Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP(C#N)(=O)OCC)C.C(N(CC)CC)C.Cl.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH3:28])=[N:25][C:24]=2[CH:29]=1.[F:30][C:31]([F:51])([F:50])[C:32]1[CH:33]=[C:34]([N:38]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[C:39]2[C:47](O)=[O:48])[CH:35]=[CH:36][CH:37]=1>CN(C)C=O>[CH3:28][C:26]1[O:27][C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:47]([C:39]3[N:38]([C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:51])([F:30])[F:50])[CH:33]=4)[C:46]4[C:41]([CH:40]=3)=[CH:42][CH:43]=[CH:44][CH:45]=4)=[O:48])=[CH:29][C:24]=2[N:25]=1
Reactant: O=C(O)c1cc2ccccc2n1-c1cccc(C(F)(F)F)c1
Reactant: Cc1nc2cc(N)ccc2o1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc2cc(NC(=O)c3cc4ccccc4n3-c3cccc(C(F)(F)F)c3)ccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
0.091 ml (0.6 mmol) of diethylcyanophosphonate, 0.168 ml (0.6 mmol) of triethylamine and 0.111 g (0.6 mmol) of 5-amino-2-methylbenzoxazole hydrochloride are added to a solution of 0.152 g (0.5 mmol) of 1-[3-(trifluoromethyl)phenyl]-1H-indole-2-carboxylic acid (JP2001151771A2) in 3 ml of dimethylformamide. The mixture is stirred overnight at room temperature and concentrated under reduced pressure, and the residue is taken up in water and dichloromethane. After separation of the phases by settling, the organic phase is dried and evaporated under reduced pressure. The residue is purified by preparative chromatography. 0.102 g of solid is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH:13]=[CH:12][CH:11]=[N:10]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(-n2cccn2)ncn1
Yield: 66.4 %

Procedure:
A mixture of 4,6-dichloropyrimidine (5.96 g, 40 mmol), 1H-pyrazole (2.72 g, 40.0 mmol), and cesium carbonate (13.03 g, 40.0 mmol) was stirred in DMF (25 mL) at room temperature for 18 h. The reaction was diluted into 100 mL water and extracted with EtOAc. The combined organic layers were concentrated and purified by flash chromatography on a 240 g silica gel cartridge with 0 to 20% ethyl acetate in hexane to yield 4-chloro-6-(1H-pyrazol-1-yl)pyrimidine (4.80 g, 66% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.77 (1H, d, J=0.76 Hz), 8.55 (1H, d, J=2.77 Hz), 7.96 (1H, d, J=1.01 Hz), 7.80 (1H, d, J=1.01 Hz), 6.51 (1H, dd, J=2.64, 1.64 Hz).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]([S:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:8]([CH3:18])(CC(O)=O)[NH:9]2)(=[O:3])[CH3:2].Cl.CN([CH2:31][C:32](Cl)=[O:33])C>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([S:19][C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[CH:13][C:5]=3[NH:4][C:1](=[O:3])[CH2:2][N:9]([CH3:10])[CH3:8])[N:9]([CH2:2][C:1]([O:33][CH2:32][CH3:31])=[O:3])[C:8]=2[CH3:18])=[CH:21][CH:22]=1
Reactant: CN(C)CC(=O)Cl
Reactant: CC(=O)Nc1cccc2c1C(Sc1ccc(Cl)cc1)C(C)(CC(=O)O)N2
Agent: Cl
Product: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c(NC(=O)CN(C)C)cccc21

Procedure:
The sub-title compound was prepared by the method of Example 1 part (iv) using the product from Example 1 part (iii) and (dimethylamino)-acetyl chloride, hydrochloride. The product was purified using column chromatography (33% EtOAc/hexane as eluent).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[C:7]([C:12]#[N:13])=[CH:8][NH:9]2)=[CH:4][C:3]=1[O:15][CH3:16].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[C:3]([O:15][CH3:16])[CH:4]=2)[N:9]=[CH:8][C:7]=1[C:12]#[N:13]
Reactant: COc1cc2c(=O)c(C#N)c[nH]c2cc1F
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2c(Cl)c(C#N)cnc2cc1F
Yield: 58.1 %

Procedure:
A mixture of 7-fluoro-6-methoxy-4-oxo-1,4-dihydro-3-quinolinecarbonitrile (1.0 g, 4.59 mmol) and 14 g of phosphorous oxychloride is heated at reflux for 30 minutes then concentrated in vacuo. The residue is partitioned between aqueous sodium bicarbonate and ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated on to silica gel. Purification by flash column chromatography eluting with a gradient of 1:5 ethyl acetate:hexane to 1:1 ethyl acetate:hexane, provides 631 mg of 4-chloro-7-fluoro-6-methoxy-3-quinolinecarbonitrile, mp 160-162° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11]C)=O.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[NH:1]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:8][C:9]1=[O:11]
Reactant: COC(=O)Cc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1Cc2ccccc2N1
Yield: 103.2 %

Procedure:
Stir the mixture of methyl 2-(2-aminophenyl)acetate (4.8 g, 29.1 mmol) and potassium carbonate (8.0 g, 58.2 mmol) in DMF (15 mL) at room temperature overnight. TLC (PE:EtOAc=2:1) shows the reaction is complete. Concentrate the reaction mixture under reduced pressure to give the crude product. Purify by chromatography (silica gel, EtOAc:PE=1:2) to afford the title compound (4.0 g, 95%). MS: (M+1): 134.2.
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:17]([OH:21])[C:18](O)=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:30]([NH:34][C:35](=[O:41])[C@@H:36]1[CH2:40][CH2:39][CH2:38][NH:37]1)([CH3:33])([CH3:32])[CH3:31].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]([C@@H:16]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C@H:17]([OH:21])[C:18]([N:37]1[CH2:38][CH2:39][CH2:40][C@H:36]1[C:35]([NH:34][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:41])=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 5 h

Procedure:
14.0 g (37.0 mmol) of (2S, 3S)-3-(N,N-dibenzylamino)-2-hydroxy-4-phenylbutyric acid [prepared as described in step (a) above] and the whole of the N-t-butyl-L-prolinamide hydrochloride were suspended in 250 ml of methylene chloride, and 6.7 g (41.1 mmol) of diethyl cyanophosphate and 11.2 g (110.9 mmol) of triethylamine were slowly added dropwise to the suspension. The mixture was then stirred for 5 hours. At the end of this time, the reaction mixture was washed with a 10% w/v aqueous solution of citric acid, with a 10% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The mixture was then dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure, and the resulting residue was recrystallized from hexane, to give 16.6 g of the title compound as colorless crystals, melting at 122°-123° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]1[C:20]([C:21](OCC)=[O:22])=[C:19]([CH3:26])[N:18]=[C:13]12.C(OCC)(=O)C>O1CCCC1>[Cl:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]1[C:20]([CH2:21][OH:22])=[C:19]([CH3:26])[N:18]=[C:13]12
Reactant: CCOC(=O)c1c(C)nc2c3cccc(Cl)c3ccn12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc2c3cccc(Cl)c3ccn2c1CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.5 %

Procedure:
Lithium aluminum hydride (0.668 g) was added portionwise to a solution of 7-chloro-3-ethoxycarbonyl-2-methylimidazo[2,1-a]isoquinoline (5.1 g) in tetrahydrofuran (100 ml) with ice-cooling under nitrogen atmosphere and the mixture was stirred at room temperature for 1.5 hours. After an addition of ethyl acetate, the mixture was evaporated in vacuo and the residue was extracted with hot ethanol. The extract was treated with activated charcoal and evaporated in vacuo. The residue was recrystallized from 90% ethanol to give 7-chloro-3-hydroxymethyl-2-methylimidazo[2,1-a]isoquinoline (1.94 g).
Reaction SMILES: [N:1]([CH:4]([C:11]1([CH3:16])[CH2:15][CH2:14][CH2:13][O:12]1)[C:5]1[O:6][C:7]([CH3:10])=[CH:8][CH:9]=1)=[N+]=[N-].[H][H]>C(O)C.[Pd]>[CH3:10][C:7]1[O:6][C:5]([CH:4]([C:11]2([CH3:16])[CH2:15][CH2:14][CH2:13][O:12]2)[NH2:1])=[CH:9][CH:8]=1
Reactant: Cc1ccc(C(N=[N+]=[N-])C2(C)CCCO2)o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C(N)C2(C)CCCO2)o1
Yield: 96.1 %

Procedure:
A solution of 2.51 g (9.7 mmol, 1 eq) of 2-[azido-(2-methyltetrahydrofuran-2-yl)methyl]-5-methylfuran in 45 ml of ethanol was stirred at hydrogen atmospheric pressure in the presence of 323 mg (15% by weight) of palladium on carbon (Pd/C) at 10% for 16 hours. The reaction medium was filtered and the filtrate was evaporated. 1.82 g of (5-methylfuran-2-yl)(2-methyltetrahydrofuran-2-yl)methanamine were obtained. Yield=96%. TLC/SiO2: heptane/EtOAc (60/40), developing with KMnO4.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:16][C@H:12]2[O:13][CH2:14][CH2:15][C@@:11]2([C:17]([OH:19])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:20]1([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:16][C@H:12]2[O:13][CH2:14][CH2:15][C@@:11]2([C:17]([N:23]2[CH2:22][CH2:21][N:20]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[CH2:25][CH2:24]2)=[O:19])[CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)O)C1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)C1

Procedure:
The product of Step F was prepared from the reaction of the product of Step E and benzyl piperazine-1-carboxylate following the procedure from Example 1, Step C. Calculated for C25H35N3O6: 496.2 (M+23). found: 496.0.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[S:12][C:13]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[C:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:15]=1>>[C:1]([NH:10][C:11]1[S:12][C:13]([C:23]([NH:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])=[C:14]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc(Cc2ccccc2)c(C(=O)NCc2ccccc2)s1
Product: O=C(Nc1nc(Cc2ccccc2)c(C(=O)NCc2ccccc2)s1)c1ccccc1
Yield: 54 %

Procedure:
Following the procedure as described in Example 16, making variations only as required to use benzoyl chloride in place of hydrocinnamoyl chloride to react with 2-amino-N,4-dibenzylthiazole-5-carboxamide, the title compound was obtained in 54% yield; 1H NMR (CDCl3, 400 MHz) δ 7.92 (d, J=7.1 Hz, 2H), 7.63 (t, J=7.6 Hz, 1H), 7.52 (t, J=8.1 Hz, 2H), 7.40-7.15 (m, 10H), 4.58 (d, J=5.6 Hz, 2H), 4.41 (s, 2H); MS (ES+) m/z 428 (M+1).
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH:27]=O>>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:27]([C:18]2[CH:19]=[CH:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCO2
Product: CC(C)N1C(=O)NC(c2ccc3ccccc3c2)c2cc3c(cc21)OCO3
Yield: 60 %

Procedure:
This compound was synthesized from N-isopropyl-N-[3,4-(methylenedioxy)-phenyl]urea (226 mg) and 2-naphthaldehyde (152 mg) by the procedure described in example 10 in 60% yield, mp: 186-178° C. 1H NMR (CDCl3): 7.86-7.75 (m, 4H), 7.52-7.42 (m, 3H), 6.70 (s, 1H), 6.32 (s, 1H), 5.91 (d, J=1.3, 1H), 5.88 (d, J=1.3, 1H), 5.47 (s, 1H), 5.16 (br s, 1H), 4.45 (m, 1H), 1.58 (m, 6H). Anal. calcd. for C22H20N2O3: C. 73.32; H, 5.59; N, 7.77. Found: C, 73.10; H, 5.49; N, 7.62.
Reaction SMILES: Br[C:2]1[C:3]([N:7]2[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]3[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]2=3)=[CH:4][S:5][CH:6]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[C:2]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:6][S:5][CH:4]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cscc2Br)CCN(C)C1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2-c2cscc2-c2ccccc2)CCN(C)C1
Temperature: 95 °C

Procedure:
To a de-aerated solution of 5-(4-bromo-thiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (40 mg, 0.111 mmol), phenylboronic acid (20 mg, 0.166 mmol) and K3PO4 (58.8 mg, 0.217 mmol) in DMF-water (4.5:0.5 mL) was added PdCl2(PPh3)2 (3.8 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(4-phenyl-thiophen-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an off white solid (4 mg). 1H NMR (TFA salt, CD3OD) δ (ppm): 7.79-7.65 (m, 2H), 7.3 (s, 1H), 7.2-7.1 (m, 4H), 7.1-7.0 (m, 2H), 6.9 (d, 1H), 4.7 (d, 1H), 4.3 (d, 1H), 3.61-3.60 (m, 1H), 3.25-3.2 (m, 1H), 3.05-3.00 (m, 1H), 2.9 (s, 3H), 2.4 (s, 3H), 2.4-2.39 (m, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[Cl:11].[NH3:12].Cl>CO>[NH2:12][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[Cl:11]
Reactant: N#Cc1ccc(CBr)c(Cl)c1
Reactant: N
Agent: Cl
Solvent: CO
Product: N#Cc1ccc(CN)c(Cl)c1
Temperature: 18 °C
Reaction time: 17 h

Procedure:
To a mixture of 4-(bromomethyl)-3-chlorobenzonitrile (11 g, 49 mmol, 1.0 equiv) and 6 M NH3 in methanol (200 mL) was stirred at 18° C. for 17 h. Aqueous HCl (1 M, 200 mL) was added, and the water layer was washed with ethyl acetate. The aqueous phase was adjusted to pH 9-10 with 1 M NaOH and extracted with ethyl acetate. The organic layer was washed with water, dried with magnesium sulfate, and concentrated. The residue was purified on silica gel to afford 2.71 g of the title compound. MS (ES+): m/e 167.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14][N:20]=[N+:21]=[N-:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1COS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1CN=[N+]=[N-]
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A mixture of (2S,4R)-4-fluoro-2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (3.3 g, 11.1 mmol) and NaN3 (721 mg, 11.1 mmol) in DMF (50 mL) was stirred at 75° C. under nitrogen overnight. The mixture was diluted with water and extracted with EtOAc (×3). The combined organic extracts were washed with water (×3), dried over Na2SO4, and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 100/0 to 0/100) to give the desired material. 1H-NMR (400 MHz, DMSO): δ (ppm) 5.25 (d, 1H), 4.03 (m, 1H), 3.92-3.70 (m, 2H), 3.5-3.25 (m, 2H), 2.27 (m, 1H), 2.2-1.8 (m, 1H), 1.43 (s, 9H).
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-])([OH:10])=[O:9].[C:12]([O:15][CH2:16][CH2:17][C:18]([N+:38]([O-:40])=[O:39])([N+:35]([O-:37])=[O:36])[CH2:19][NH:20][CH2:21][C:22]([N+:32]([O-:34])=[O:33])([N+:29]([O-:31])=[O:30])[CH2:23][CH2:24][O:25][C:26](=[O:28])[CH3:27])(=[O:14])[CH3:13]>>[C:26]([O:25][CH2:24][CH2:23][C:22]([N+:32]([O-:34])=[O:33])([N+:29]([O-:31])=[O:30])[CH2:21][N:20]([N+:8]([O-:10])=[O:9])[CH2:19][C:18]([N+:38]([O-:40])=[O:39])([N+:35]([O-:37])=[O:36])[CH2:17][CH2:16][O:15][C:12](=[O:14])[CH3:13])(=[O:28])[CH3:27]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)OCCC(CNCC(CCOC(C)=O)([N+](=O)[O-])[N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCCC(CN(CC(CCOC(C)=O)([N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic anhydride (315 ml) was stirred in an ice bath to maintain a temperature of 20°-23° C. during the slow addition of 95 ml of 90 percent nitric acid. The solution was then cooled to 5° C. while 3,3,7,7-tetranitro-5-azanonane-1,9-diol-1,9-diacetate was added in portions with good stirring. The solution was stirred at ambient temperature overnight before it was poured into ice water. The mixture was stirred for one hour and the solid (66.5 g, 97 percent, mp 87°-89° C.) was removed by filtration. A recrystallized sample (CH2Cl2 /hexane) had mp 88°-89° C.; 1H NMR (CDCl3): δ2.09 (s, 3H), 3.00 (t, 2H), 4.35 (t, 2H), 5.20 (s, 2H).
Reaction SMILES: [C:1]1([CH:7](O)[C:8]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[H][H]>[Pd].O>[C:1]1([CH2:7][CH:8]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: CCCCCCC(=Cc1ccccc1)C(O)c1ccccc1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCCCCC(Cc1ccccc1)Cc1ccccc1
Temperature: 50 °C
Yield: 61.2 %

Procedure:
In a 2-liter three-necked flask equipped with a stirring device and a nitrogen substituting device, 169.6 g of 1,3-diphenyl-2-n-hexyl-2-propen-1-ol, 0.4 milliliters of trifluoroacetic acid and 17 g of a Pd-C catalyst (a 5% product, containing 55.9% of water) were introduced, and stirred at 50° C. and contacted with hydrogen gas. After stirring for 30 hours, the catalyst was filtered off, water was added, and an extraction was carried out with n-heptane. After washing with sodium hydrogencarbonate and water, the solution was dried with anhydrous sodium sulfate. After removing off the solvent by a rotary evaporator and dissolving the residue in a small amount of n-heptane, a separating operation was carried out by a column chromatography with silica gel. By removing off the solvent again and carrying out a distillation under a decreased pressure, to obtain 98.9 g of 1,3-diphenyl-2-n-hexyl propane as colorless liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][CH:21]=1)[C:12]([O:14]C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCCC1.C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(Cc2ccc(C(=O)OC)cc2OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1ccc(Cc2ccc(C(=O)O)cc2OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Methyl 3-benzyloxy-4-(4-ethylbenzyl)benzoate (1.6 g) was dissolved in a mixture of tetrahydrofuran (5 mL) and ethanol (5 mL). To the solution was added 2 mol/L aqueous sodium hydroxide solution (10 mL), and the mixture was stirred at 80° C. for 1 hour. After cooling to room temperature, the resulting solution was acidified with 2 mol/L hydrochloric acid. The mixture was stirred under ice-cooling for 3 minutes, and the precipitates were collected by filtration, washed with water and dried to give 3-benzyloxy-4-(4-ethylbenzyl)benzoic acid (1.4 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[C:16]1([CH:23]=[CH:22][CH:21]=[C:19]([OH:20])[CH:18]=1)[OH:17].[N+](C1C=CC=CC=1)([O-])=O.Cl>>[OH:17][C:16]1[CH:18]=[C:19]([OH:20])[CH:21]=[CH:22][C:23]=1[C:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:14]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)c2ccc(O)cc2O)cc1
Temperature: 0 °C

Procedure:
Aluminum chloride (48 gm, 0.36 moles) was added gradually, with stirring to a mixture of 31 grams (0.18 moles) of anisoyl chloride, 19.82 grams (0.18 moles) of resorcinol and 300 ml. of dry nitrobenzene during 60 minutes. Sixty hours later the reaction mixture was poured on 200 grams of ice and 100 ml. of concentrated hydrochloric acid. After removal of the nitrobenzene with steam the residual crystalline solid product was washed with water and collected. The cake was then washed withd cold (-50 degrees C.) methanol to remove tarry impurities and dried.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[CH:11][N:10]=2)=[CH:5][C:4]=1[F:30])#[N:2].[CH2:31]([C:33]1[CH:34]=[N:35]C(Br)=[N:37][CH:38]=1)[CH3:32]>>[C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:16][CH2:17][N:18]([C:21]4[N:37]=[CH:38][C:33]([CH2:31][CH3:32])=[CH:34][N:35]=4)[CH2:19][CH2:20]3)=[CH:11][N:10]=2)=[CH:5][C:4]=1[F:30])#[N:2]
Reactant: CCc1cnc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3ccc(C#N)c(F)c3)nc2)CC1
Product: CCc1cnc(N2CCC(c3ccc(COc4ccc(C#N)c(F)c4)nc3)CC2)nc1

Procedure:
The title compound was prepared from tert-butyl 4-[2-(4-cyano-3-fluorophenoxymethyl)pyridin-5-yl]piperidine-1-carboxylate (Example 13) (50 mg, 0.12 mmol) and 5-ethyl-2-bromopyrimidine (29 μL, 0.24 mmol) following a procedure analogous to that in Example 48 as a white crystal (37 mg, yield 73%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CO.O>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[CH2:18][CH2:17]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Solvent: CO
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Fluoro-5-nitrobenzotrifluoride (2 g) and 1-methylpiperazine (2 mL) were dissolved in methanol (5 mL). The yellow solution was stirred at rt overnight. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic solutions were evaporated to give 2-(4-methylpiperazino)-5-nitrobenzotrifluoride.