Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][OH:23])[O:19][C:18]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[C:10](=[O:16])[CH2:9]1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][O:23][S:33]([CH3:32])(=[O:35])=[O:34])[O:19][C:18]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH3:15])[C:10](=[O:16])[CH2:9]1
Reactant: CCN1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCN1CCN(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(5R)-3-(3-Fluoro-4-{4-ethyl-3-oxopiperazin-1-yl}phenyl)-5-hydroxymethyloxazolidin-2-one (830 mg) was dissolved in pyridine (20 ml), and cooled to 0° C. Triethylamine (0.41 ml) and methanesulfonyl chloride (0.21 ml) were added, and stirring continued at ambient temperature for 2 hours. Solvent was evaporated and the residue dissolved in ethyl acetate. The resulting solution was washed with water, dried (MgSO4), and evaporated to give (5R)-3-(3-fluoro-4-{4-ethyl-3-oxopiperazin-1-yl}phenyl)-5-(methanesulfonyloxymethyl)-oxazolidin-2-one (1.0 g) which was used without further purification.
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:27]1[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=1)=[N:9][C:10]=2[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[S:41](Cl)([CH3:44])(=[O:43])=[O:42]>O1CCCC1>[CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([S:41]([CH3:44])(=[O:43])=[O:42])[C@@H:16]([CH3:20])[CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:27]1[CH:32]=[N:31][C:30]([NH2:33])=[N:29][CH:28]=1)=[N:9][C:10]=2[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1c(N2CCN[C@@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)Cn1c(N2CCN(S(C)(=O)=O)[C@@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
5-{9-Isobutyl-8-[(3S)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (140 mg, 0.32 mmol) was dissolved in tetrahydrofuran (5 ml) followed by the addition of triethylamine (68 μl) and mesyl chloride (28 μl) with ice cooling and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned with ethyl acetate and water, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=5:5 to 0:10) to give a white solid (115 g, 67%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[C:16]([F:18])[C:13]([C:14]#[N:15])=[C:12]([F:19])[CH:11]=2)=[N:6]1)[CH3:4].[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26](O)=[O:27])[N:25]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26]([NH:1][CH2:2][C@H:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[C:16]([F:18])[C:13]([C:14]#[N:15])=[C:12]([F:19])[CH:11]=3)=[N:6]2)[CH3:4])=[O:27])[N:25]=1
Reactant: Nc1nc(C(=O)O)cs1
Reactant: C[C@H](CN)n1ccc(-c2cc(F)c(C#N)c(F)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](CNC(=O)c1csc(N)n1)n1ccc(-c2cc(F)c(C#N)c(F)c2)n1

Procedure:
The title compound was synthesized from (R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (380 mg, 1.45 mmol), 2-aminothiazole-4-carboxylic acid (217 mg, 1.5 mmol), HOBt (235 mg, 1.74 mmol), DIPEA (0.303 mL, 1.74 mmol) and EDCI (333 mg, 1.74 mmol) using DCM as solvent using the method of Example 34(d). Yield 92 mg. 1H NMR (400 MHz; CDCl3): δ 1.60 (d, 3H), 3.81 (m, 2H), 4.61 (m, 1H), 4.91 (s, 2H), 6.60 (d, 1H), 7.37 (s, 1H), 7.50 (d, 1H), 7.58 (m, 2H), 7.80 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][CH2:7][C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9].[C:17]([S:20][C@@H:21]1[CH2:25][N:24]([C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])[C@H:23]([C:32](O)=[O:33])[CH2:22]1)(=[O:19])[CH3:18].NC1C=C(C=CC=1)OCC(OCC=C)=O>>[C:17]([S:20][C@@H:21]1[CH2:25][N:24]([C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])[C@H:23]([C:32](=[O:33])[NH:1][C:2]2[CH:16]=[CH:15][CH:14]=[C:4]([CH2:5][O:6][CH2:7][C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[CH:3]=2)[CH2:22]1)(=[O:19])[CH3:18]
Reactant: C=CCOC(=O)COCc1cccc(N)c1
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C(=O)O
Agent: C=CCOC(=O)COc1cccc(N)c1
Product: C=CCOC(=O)COCc1cccc(NC(=O)[C@@H]2C[C@H](SC(C)=O)CN2C(=O)OCC=C)c1

Procedure:
Allyl 3-aminobenzyloxyacetate was condensed with (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-carboxypyrrolidine by the method described in example 3 for allyl 3-aminophenoxyacetate, except that crude product was purified by chromatography on silica, using a gradient from di-chloromethane to dichloromethane/diethyl ether (85:15), to give (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(3(allyloxycarbonylmethoxymethyl)phenylcarbamoyl)pyrrolidine.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:12](Br)[CH:13]=[CH2:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:14]([O:11][C:3]1[C:2]([Br:1])=[CH:9][C:6]([C:7]#[N:8])=[C:5]([Cl:10])[CH:4]=1)[CH:13]=[CH2:12]
Reactant: N#Cc1cc(Br)c(O)cc1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(Cl)c(C#N)cc1Br
Reaction time: 3 h
Yield: 65 %

Procedure:
A mixture of compound 37 (20.5 g, 88.1 mmol), allyl bromide (11.2 mL, 132 mmol) and K2CO3 (24.4 g, 176 mmol) in acetone (440 mL) was stirred for 3 hours under reflux. The mixture was filtrated and concentrated in vacuo. The resultant was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the product 38 (15.6 g, 65%) as a white solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[O:16][CH2:17][CH2:18]Cl)[CH3:5])[CH:2]=[CH2:3].[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>CC(N(C)C)=O>[CH2:1]([N:4]([CH2:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[O:16][CH2:17][CH2:18][N:22]([CH2:23][CH3:24])[CH2:20][CH3:21])[CH3:5])[CH:2]=[CH2:3]
Reactant: C=CCN(C)Cc1cc([N+](=O)[O-])ccc1OCCCl
Reactant: CCNCC
Solvent: CC(=O)N(C)C
Product: C=CCN(C)Cc1cc([N+](=O)[O-])ccc1OCCN(CC)CC
Temperature: 60 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a solution of (xxiv) (1 g, 3.68 mmol) in DMA (10 mL) was added diethylamine (7.36 mmol) and the resulting mixture was stirred overnight at 60° C. The reaction mixture was quenched with water. The product was extracted with CH2Cl2 thrice and the combined organic extracts were washed with H2O followed by brine, dried over Na2SO4 and concentrated under reduced pressure to furnish without purification 750 mg of compound (xxv) in 70% yield. MS (m/z) 322 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].[CH3:29][O:30][CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:29][O:30][CH2:31][CH2:32][NH:33][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:14]
Reactant: COCCN
Reactant: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCCOC)ccc21
Yield: 37.4 %

Procedure:
1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (64.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (150.0 mg), 2-methoxy-ethylamine (38.0 mg), HBTU (200.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 465; and 1H NMR (DMSO-d6, 400 MHz): δ 8.50 (1H, m), 8.25 (1H, br. s), 8.12 (1H, br. s), 7.82-7.78 (2H, m), 7.70-7.68 (1H, m), 7.57-7.54 (1H, m), 4.24 (2H, m), 3.51-3.43 (4H, m), 3.29 (3H, s), 1.35-1.31 (3H, t), —NH proton signal was not observed.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:9][CH:8]=1.O1CCCC1.[OH-].[K+]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1ccc(-c2ccccn2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
700 mg (3.11 mol) of methyl [4-(2-pyridyl)phenyl]acetate are introduced into 5 ml of tetrahydrofuran and, at room temperature, 6.2 ml of a 1M potassium hydroxide solution in water are added. The mixture is stirred at room temperature for 18 h and then the solvent is substantially removed in vacuo, the residue is taken up in 10 ml of water and the pH was adjusted to about 5 with 2N hydrochloric acid. Extraction of the aqueous phase twice with 10 ml of dichloromethane each time affords, after drying the combined organic phases over magnesiumsulfate and removing the solvent in vacuo, the compound of Example VIII in the form of a solid.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][Br:6])C.Br.[Br:11][C:12]1[C:17]([NH2:18])=[N:16][C:15](Br)=[CH:14][N:13]=1>CC(O)C>[Br:11][C:12]1[N:13]2[CH:14]=[CH:15][N:16]=[C:4]2[C:5]([Br:6])=[N:18][CH:17]=1
Reactant: Nc1nc(Br)cnc1Br
Reactant: CCOC(CBr)OCC
Agent: Br
Solvent: CC(C)O
Product: Brc1ncc(Br)n2ccnc12

Procedure:
Bromoacetaldehyde diethyl acetal (49 mL, 326 mmol) and 48% hydrobromic acid is heated to reflux for 1.5 h, then poured into propan-2-ol (600 mL) and quenched with NaHCO3. After filtering, 2,5-dibromo-3-aminopyrazine (41.34 g, 163 mmol) is added to the solution and heated at reflux overnight. The reaction is cooled and solvents removed in vacuo, followed by addition of aq. NaHCO3 and extraction with EtOAc. The organic phase is dried over MgSO4, filtered, and concentrated in vacuo to afford a brown solid. 1H NMR (250 MHz, CDCl3) δ(ppm)7.86 (1H, s), 7.93-7.94 (1H, d), 7.98-7.99 (1H,d); m/z (APCI) 278 (M+H)+; m.p 132-135° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:27])=[CH:24][CH:23]=1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCOC(=NC(=O)c1ccc(F)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and p-fluorobenzoyl chloride, there is obtained ethyl N-(p-fluorobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 109°-110° C.;
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH:37]3[CH2:41][CH2:40][NH:39][CH2:38]3)[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:44]([BH3-])#N.[Na+]>CC#N.CO>[CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH:37]3[CH2:41][CH2:40][N:39]([CH3:44])[CH2:38]3)[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCC3CCNC3)c2)cc1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCC3CCN(C)C3)c2)cc1

Procedure:
The product from Example 93D (0.030 g, 0.0525 mmoles) in 1:1 CH3CN/MeOH (2 mL) was treated with 37% aqueous formaldehyde (0.020 mL, 0.263 mmoles) and sodium cyanoborohydride (0.008 g, 0.131 mmoles). Reaction mixed overnight at room temperature. Reaction quenched with two drops acetic acid and concentrated under reduced pressure. The residue was purified by preparative HPLC (CH3CN:0.1% TRIFLUOROACETIC ACID in H2O) on a YMC ODS Guardpak column to provide the title compound. 1H NMR (500 MHz, DMSO) δ8.96 (s, 1 H), 7.25 (m, 7 H), 7.20 (m, 1 H), 7.05 (m, 1 H), 6.97 (d, 2 H), 6.92 (d, 2 H), 6.70 (m, 1 H), 6.56 (dd, 1 H), 6.53 (dd, 1 H), 4.06 (s, 2 H), 4.03 (s, 2 H), 3.95 (m, 1 H), 3.50-3.80 (m, 1 H), 3.30-3.50 (m, 1 H), 3.00-3.20 (m, 2 H), 2.92 (s, 3 H), 2.80 (m, 5 H), 2.40 (s, 3 H), 2.00-2.30 (m, 1 H), 1.80 (m, 1 H); MS (ESI+) m/z 586 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]3[NH:15][CH2:14][C:13]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:10]3=[N:11][CH:12]=2)[CH2:3][CH2:2]1.Cl[C:22]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[C:24]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:23]=1[CH3:38].CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[CH3:38][C:23]1[C:24]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[N:25][C:26]2[C:31]([C:22]=1[N:15]1[C:9]3[C:10](=[N:11][CH:12]=[C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH:8]=3)[C:13]3([CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:14]1)=[CH:30][CH:29]=[CH:28][N:27]=2
Reactant: Cc1c(-c2ccccn2)nc2ncccc2c1Cl
Reactant: c1nc2c(cc1N1CCOCC1)NCC21CCOCC1
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2ncccc2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y by using 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (70 mg, 0.254 mmol), 4-chloro-3-methyl-2-(pyridin-2-yl)-1,8-naphthyridine (65.0 mg, 0.25 mmol), sodium tert-butoxide (48.9 mg, 0.51 mmol) and XPhos precatalyst (18.7 mg, 0.025 mmol) in toluene (5 mL) for 2 h at 100° C. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 1′-(3-methyl-2-(pyridin-2-yl)-1,8-naphthyridin-4-yl)-6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]. 1H NMR (400 MHz, chloroform-d) δ ppm 9.13 (1H, dd, J=4.1, 2.0 Hz), 8.72 (1H, ddd, J=4.8, 1.8, 1.0 Hz), 8.19 (1H, dt, J=7.8, 1.2 Hz), 8.13 (1H, dd, J=8.4, 2.0 Hz), 7.93 (1H, td, J=7.7, 1.8 Hz), 7.64 (1H, d, J=2.3 Hz), 7.39-7.47 (2H, m), 5.82 (1H, d, J=2.3 Hz), 4.13-4.20 (2H, m), 4.08 (1H, d, J=9.8 Hz), 3.97 (1H, d, J=9.6 Hz), 3.72-3.78 (4H, m), 3.55-3.62 (2H, m), 2.95-3.04 (4H, m), 2.51 (3H, s), 2.20-2.35 (2H, m), 1.74-1.87 (2H, m). Mass Spectrum (ESI) m/e=495.2 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17].[P:26]([O:33]CC)([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29]>>[CH2:28]([O:27][P:26]([CH:12]([C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2])([O:30][CH2:31][CH3:32])=[O:33])[CH3:29]
Reactant: CCOP(OCC)OCC
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCCCCCCCCBr
Product: CCCCCCCCCCC(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)P(=O)(OCC)OCC
Temperature: 150 °C
Reaction time: 18 h
Yield: 94.9 %

Procedure:
A mixture of 15.03 g of 1-bromo-11-(nonafluorobutyl)undecane and 15.00 g of triethyl phosphite was heated at 150° C. After 18 hr, an additional 9.00 g of triethyl phosphite was added, and heating was continued for 24 hr. Diethyl ethylphosphonate and other volatiles were removed by distillation, b.p. 30-50° C. at 0.05 torr (7 Pa). Bulb-to-bulb distillation of the concentrate provided 16.07 g of 1-(diethylphosphono)-1-(nonafluorobutyl)undecane as a clear, colorless liquid, b.p. 170-200° C. at 0.05 torr (7 Pa).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]1=2.C(N(CC)CC)C.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:30](=[O:31])[CH2:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(NC(=O)Cc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (1) (0.5 g, 2.46 mmole) in 20 mL of dicloromethane was treated successively with 0.51 mL of triethylamine (1.5 eq.) and 0.33 mL of phenylacetyl chloride (1 eq.), stirred at room temperature for two hours and then diluted with an additional 20 mL of dichloromethane. The organic solution was washed with two 50 mL portions of water and one 50 mL portion of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give 790 mg (100%) of phenylacetic acid (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amide (7) as a pale yellow foam.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]([CH3:14])[CH3:13])=[C:8]([C:15](OCC)=[O:16])[CH:7]=1.[H-].[Al+3].[H-].[H-].O>O1CCCC1>[NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]([CH3:13])[CH3:14])=[C:8]([CH2:15][OH:16])[CH:7]=1
Reactant: CCOC(=O)c1cc(CSCCN)oc1CN(C)C
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1oc(CSCCN)cc1CO
Yield: 62.5 %

Procedure:
A solution of 5-[[2-(amino)ethyl]thio]methyl-2-(dimethylaminomethyl)-3-furancarboxylic acid, ethyl ester (0.75 g) in dry tetrahydrofuran (50 ml) at 0° was treated with a 0.5 molar solution of aluminium hydride in tetrahydrofuran (35 ml). After 2 hours water (6 ml) was added, and the filtered solution evaporated in vacuo. The oily residue was distilled affording the title compound (0.4 g), b.p. 170°/10-1 mm Hg.
Reaction SMILES: C(Cl)(C)(C)C.[Li].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1.FC1C=CC=C(F)C=1[Li].[C:24](OC(=O)C)(=[O:26])[CH3:25]>C1COCC1>[CH3:25][C:24]([C:9]1[C:8]([F:7])=[CH:13][CH:12]=[CH:11][C:10]=1[F:14])=[O:26]
Reactant: CC(=O)OC(C)=O
Reactant: Fc1cccc(F)c1
Agent: [Li]
Agent: [Li]c1c(F)cccc1F
Solvent: CC(C)(C)Cl
Solvent: C1CCOC1
Product: CC(=O)c1c(F)cccc1F
Temperature: -65 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution of tert-butyllithium in THF is firstly produced by reacting 9.25 g of tert-butyl chloride with 1.4 g of lithium granules in 100 g of THF at −78° C. After a conversion of >97% (GC a/a) has been reached, 1,3-difluorobenzene (11.4 g) is added and the mixture is stirred for another 30 minutes at −78° C. and subsequently for 2 hours at −65° C. The resulting solution of 2,6-difluoro-1-lithiobenzene is added dropwise to a solution of 22 g of acetic anhydride in 35 g of THF which has been cooled to −5° C. After the usual aqueous work-up, 2,6-difluoroacetophenone is obtained in a yield of 92%.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Br.Br[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1>>[CH3:23][N:20]1[CH2:21][CH2:22][CH:17]([CH2:16][N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=3)[N:3]=[CH:2]2)[CH2:18][CH2:19]1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Reactant: CN1CCC(CBr)CC1
Agent: Br
Product: CN1CCC(Cn2cnc(-c3cc(C#N)ccn3)c2)CC1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-bromomethyl-1-methylpiperidine hydrogen bromide according to the procedure for the preparation of Example 43, part A (heating to 120°). [M+H] Calc'd for C16H19N5, 282. Found, 282.
Reaction SMILES: Cl.Cl[CH2:3][C:4]([O:6][C:7]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:5].[Na].[F:21][C:22]([F:44])([F:43])[C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[C:28]2[NH:33][C:34]1[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:36]([OH:38])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:43][C:22]([F:21])([F:44])[C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[C:28]2[NH:33][C:34]1[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:36]([O:38][CH2:3][C:4]([O:6][C:7]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:5])=[O:37]
Reactant: CN1CCC(OC(=O)CCl)(c2ccccc2)CC1
Reactant: O=C(O)c1ccccc1Nc1ccnc2c(C(F)(F)F)cccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCC(OC(=O)COC(=O)c2ccccc2Nc2ccnc3c(C(F)(F)F)cccc23)(c2ccccc2)CC1
Reaction time: 48 h

Procedure:
A mixture of 1.52 g of N-methyl-4-phenyl-4-piperidyl chloroacetate hydrochloride, 1.77 g of the sodium salt of N-(8-trifluoromethyl-4-quinolyl)-anthranilic acid and 0.7 g of potassium carbonate in 10 ml of dimethylformamide was stirred for 48 hours at 20°-25° C. Upon completion of the reaction, the inorganic salts were filtered off. The solution was evaporated to dryness and treated with water, and the solid collected by filtration. This solid was then refluxed with hexane, filtered and recrystallized from hexane to provide the title compound. M.p. 144°-145° C., yield 1 g (35%).
Reaction SMILES: ClCl.[N+:3]([C:6]([N+:23]([O-:25])=[O:24])([CH2:9][O:10][CH2:11][O:12][CH2:13][C:14]([N+:20]([O-:22])=[O:21])([N+:17]([O-:19])=[O:18])[CH2:15][OH:16])[CH2:7][OH:8])([O-:5])=[O:4].ClC(SS[C:32]([O:53][CH2:54][C:55]([F:62])([N+:59]([O-:61])=[O:60])[N+:56]([O-:58])=[O:57])([O:43][CH2:44][C:45]([N+:50]([O-:52])=[O:51])([N+:47]([O-:49])=[O:48])[F:46])[O:33][CH2:34][C:35]([N+:40]([O-:42])=[O:41])([N+:37]([O-:39])=[O:38])[F:36])(Cl)Cl>ClCCCl>[F:36][C:35]([N+:37]([O-:39])=[O:38])([N+:40]([O-:42])=[O:41])[CH2:34][O:33][C:32]([O:53][CH2:54][C:55]([N+:56]([O-:58])=[O:57])([N+:59]([O-:61])=[O:60])[F:62])([O:43][CH2:44][C:45]([N+:47]([O-:49])=[O:48])([N+:50]([O-:52])=[O:51])[F:46])[O:16][CH2:15][C:14]([N+:17]([O-:19])=[O:18])([N+:20]([O-:22])=[O:21])[CH2:13][O:12][CH2:11][O:10][CH2:9][C:6]([N+:23]([O-:25])=[O:24])([N+:3]([O-:5])=[O:4])[CH2:7][OH:8]
Reactant: O=[N+]([O-])C(CO)(COCOCC(CO)([N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-]
Reactant: O=[N+]([O-])C(F)(COC(OCC(F)([N+](=O)[O-])[N+](=O)[O-])(OCC(F)([N+](=O)[O-])[N+](=O)[O-])SSC(Cl)(Cl)Cl)[N+](=O)[O-]
Agent: ClCl
Solvent: ClCCCl
Product: O=[N+]([O-])C(F)(COC(OCC(F)([N+](=O)[O-])[N+](=O)[O-])(OCC(F)([N+](=O)[O-])[N+](=O)[O-])OCC(COCOCC(CO)([N+](=O)[O-])[N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 22 h

Procedure:
Chlorine gas was passed into a solution of 3.78 g (0.011 mol) of 2,2,8,8-tetranitro-4,6-dioxanonane-1,9-diol and 6.53 g (0.01 mol) of tris(2-fluoro-2,2-dinitroethoxy)methyl trichloromethyl disulfide in 20 ml of dry 1,2-dichloroethane at 65° C. for two hours. Heating at 65° C. was continued for 22 hours at which time the solvent was removed and the oily residue was washed with 2×30 ml of hexane. Thin layer chromatography indicated the product was a mixture of the mono-(XI) and the bis-orthocarbonate (XII). The mono-orthocarbonate (XI) was isolated by column chromatography (silica gel 60, methylene chloride-ethyl acetate (90:10) as eluent) as a viscous gummy oil; H-NMR [(CD3)2C=O]: δ 5.20 (d), 4.96 (s), 4.83 (s), 4.68 (s), 4.58 (s), 4.54 (s). IR (film on NaCl plate) 3600 (OH), 1600 (NO2) cm-1.