Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH3:8].[S:9]1(=[O:20])(=[O:19])[C:14]2[N:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][CH:11]=[N:10]1>C(#N)C>[CH3:8][N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[S:9](=[O:20])(=[O:19])[N:10]=[CH:11]1
Reactant: O=S1(=O)N=CNc2cccnc21
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1C=NS(=O)(=O)c2ncccc21
Temperature: 50 °C

Procedure:
1.2 g of potassium carbonate and 1.37 g of iodomethane are added to a solution of 0.6 g of 4H- pyrido[3,2-e][1,2,4]thiadiazine 1,1-dioxide (Example 16) in 15 cm3 of acetonitrile. The suspension is heated at 50° C. for 3 hours. The acetonitrile is then removed by evaporation under partial vacuum. The residue is taken up in 20 cm3 of water. The title product, which has little solubility in water, is collected on a filter, washed with water and dried.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])=[CH:28][CH:29]=1
Reactant: COc1ccc(Br)cc1
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1ccc(C(=O)c2cn(-c3cccc(-c4ccccc4OC)c3)cn2)cc1

Procedure:
This compound is prepared by method C using compound 12c and 4-bromoanisole
Reaction SMILES: [O:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[OH:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>>[O:1]([C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([N:20]3[CH2:21][CH2:22][CH:17]([OH:16])[CH2:18][CH2:19]3)=[CH:24][CH:25]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([N:20]3[CH2:21][CH2:22][CH:17]([OH:16])[CH2:18][CH2:19]3)=[CH:31][CH:30]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Reactant: Nc1ccc(Oc2ccc(N)cc2)cc1
Product: O=C(Nc1ccc(Oc2ccc(NC(=O)c3ccc(N4CCC(O)CC4)cc3)cc2)cc1)c1ccc(N2CCC(O)CC2)cc1

Procedure:
Compound 914 was prepared according to the procedure described in Scheme IV from 4,4′-oxydianiline and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C36H38N4O5: 607.28; found 607.21.
Reaction SMILES: [C:1]1([OH:14])[C:2]([C:7]2[C:8]([OH:13])=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1.[P:15](Cl)(Cl)[Cl:16]>>[P:15]1([Cl:16])[O:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[O:14]1
Reactant: ClP(Cl)Cl
Reactant: Oc1ccccc1-c1ccccc1O
Product: Clp1oc2ccccc2c2ccccc2o1
Yield: 81 %

Procedure:
A solution of 2,2′-biphenol (28.1 g, 0.151 mol) in 49 mL phosphorus trichloride was heated at reflux for 2 hours. The excess PCl3 was removed by distillation. The residue was purified by vacuum distillation (140-143° C. at 0.5 mm Hg) to give 30.70 g (81% yield) 1,1′-biphenyl-2,2′-diyl phosphorochloridite (as a clear viscous oil which solidified to a white solid upon standing at room temperature in an inert atmosphere for an extended period of time). 31P{1H}NMR (121.4 MHz, d8-toluene): δ 180.1 (s), 85% H3PO4 external reference. To a solution containing 1.018 g (2.84 mmoles) of 2,2′-dihydroxy-3,3′-di-t-butyl-5,5′-dimethoxy-1,1′-biphenyl and 0.575 g (5.68 mmoles) of NEt3 in 15 ml of tetrahydrofuran (THF) was added 1.412 g (5.68 mmoles) of 1,1′-biphenyl-2,2′-diyl phosphorochloridite in 5 ml of THF. The mixture was stirred overnight at room temperature. The mixture was filtered through celite, washed with THF and solvent removed to give 2.2 g of white solid. 31P{1H} nmr (121.4 MHz, C6D6): 145.15 s and 138.5 s. 1H nmr (300 MHz, C6D6): singlet at 3.15 and 1.3 along with aromatic resonances.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([C:12]#[N:13])=[C:7]([O:14][CH2:15][CH3:16])[N:6]=1)=O.[NH3:17]>CO>[NH2:11][C:9]1[C:8]([C:12]#[N:13])=[C:7]([O:14][CH2:15][CH3:16])[N:6]=[C:5]([C:3]([NH2:17])=[O:2])[CH:10]=1
Reactant: N
Reactant: CCOc1nc(C(=O)OC)cc(N)c1C#N
Solvent: CO
Product: CCOc1nc(C(N)=O)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 231 mg (1.00 mmol) of 4-amino-5-cyano-6-ethoxy-pyridine-2-carboxylic acid methyl ester from Example 104A was added 5 mL of 7 M NH3 in methanol. The reaction was stirred at ambient temperature for 5 h, and concentrated in vacuo to 214 mg (100%) of the titled compound as a solid.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:23][C:24]1[C:25]([O:34][C:35]2[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=2)=[N:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1.[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:40]=[C:39]([C:38]2[CH:37]=[CH:36][C:35]([O:34][C:25]3[C:24]([Cl:23])=[CH:29][C:28]([C:30]([F:33])([F:31])[F:32])=[CH:27][N:26]=3)=[CH:42][CH:41]=2)[N:2]([CH3:1])[N:3]=1
Reactant: N#Cc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
A mixture of 1.30 g of N-methyl-N-phenylsulfonyl-2-chloro-6-fluorobenzohydrazonoyl chloride, 1.00 g of 4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)benzonitrile, 0.50 g of anhydrous aluminum chloride and 3 ml of o-dichlorobenzene was stirred in an oil bath at a temperature of 140° C. for 30 minutes. After the cooling, the resulting solution was dissolved in 100 ml of chloroform, washed with diluted hydrochloric acid solution, diluted sodium hydroxide solution and saline water in this order, dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The resulting concentrate was purified through a chromatography of silica gel column using a mixed solution of hexane and ethyl acetate as a developing solvent to obtain 0.70 g of the given compound (measurement of nD20 was impossible). NMR data (60 MHz, CDCl3 solvent, δ value)
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[S:10][C:11]=2[C:12](O)=[O:13])=[CH:4][CH:3]=1.C1C=[CH:25][C:26]2N(O)N=[N:29][C:27]=2C=1.CCN=C=NCCCN(C)C.C(N)C=C>C(Cl)Cl>[CH2:27]([NH:29][C:12]([C:11]1[S:10][C:9]([C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[N:8][C:7]=1[CH2:6][C:5]1[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:13])[CH:26]=[CH2:25]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: C=CCN
Product: C=CCNC(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a stirred solution of 4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboxylic acid (220 mg, 0.665 mmol) in DCM (4.05 mL) was added HOBT (98.8 mg, 0.732 mmol) and EDCI (204 mg, 1.06 mmol) at room temperature and the mixture was stirred for 30 min. To the solution was added 2-propen-1-amine (0.200 mL, 2.66 mmol) then the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (10 mL) and washed with water (3 mL) and brine (2 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=0/100→75/25) to give 150 mg of the title compound as a yellow solid (61% yield). LC/MS (FA) ES+ 370. 1H NMR (400 MHz, CDCl3) δ: 8.74-8.72 (m, 2H), 7.79-7.77 (m, 2H), 7.35-7.32 (m, 2H), 7.27-7.25 (m, 2H), 5.94-5.80 (m+bs, 2H), 5.25-5.20 (m, 2H), 4.48 (s, 2H), 4.06-4.02 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13](Cl)=[O:14].[CH3:16][O:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1.C(N(CC)CC)C.Cl>ClCCl>[CH3:16][O:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:13]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1])=[O:14]
Reactant: COC[C@@H]1CCCN1
Reactant: COc1ccc2ccccc2c1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@@H]1CCCN1C(=O)c1c(OC)ccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methoxy-naphthalene-1-carbonyl chloride (0.50 g, 2.27 mmol) in dry dichloromethane (5 mL) at 0° C. under a N2 atmosphere was added 2-(S)-methoxymethylpyrrolidine (0.32 g, 2.75 mmol) and triethylamine (0.47 mL, 3.39 mmol). The mixture was allowed to warm to rt and stirred overnight, after which time it was poured into N HCl (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were dried over Na2SO4, and the crude product was purified by column chromatography on silica gel using a solvent gradient of 10-30% ethyl acetate in hexane. The title compound was obtained as a colorless solid (0.374 g, 55%). 1H NMR (300 MHz, CDCl3) δ 1.90 (m, 6 H), 2.99 (m, 1 H), 3.21 (m, 1 H), 3.48 (m, 3 H), 3.95 (m, 3 H), 4.59 (m, 1 H), 7.29 (m, 1 H), 7.37 (m, 1 H), 7.48 (m, 1 H), 7.76 (m, 3 H); MS (ESI) m/z=300 [M+H].
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH2:22]1[C@@H:26]2[CH2:27][NH:28][CH2:29][C@@H:25]2[CH2:24][O:23]1>>[CH2:22]1[C@@H:26]2[CH2:27][N:28]([C:12]([C:10]3[CH:9]=[CH:8][C:7]([N:15]4[CH2:18][C:17]([F:20])([F:19])[CH2:16]4)=[C:6]([O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[N:11]=3)=[O:14])[CH2:29][C@@H:25]2[CH2:24][O:23]1
Reactant: C1NC[C@H]2COC[C@@H]12
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Cl
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1C[C@H]2COC[C@H]2C1
Yield: 54.7 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 30 mg, 106 μmol) was reacted with (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride (CAN 57710-36-8, 15.8 mg, 106 μmol) to obtain the title compound (22 mg, 55%) as white solid, MS (EI): m/e=380.3 [MH+].
Reaction SMILES: [CH2:1]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:12]N1C(=O)CCC1=O.O.CCCCCC>CN(C)C=O>[Br:12][C:8]1[S:9][CH:10]=[CH:11][C:7]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccsc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCCCCc1ccsc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.4 %

Procedure:
60 g of 3-n-hexylthiophene was dissolved in 400 ml of dimethylformamide, and to this, 50 g of N-bromosuccinimide was added. The resulting solution was stirred at room temperature for 4 hours under a nitrogen atmosphere. 200 ml of water and 200 ml of hexane were added to the resulting solution to separate the organic layer. The organic layer was washed with 200 ml of water and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure with a rotary evaporator to obtain 60 g of 2-bromo-3-n-hexylthiophene.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH2:31]([NH:35][CH2:36][CH3:37])[CH2:32][CH2:33][CH3:34]>>[CH2:31]([N:35]([CH2:36][CH3:37])[C:26]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:25])[CH2:32][CH2:33][CH3:34]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: CCCCNCC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Product: CCCCN(CC)C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and butyl-ethyl-amine. The reaction mixture was stirred for 1 h at room temperature, 2 h at 50° C. and 1 h at 80° C. before subjecting to work-up and purification. MS (ESI): 442.4 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[C:10]([C:20]2[O:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:24]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CO.C1COCC1.O>[NH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[N:9]=[C:10]2[C:20]1[O:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccc([N+](=O)[O-])cc23)o1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccc(N)cc23)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.9 g (2.4 mmol) of 1-benzyl-3-(5-methoxycarbonyl-2-furyl)-5-nitroindazole were dissolved in 100 ml of methanol/THF (1:1) by gentle warming, a solution of 2.5 g (14.4 mmol) of sodium dithionite in 50 ml of water was added and the mixture was stirred at RT for 16 h. For work-up, the mixture was concentrated and the residue was chromatographed over silica gel using dichloromethane/methanol (98.5:1.5). This gave 140 mg (17%) of the title compound. m.p.: 195-196° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:29])[CH2:18][CH2:17][N:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([N:16]1[CH2:15][CH2:14][C:13]([F:29])([F:12])[CH2:18][CH2:17]1)[C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ncc(C(CN)N2CCC(F)(F)CC2)cn1
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCC(F)(F)CC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4,4-difluoropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[NH2:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:20][C:19]1[CH:21]=[C:22]([C:24]([F:26])([F:27])[F:25])[CH:23]=[C:17]([O:16][CH3:15])[CH:18]=1)=[O:11]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Product: COc1cc(NC(=O)c2cc(C(N)=O)ccc2OC)cc(C(F)(F)F)c1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 3-methoxy-5-trifluoromethylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [C:1](=[O:5])([O:3][CH3:4])[NH2:2].[C:6](Cl)(=[O:10])[CH:7]=[CH:8][CH3:9].C=CC1C=CC=CC=1>C(Cl)Cl.Cl[Cu]>[C:6]([NH:2][C:1](=[O:5])[O:3][CH3:4])(=[O:10])/[CH:7]=[CH:8]/[CH3:9]
Reactant: CC=CC(=O)Cl
Reactant: COC(N)=O
Agent: Cl[Cu]
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: C/C=C/C(=O)NC(=O)OC
Temperature: 114 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a mixture of methyl carbamate (1.0 g, 8.54 mmol) and 2-butenoyl chloride (2.4 mL, 25.0 mmol) was added styrene (30 mL), followed by CuCl (0.1 g). The reaction mixture was stirred at 114° C. for 16 h. It was then cooled to room temperature and evaporated to give a white residue, which was dissolved in DCM and washed with water, brine and dried over MgSO4. The solution was concentrated and the addition of pentane to the residue furnished the product as a white precipitate. Yield 76% (0.93 g). m.pt. 149–150° C. 1H NMR: δ 1.94 (dd, 1H, CH3CH, 2JHH=6.8 Hz, 3JHH=1.4 Hz); 3.78 (s, 3H, OCH3); 6.84 (dd, 1H, COCH, 2JHH=15.0 Hz, 3JHH=1.3 Hz); 7.10–7.20 (m, 1H, CH3CH); 7.89 (s, br, 1H, NH). 13C NMR: δ 18.4 (CH3CH), 53.0 (OCH3), 122.7 (COCH), 146.6 (CH3CH), 152.4 (CO2), 166.1 (COCH). m/z (HR-EIMS) Expected 143.0582 (M+), observed 143.0577. Anal. calcd for C9H9NO3: C, 50.35; H, 6.34; N, 9.79%. Found: C, 50.44; H, 6.59; N, 9.94%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8]O)=[N:4][CH:5]=[CH:6][CH:7]=1.C1(P([N:24]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[ClH:1].[ClH:1].[NH2:24][CH2:8][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1ncccc1Cl
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cl
Product: NCc1ncccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of 738 mg (5.16 mmol) of 3-chloro-2-(hydroxymethyl)pyridine in 10 mL of toluene, was added 2.13 g (7.74 mmol) of diphenylphosphoryl azide followed by 1.18 g (7.74 mmol) of DBU. After stirring at room temperature overnight, the reaction was partitioned between EtOAc and sat. aq. NaHCO3. The organic layer was separated and the aqueous phase was washed with EtOAc (3×). The combined organic extracts were dried (MgSO4) and concentrated to a dark oil. This resultant crude residue was chromatographed on SiO2 using 10:90 EtOAc-hexanes to afford the title compound contaminated with an aromatic impurity. Triphenylphosphine (1.63 g, 6.20 mmol) was added to a solution of the crude azide in THF:H2O (10:0.5 mL). After stirring overnight, the reaction was concentrated. This residue was diluted with EtOAc, and HCl (2.6M in ]EtOAc) was added dropwise to precipitate out the amine hydrochloride. Stirring was continued for 20 min, after which time the mixture was filtered and rinsed with EtOAc to afford the title compound as a white solid: 1H NMR (CD3OD) δ8.57 (d, 1H, 4.7 Hz), 7.94 (d, 1H, 8.1 Hz), 7.44 (dd, 1H, 4.7, 8.0 Hz), 4.40 (s, 2 Hz).
Reaction SMILES: Cl[Si:2]([Cl:16])([Cl:15])[CH2:3][CH:4]([CH3:14])[CH2:5][C:6]([CH3:13])([CH3:12])[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9].[CH:17]([Mg]Cl)([CH3:19])[CH3:18]>C1(C)C=CC=CC=1.C1COCC1>[Cl:16][Si:2]([Cl:15])([CH2:3][CH:4]([CH3:14])[CH2:5][C:6]([CH3:12])([CH3:13])[CH2:7][C:8]([CH3:9])([CH3:10])[CH3:11])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(CC(C)(C)CC(C)(C)C)C[Si](Cl)(Cl)Cl
Reactant: CC(C)[Mg]Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(CC(C)(C)CC(C)(C)C)C[Si](Cl)(Cl)C(C)C
Temperature: 100 °C
Reaction time: 20 h

Procedure:
137.8 g trichloro(2,4,4,6,6-pentamethylheptyl)silane, prepared according to example 7, were dissolved in toluene and heated to 100° C. under argon. By means of a dropping funnel were added 220 ml isopropylmagnesium chloride as a 2 molar solution in THF were added to this solution within 1 h. Subsequently the THF was distilled off by means of a column and the reaction mixture was stirred at 100° C. for 20 h. Filtration was carried out for separating the precipitated solid and the product was isolated by vacuum distillation.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH:24]([CH3:26])[CH3:25].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[CH2:23]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1)[CH:24]([CH3:26])[CH3:25]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CC(C)CI
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
A mixture of 1-(4-nitrophenyl)piperazine (8 g, 38.6 mmol) (Acros Organics), powdered potassium carbonate (3.58 g, 25.98 mmol), 1-Iodo-2-methylpropane (4.66 ml, 40.5 mmol), and a catalytic amount of 18-crown-6 in acetonitrile (60 mL) was heated at reflux overnight. The mixture was filtered, and the filter cake was washed with acetonitrile. The solvent was evaporated from the combined filtrates and the residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, evaporated and dried under vacuum to give 1-(isobutyl)-4-(4-nitrophenyl)piperazine) (9.4 g, 92%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:3]=12.[H-].[Na+].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1F)[C:20]#[N:21].O>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([Cl:1])=[C:3]2[C:10]([CH:11]([CH3:13])[CH3:12])=[N:9]1)[C:20]#[N:21]
Reactant: CC(C)c1n[nH]c2nccc(Cl)c12
Reactant: N#Cc1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nn(-c2ccc(C#N)cc2Cl)c2nccc(Cl)c12
Reaction time: 0.5 h

Procedure:
Compound (6b) (0.5 g) was dissolved in DMF (13 mL), and sodium hydride (0.145 g, a 55% dispersion in paraffin liquid) was added to the resulting solution at 0° C., followed by stirring for 30 min. Then, 3-chloro-4-fluorobenzonitrile was added to the reaction solution, followed by stirring at 60° C. for 1 hr. Water was added to the reaction solution. The precipitate was collected by filtration and washed by sprinkling water to obtain compound (99a) (0.72 g, 85′. %) as a brown solid.
Reaction SMILES: [NH2:1][CH:2]1[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][C:3]1([C:12]([OH:14])=[O:13])[CH2:4]3)[CH2:8]2.S(Cl)([Cl:17])=O.[CH3:19]O>>[ClH:17].[CH3:19][O:13][C:12]([C:3]12[CH2:11][CH:7]3[CH2:6][CH:5]([CH2:10][CH:9]([CH2:8]3)[CH:2]1[NH2:1])[CH2:4]2)=[O:14]
Reactant: O=S(Cl)Cl
Reactant: NC1C2CC3CC(C2)CC1(C(=O)O)C3
Reactant: CO
Product: COC(=O)C12CC3CC(CC(C3)C1N)C2
Product: Cl
Reaction time: 8 h

Procedure:
To a stirred solution of 4.4 g of 2-amino-1-adamantanecarboxylic acid in 100 ml of dry methanol at -70° C. is added 3.21 ml of thionyl chloride. The reaction mixture is allowed to stand at room temperature overnight. Removal of the solvent under reduced pressure gives methyl-2-amino-1-adamantanecarboxylate hydrochloride which is represented by the formula ##STR46## The residue containing the methyl 2-amino-1-adamantanecarboxylate hydrochloride is dissolved in 150 ml of chloroform, filtered through Filter Cel, washed with 10 ml of 5 M potassium carbonate solution, separated and then combined with a second chloroform extract of the aqueous phase. The chloroform extract is dried over sodium sulfate, filtered through Filter Cel and concentrated en vacuo. The syrup-like residue is dissolved in 10 ml of tetrahydrofuran and dried over sieves for 30 minutes before used in the mixed anhydride reaction. A dry (sieves) solution of 6.37 g of Boc-L-phenylalanine and 2.66 ml of N-methylmorpholine is stirred under a nitrogen atmosphere at -60° C. To this solution is added 2.12 ml of isobutylchloroformate. The solution is allowed to warm to -10° C. then is cooled to -40° C. over a 10 minute time period, and the tetrahydrofuran solution of methyl 2-amino-1-adamantane-carboxylate from above is added. The reaction mixture is warmed to room temperature and stirred overnight. 150 ml of chloroform is added and the chloroform solution is washed twice with 10 ml of 2 M potassium carbonate solution and once with 20 ml of 1 M potassium bisulfate solution. The chloroform layer is collected, dried over sodium sulfate and concentrated under reduced pressure to give an oily residue. Thin layer chromatography using 2.5% methanol-chloroform as eluent and NMR (CDCl3, 60 MHz, tetramethylsilane internal standard) on the oily residue indicates two disastereoisomers, A and B, of methyl Boc-L-phenylalanyl-2-amino-1-adamantanecarboxylate. Isomer A (Rf=0.41, --CO2Me at 216 cps) is obtained from ether as a crystalline solid melting at 153°-158° C. Isomer B (Rf=0.46, --CO2Me at 212 cps) and additional Isomer A are obtained by chromatographic separation on silica gel using a hexanechloroform gradient.