Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:19]=[C:20]([N:25]=[C:26]=[O:27])[CH:21]=[CH:22][C:23]=1[F:24]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:20]2[CH:21]=[CH:22][C:23]([F:24])=[C:18]([F:17])[CH:19]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccc(F)c(F)c1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)c(F)c2)cc1-c1c(Br)cnn1C
Yield: 39.2 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.035 g, 0.12 mmol) was treated with 3,4-difluorophenyl isocyanate (0.021 g, 16.0 μL, 0.13 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 10 (0.021 g, 0.047 mmol, 38%) as a white solid. LCMS m/z (%)=437 (M+H79Br, 100), 439 (M+H81Br, 99). 1H NMR (400 MHz, acetone-d6) δ: 8.29 (s, 1H), 8.16 (s, 1H), 7.74 (dddd, J=2.5, 7.4, 13.4 Hz, 1H), 7.68 (dd, J=2.7, 9.0 Hz, 1H), 7.49 (s, 1H), 7.42 (d, J=2.7 Hz, 1H), 7.11-7.26 (m, 2H), 7.13 (d, J=9.0 Hz, 1H), 3.82 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: CC(P(C(C)(C)C)C1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=[CH:8][CH:7]=1)(C)C.C(N(CC)CC)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][P:38](=[O:43])([OH:42])[O:39][CH2:40][CH3:41])=[CH:32][CH:31]=1.C(C1C=CC=CC=1)CCC#C>[Au].ClC(Cl)C>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]#[C:37][P:38](=[O:42])([O:43][C:8]([CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH2:7])[O:39][CH2:40][CH3:41])=[CH:34][CH:35]=1
Reactant: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Reactant: CCOP(=O)(O)C#Cc1ccc(Cl)cc1
Agent: [Au]
Agent: C#CCCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: C=C(CCCc1ccccc1)OP(=O)(C#Cc1ccc(Cl)cc1)OCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44 %

Procedure:
A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) and triethylamine (Et3N) (3.0 mg, 0.03 mmol) were put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen (4-chlorophenyl)ethynylphosphonate (73.4 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, pent-4-ynylbenzene (86.5 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain ethyl 5-phenylpent-1-en-2-yl 2-(4-chlorophenyl)ethynylphosphonate (51.2 mg, 44%) which is a title compound.
Reaction SMILES: [N+:1]1([O-:10])[O:5][N:4]=[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=12.[N+]([CH2:14][CH3:15])([O-])=O.C(NCC)C>O1CCCC1>[CH3:14][C:15]1[N:4]([OH:5])[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[N+:1]=1[O-:10]
Reactant: CC[N+](=O)[O-]
Reactant: [O-][n+]1onc2ccccc21
Solvent: C1CCOC1
Solvent: CCNCC
Product: Cc1n(O)c2ccccc2[n+]1[O-]
Reaction time: 1 h
Yield: 58.5 %

Procedure:
In the typical procedure, 0.1 mole of benzofurazan 1-oxide and 0.12 mole of nitroethane is dissolved at 100 ml. of tetrahydrofuran. To this mixture there is added at room temperature, 0.12 mole of diethylamine over a period of 0.5 hour. An instantaneous exothermic reaction is observed (40° C.) and within one hour, the product crystallizes from the solution. The solution is allowed to stand overnight at room temperature and filtered to yield 9.6 grams of 2-methyl-1-hydroxy-1-H-benzimidazole 3-oxide (Table III, Example H-77). The product can be recrystallized from methanol.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:8][NH:9][NH2:10]>>[CH3:8][N:9]([C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1)[NH2:10]
Reactant: Clc1cnccn1
Reactant: CNN
Product: CN(N)c1cnccn1
Yield: 35.9 %

Procedure:
2-Chloropyrazine (1 g, 8.3 mmol) and methylhydrazine (1.31 mL, 25 mmol) were mixed together in a flask fitted with a water condenser. After a few minutes an exotherm was observed. After 16 h the excess methylhydrazine was removed under reduced pressure. The cooled residue was stirred with aqueous sodium hydroxide solution (20 ml of 20%), and the resulting solution was extracted with ether (6×100 ml). The combined extracts were dried (K2CO3) and concentrated to give a light orange solid 370 mg of N-Methyl-N-pyrazin-2-yl-hydrazine.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])(C)C)=[O:26])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(C(F)(F)[F:35])=O.C(N(C(C)C)CC)(C)C.ClC(OCCF)=O>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH2:31][F:35])=[O:26])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(Cl)OCCF
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)OCCF)CC3)cn2)cc1

Procedure:
The title compound (0.105 g, 90%) was prepared as a white solid from 1,1-dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (0.12 g, 0.27 mmol) and TFA (0.20 mL) in CH2Cl2 (6 mL) then diisopropylethylamine (1.2 mL) and 2-fluoroethyl chloroformate (42 μL, 0.32 mmol) in a manner similar to Example 74. The crude material was purified by chromatography on a silica gel column eluted with 1:7 acetone/CH2Cl2 to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.39 (d, 1H, J=2.7 Hz), 8.13 (d, 2H, J=8.3 Hz), 8.00 (d, 2H, J=8.5 Hz), 7.73 (d, 1H, J=8.8 Hz), 7.35-7.25 (m, 1H, 4.70-4.55 (m, 2H), 4.40-4.15 (m, 4H), 3.91 (d, 2H, J=6.4 Hz), 3.06 (s, 3H), 2.84 (bs, 2H), 2.10-1.95 (m, 1H), 1.95-1.80 (m, 2H), 1.40-1.25 (m, 2H); LRMS (ESI), m/z 437 (M+H).
Reaction SMILES: [N:1]1[C:10]2[C@H:9]([NH2:11])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[CH2:23][CH2:24][CH2:25][CH:26]=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[N:1]1[C:10]2[C@H:9]([NH:11][CH2:26][CH2:25][CH2:24][CH2:23][N:14]3[C:15](=[O:22])[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:13]3=[O:12])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1CCCc2cccnc21
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCCN[C@@H]1CCCc2cccnc21
Temperature: -20 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a solution of (R)-(5,6,7,8-tetrahydro-quinolin-8-yl)amine (70.0 g, 0.47 mol) and 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (102.59 g, 0.47 mol) in tetrahydrofuran (160 mL) at room temperature was added potassium carbonate (65.28 g, 0.47 mol) and the mixture stirred for 1 hour. The suspension was then filtered and chilled to −20° C. The cold filtrate was slowly added to Solution A via canula over 35 minutes. The resulting mixture was stirred at −20° C. for 1 hour, until reaction was complete by NMR aliquot. The reaction was then neutralized by the careful addition of 6N HCl until pH=2-3, keeping the temperature below −7° C. The solution was then warmed to 22° C. and basified with 13w/v % Na2CO3(aq) until pH=4. The tetrahydrofuran was removed under reduced pressure and the concentrate diluted with water (700 mL) and CH2Cl2 (530 mL). The phases were separated and the organic phase washed with concentrated ammonium hydroxide (1×230 mL) and water (1×315 mL). The organic phase was then concentrated to 200-250 mL and filtered through a conditioned silica gel pad (14 g). The silica gel was rinsed with CH2Cl2 (2×20 mL). The combined filtrate was concentrated to 100-150 mL and diluted with diisopropyl ether (1000 mL). The solution was concentrated to 300-350 mL and chilled to −10° C., at which temperature the product began to precipitate. Mechanical stirring was continued for 45 minutes at −10° C., after which time the product was collected by filtration. The product was washed with diisopropyl ether (100 mL) and dried under reduced pressure to give pure 2-{4-[(R)-(5,6,7,8-tetrahydro-quinolin-8-yl)amino]-butyl}-isoindole-1,3-dione (135.3 g, 82%). 1H NMR (300 MHz, CDCl3, δ ppm) 1.55-1.85 (m, 6H), 1.95-2.05 (m, 1H), 2.05-2.20 (m, 1H), 2.50 (b, 1H), 2.65-2.85 (m, 4H), 3.65-3.80 (m, 3H), 7.04 (dd, 1H, J=4.5 & 7.5 Hz), 7.35 (d, 1H, J=7.5 Hz), 7.65-7.75 (m, 2H), 7.75-7.85 (m, 2H), 8.36 (d, 1H, J=4.5 Hz).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:34]1([CH2:37][N:38]2[C:43](=[O:44])[C:42]([CH2:45]OS(C)(=O)=O)=[CH:41][C:40]([C:51]3[CH:56]=[CH:55][C:54]([S:57][CH3:58])=[CH:53][CH:52]=3)=[N:39]2)[CH2:36][CH2:35]1.CN1CCNCC1>>[CH:34]1([CH2:37][N:38]2[C:43](=[O:44])[C:42]([CH2:45][N:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)=[CH:41][C:40]([C:51]3[CH:56]=[CH:55][C:54]([S:57][CH3:58])=[CH:53][CH:52]=3)=[N:39]2)[CH2:35][CH2:36]1
Reactant: CSc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CN1CCNCC1
Product: CSc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC3CC3)n2)cc1
Yield: 85.7 %

Procedure:
Following the procedure of Example 1 (10), 2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and 1-methyl-piperazine were reacted to yield the title compound as a yellow oil (yield: 85.7 %)
Reaction SMILES: [C:1]([N:4]([CH3:36])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH2:19][NH:20][CH:21]3[CH2:26][CH2:25][CH:24]([N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH2:22]3)[CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl:37][C:38]1[C:39]2[C:49]([F:50])=[CH:48][CH:47]=[C:46]([F:51])[C:40]=2[S:41][C:42]=1[C:43](Cl)=[O:44]>>[C:1]([N:4]([CH3:36])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH2:19][N:20]([C:43]([C:42]3[S:41][C:40]4[C:46]([F:51])=[CH:47][CH:48]=[C:49]([F:50])[C:39]=4[C:38]=3[Cl:37])=[O:44])[CH:21]3[CH2:26][CH2:25][CH:24]([N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:23][CH2:22]3)[CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(-c2ccc(N(C)C(C)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(N(C)C(C)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 106 (420 mg, 0.84 mmol) is treated with acid chloride 8 (249 mg, 0.93 mmol) using Method D to give the title compound.
Reaction SMILES: [O:1]=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:15]([C:17]1(O)[CH2:22][CH2:21][CH2:20][C:19]([CH3:24])([CH3:23])[CH2:18]1)#[CH:16]>CC1C=CC=CC=1>[CH3:16][C:15]([C:17]1[CH2:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][CH:22]=1)=[O:1]
Reactant: C#CC1(O)CCCC(C)(C)C1
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Product: CC(=O)C1=CCCC(C)(C)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 38.9 %

Procedure:
Phosphorus pentoxide (33.1 g, 233 mmol) was added to a solution of 1-ethynyl-3,3-dimethylcyclohexanol (152 g, 1.00 mol) in MePh (800 ml). The slurry was heated to reflux, and stirred at this temp. for 90 min. The reaction mixture was allowed to cool to room temp., and then poured into ice/water (1:1, 500 ml). The product was extracted with Et2O (2×500 ml), and the combined organic extracts were washed with water (500 ml) and brine (100 ml), dried (Na2SO4) and concentrated under reduced pressure. Silica-gel FC (pentane/Et2O, 9:1, Rf=0.70) provided 13.8 g (9%) of 1-(5′,5′-dimethylcyclohex-1′-enyl)ethanone.
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH3:20])[CH:4]([N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[S:13])=[CH:7][CH:6]=1)[CH3:2].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1S.O>C1COCC1>[CH2:19]([CH:3]([CH2:1][CH3:2])[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[S:13][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=2)=[CH:9][CH:10]=1)[N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[CH3:20]
Reactant: CCC(CC)C(c1ccc(N=C=S)cc1)n1cncn1
Reactant: Nc1ccccc1S
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)C(c1ccc(Nc2nc3ccccc3s2)cc1)n1cncn1
Yield: 49.6 %

Procedure:
A mixture of intermediate (19b) (0.1665 mol) and 2 aminobenzenethiol (0.2 mol) in THF (500 ml) was stirred and refluxed overnight. The mixture was cooled, poured out into water, extracted with CH2Cl2 and decanted. The organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97.5/2.5/0.1. The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-butanone/diethyl ether. The precipitate was filtered off and dried, yielding 31.2 g (49.6%) of (±)-N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]-2-benzothiazolamine (comp. 25).
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][O:6][C:5]2[CH:9]=[C:10]([F:14])[C:11]([Br:13])=[CH:12][C:4]=2[C:3]1=O.[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[S:18])[NH2:17]>C(O)C.CN1C(=O)CCC1>[CH2:22]([O:21][C:19]([C:16]1[S:18][C:2]2[CH2:8][CH2:7][O:6][C:5]3[CH:9]=[C:10]([F:14])[C:11]([Br:13])=[CH:12][C:4]=3[C:3]=2[N:17]=1)=[O:20])[CH3:23]
Reactant: CCOC(=O)C(N)=S
Reactant: O=C1c2cc(Br)c(F)cc2OCCC1Br
Solvent: CCO
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Temperature: 80 °C
Reaction time: 3 h
Yield: 25.3 %

Procedure:
Into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 4,7-Dibromo-8-fluoro-3,4-dihydro-2H-benzo[b]oxepin-5-one (1400 g, 4.14 mol, 1.00 equiv), NMP (0 mg), and ethyl carbamothioylformate (554 g, 4.16 mol, 1.00 equiv). The resulting solution was stirred at 80° C. for 3 h, cooled to 25° C. and diluted with 6 L of ethanol. The solids were collected by filtration, washed with 3×1 L of ethanol and dried to afford 390 g (25%) of 9-Bromo-8-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)(Cl)Cl>[CH:13](=[N:5][CH2:4][CH2:3][CH2:2][Br:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: NCCCBr
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: BrCCCN=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
The hydrobromide salt of 3-bromopropylamine (5.364 g, 24.50 mmol) was treated with triethylamine (4 mL) in CHCl3 (100 mL) and allowed to stir at room temperature for 5 min. Benzaldehyde (2.000 g, 18.85 mmol) and magnesium sulfate (6.000 g) were added and the reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was filtered and the filter pad was washed with CHCl3 (50 mL). The filtrate was washed with water (3×50 mL), sat NaCl (50 mL), dried over sodium sulfate, and concentrated to provide a yellow oil (4.262 g, 100%). IR (film) 1645, 754, and 693 cm−1; 1H NMR (CDCl3) δ 8.34 (s, 1H), 7.76 (m, 2H), 7.44 (m, 3H), 3.78 (dt, J=6.3 Hz and 1.3 Hz, 2H), 3.52 (t, J=6.5 Hz, 2H), 2.31 (pent, J=6.4 Hz, 2H); ESIMS m/z (rel intensity) 226/228 (MH+, 100/91). Anal. (C10H12BrN) C, H, N.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:36])[CH2:13][C:14]1[N:15]=[C:16]([N:19]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[S:17][CH:18]=1)[CH3:10].CI>C1COCC1>[CH2:9]([O:11][C:12](=[O:36])[CH:13]([C:14]1[N:15]=[C:16]([N:19]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[S:17][CH:18]=1)[CH3:1])[CH3:10]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)Cc1csc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)n1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1csc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of lithium diisopropylamide (prepared in situ) (4.24 g, 39.6 mmol) in dry THF (40 mL) was added the solution of {2-[tert-butoxycarbonyl-(4-methoxy-benzyl)-amino]-thiazol-4-yl}-acetic acid ethyl ester (8.0 g, 19.68 mmol) in 20 mL of dry THF in a dropwise fashion at −78° C. The reaction mixture was continued to stir at −78° C. for 1 hour followed by the addition of methyl iodide (4.19 g, 29.52 mmol) at the same temperature. The reaction mixture was kept on stirring and slowly allowed to come to room temperature. The reaction mixture was quenched with saturated ammonium chloride solution and diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with brine and dried over anhydrous sodium sulphate and the solvent was removed in vacuo to get the sticky compound (8.2 g). The compound was used for the next reaction without any purification.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH3:12][NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C>C(O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][O:23][CH2:22][CH2:21][CH2:20][N:17]2[CH2:16][CH2:15][CH:14]([N:13]([CH3:12])[C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[S:9])[CH2:19][CH2:18]2)=[CH:27][CH:28]=1
Reactant: CNC1CCN(CCCOCCc2ccc(F)cc2)CC1
Reactant: S=C=Nc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C(=S)Nc1ccccc1)C1CCN(CCCOCCc2ccc(F)cc2)CC1
Reaction time: 1 h

Procedure:
A solution of 736 mg (5.44 mmol) of phenyl isothiocyanate in 15 ml of ethanol is treated with 2 g (5.44 mmol) of the preceding hydrochloride 22.3 and then 1.51 ml (10.9 mmol) of triethylamine. After stirring for 1 h, the mixture is evaporated to dryness and treated as in Example 1.1 to give 1.88 g (Yd: 81%) of compound of formula 22.4:
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.Cl.[O:14]([NH2:16])[CH3:15]>>[CH3:15][O:14][N:16]=[CH:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: CON
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Cl
Product: CON=Cc1ccc(C(=O)OC)cc1
Yield: 96 %

Procedure:
Reaction of methyl 4-formylbenzoate with methoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether (96% yield) as a white solid (mixture of E- and Z-isomers). The E-isomer was obtained as white crystals from hexane; mp 66–67° C. (Lit. mp 65–66° C., Cooks, Org. Mass Spectrum., 5, 1971, 687). 1HNMR 400 MHz (DMSO-d6) δ (ppm): (E-isomer) 3.86 (3H, s, OCH3), 3.93 (3H, s, OCH3), 7.75 (2H, d, aromatics), 7.98 (2H, d, aromatics), 8.32 (1H, s, CH).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C:21]([N:23]3[CH2:28][CH2:27][N:26](CCC#N)[CH2:25][CH2:24]3)=[O:22])[C:11]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:34]=3[O:43][CH2:44][CH3:45])=[N:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[Cl:55][CH2:56][C:57](Cl)=[O:58]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:57](=[O:58])[CH2:56][Cl:55])[CH2:25][CH2:24]3)=[O:22])[C:11]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:41])([F:40])[F:42])=[CH:35][C:34]=3[O:43][CH2:44][CH3:45])=[N:10]2)=[CH:7][CH:8]=1
Reactant: O=C(Cl)CCl
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCC#N)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)CCl)CC1
Reaction time: 0.5 h
Yield: 46 %

Procedure:
[4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (372 mg, 0.63 mmol, example 8A) and diisopropylethylamine (230 uL, 1.32 mmol) were dissolved in methylene chloride (4 mL) and cooled to ice temperature. Chloroacetyl chloride (100 uL, 1.26 mmol) in methylene chloride (1 mL) was added dropwise and this mixture was stirred for 30 min at ice temperature. The reaction was diluted with methylene chloride and washed with water. The organic layers were dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated. Purification of the crude material by flash chromatography using ethyl acetate and hexanes gave 1-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-2-chloro-ethanone (193 mg, 0.29 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH:3]=1.[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[C:17](=O)[CH2:16]2.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:17]2[CH:18]3[CH2:21][CH2:22][N:15]([CH2:20][CH2:19]3)[CH2:16]2)=[C:4]([CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH:3]=1
Reactant: COC(Cc1cc(Br)ccc1N)OC
Reactant: O=C1CN2CCC1CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(Cc1cc(Br)ccc1NC1CN2CCC1CC2)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.3 %

Procedure:
Compound 67 (160 mg, 0.615 mmol) and quinuclidin-3-one (115.5 mg, 0923 mmol) were stirred in acetic acid (5 mL) under argon in the presence of anhydrous sodium sulfate (874 mg, 6.150 mmol) at room temperature for 30 minutes. Sodium triacetoxyborohydride (391 mg, 1.845 mmol) was then added and the mixture stirred for 24 hours at room temperature. Thin layer chromatography in a solvent system of 2M NH3 in methanol:CH2Cl2, 5:95 shows incomplete consumption of 67, thus a second portion of quinuclidin-3-one (38.4 mg, 0.307 mmol) is added and the mixture stirred for a further 20 hours. After dilution with a mixture of 8:1 ethyl acetate:hexanes, the reaction is quenched with saturated sodium bicarbonate. The mixture was transferred to a separatory funnel and the organic layer separated. The organic layer was dried over sodium sulfate and concentrated under reduced pressure and the residue purified via chromatography on silica gel (2M NH3 in methanol:CH2Cl2, 2.5:97.5 to 5:95) to yield a colorless residue, 68 (137 mg, 60.3%). 1H NMR (DMSO-d6) δ 1.25-1.39 (m, 1H), 1.53-1.80 (2×m, 3H), 1.86-1.94 (m, 1H), 2.64-2.77 (m, 4H), 2.80 (d, 2H, J=5.2 Hz), 3.14-3.24 (m, 1H), 3.27 and 3.29 (2×s, 6H), 3.34-3.40 (m, 1H), 4.54 (t, 1H, J=5.2 Hz), 5.04 (d, 1H, J=5.8 Hz), 6.43 (d, 1H, J=8.3 Hz), 7.13-7.15 (m, 1H), 7.17 (s, 1H); ESI-MS (m/z, %): 369/371 (MH+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][OH:15])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1.O>C1COCC1>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][C:19]([O:15][CH2:14][C:9]2[N:10]([CH3:13])[N:11]=[N:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:20][CH:21]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)nnn2C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
A solution of [5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-methanol (380 mg, 2.02 mmol) in THF (5.5 mL) was added dropwise at 0° C. to a suspension of NaH (55% in oil, 88 mg, 2.02 mmol) in THF (2.7 mL) and the reaction mixture was then stirred at room temperature for 30 min. Then a solution of methyl 6-chloronicotinate (346 mg, 2.02 mmol) in THF (5.5 mL) was added dropwise at 0° C. and the reaction mixture stirred at room temperature for 16 h. The mixture was then poured into water extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (449 mg, 72%) as a white solid. MS: m/e=343.1 [M+H]+.