Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])[CH2:18][CH2:17]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N+:34]([O-:36])=[O:35])[CH2:20][CH2:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccccc1OCCCCCN1CCC(O)CC1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: O=[N+]([O-])c1ccccc1OCCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1

Procedure:
The procedure of Example 1 (a) was repeated except for using diphenylmethyl bromide and 4-hydroxy-1-[5-(2-nitrophenoxy)pentyl]piperidine instead of diphenylmethyl bromide and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-diphenylmethoxy-1-[5-(2-nitrophenoxy)pentyl]piperidine.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([O:18][C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH3:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:37]([O:41][C:42](=[O:46])[CH2:43][CH2:44][NH2:45])(C)(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([O:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH:45][CH2:44][CH2:43][C:42]([O:41][CH3:37])=[O:46])=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH3:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCC(Oc1ccc(C(=O)O)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: CC(C)(C)OC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(Oc1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a mixture of 4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-propoxy}-benzoic acid (345 mg, 0.86 mmol) in methylene chloride (10 mL) are added triethyl amine (0.36 mL, 2.58 mmol), DMAP (5.0 mg), 3-amino-propionic acid tert-butyl ester (468.2 mg, 2.58 mmol) and EDCI (495.6 mg, 2.58 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving methyl 3-(4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-propoxy}-benzoylamino)-propionoate (400 mg).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:27]=[CH:26][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:34][CH2:35][CH2:36]I>CN(C)C=O.O.C(Cl)Cl>[F:34][CH2:35][CH2:36][N:1]1[CH2:4][CH:3]([C:5]2[CH:27]=[CH:26][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1
Reactant: FCCI
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CNC4)ccc2-3)n(C(C)C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CN(CCF)C4)ccc2-3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8-azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene, from Example 519, (0.300 g, 0.000786 mol) and cesium carbonate (0.384 g, 0.00118 mol) in N,N-dimethylformamide (7.9 mL) was added 2-fluoro-1-iodoethane (0.137 g, 0.000786 mol) dropwise. The reaction was stirred at room temperature overnight. The mixture was diluted with water and methylene chloride and extracted 3 times with methylene chloride. The crude was purified by column chromatography then reverse-phase HPLC to obtain 521 as a white solid (84.0 mg). m+1 428.1 MS(ESI+) 428.1. 1H NMR (400 MHz, DMSO) δ 8.29 (d, J=8.2 Hz, 1H), 7.20 (dd, J=8.2, 1.3 Hz, 1H), 7.04 (d, J=1.1 Hz, 1H), 5.84-5.66 (m, 1H), 4.48 (t, J=4.9 Hz, 1H), 4.40-4.32 (m, 3H), 3.70-3.56 (m, 3H), 3.42 (t, J=5.0 Hz, 2H), 3.20-3.14 (m, 2H), 2.73 (dt, J=28.8, 4.9 Hz, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6 Hz, 6H)
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[CH2:3][CH2:4][NH:5]C(=O)OC(C)(C)C.[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20]>C(Cl)Cl>[F:22][C:21]([F:24])([F:23])[C:19]([OH:25])=[O:20].[CH3:1][N:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[CH2:3][CH2:4][NH2:5]
Reactant: CN(CCNC(=O)OC(C)(C)C)c1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCN)c1ccccn1

Procedure:
tert-Butyl 2-[methyl(pyridin-2-yl)amino]ethylcarbamate was stirred with DCM (0.5 ml) and TFA (0.5 ml) for 30 min. The volatiles were removed under reduced pressure to yield the product.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:18]([OH:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.CN(NC1SC=C(C2OC([N+]([O-])=O)=CC=2)N=1)C>>[CH3:3][CH2:4]/[C:5](=[C:14](/[CH2:13][CH3:12])\[C:15]1[CH:16]=[CH:17][C:18]([OH:19])=[CH:1][CH:2]=1)/[C:6]1[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][CH:11]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: CN(C)Nc1nc(-c2ccc([N+](=O)[O-])o2)cs1
Product: CC/C(=C(/CC)c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
[6,73H] estradiol (40-60) Ci/mmol) ([3H]E2), 7α, 17 α-dimethyl [17α-methyl 3H]-19-nortestosterone (70-85 Ci/mmol) ([3H] DMNT) 16 α-ethyl-21-hydroxy-19-nor [6,73 H]-pregn-4-ene-3,20-dione (40-60 Ci/mmol) (3H! ORG 2058), [3 H]-triamcinolone acetonide (20-40 Ci/mmol) (3H!TA), unlabeled DMNT, and ORG 2058 were obtained from Amersham, Arlington Heights, Ill. Unlabeled TA was obtained from Sigma Chemical Co., St. Louis, Mo., unlabeled diethylstilbestrol (DES) and E2 were obtained from Steroids, Wilton, N.H. All other chemicals were reagent grade and were obtained from commercial sources.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]2[N:11]3[CH2:15][CH2:16][NH:17][C:18](=[O:19])[C:10]3=[CH:9][C:8]=2[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(=O)(O)[O-].[Na+]>CC(=O)CC>[N:28]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]3[N:11]4[CH2:15][CH2:16][NH:17][C:18](=[O:19])[C:10]4=[CH:9][C:8]=3[CH:7]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C1CCNCC1
Reactant: O=C1NCCn2c1cc1cc(OCCCCl)ccc12
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCC(C)=O
Product: O=C1NCCn2c1cc1cc(OCCCN3CCCCC3)ccc12
Temperature: 25 °C
Yield: 37.8 %

Procedure:
The suspension consistent of 0.27 g (0.97 mmol) 8-(3-chloro-propoxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 0.16 g (1.2 mmol) potassium carbonate, 0.16 g (0.97 mmol) potassium iodide and 0.12 ml (99 μg, 1.2 mmol) piperidine (commercially available) in 10 mL 2-butanone was heated under reflux for 19 hours. After cooling down to room temperature the reaction mixture was poured on saturated aqueous sodium bicarbonate solution water and was extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was flash-chromatographed on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) as eluant to give 0.12 g (39%) of the desired compound as a colorless solid.
Reaction SMILES: [C:1]1([O:7][P:8]([O:17][CH2:18][CH2:19][CH:20]([NH:24]C(=O)C[C@H](OCC2C=CC=CC=2)CCCCCCCCCCC)[C:21]([OH:23])=[O:22])([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:48]([O:61][C@H:62]([CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH3:77])[CH2:63][C:64]([OH:66])=O)(=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59].C(O[C@H](CCCCCCCCCCC)CC(O)=O)C1C=CC=CC=1>>[C:1]1([O:7][P:8]([O:17][CH2:18][CH2:19][CH:20]([NH:24][C:64](=[O:66])[CH2:63][C@H:62]([O:61][C:48](=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH3:77])[C:21]([OH:23])=[O:22])([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCCCCC[C@H](CC(=O)NC(CCOP(=O)(Oc1ccccc1)Oc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O
Agent: CCCCCCCCCCC[C@H](CC(=O)O)OCc1ccccc1
Product: CCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)NC(CCOP(=O)(Oc1ccccc1)Oc1ccccc1)C(=O)O

Procedure:
The 4-(diphenyloxyphosphoryloxy)-2-[(R)-3-benzyloxytetradecanoylamino]-butanoic acid can be prepared using the same reaction scheme by replacing in step 5 of example I, (R)-3-dodecanoyloxytetradecanoic acid by (R)-3-benzyloxytetradecanoic acid.
Reaction SMILES: [CH:1]1([C:4](=[O:16])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][N:9]=2)=[O:7])[CH2:3][CH2:2]1.CC(C)C(O)=O.[CH3:23][N:24]([CH3:27])[CH:25]=O>O1CCOCC1>[CH:1]1([C:4](=[O:16])[C:5](=[CH:23][N:24]([CH3:27])[CH3:25])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][N:9]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: CSc1ccc(C(=O)CC(=O)C2CC2)nc1
Solvent: C1COCCO1
Solvent: CC(C)C(=O)O
Product: CSc1ccc(C(=O)C(=CN(C)C)C(=O)C2CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-cyclopropyl- 1-[5-(methylsulphenyl )-pyrid-2-yl]propan- 1,3-dione (2.9 g), dimethylformamide dimethyl acetate and dioxane was stirred at room temperature overnight. It was evaporated to dryness and the residue was triturated with ether and filtered to give 3-cyclopropyl-2-(N,N-dimethylaminomethylene)-1-[5-(methylsulphenyl)-pyrid-2-yl]propan- 1,3-dione (3.24 g) as a brown solid which was used without further characterization.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18][CH2:19][CH2:20][NH2:21]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:21][CH2:20][CH2:19][CH2:18][O:17][CH3:16])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Reactant: COCCCN
Product: COCCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Yield: 94.2 %

Procedure:
7-Bromo-4-chloro-3-nitroquinoline (29.54 g, 102.7 mmol) was reacted with 3-methoxy propyl amine (10.07 g, 113.0 mmol) according to the method described in Part A of Examples 125-135 to provide 32.9 g of (7-bromo-3-nitroquinolin-4-yl)-(3-methoxypropyl)amine as a yellow solid. The product was not recrystallized.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:48]([CH3:49])=[CH:47][C:39]([CH2:40][CH2:41][NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:49][C:48]1[CH:47]=[C:39]([CH2:40][CH2:41][NH:42][S:43]([CH3:46])(=[O:44])=[O:45])[CH:38]=[C:37]([CH3:50])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(CCNS(C)(=O)=O)cc(C)c1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(CCNS(C)(=O)=O)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and N-(4-bromo-3,5-dimethylphenethyl)methanesulfonamide following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.58 min; Mass spectrum (ESI+): m/z=568 [M+H]+.
Reaction SMILES: C([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[O:16][CH:17]=2)[CH2:6]1)(=O)C.C(OC1CCCC(O)C1)C1C=CC=CC=1.C(OC(=O)C)(=O)C.C(OC1CCCC(OCC2C=CC=CC=2)C1)(=O)CCCC([O-])=O>P([O-])([O-])([O-])=O.COCCOC>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:15]2[O:16][CH:17]=[C:13]([CH2:12][O:11][C@H:7]3[CH2:8][CH2:9][CH2:10][C@@H:5]([OH:4])[CH2:6]3)[N:14]=2)=[CH:23][CH:22]=1
Reactant: CC(=O)OC1CCCC(OCc2coc(-c3ccc(F)cc3)n2)C1
Agent: O=C([O-])CCCC(=O)OC1CCCC(OCc2ccccc2)C1
Agent: O=P([O-])([O-])[O-]
Agent: OC1CCCC(OCc2ccccc2)C1
Solvent: COCCOC
Solvent: CC(=O)OC(C)=O
Product: O[C@@H]1CCC[C@H](OCc2coc(-c3ccc(F)cc3)n2)C1

Procedure:
Approx. 10 mg of 3-[2-(4-fluorophenyl)oxazol-4-ylmethoxyl]cyclohexyl acetate (prepared by reacting 3-benzyloxycyclohexan-1-ol with acetic anhydride, in a similar manner to the synthesis of mono(3-benzyloxycyclohexyl) glutarate see Example 39) were taken up in 2 ml of phosphate buffer (0.1 M, pH=7.0) and 2 ml of DME and stirred with approx. 5 mg of Chirazyme L-2, lyo., at 20–23° C. for approx. 20–24 h. The reaction mixture was extracted with dichloromethane. The organic phase was admixed with toluene and concentrated by evaporation under reduced pressure. The determination of the optical purity for (1R,3S)-3-[2-(4-fluorophenyl)oxazol4-ylmethoxy]cyclohexan-1-ol gave 99.4% ee (HPLC on Chiralpak AD 250×4.6; 1 ml/min, acetonitrile) and 98.9% ee for the (1S,3R)-acetate (HPLC on Chiralcel OD 250×4.6; 1 ml/min, 110:5:1 heptane/EtOH/CH3CN+0.1% TFA).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]#[N:15])=[CH:5][CH:4]=1.N.[H][H]>C(O)C.[Ni]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH2:15])=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc2cccc(CC#N)c2c1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COc1ccc2cccc(CCN)c2c1

Procedure:
A solution of (7-methoxynaphth-1-yl)acetonitrile in ethanol saturated with ammonia is placed in an autoclave. Raney nickel and hydrogen are added under 300 atmospheres.
Reaction SMILES: Cl[Si:2]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.[CH:12]([Mg]Br)=[CH2:13]>C1COCC1>[C:6]1([Si:2]2([CH:12]=[CH2:13])[CH2:5][CH2:4][CH2:3]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=C[Mg]Br
Reactant: Cl[Si]1(c2ccccc2)CCC1
Solvent: C1CCOC1
Product: C=C[Si]1(c2ccccc2)CCC1
Yield: 70 %

Procedure:
A dry 250 ml three neck round bottom flask equipped with a dropping funnel and condenser with nitrogen inlet system. Was placed 4.2 g (23 mmole) 1-chloro-1-phenyl-1-silacyclobutane in 40 ml THF. With stirring, 25 ml (0.1M) vinyl magnesium bromide (in THF) was added dropwise. The mixture was stirred for additional 6 h. Work up, the mixture was distilled to collect 2.8 g 82°-83° C./3.0 mmHg 70% yield was obtained.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[NH2:13][C@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1>>[C@H:14]1([NH:13][C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[I:1])[N:7]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: N[C@@H]1CCc2ccccc21
Product: Ic1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12

Procedure:
5-Iodo-2-chloroquinoline (CAS 455955-26-7, 5.0 g, 17 mmol) and (R)-1-aminoindane (4.75 g, 35 mmol) were stirred in a sealed tube at 120° C. for 2 days. The reaction mixture was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0→80:20 gradient). (R)-Indan-1-yl-(5-iodo-quinolin-2-yl)-amine was obtained as a brown solid (4.30 g, 64%), MS: m/e=387.3 (M+H|).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH2:13][CH:14]3[CH2:16][CH2:15]3)[C:11]([CH3:17])=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][O:19][CH2:20][CH2:21][N:22]([C:33]([CH3:36])([CH3:35])[CH3:34])[S:23]([C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1)(=[O:25])=[O:24].C(O)(=O)C>O>[CH:14]1([CH2:13][N:12]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:29]4[CH:28]=[CH:27][C:26]([S:23](=[O:24])(=[O:25])[N:22]([CH2:21][CH2:20][O:19][CH3:18])[C:33]([CH3:36])([CH3:34])[CH3:35])=[CH:31][CH:30]=4)[N:7]=3)=[CH:9][N:10]=[C:11]2[CH3:17])[CH2:15][CH2:16]1
Reactant: COCCN(C(C)(C)C)S(=O)(=O)c1ccc(I)cc1
Reactant: Cc1ncc(-c2ccnc(N)n2)n1CC1CC1
Solvent: O
Solvent: CC(=O)O
Product: COCCN(C(C)(C)C)S(=O)(=O)c1ccc(Nc2nccc(-c3cnc(C)n3CC3CC3)n2)cc1
Yield: 32.2 %

Procedure:
2-Amino-4-(1-cyclopropylmethyl-2-methylimidazol-5-yl)pyrimidine (Method 54; 2 g, 8.73 mmol) was treated with N-(2-methoxyethyl)-N-(t-butyl)-4-iodobenzenesulphonamide (Method 77; 3.82 g, 9.61 mmol) under the conditions described in Example 22. The reaction was quenched by the addition of acetic acid (250 μl, 4.37 mmol), the mixture was poured into water and extracted with EtOAc. The extracts were combined, washed with water and then brine, dried and the solvent removed by evaporation. The residue was purified by chromatography on silica gel eluting with DCM/MeOH (97:3) to give the title compound (1.4 g, 32%) as a pale yellow foam. NMR: 0.01 (m, 2H) 0.18 (m, 2H) 1.90 (m, H) 2.26 (s, 3H) 3.15 (s, 3H) 3.37 (m, 4H) 4.42 (d, 2H) 7.08 (d, H) 7.52 (s, H) 7.58 (d, 2H) 7.75 (d, 2H) 8.30 (d, H) 9.75 (s, H); m/z 499.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C([Li])CCC.[C:15](#[N:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[O:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:15](=[NH:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][CH2:6]1
Reactant: NCCN1CCOCC1
Reactant: N#Cc1ccccc1
Agent: [Li]CCCC
Solvent: O
Product: N=C(NCCN1CCOCC1)c1ccccc1
Reaction time: 1 h
Yield: 70 %

Procedure:
Procedure as described for Amidine I using the following amounts and modifications: 6.6 mL of 4-(2-aminoethyl) morpholine (50.0 mmol); 25.0 mL of 2.0 M butyllithium (50.0 mmol), 5.20 mL of benzonitrile (51.0 mmol). After refluxing overnight, the solution was green-brown. Addition of water yielded a light brown solution with suspended solid. Solution was filtered, taken to dryness, resuspended in 100 mL of pentane and stirred vigorously for 1 hour. A white solid deposited, which was filtered, washed with 10 mL of pentane and dried in vacuo yielding 8.17 g (70%) of white powder. NMR (400 MHz, CDCl3): 7.57 (br, 2H), 7.43 (m, 3H), 6.4 (br, 1H), 5.3 (br, 1H), 3.71 (m, 4H), 3.47 (br, 2H), 2.65 (m, 2H), 2.51 (br, 4H).
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16].Cl[CH2:20][CH2:21][F:22]>CO>[F:22][CH2:21][CH2:20][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16]
Reactant: FCCCl
Reactant: NS(=O)(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: CO
Product: NS(=O)(=O)c1ccccc1SCCF
Reaction time: 23 h
Yield: 74.5 %

Procedure:
A mixture of 5.8 g of the 2-mercaptophenylsulfonamide triethylamine salt obtained in accordance with Example H6 and 1.7 g of 2-chloro-1-fluoroethane in 40 ml of methanol is stirred in a bomb tube for 23 hours at a temperature of +50° to +55° C. The reaction mixture is then evaporated and water is added to the residue which remains. The mixture is extracted with ethyl acetate, and the organic phase is washed and dried. Evaporation of the solution gives 3.5 g of 2-(2-fluoroethylthio)-phenylsulfonamide (74.5% of theory) having a melting point of +83° to +85° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[O:10][CH2:9][CH2:8][O:7]2)=[CH:2]1.[CH2:11]([Sn:15](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>CCOCC.C([Li])CCC.O1CCCC1>[CH2:20]([Sn:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:16][CH2:17][CH2:18][CH3:19])[C:2]1[S:1][CH:5]=[CH:4][C:3]=1[CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[CH2:21][CH2:22][CH3:23]
Reactant: c1cc(C2OCCO2)cs1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1sccc1C1OCCO1
Temperature: -78 °C

Procedure:
To a stirred solution of 15.6 g (0.10 mol) of 2-(3-thienyl)-1,3-dioxolane in 100 ml of anhydrous ether, n-butyl-lithium (1.48N, in hexane, 74.3 ml) is added dropwise under nitrogen at room temperature. After being refluxed for 15 minutes, the reaction mixture is cooled to -78° C. and tri-n-butyltin chloride (34.18 g, 0.105 mol) in 100 ml of dry tetrahydrofuran is added dropwise. After the addition is complete, the mixture is warmed to room temperature and the solvent evaporated. To the oily residue 100 ml of hexane is added, and the resulting precipitate (LiCl) is filtered off. The filtrate is evaporated and the residue distilled at reduced pressure, given 34.16 g (77%) of the desired product.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[N:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27][CH:26]=1>>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:29]4[CH:30]=[N:25][CH:26]=[N:27][CH:28]=4)[N:3]=[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:5]=3[CH:10]=2)[CH2:13][CH2:14]1
Reactant: CN1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: OB(O)c1cncnc1
Product: CN1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cncnc4)nc3s2)CC1

Procedure:
2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine was reacted with pyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 169. NMR (CDCl3): 2.30 (3H, s, Me), 2.48-2.64 (8H, m, CH2), 3.71 (2H, s, CH2), 3.88-3.93 (4H, m, CH2), 3.98-4.03 (4H, m, CH2), 7.15 (1H, s, Ar), 9.21 (1H, s, Ar) and 9.62 (2H, s, Ar). MS: (ESI+): MH+ 412.33
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][C:8]1=O.C(=O)([O-])[O-].[Na+].[Na+].O>C(Cl)Cl>[C:1]([N:10]1[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: CN1CCNCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acryloyl chloride (90.5 g) in methylene chloride (100 ml) was added into a methylene chloride (500 ml) solution of N-methyl piperazone (100 g) over a period of one hour. The reaction temperature was kept below 25° C. with cooling. After the addition was completed, the reaction mixture was stirred at ambient temperature for two hours. Then, sodium carbonate (53 g) in 250 ml. of water was added into the reaction mixture with stirring. A crude product (76 g) of 1-acryloyl-4-methyl piperazine was recovered from the methylene chloride solution. The product was distilled and the fraction collected at 65°-69° C./1.5 mm Hg was characterized by I.R. and C13 NMR and was found to be 97% pure by G. C.
Reaction SMILES: [CH:1]1[C:12]2=[C:13]3[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7][CH2:6][CH2:5][C:4]3=[CH:3][C:2]=1[NH:14][C:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=1)=[O:16].[OH-].[Na+].Cl>C(O)C>[CH:3]1[C:4]2=[C:13]3[CH:8]([CH2:7][CH2:6][CH2:5]2)[CH2:9][CH2:10][CH2:11][C:12]3=[CH:1][C:2]=1[NH:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=1)=[O:16]
Reactant: COC(=O)c1ccc(C(=O)Nc2cc3c4c(c2)CCCC4CCC3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(C(=O)Nc2cc3c4c(c2)CCCC4CCC3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
A suspension of methyl 4-[(5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)carbamoyl]benzoate (0.093 g) in ethanol (10 ml) was added with 2 N aqueous sodium hydroxide (3 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was made acidic with 2 N aqueous hydrochloric acid, and extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from ethyl acetate-n-hexane to obtain the title compound (0.080 g, yield: 90%) as colorless prisms (melting point: 283-284° C.).