic acid (0.53 g, 1.2 mmol) in acetonitrile with cooling in an ice-bath, followed by stirring at 0° C. for 3 hours. 28% Aqueous ammonia (0.15 ml) was added thereto and the reaction mixture was stirred at room temperature for 5 minutes. Ethyl acetate was further added thereto, then the reaction mixture was washed with water and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=3:1), and concentrated under reduced pressure. The residue (0.2 g) was dissolved and recrystallized from the mixed solvent of ethyl acetate and isopropyl ether to obtain 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-quinolin-2-carboxamide (79 mg, yield: 16%) as white powder.
Reaction SMILES: [CH:1]([CH:3]([CH2:8][CH2:9][CH3:10])[CH2:4][CH2:5][C:6]#[N:7])=[O:2].[BH4-].[Na+].Cl>CO>[OH:2][CH2:1][CH:3]([CH2:8][CH2:9][CH3:10])[CH2:4][CH2:5][C:6]#[N:7]
Reactant: CCCC(C=O)CCC#N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCC(CO)CCC#N
Temperature: 5 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of 46.94 g (0.338 mol) of 4-formylheptanenitrile in 250 mL of methanol at 3° C., under argon, was added 4.55 g (0.120 mol) of sodium borohydride portionwise over 1 hr. After stirring at 5° C. for 1 hr, the reaction mixture was poured into a mixture of 100 g of ice and 200 mL of 2N hydrogen chloride solution and extracted with 500 mL followed by 4×250 mL of ether. The combined extracts were washed with 2×150 mL of saturated brine, dried (Na2SO4), filtered and concentrated. The residue was dried (40° C./1.0 mm Hg) to give 45.50 g (95.6%) of crude 4-(hydroxymethyl)heptanenitrile; TLC ((SiO2, 1:1 ethyl acetate:hexane) Rf 0.28 (PMA); IR (chloroform): μmax 3625 (OH), 3490 (OH), 2245 (C≡N) cm-1.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-])=O.[C:13]1([NH:19][CH:20]=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[N:10]=[CH:20][N:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:2]=2[CH:7]=1
Reactant: O=CNc1ccccc1
Reactant: COc1ccc([N+](=O)[O-])c(I)c1
Product: COc1ccc2ncn(-c3ccccc3)c2c1
Yield: 55.3 %

Procedure:
The title compound was prepared with the analogous procedure described in example 1 using 2-Iodo-4-methoxy-1-nitrobenzene (140 mg, 0.5 mmol) and N-Phenyl-formamide (73 mg, 0.6 mmol) as starting materials to yield the title compound as viscous oil (62 mg, 56%). 1H NMR (DMSO) δ 2.58 (s, 3 H), 2.64 (s, 3 H), 7.37 (d, J=8.1 Hz, 1 H), 7.44 (dd, J=8.1, 7.3 Hz, 1 H), 7.48-7.52 (m, 1 H), 7.54 (d, J=8.8 Hz, 2 H), 7.61 (d, J=8.8 Hz, 2 H), 7.86 (d, J=7.3 Hz, 1 H).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)[N:3]=1.[H-].[Na+].I[CH2:38][CH2:39][CH3:40].O>CN(C)C=O>[CH3:28][C:27]1[O:26][C:25]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[N:24][C:23]=1[CH2:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:4]2[CH:5]=[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[C:2]([O:1][CH2:38][CH2:39][CH3:40])=[N:3]2)=[CH:20][CH:19]=1
Reactant: CCCI
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (710 mg) in N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 72.0 mg) was added at 0° C., and the solution was stirred at room temperature for 30 minutes. Iodopropane (0.33 g) was added to the reaction mixture, which was stirred at room temperature for two hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). A mixture of the obtained oily substance, 1 N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for two hours, diluted with 1 N hydrochloric acid (3 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-propyloxy-1H-pyrazol-4-yl]propionic acid was obtained (0.59 g, yield. 81%). This was recrystallized from acetone-hexane. Melting point: 108–109° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:37]([N:39]1[N:43]=[C:42]([C:44]([CH3:47])([CH3:46])[CH3:45])[S:41][C@@H:40]1[C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])=[O:38])[NH:17][C@H:18]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCC1>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:37]([N:39]1[N:43]=[C:42]([C:44]([CH3:47])([CH3:45])[CH3:46])[S:41][C@H:40]1[C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])=[O:38])[NH:17][C@H:18]([C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C1=NN(C(=O)[C@H](CCCCNC(=O)OCc2ccccc2)N[C@@H](CCc2ccccc2)C(=O)OCc2ccccc2)[C@@H](C(=O)OCc2ccccc2)S1
Solvent: C1CCNC1
Solvent: CC#N
Product: CC(C)(C)C1=NN(C(=O)[C@H](CCCCNC(=O)OCc2ccccc2)N[C@@H](CCc2ccccc2)C(=O)OCc2ccccc2)[C@H](C(=O)OCc2ccccc2)S1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of the product of step (c) (2.lg) and pyrrolidine (1.6ml) in dry acetonitrile (60ml) was treated with crushed 3A molecular sieves and the mixture stirred at room temperature for 24 hours under nitrogen. The volatile materials were removed by evaporation and the SSS isomer separated from the more polar SSR isomer by flash chromatography. The SSS sub-title product (0.47g) was isolated as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1)=[O:26]>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][S:13]([C:10]2[CH:11]=[CH:12][C:7]([C:4]3[O:3][C:2]([CH3:1])=[N:6][CH:5]=3)=[CH:8][CH:9]=2)(=[O:15])=[O:14])=[C:19]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)=[O:26])[CH:20]=1
Reactant: Cc1ncc(-c2ccc(S(=O)(=O)Cl)cc2)o1
Reactant: Cc1cccc(C(=O)c2cc(Cl)ccc2N)n1
Product: Cc1cccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(-c3cnc(C)o3)cc2)n1

Procedure:
The title compound was prepared according to the general procedure for the preparation of N-aryl-benzenesulfonamides using 4-(2-methyl-oxazol-5-yl)-benzenesulfonyl chloride and (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)-methanone and purified by HPLC. MS: m/z 468.0 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[CH2:11][C:10](NC)=[C:9]1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C1C[O:28]CC1.Cl>O>[OH:28][C:10]1[CH2:11][C:12]2[CH2:16][O:15][C:14](=[O:17])[C:13]=2[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:9]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C1=C(NC)CC2=C(C(=O)OC2)C1c1ccccc1C
Reactant: C1CCOC1
Agent: Cl
Solvent: O
Product: CCOC(=O)C1=C(O)CC2=C(C(=O)OC2)C1c1ccccc1C
Reaction time: 1 h

Procedure:
10 mmol of ethyl 7-(2-methylphenyl)-5-methylamino-1-oxo-1,3,4,7-tetrahydrobenzo[c]furan-6-carboxylate are dissolved in 50 mmol of THF, 3 ml of concentrated HCl and 5 ml of water are added, and the mixture is boiled for 1 hour and then concentrated. The substance is identical to that from Example 3a.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CI.[H-].[Na+].[CH3:25]N(C)C=O>O1CCCC1>[C:1]([N:8]([CH3:25])[C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([I:17])=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccc(I)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Following the procedure of Boger and Yohannes (J. Org. Chem. 53, 487 (1988), a solution of N-BOC-4-iodophenylalanine (391 mg, 1 mmol) and methyl iodide (156 μL, 2.5 mmol) in tetrahydrofuran (5 mL) at 0° C. was added 60% sodium hydride in oil suspension (100 mg, 2.5 mmol). The resulting mixture was stirred at 0° C. for 1 hr and then at room temperature for 16 hr. Added dimethylformamide (1 mL) and additional methyl iodide (156 μL, 2.5 mmol) and 60% sodium hydride (100 mg, 2.5 mmol) and heated at 75° C. overnight. The reaction was worked up as described in the reference to yield N-BOC-N-methyl-4-iodophenylalanine.