Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:13]([O:26][C:27]([C:29]1[N:30]2[CH:33]([S:34][CH2:35][C:36]=1[CH:37]=[CH:38][O:39][S:40]([C:43]1[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=1)(=[O:42])=[O:41])[CH:32]([NH:50]C(OC(C)(C)C)=O)[C:31]2=[O:58])=[O:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[NH2:50][CH:32]1[C:31](=[O:58])[N:30]2[CH:33]1[S:34][CH2:35][C:36]([CH:37]=[CH:38][O:39][S:40]([C:43]1[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=1)(=[O:42])=[O:41])=[C:29]2[C:27]([O:26][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:28]
Reactant: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3SC2)cc1
Temperature: 35 °C
Reaction time: 0.75 h
Yield: 90.8 %

Procedure:
A solution of p-toluenesulphonic acid hydrate (3.49 g) in acetonitrile (25 cc) is added dropwise, in the course of 25 minutes, to a solution, at 35° C., of 2-benzhydryloxycarbonyl-7-tert.-butoxycarbonylamino-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (E-form) (6.1 g) in acetonitrile (75 cc). The mixture is stirred for 45 minutes at 35° C. and is then poured into a saturated sodium bicarbonate solution (500 cc). After 30 minutes' contact, with stirring, the mixture is extracted with ethyl acetate (500 cc) and the organic phase is washed with water (100 cc), dried over sodium sulphate, filtered and concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa). 7-Amino-2-benzhydryloxycarbonyl-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (E-form) (4.7 g) is obtained in the form of a brown froth.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH:8][CH2:9][CH2:10][N:11]([CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)C(OC(C)(C)C)=O)=[CH:6][C:5](=[O:31])[N:4]([CH3:32])[C:3]1=[O:33].[ClH:34].O1CCOCC1>>[ClH:34].[CH3:1][N:2]1[C:7]([NH:8][CH2:9][CH2:10][NH:11][CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)=[CH:6][C:5](=[O:31])[N:4]([CH3:32])[C:3]1=[O:33]
Reactant: Cn1c(NCCN(CCCc2ccc([N+](=O)[O-])cc2)C(=O)OC(C)(C)C)cc(=O)n(C)c1=O
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(NCCNCCCc2ccc([N+](=O)[O-])cc2)cc(=O)n(C)c1=O

Procedure:
30 ml of 0.5 N HCl/dioxane were added to 4.9 g of 1,3-dimethyl-6-{2-[N-(t-butoxycarbonyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione (Compound 173). The resultant mixture was stirred at room temperature for 24 hours. Precipitated crystals were collected by filtration and then washed with a chilled solvent consisting of a 1:2 mixture (by volume) of ethanol and ether, thereby obtaining 3.9 g of 1,3-dimethyl-6-{2-[3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione hydrochloride (Compound e).
Reaction SMILES: [OH-].[CH2:2]([N+:9]([CH3:12])([CH3:11])[CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:19]=[C:20]([C:35]([OH:37])=[O:36])[CH:21]=[C:22]([S:31]([NH2:34])(=[O:33])=[O:32])[C:23]=1[O:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1.CCCCCCC>O>[NH2:34][S:31]([C:22]1[CH:21]=[C:20]([CH:19]=[C:18]([NH:17][CH2:16][CH2:15][CH2:14][CH3:13])[C:23]=1[O:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:35]([O-:37])=[O:36])(=[O:32])=[O:33].[CH2:2]([N+:9]([CH3:12])([CH3:11])[CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CCCCCCC
Solvent: O
Product: CCCCNc1cc(C(=O)[O-])cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 0.17 h
Yield: 49.8 %

Procedure:
To a solution of benzyltrimethylammonium hydroxide (451 mg, 2.7 mmol) in water (1 mL) was added bumetanide (1 g, 2.7 mmol) over a period of 5 minutes. The reaction mixture became clear after 10 minutes of stirring. The water was removed under reduced pressure to yield a crude colorless oil. Pure product was obtained from recrystallization of the oil with water and heptane to yield 690 mg of benzyltrimethylammonium 3-aminosulfonyl-5-butylamino-4-phenoxybenzoate as light pink crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH:17]=[O:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[I-].[CH3:20][S+](C)C.CC([O-])(C)C.[K+].O>CS(C)=O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH:17]3[CH2:20][O:18]3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C=O)nn1-c1ncccc1Cl
Reactant: C[S+](C)C
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(C2CO2)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 20.9 %

Procedure:
5.00 g (18.8 mmol) of methyl 1-(3-chloropyridin-2-yl)-3-formyl-1H-pyrazole-5-carboxylate (known from WO 2006/000336) and 5.76 g (28.2 mmol) of trimethylsulphonium iodide were initially charged in 12.5 ml of dimethyl sulphoxide, and 2.64 g (23.5 mmol) of t-BuOK in 12.5 ml of dimethyl sulphoxide were added dropwise at room temperature. After 1.5 hours of stirring at room temperature, 60 ml of water were carefully added dropwise with ice cooling, whereupon the reaction mixture was extracted repeatedly with ethyl acetate. The combined organic phases were washed three times with water and then dried over magnesium sulphate. The solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel, which gave 1.10 g (21% of theory) of methyl 1-(3-chloropyridin-2-yl)-3-(oxiran-2-yl)-1H-pyrazole-5-carboxylate. (logP: 1.67; MH+: 280.0; 1H-NMR (400 MHz, CD3CN, δ, ppm): 3.10 (m, 2H), 3.71 (s, 3H), 3.98 (s, 1H), 6.92 (s, 1H), 7.56 (m, 1H), 8.07 (m, 1H), 8.51 (m, 1H).)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[CH:7]=[CH2:8]>[Cl-].[Zn+2].[Cl-]>[CH2:11]([O:10][C:6]([CH:7]1[CH2:8][CH:2]2[O:1][CH:5]1[CH:4]=[CH:3]2)=[O:9])[CH3:12]
Reactant: c1ccoc1
Reactant: C=CC(=O)OCC
Agent: [Cl-]
Agent: [Zn+2]
Product: CCOC(=O)C1CC2C=CC1O2
Temperature: 3 °C
Reaction time: 27 h

Procedure:
A mixture of 300 g of furan (4.32 mol) and 611 g (6.05 mol) of ethyl acrylate was cooled to 3° C. in an ice bath under an inert atmosphere. 706 g (5.2 mol) of zinc chloride were added portionwise to the solution during 30 min, maintaining the temperature at between 10° C. and 20° C. After completed addition, the cooling bath was removed and the mixture was allowed to gradually heat up during 30 min to 50° C. by exothermy. It was subsequently kept at 50° C. during 27 h by means of an oil bath, then cooled to 40° C. and diluted with 200 ml of dichloromethane in order to reduce its viscosity. The solution was subsequently cooled to room temperature, poured on a mixture of 1.0 kg of crushed ice and 1.5 l of water and extracted. The aqueous phase was extracted with 2.5 l of ethyl acetate, and the combined organic phases were subsequently washed with 2.5 l of water, a solution of 109 g sodium bicarbonate in 2.5 l water, and 250 ml of brine. The organic phase was dried over sodium sulfate, filtered, evaporated at 45° C./1 mbar and dried at 40° C./0.06 mbar for 45 min, to yield 580 g (80%) of a 87:13 exo/endo mixture of product. Purity: 98% (HPLC; ISTD).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[CH:16][CH:15]=1>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:18][CH:19]=2)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1
Reactant: N#Cc1ccccc1-c1ccc(CN)cc1
Reactant: Clc1cc(Cl)n2nccc2n1
Solvent: CCO
Product: N#Cc1ccccc1-c1ccc(CNc2cc(Cl)nc3ccnn23)cc1

Procedure:
5.7 g (30.3 mmol) 5,7-dichloropyrazolo[1,5-a]pyrimidine (prepared according to T. Novinson, B. Bhooshan, T. Okabe, G. R. Revankar, R. K. Robins, K. Senga, H. R. Wilson, J. Med. Chem. 1976, 19, 512) and 6.3 g (30.25 mmol) 4-aminomethyl-2'-cyanobiphenyl were dissolved in 150 ml dry ethanol and heated with reflux for 10 h. The solvent was removed in vacuo, the residue dissolved in ethyl acetate, washed with 10% aqueous sodium carbonate solution, and dried over sodium sulfate. After evaporation in vacuo the title compound crystallized from ethyl acetate/ether in colorless crystals, m.p. 162°-163° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]([NH2:26])([CH3:25])[CH3:24]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:26][CH:23]([CH3:25])[CH3:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: BrCCCCCCOc1ccc(OCc2ccccc2)cc1
Product: CC(C)NCCCCCCOc1ccc(OCc2ccccc2)cc1

Procedure:
As described in Example 19, 1-benzyloxy-4-(6-bromohexyloxy)benzene was reacted with isopropylamine at 100° (12 hours; 500 psi) to give 1-benzyloxy-4-[6-(1-methylethyl)aminohexyloxy]benzene. The crude oil was crystallized from pentane yielding the purified product, mp 47°-49°.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.Cl.N12CCC(CC1)C(=O)C2.[H][H]>[OH-].[Zr+4].[OH-].[OH-].[OH-]>[OH:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1
Reactant: [H][H]
Reactant: O=C1CN2CCC1CC2
Agent: [Zr+4]
Agent: Cl
Agent: [OH-]
Product: OC1CN2CCC1CC2

Procedure:
It has also been found that quinuclidin-3-one or a corresponding salt, such as, quinuclidin-3-one hydrochloride, can be reduced by means of a secondary alcohol as the hydrogen donor in the presence of amorphous, partially dehydrated zirconium hydroxide (ZrO2.xH2O) in the manner of a Meerwein-Ponndorf-Verley reduction to give a good yield of 3-hydroxyquinuclidine or the corresponding salt. If the reduction is carried out using a salt of quinuclidin-3-one, the resulting 3-hydroxyquinuclidine salt can, if desired, be converted into the free 3-hydroxyquinuclidine by addition of a strong base during the work-up of the reaction mixture.
Reaction SMILES: Cl.NO.C([N:6](C(C)C)C(C)C)C.C(OC([NH:18][C:19]([NH:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][N:23]=1)=S)=O)C>C(O)C>[Cl:28][C:26]1[CH:25]=[CH:24][N:23]2[N:6]=[C:19]([NH2:18])[N:21]=[C:22]2[CH:27]=1
Reactant: CCOC(=O)NC(=S)Nc1cc(Cl)ccn1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CCO
Product: Nc1nc2cc(Cl)ccn2n1
Temperature: 25 °C
Yield: 78.2 %

Procedure:
A mixture of hydroxylamine hydrochloride (5.35 g, 77.0 mmol, Eq: 5) and N-ethyldiisopropylamine (5.97 g, 8.07 ml, 46.2 mmol, Eq: 3) in ethanol (80 ml) was stirred for a few minutes at 25° C., then the mixture was added to 1-ethoxycarbonyl-3-(4-chloro-pyridin-2-yl)-thiourea (4.0 g, 15.4 mmol, Eq: 1.00) and the resulting mixture was refluxed for 2.5 days (over the weekend). The crude material was applied on SiO2 and purified by flash chromatography over a 20 g SiO2 column using ethyl acetate 100% as eluent affording 7-chloro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (2.03 g/78.2%) as a white solid. MS: m/e=169.1 (M+H+), mp: 189-190° C.
Reaction SMILES: NC1C=C(C2C=CC=CC=2)C(OC)=CC=1C(C1C=CC=CC=1Cl)=O.NC1C(C)=NN(CC=C)C=1Cl.[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]1[C:49]2[CH:50]=[C:51]([O:60][CH3:61])[C:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:53][C:48]=2[N:47]=[C:46]2[N:62](CC=C)[NH:63][C:64]([CH3:65])=[C:45]2[N:44]=1.[H-].C([Al+]CC(C)C)C(C)C>>[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]1[C:49]2[CH:50]=[C:51]([O:60][CH3:61])[C:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:53][C:48]=2[N:47]=[C:46]2[NH:62][NH:63][C:64]([CH3:65])=[C:45]2[N:44]=1
Reactant: C=CCN1NC(C)=C2N=C(c3ccccc3Cl)c3cc(OC)c(-c4ccccc4)cc3N=C21
Agent: C=CCn1nc(C)c(N)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: COc1cc(C(=O)c2ccccc2Cl)c(N)cc1-c1ccccc1
Product: COc1cc2c(cc1-c1ccccc1)N=C1NNC(C)=C1N=C2c1ccccc1Cl

Procedure:
5-(2-chlorophenyl)-1,2-dihydro-7-methoxy-3-methyl-8-phenyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVff) was prepared by reacting 0.0023 moles of (2-amino-5-methoxy-4-phenylphenyl)-(2-chlorophenyl)-methanone (Xff) with 4-amino-5-chloro-3-methyl-1-(2-propenyl)-1H-pyrazole (XIII), and subsequent dealkylation of the intermediate, 5-(2-chlorophenyl)-1,2-dihydro-7-methoxy-3-methyl-8-phenyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine (XIVff) with diisobutylaluminum hydride in a manner analogous to Example 72. MH+/Z=415.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.C([O:17][B:18]([CH:24]=[CH2:25])OCCCC)CCC.Cl>C1COCC1.O>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH:25]=[CH:24][BH:18][OH:17])[CH:8]=1
Reactant: Brc1cccnc1
Reactant: C=CB(OCCCC)OCCCC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: OBC=Cc1cccnc1
Reaction time: 1 h
Yield: 78 %

Procedure:
Isopropylmagnesium chloride (2.0 M in THF) (5.0 mL, 10 mmol) was added to a solution of 3-bromopyridine (1.60 g, 10.0 mmol) in THF (15 mL) under nitrogen atmosphere at room temperature and the mixture was stirred for 1 h. Vinylboronic acid dibutyl ester (3.4 mL) was added to the reaction dropwise and the mixture was stirred at room temperature for 18 h. Water was added and the pH was adjusted to 7 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (1.04 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:22][OH:23])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.[Br:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([CH2:35]Br)[CH:26]=1.CC(C)([O-])C.[Na+].CO>O1CCCC1.C(=O)(O)[O-].[Na+]>[Br:24][C:25]1[CH:26]=[C:27]([CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)[CH2:35][O:23][CH2:22][C:9]1([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH2:10]1
Reactant: FC(F)(F)c1cc(Br)cc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2F)CC1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(C(F)(F)F)c2)(c2ccc(F)cc2F)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
tert-Butyl 4-(2,4-difluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (220 mg, 0.67 mmol) and 1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (450 mg, 1.41 mmol) were combined in tetrahydrofuran (2 mL) and cooled to 0° C. The reaction was treated with sodium tert-butoxide (75 mg, 0.355 mmol) and stirred at 0° C. for 20 min. The reaction was treated with another aliquot of sodium tert-butoxide (75 mg, 0.355 mmol), allowed to warm to room temperature, and stirred for 30 min. The reaction was diluted with 10% sodium bicarbonate and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (1×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (0%→25% ethyl acetate/hexanes) gave 200 mg (50%). Mass spec.: 586.04 (MH)+ LC tr=2.552 min. (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=2 min, Flow rate=4 mL/min).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=O)[CH:9]=[CH:10][CH:11]=2)=[CH:2]1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:29]=1[C:30]([O:32][CH3:33])=[O:31]>C1COCC1.C(OCC)(=O)C.CC(N(C)C)=O>[Cl:38][C:35]1[CH:36]=[CH:37][C:28]([NH:27][C:13](=[O:15])[CH2:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:7]=2)=[C:29]([CH:34]=1)[C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: O=C(O)Cc1cccc(-c2ccoc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)ccc1NC(=O)Cc1cccc(-c2ccoc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.6 %

Procedure:
0.25 g (1.2 mmol) of [3-(furan-3-yl)phenyl]acetic acid, a catalytic amount of DMF, and 0.36 g (1.7 mmol) of oxalyl chloride were stirred in 10 mL of THF at 0° C. for 1.5 hours. Thereafter, the solvent was distilled off under reduced pressure. 0.23 g (1.2 mmol) of methyl 2-amino-5-chlorobenzoate and 5 mL of DMAc were added to the residue at 0° C., and the mixture was stirred at room temperature for 1.5 hours. After the completion of the reaction, the mixture was diluted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution and saturated saline, and dried over anhydrous sodium sulfate. The obtained crude product was separated and purified by silica gel column chromatography, thereby giving 0.3 g of methyl 5-chloro-2-({[3-(furan-3-yl)phenyl]acetyl}amino)benzoate (yield: 89%).
Reaction SMILES: Br[C:2]1[C:3]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.BrC1[C:15](C#N)=[N:16]C=CC=1.O>CN(C=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.[Fe+2]>[NH:12]1[CH:11]=[CH:10][N:9]=[C:8]1[C:3]1[N:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:15]#[N:16]
Reactant: N#Cc1ncccc1Br
Reactant: Brc1cccnc1-c1ncc[nH]1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccnc1-c1ncc[nH]1
Temperature: 40 °C

Procedure:
A mixture of 3-bromo-2-(1H-imidazol-2-yl)-pyridine (prepared from 3-bromo-pyridine-2-carbonitrile essentially as described by Clews et al., Synthesis (2001):1549) (675 mg, 3 mmol), zinc cyanide (223 mg, 1.9 mmol), Pd2(dba)3 (137 mg, 0.15 mmol), DPPF (160 mg, 0.3 mmol) and water (0.2 mL) in DMF (15 mL) is degassed with argon for 15 minutes. The mixture is then heated at 40° C. overnight in a sealed tube. Solvent is removed, water (30 mL) is added and the mixture is extracted with methylene chloride. On drying (MgSO4), the solvent is removed and the resulting solid is washed with ether (5×10 mL) to give the product (170).
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5](CO)[CH:6]=[CH:7][CH:8]=1.[Br:12][C:13]1[C:14]([F:20])=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.CC1(C)C(C)(C)OB(C2C=NNC=2)O1>>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[C:14]=1[F:20]
Reactant: CN(C)c1cccc(CO)c1
Reactant: Oc1cccc(Br)c1F
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Fc1c(Br)cccc1OC1CCCCC1

Procedure:
The title compound was prepared by substituting cyclohexanol for (3-(dimethylamino)phenyl)methanol and 3-bromo-2-fluorophenol for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 34A.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([N:18]2[CH2:22][CH:21]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]3([C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:37])[CH:19]2[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=2[F:45])=[O:17])[CH2:10][CH2:9]1.C(N(CC)CC)C.C(Cl)(=O)C>O1CCCC1>[C:3]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([N:18]2[CH2:22][CH:21]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]3([C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:37])[CH:19]2[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=2[F:45])=[O:17])[CH2:10][CH2:9]1)(=[O:4])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)CC1CN(C(=O)NCC2CCNCC2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Product: CC(=O)N1CCC(CNC(=O)N2CC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)CC1

Procedure:
In a manner similar to the method described in Example 26, rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid (piperidin-4-ylmethyl)-amide trifluoroacetic acid (25 mg, 0.04 mmol) was reacted with triethylamine and acetyl chloride (3.2 mg, 0.04 mmol) in tetrahydrofuran to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid (1-acetyl-piperidin-4-ylmethyl)-amide as a white solid (Yield, 17 mg, 77%).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][S:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:19]=1[C:15]1=[N:16][O:17][CH2:18][CH:14]1[CH2:13]2.[Br:20]Br>O>[Br:20][C:11]1[CH:10]=[CH:9][C:8]([S:7][CH3:6])=[C:19]2[C:12]=1[CH2:13][CH:14]1[CH2:18][O:17][N:16]=[C:15]12
Reactant: BrBr
Reactant: CSc1cccc2c1C1=NOCC1C2
Agent: O=S(=O)(O)O
Solvent: O
Product: CSc1ccc(Br)c2c1C1=NOCC1C2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
120 ml of sulfuric acid (98 percent strength) were cooled to 0° C., and 11.2 g (54.8 mmol) of 8-methylthio-3a,4-dihydro-3H-indeno[1,2-c]isoxazol were added a little at a time. 9.2 g (57.5 mmol) of bromine were then added dropwise, and the mixture was stirred at 0° C. for 2 hours. The resulting solution was poured into 2 l of a mixture of water and ice, the mixture was stirred for 1.5 hours and the precipitated solid was filtered off with suction and then washed and dried. This gave 11.4 g (73%) of 5-bromo-8-methylthio-3a,4-dihydro-3H-indeno[1,2-c]isoxazol of a brown solid of m.p. 127-135° C.
Reaction SMILES: COP([C:7](=[N+:11]=[N-])[C:8](=O)[CH3:9])(=O)OC.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=C(C=O)N=[C:27]2[CH3:33])=[CH:22][CH:21]=1>CO>[C:8]([C:7]1[N:11]=[C:27]([CH3:33])[N:26]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[CH:30]=1)#[CH:9]
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: Cc1nc(C=O)cn1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cn(-c2ccc(F)cc2)c(C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1-Diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (6.51 g, 33.9 mmol) was dissolved in 100 mL methanol. Potassium carbonate (7.81 g, 56.5 mmol) was added. A solution of 1-(4-fluoro-phenyl)-2-methyl-1H-imidazole-4-carbaldehyde (5.77 g, 45 mmol) in 100 mmol methanol was added dropwise at RT. The reaction mixture was stirred at RT overnight. The solvent was evaporated. The residue was taken up in 150 mL water and extracted three times with ethyl acetate (150 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0→0:100 gradient) and the desired compound was obtained as a white solid (3.81 g, 67%), MS: m/e=200.1 (M+). 1-(3,4-Dichloro-phenyl)-4-ethynyl-2-methyl-1H-imidazole (IV-2) [MS: m/e=252.1 (M+)] was prepared in accordance with the method of example IV-1 from 3,4-dichloroaniline.