Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][C:44]([CH3:76])([CH2:68][CH2:69][N:70]1[CH2:75][CH2:74][O:73][CH2:72][CH2:71]1)[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][C:52]=2[N:58]([CH3:67])[S:59]([C:62]1[S:63][CH:64]=[CH:65][CH:66]=1)(=[O:61])=[O:60])=O)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:67][N:58]([C:52]1[CH:53]=[CH:54][CH:55]=[C:56]2[C:51]=1[NH:50][C:49]([C:47]1[S:43][C:44]([CH3:76])([CH2:68][CH2:69][N:70]3[CH2:75][CH2:74][O:73][CH2:72][CH2:71]3)[CH2:45][N:46]=1)=[CH:57]2)[S:59]([C:62]1[S:63][CH:64]=[CH:65][CH:66]=1)(=[O:61])=[O:60]
Reactant: CN(c1cccc2cc(C(=O)NCC(C)(CCN3CCOCC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: CN(c1cccc2cc(C3=NCC(C)(CCN4CCOCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 0.17 h
Yield: 69.9 %

Procedure:
To a solution of triphenylphosphine oxide (1.90 g) in acetonitrile (25 ml) was slowly added trifluoromethanesulfonic anhydride (0.57 ml) at 0° C., and the mixture was stirred for 10 min. N-[2-(Benzylthio)-2-methyl-4-(morpholino)butyl]-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.39 g) was added, and the reaction mixture was stirred at 0° C. for 30 min. Saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to basic silica gel column chromatography to give the title compound (0.80 g, yield 70%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (5:1, volume ratio). melting point 154-155° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#N)=[C:17]([C:23]#[C:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:16]=1)([CH3:14])([CH3:13])[CH3:12].S(=O)(=O)(O)[OH:30].[OH-].[Na+]>C1(C)C=CC=CC=1.ClCCl.O.C1COCC1>[C:11]([C:15]1[N:16]=[C:17]([C:23]#[C:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:18]([CH:19]=[O:30])=[CH:21][CH:22]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C#Cc1nc(C(C)(C)C)ccc1C#N
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)C#Cc1nc(C(C)(C)C)ccc1C=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
310 ml (315 mmol) of diisobutylaluminium hydride, 1M in toluene, are added dropwise to a solution, cooled to −78° C., of 72.1 g (300 mmol) of 6-tert-butyl-2-(3,3-dimethylbut-1-ynyl)nicotinonitrile, S62, in 1500 ml of dichloromethane at such a rate that the temperature does not exceed −65° C. When the addition is complete, the reaction mixture is stirred at −78° C. for a further 2 h, then allowed to warm slowly to room temperature and stirred for a further 12 h. After re-cooling to −10° C., 300 ml of THF and then, with vigorous stirring, 400 ml of 2 N sulfuric acid (exothermic!) are added, and the mixture is stirred at room temperature for a further 12 h. After re-cooling to −10° C., a solution of 70 g of NaOH in 300 ml of water is added, the aqueous phase is separated off, the organic phase is washed three times with 1000 ml of water each time, once with 500 ml of saturated sodium chloride solution, dried over magnesium sulfate, and the solvent is removed in vacuo.
Reaction SMILES: [BH4-].[Na+].[Si:3]([O:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[O:19])[S:16][CH:17]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>C(O)C>[Si:3]([O:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([CH2:18][OH:19])[S:16][CH:17]=1)([C:6]([CH3:8])([CH3:9])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OCCc1csc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCc1csc(CO)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (1.40 g) was added portionwise to a stirred solution at 0° C. of 4-(2-(tert-butyldimethylsilyloxy)ethyl)thiophene-2-carbaldehyde [Aromatic Intermediate 6] (10 g) in ethanol (70 mL). The reaction mixture was stirred for 1 hour at 0° C. and then partitioned between ethyl acetate and aqueous brine and separated. The organic layer was dried, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 12% ethyl acetate in isohexane as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 6.00 g.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:8])[CH3:7].CCN(CC)CC.FC(F)(F)S(O[Si:22]([CH3:25])([CH3:24])[CH3:23])(=O)=O>C(Cl)Cl.C(OCC)(=O)C>[CH3:23][Si:22]([CH3:25])([CH3:24])[O:8][C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[CH2:7]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)c1ccc[nH]1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(O[Si](C)(C)C)c1ccc[nH]1
Reaction time: 0.5 h

Procedure:
1-(1H-pyrrol-2-yl)-ethanone (2.67 mmol, 0.29 g) in CH2Cl2 (10 ml) and Et3N (13.3 mmol, 1.90 ml) was cooled to 0° C. and treated with trimethylsilyl trifluoromethanesulfonate (5.34 mmol, 1.00 ml). The solution was held at 0° C. for 30 minutes, then diluted with ethyl acetate (75 ml) and washed with saturated aqueous sodium bicarbonate (2×20 ml) then brine (30 ml). The solution was concentrated under reduced pressure to provide crude 2-[1-(trimethyl-silanyloxy)-vinyl]-1H-pyrrole. 1H NMR (CDCl3) δ 6.77 (1H, dd, J=2.7, 1.6), 6.34 (1H, dd, J=3.2, 1.6), 6.15 (1H, t, J=2.8), 4.56 (1H, d, J=1.0), 4.31 (1H, d, J=1.0), 0.45 (9H, s), 0.25 (9H, s).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[Mg].Br[C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[N:12]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.CCOCC.[Zn+2].[Br-].[Br-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:20]([N:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]1[CH:10]=[CH:9][CH:29]=[C:28]([CH:2]2[CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:27]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Brc1cccc(N(Cc2ccccc2)Cc2ccccc2)c1
Reactant: BrC1CCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1ccc(CN(Cc2ccccc2)c2cccc(C3CCCC3)c2)cc1
Temperature: 47.5 °C
Yield: 99.9 %

Procedure:
A solution of bromo cyclopentane (7.62 g, 51.1 mmol) in dry THF (25 ml) was added dropwise to a suspension of magnesium turnings (1.24 g, 51 mmol) in ether (3 ml) under nitrogen at such a rate so to maintain the inner temperature between 45 to 50° C. (After addition of a few drops of solution the mixture was heated to about 50° C. to initiate the Grignard reagent formation) After 1.5 h the Grignard reagent was canulated into a dropping funnel, diluted with 25 ml of dry THF and added dropwise over 30 minutes to a cold (0° C.) solution of dried ZnBr2 (11.5 g, 51 mmol) in dry THF (90 ml) under a nitrogen atmosphere. After 15 minutes the reaction mixture was cooled to −60° C. and PdCl2(dppf)2 (249 mg, 0.34 mmol) was added (the solution became red). A solution of 3-bromo-N,N-Dibenzyl-aniline (6 g, 17 mmol) in dry THF (50 ml) was added to this solution over 35 minutes. The dry ice bath was then removed and the solution was allowed to warm to room temperature overnight. After addition of 3N HCl (70 ml), the THF was removed under reduced pressure. The aqueous residue was extracted three times with AcOEt (3×70 ml). The combined organic layers were washed with brine (50 ml), then with a saturated NaHCO3 solution (50 ml). The insoluble material was filtered off and the solution was washed again with brine (50 ml). The organic layer was dried over MgSO4 and concentrated under reduced pressure to give the above titled compound (5.8 g) which was used in the next step without any further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)[CH:23]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)CC1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 1-(3-bromo-phenyl)-4-methyl-piperazine (80.0 mg, 0.314 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d and was isolated as a yellow solid (0.072 g, 60%). MP=232-234° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=7.2 Hz, 1H), 8.25 (d, J=7.5 Hz, 2H), 8.08 (d, J=7.9 Hz, 2H), 7.65 (d, J=7.7 Hz, 1H), 7.38 (s, 1H), 7.27-7.20 (m, 1H), 7.04-6.95 (m, 2H), 6.84 (s, 1H), 6.60 (d, J=8.0 Hz, 1H), 3.30-3.25 (m, 4H), 3.10 (s, 3H), 2.63-2.58 (m, 4H), 2.38 (s, 3H). MS=463 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:15])[S:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22]>>[CH3:30][O:29][C:25]1[CH:24]=[C:20]([CH:19]=[C:18]([O:17][CH3:16])[C:26]=1[O:27][CH3:28])[C:21]([NH:15][C:11]1[S:12][C:13]([CH3:14])=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)=[O:22]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COc1ccc(-c2nc(N)sc2C)cc1
Product: COc1ccc(-c2nc(NC(=O)c3cc(OC)c(OC)c(OC)c3)sc2C)cc1
Yield: 63 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-methoxy-phenyl)-5-methyl-thiazol-2-ylamine prepared in Example 52 and 3,4,5-trimethoxy-benzoyl chloride prepared in the step 1 of Example 37 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to give a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (15:1) to obtain a product as a white solid in a yield of 63.0%, mp: 105-106 └. 1H-NMR (CDCl3, 400 MHz) δ: 2.51 (3H, s, ArCH3), 3.78 (3H, s, OCH3), 3.79 (3H, s, OCH3), 3.80 (3H, s, OCH3), 3.89 (3H, s, OCH3), 6.78 (2H, d, J=8.44 Hz, ArH), 6.98 (2H, s, ArH), 7.35 (2H, d, J=8.44 Hz, ArH); EI-MS m/e (%): 414.1 (M+, 70), 195.1 (100); HREI-MS Calcd. for C21H22N2O5S: 414.1249. found: 414.1258.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:15]1[N:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[N:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Oc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CS(=O)(=O)c1ccc(-c2ccc(O)cn2)cc1
Temperature: 80 °C
Yield: 61.4 %

Procedure:
(4-Methylsulfonylphenyl)boronic acid (4.40 g, 21.55 mmol) was added to a solution of 6-bromo-3-pyridinol (2.5 g, 14.37 mmol) in DME (125 mL), followed by addition of 2M Na2CO3 (75 mL) and Pd(PPh3)4 (0.83 g, 0.72 mmol). The reaction mixture was degassed with N2 and heated at 80° C. overnight, then cooled to ambient temperature. Water (50 mL), 1N NaOH (50 mL), brine (50 mL) and CH2Cl2 (150 mL) were added. The CH2Cl2 layer was separated and the aqueous layer was washed with CH2Cl2 (100 mL). The combined CH2Cl2 extract was further washed with a mixture of water (50 mL), 1N NaOH (50 mL) and brine (50 mL). The aqueous layers were combined and washed with CH2Cl2 (100 mL), neutralized with concentrated HCl and extracted with EtOAc (250 mL×2). The combined EtOAc extract was filtered through celite on top of a layer of silica gel, which was further washed with EtOAc (100 mL). The EtOAc filtrate was washed with brine and dried over Na2SO4, filtered, and concentrated to a light yellow solid, which was triturated with small amount of hot MeOH to give 2.20 g (61%) of 6-[4-(methylsulfonyl)phenyl]-3-pyridinol as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>>[CH3:13][N:10]1[CH2:9][CH2:8][C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([O:6][C:5]2[CH:20]=[CH:21][C:2]([NH:1][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CN1CCC(Oc2ccc(N)cc2)(c2ccccc2)CC1
Product: CN1CCC(Oc2ccc(NC(=O)C(C)(C)C)cc2)(c2ccccc2)CC1

Procedure:
from 4-(4-aminophenoxy)-1-methyl-4-phenylpiperidine and pivaloyl chloride.
Reaction SMILES: Br.Br.[CH2:3]([NH:5][CH:6]1[CH2:15][CH2:14][C:9]2[N:10]=[C:11](N)[S:12][C:8]=2[CH2:7]1)[CH3:4].C(NC1CCC2N=CSC=2C1)CC>>[CH2:3]([NH:5][CH:6]1[CH2:15][CH2:14][C:9]2[N:10]=[CH:11][S:12][C:8]=2[CH2:7]1)[CH3:4]
Reactant: CCNC1CCc2nc(N)sc2C1
Agent: Br
Agent: CCCNC1CCc2ncsc2C1
Product: CCNC1CCc2ncsc2C1
Yield: 45 %

Procedure:
Ethyl-(4,5,6,7-tetrahydro-benzothiazol-6-yl)-amine (4C) is prepared from 4B as described for 1C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18].[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21]>>[CH3:21][CH:20]([CH3:22])[C:19]([O:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18])=[O:23]
Reactant: CC1=C2C[C@@]3(C)C(=CC[C@H](O)[C@@H]3C)C=C2OC1=O
Reactant: CC(C)C(=O)Cl
Product: CC1=C2C[C@@]3(C)C(=CC[C@H](OC(=O)C(C)C)[C@@H]3C)C=C2OC1=O

Procedure:
The title compound was prepared in the same manner as in Example B2, except that the compound prepared in Example B1 was reacted with isobutyryl chloride.
Reaction SMILES: [CH:1]1([C:5]([NH:7][NH:8][C:9]([C:11]2[C:15]([CH3:16])=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:12]=2)=O)=O)[CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>O1CCOCC1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[N:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:12]=[C:11]([C:9]3[S:41][C:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)=[N:7][N:8]=3)[C:15]=2[CH3:16])=[CH:18][CH:19]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1c(C(=O)NNC(=O)C2CCC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: C1COCCO1
Product: Cc1c(-c2nnc(C3CCC3)s2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 180 °C
Yield: 55.2 %

Procedure:
N-cyclobutanoyl-N′-[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl]-hydrazine (0.14 g, 0.29 mmol) was added to a microwave reactor containing Lawesson's reagent (0.18 g, 0.44 mmol) in 1,4-dioxane (3 mL). The capped reactor was placed into a microwave reactor and the mixture was heated at 180° C. for 15 min, and the process was repeated one more time. The reaction mixture was then purified by preparative HPLC to provide the title compound (60 mg, 0.16 mmol, 43%) as yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH3:19])[C@H:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[CH3:30][S:31]([N:34]1[CH2:39][CH2:38][N:37]([C:40](Cl)=[O:41])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[N:7]([C@H:8]1[C@H:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][N:10]([C:40]([N:37]2[CH2:36][CH2:35][N:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:39][CH2:38]2)=[O:41])[CH2:9]1)[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CNC[C@H]1c1ccccc1
Reactant: CS(=O)(=O)N1CCN(C(=O)Cl)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccccc1
Yield: 65.3 %

Procedure:
To a solution of rac-methyl-((3S,4R)-4-phenyl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (0.57 g, 2.1 mmol) in CH2Cl2 (15 ml) was added ethyl-diisopropyl-amine (0.53 ml, 3.11 mmol) and 4-methanesulfonyl-piperazine-1-carbonyl chloride (0.56 g, 2.5 mmol). Stirring was continued over night at RT, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/Hx 1:1) afforded 0.64 g (66%) of rac-[(3S,4R)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-4-phenyl-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester as a white solid. ES-MS m/e: 467.3 (M+H+).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[CH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][NH2:15]>>[CH3:14][NH:15][CH:9]1[CH2:10][C:11](=[O:12])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:13]
Reactant: O=C1C=CC(=O)N1c1ccccc1
Reactant: CN
Product: CNC1CC(=O)N(c2ccccc2)C1=O

Procedure:
Furthermore, it is known that N-phenylmaleimide can be reacted with methylamine to give 3-methylamino-1-phenylpyrrolidine-2,5-dione which can be reduced with lithium aluminum hydride to give 3-methylamino-1-phenylpyrrolidine (J. Med. Chem. 10, 1015 (1967)).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH:7]([CH3:9])[C:6](O[Si](C)(C)C)=[C:5](O[Si](C)(C)C)[CH:4]([CH3:20])[CH2:3]1.[ClH:21].Cl.[NH2:23][CH2:24][C:25]([NH2:27])=[NH:26]>>[ClH:21].[ClH:21].[NH2:27][C:25]1[CH:24]=[N:23][C:6]2[CH:7]([CH3:9])[CH2:8][N:2]([CH3:1])[CH2:3][CH:4]([CH3:20])[C:5]=2[N:26]=1
Reactant: CC1CN(C)CC(C)C(O[Si](C)(C)C)=C1O[Si](C)(C)C
Reactant: N=C(N)CN
Agent: Cl
Product: CC1CN(C)CC(C)c2nc(N)cnc21

Procedure:
This compound was prepared analogous to Example 22 from 1,3(R,S),6(R,S)-trimethyl-2,3,6,7-tetrahydro-4,5-bis(trimethylsilyloxy)-azepine and α-amino-acetamidine dihydrochloride.
Reaction SMILES: C[O:2][C:3](=O)/[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[N:5]/[OH:6].[CH3:22][NH2:23]>CO>[OH:6]/[N:5]=[C:4](\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)/[C:3]([NH:23][CH3:22])=[O:2]
Reactant: CN
Reactant: COC(=O)/C(=N/O)c1ccccc1Oc1ccc(C)cc1
Solvent: CO
Product: CNC(=O)/C(=N/O)c1ccccc1Oc1ccc(C)cc1
Yield: 100 %

Procedure:
E-α-hydroxyimino-2-(4-methylphenoxy)phenylacetic acid methyl ester (1.00 g, 0.0035 mole) was dissolved in methanol (7 ml) and 40% methylamine solution in methanol (0.54 g, 0.007 mole) was added to the mixture, which was refluxed for 70 minutes. A 40% methylamine solution in methanol (1.36 g, 0.0175 mole) was further added to the mixture, which was refluxed for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give E-2-hydroxyimino-N-methyl-2-[2-(4-methylphenoxy)phenyl]acetamide (1.00 g, yield: 100.0 %) as an amorphous.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.Cl[CH2:29][CH2:30][CH2:31][S:32](Cl)(=[O:34])=[O:33]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]3[CH2:29][CH2:30][CH2:31][S:32]3(=[O:34])=[O:33])=[CH:3][C:4]=2[C:24]([F:27])([F:26])[F:25])=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3C(F)(F)F)CC2)c(C)c1
Reactant: O=S(=O)(Cl)CCCCl
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(F)(F)F)CC2)c(C)c1

Procedure:
Using (4-amino-2-trifluoromethylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (850 mg) described in Preparation Example 149 and 3-chloropropane-1-sulfonyl chloride (0.37 mL) and by the reaction and treatment in the same manner as in Example 78, the title compound (544 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:30])[CH:24]=[CH:23][CH:22]=[C:21](/[CH:25]=[CH:26]/[C:27](O)=[O:28])[CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:27](=[O:28])/[CH:26]=[CH:25]/[C:21]3[CH:20]=[C:19]([CH3:30])[CH:24]=[CH:23][CH:22]=3)=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1cccc(/C=C/C(=O)O)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3cccc(C)c3)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-m-tolyl-acrylic acid.
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[CH2:10][C@H:9]([C:11]([O:13]C(C)(C)C)=[O:12])[CH2:8][S:7]1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([S:4][CH2:5][C@H:6]1[CH2:10][C@H:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)SC[C@H]1C[C@H](C(=O)OC(C)(C)C)CS1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SC[C@H]1C[C@H](C(=O)O)CS1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of trans-2-acetylthiomethyl-4-tert-butoxycarbonyltetrahydrothiophene (compound No. 4-1, 130 mg) in methylene chloride (2 ml), trifluoroacetic acid (1 ml) was added and the mixture was stirred for 2 hours at room temperature. The mixture was concentrated in vacuo and the oily residue was purified by a silica gel column chromatography to give 112 mg (quantitative yield) of the titled compound (compound No. 6-1) as white powder.
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.C1C2C(COC(NC(C)CCCCCCCCCC(O)=O)=O)C3C(=CC=CC=3)C=2C=CC=1.[CH:58]1([N:64]=[C:65]=[N:66][CH:67]2[CH2:72][CH2:71][CH2:70]CC2)CCCCC1>O1CCCC1>[CH3:1][N:64]([C:65]1[CH:70]=[CH:71][CH:72]=[CH:67][N:66]=1)[CH3:58]
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(CCCCCCCCCC(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 67 mg of radicicol, 280 mg of 11-(9-fluorenyl)methoxycarbonylaminododecanoic acid, 10 ml of dry tetrahydrofuran, 132 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 194 mg of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:10][CH3:11])=[CH:7][C:8]#[N:9])=[CH:4][CH:3]=1.[Br:14]Br.O1CCCC1>C(Cl)(Cl)(Cl)Cl>[Br:14][C:7](=[C:6]([NH:10][CH3:11])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=1)[C:8]#[N:9]
Reactant: CNC(=CC#N)c1ccc(Cl)cc1
Reactant: BrBr
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CNC(=C(Br)C#N)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A solution of p-chloro-β-(methylamino)cinnamonitrile (19.3 g, 0.1 mol) in carbon tetrachloride at 70° C. is treated dropwise with a solution of bromine (16.8 g, 0.105 mol) in carbon tetrachloride over a 30-40 minute period (tetrahydrofuran is added as needed during the bromine addition to aid dissolution of the reaction mixture). The reaction mixture is stirred for 30 minutes at 70° C., cooled to room temperature and concentrated to give a yellow crystalline precipitate. The mixture is filtered, the filter cake is washed with carbon tetrachloride and dried to give the title product as a yellow solid, 18.8 g (69% yield), mp 178.0°-178.5° C., identified by IR, NMR and mass spectral analyses.