Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC.O1CCOCC1>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9][N:10]([CH2:20][CH2:21][CH2:22][OH:23])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCCCO
Product: OCCCN1CCC(c2ccccc2)(c2ccccc2)CC1

Procedure:
40 g of 4,4-diphenylpiperidine, 24.7 g of 3-bromopropanol, 116.4 g of powdered potassium carbonate and about 1 g of potassium iodide are heated at the boiling point under reflux and with vigorous stirring in 500 ml of a 1:1 mixture of dioxane and 1-butanol for about 48 hours. After cooling, the mixture is filtered and the filtrate is concentrated. The oily residue is taken up in ethyl acetate, and the solution is filtered again. After the filtrate has been concentrated to dryness, the title product is obtained as a yellowish oily residue which slowly solidifies as a wax. Yield: 44.8 g. With ethereal hydrochloric acid, the hydrochloride is obtained, and is recrystallized from 2-propanol. m.p.: 226°-227° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:10][C:11]([C:18]([OH:20])=O)=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=1.[CH3:21][O:22][CH2:23][CH2:24][N:25]([CH3:33])[C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][N:27]=1>>[CH3:21][O:22][CH2:23][CH2:24][N:25]([CH3:33])[C:26]1[N:27]=[CH:28][C:29]([NH:32][C:18]([C:11]2[O:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[N:13][C:12]=2[C:14]([F:15])([F:16])[F:17])=[O:20])=[CH:30][CH:31]=1
Reactant: COCCN(C)c1ccc(N)cn1
Reactant: COc1ccccc1-c1nc(C(F)(F)F)c(C(=O)O)o1
Product: COCCN(C)c1ccc(NC(=O)c2oc(-c3ccccc3OC)nc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 1 above, 2-(2-methoxy-phenyl)-4-trifluoromethyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-(2-methoxy-phenyl)-4-trifluoromethyl-oxazole-5-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C21H21F3N4O4 (m/e) 450, obsd 451 (M+H).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[CH:13]([C:17]#[N:18])[CH2:12][CH2:11][CH2:10][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:21]I>O1CCCC1>[CH3:21][C:13]1([C:17]#[N:18])[CH2:12][CH2:11][CH2:10][C:9]2[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:16]=[CH:15][C:14]1=2
Reactant: CI
Reactant: N#CC1CCCc2nc(-c3ccccc3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C#N)CCCc2nc(-c3ccccc3)ccc21

Procedure:
4.7 g. of 2-phenyl-5,6,7,8-tetrahydro-5-quinoline carbonitrile in 80 ml. of absolute tetrahydrofuran is combined with 0.660 g. of 80% sodium hydride, agitated for 30 minutes at room temperature and for 30 minutes at 60° C. under nitrogen, and combined with 2.5 ml. of methyl iodide. After heating the mixture for 2 hours to 60° C., it is concentrated, distributed between ethyl acetate/water, and the ethyl acetate phase is concentrated. Recrystallization from diisopropyl ether/hexane yields 5-methyl-2-phenyl-5,6,7,8-tetrahydro-5-quinoline carbonitrile, m.p. 114.5° - 115.5° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([Li])CCC.[CH3:15][O:16][CH:17]([O:27][CH3:28])[C:18]1[CH:19]=[CH:20][C:21]([F:26])=[C:22]([CH:25]=1)[CH:23]=[O:24].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:23]([C:22]1[CH:25]=[C:18]([CH:17]([O:16][CH3:15])[O:27][CH3:28])[CH:19]=[CH:20][C:21]=1[F:26])[OH:24]
Reactant: c1ccc2scnc2c1
Reactant: COC(OC)c1ccc(F)c(C=O)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(OC)c1ccc(F)c(C(O)c2nc3ccccc3s2)c1
Reaction time: 0.08 h
Yield: 79.3 %

Procedure:
A total of 1.08 g of benzothiazole was dissolved in 15 ml of dry tetrahydrofuran. After cooling to −78° C. in an atmosphere of nitrogen gas, 6.4 ml of 1.56 M solution of n-butyllithium in hexane was added. After stirring for 5 minutes, 8 ml of a solution of 1.35 g of 5-(dimethoxymethyl)-2-fluorobenzaldehyde in dry tetrahydrofuran was added, followed by stirring for 10 minutes. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=3:7), to give 1.8 g of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#N)=[CH:9][CH:8]=1)=[O:6])[CH3:2].C(O)=[O:17]>[Ni]>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:17])=[CH:9][CH:8]=1)[OH:6])[CH3:2]
Reactant: O=CO
Reactant: CCOC(=O)C(=O)c1ccc(C#N)cc1
Agent: [Ni]
Product: CCOC(=O)C(O)c1ccc(C=O)cc1

Procedure:
A mixture of (4-cyano-phenyl)-oxo-acetic acid ethyl ester 0.41 g, 2.0 mmol) in 25 mL of 90% formic acid and a large excess of Raney nickel (50% slurry in water) was refluxed for 1 hr. The solid was filtered off and the liquid was concentrated. The crude material was purified by silica gel chromatography (5˜100% ethyl acetate/hexane) to give 0.35 g of (4-formyl-phenyl)-hydroxy-acetic acid ethyl ester as an oil.
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:10][CH:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][CH3:24])=[C:19]([NH2:25])[CH:18]=2)=[N:15][NH:14][C:13](=[O:26])[CH2:12]1.C1COCC1>C(O)(=O)C>[CH3:10][CH:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]3[N:23]([CH3:24])[C:1]([C:2]4[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=4)=[N:25][C:19]=3[CH:18]=2)=[N:15][NH:14][C:13](=[O:26])[CH2:12]1
Reactant: O=C(O)c1ccncc1
Reactant: CNc1ccc(C2=NNC(=O)CC2C)cc1N
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1CC(=O)NN=C1c1ccc2c(c1)nc(-c1ccncc1)n2C
Reaction time: 16 h

Procedure:
A mixture of 12.3 g of isonicotinic acid, 23.2 g of 5-methyl-6-(3-amino-4-methylaminophenyl)-4,5-dihydropyridazin-3-one, 16.2 g of N,N'-carbonyldiimidazole and 600 ml of THF is stirred at 25° for 16 hours. After the usual working up, an oily mixture of 5-methyl-6-(3-amino-4-N-methylisonicotinamidophenyl)- and 5-methyl-6-(3-isonicotinamido-4-methylaminophenyl)-4,5-dihydropyridazin-3-one is obtained and is dissolved in 400 ml of acetic acid. After the solution has been boiled for 3 hours, then cooled and submitted to the usual working up, 5-methyl-6-[1-methyl-2-(4-pyridyl)-5-benzimidazolyl]-4,5-dihydropyridazin-3-one is obtained; dihydrochloride, decomposition above 298°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.C1(C(C2C=CC=CC=2)=CC[N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]3=[O:32])[CH2:19][CH2:18]2)C=CC=CC=1.F[C:40]1[CH:47]=[CH:46][C:43]([CH:44]=[O:45])=[CH:42][CH:41]=1>CN(C)C(=O)C.C(Cl)Cl>[OH:45][CH:44]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:43]1[CH:46]=[CH:47][C:40]([N:17]2[CH2:18][CH2:19][CH:20]([N:23]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]3=[O:32])[CH2:21][CH2:22]2)=[CH:41][CH:42]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C1c2ccccc2CN1C1CCN(CC=C(c2ccccc2)c2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: O=C1c2ccccc2CN1C1CCN(c2ccc(C(O)c3ccccc3)cc2)CC1
Temperature: 125 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
Potassium carbonate (10.6 g, 76.5 mmol) was added to a solution of Example 2 Part A compound (15.0 g, 69.6 mmol) and 4-fluorobenzaldehyde (Aldrich) (8.61 g, 69.6 mmol) in N,N-dimethylacetamide (100 mL) and the reaction was stirred at 125° C. for 24 h, then cooled to RT. The reaction was dissolved in CH2Cl2 (500 mL) and washed with water (4×180 mL) and brine (2×200 mL), then dried over MgSO4. Evaporation gave a solid mass. The crude product was triturated with EtOAc (10 mL), then washed with EtOAc (10 mL) and filtered to give title compound (17.8 g, 80%) as a white solid (mp 211-214° C.).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:9]1[O:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1>CN(C=O)C>[N:1]1([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCNC1
Reactant: Clc1nc2ccccc2o1
Solvent: CN(C)C=O
Product: c1ccc2oc(N3CCCNCC3)nc2c1
Reaction time: 1 h

Procedure:
A 978 mg portion of homopiperazine was dissolved in 3 ml of DMF. Under cooling with ice, 500 mg of 2-chloro-benzoxazole was added to the thus prepared solution, and the reaction was carried out for 1 hour at the same temperature and then for 24 hours at room temperature. The reaction solution was concentrated under a reduced pressure, and the resulting residue was dissolved in 200 ml of ethyl acetate, washed with sodium hydrogencarbonate aqueous solution (pH 8) and water in that order, dehydrated with sodium sulfate and then concentrated under a reduced pressure. Thereafter, the resulting residue was purified by a silica gel column chromatography (chloroform:methanol=10:1) to obtain 540 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12]/[CH:13]=[CH:14]/[CH2:15]O)=[CH:10][C:9]([CH3:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:18])[NH:7]2.B(F)(F)F.C(=O)(O)[O-].[Na+].O>ClCCCl>[CH3:17][C:9]1[CH:10]=[C:11]2[CH2:12][CH:13]([CH:14]=[CH2:15])[O:1][C:2]2=[C:3]2[C:8]=1[NH:7][C:6](=[O:18])[CH:5]=[CH:4]2
Reactant: Cc1cc(C/C=C/CO)c(O)c2ccc(=O)[nH]c12
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: C=CC1Cc2cc(C)c3[nH]c(=O)ccc3c2O1
Temperature: 60 °C
Reaction time: 5 h
Yield: 97.5 %

Procedure:
5-Hydroxy-6-(trans-4-hydroxy-2-butenyl)-8-methylcarbostyril (2.6 g) was suspended in 1,2-dichloroethane (50 ml). Boron trifluoride.ether complex (7.5 ml) was added to the suspension, and the mixture was stirred at 60° C. for 5 hours. After the reaction, saturated sodium bicarbonate (50 ml) was added thereto, followed by stirring at room temperature for 1.5 hours. Water was added thereto and extraction was performed with chloroform. The extract was dried and condensed under reduced pressure, and the residue was recrystallized from a solvent mixture of chloroform-ether. As a result, 2.35 g of 5-methyl-2,3,6,7-tetrahydro-2-vinylfuro[2,3-f]quinoline-7-one was obtained as pale brown powdery crystals (97.6%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10]([NH:12][NH2:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].CO[C:27]1[C:32]2[N:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[N:35]=[CH:36][C:31]=2[CH2:30][CH2:29][N:28]=1.CO>C(OCC)C>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10](=[O:11])[NH:12][NH:13][C:27]1[C:32]2[N:33]=[C:34]([C:37]([F:39])([F:40])[F:38])[N:35]=[CH:36][C:31]=2[CH2:30][CH2:29][N:28]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC1=NCCc2cnc(C(F)(F)F)nc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NN)Cc1cc(F)c(F)cc1F
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NNC1=NCCc2cnc(C(F)(F)F)nc21)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
A mixture of 150 mg (0.433 mmol) of tert-butyl[(1R)-3-hydrazino-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamate (Intermediate 4), 100 mg (0.433 mmol) of 8-methoxy-2-(trifluoromethyl)-5,6-dihydropyrido[3,4-d]pyrimidine (Intermediate 5) and 4 mL of anhydrous methanol was stirred at room temperature for 5.5 h and then diluted with diethyl ether. The solid was collected on a filter and dried to give the title compound. LC-MS 547 (M+1).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]2=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>O1CCCC1>[CH2:25]([Sn:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:21][CH2:22][CH2:23][CH3:24])[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:5]2=[N:4][CH:3]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1cnc2ncccn12
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc2ncccn12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a cooled (−78° C.) solution of 3-bromoimidazo[1,2-α]pyrimidine (500 mg, 2.5 mmol) in tetrahydrofuran (20 ml) was added isopropylmagnesium chloride (1.39 ml of a 2.0M solution in tetrahydrofuran, 2.78 mmol). After stirring for 5 min tri-n-butyltin chloride (0.8 ml, 2.90 mmol) was added and the reaction stirred for 10 min at −78° C. then allowed to warm to ambient temperature to give a solution of 3-tributylstannylimidazo[1,2-α]pyrimidine in tetrahydrofuran: m/z (ES+) 407, 409, 411 (M++H).
Reaction SMILES: [CH2:1]([CH:3]1[C:8]([C:9]2[CH:24]=[CH:23][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:25])[CH2:4]1)[CH3:2].Br[CH:27]([CH3:33])[CH:28]([O:31][CH3:32])[O:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CC(=O)OCC>[CH3:30][O:29][CH:28]([O:31][CH3:32])[CH:27]([CH3:33])[O:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[O:15][C:11]3[CH:10]=[C:9]([C:8]4[CH:3]([CH2:1][CH3:2])[CH2:4][C:5](=[O:25])[NH:6][N:7]=4)[CH:24]=[CH:23][C:12]=3[N:13]=2)=[CH:17][CH:18]=1
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(O)cc3)oc2c1
Reactant: COC(OC)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OC(C)C(OC)OC)cc3)oc2c1

Procedure:
146 mg (435 μmol) 5-ethyl-6-[2-(4-hydroxy-phenyl)-benzoxazol-6-yl]-4,5-dihydro-2H-pyridazin-3-one, 910 mg (4.89 mmol) 2-bromo-1,1-dimethoxy-propane, 720 mg (5.21 mmol) potassium carbonate and 5 ml DMF are stirred overnight at 150° C. under protective gas. Then the mixture is diluted with EA, and extracted with 10% sodium carbonate solution and then with sat. saline solution. The solv. of the org. phase is eliminated i.V. The residue is purified on silica gel (eluant: DCM/methanol)
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:33]([CH2:35][NH2:36])[OH:34]>>[OH:34][CH2:33][CH2:35][NH:36][C:2]1[C:7]([S:8]([N:11]2[CH2:12][CH2:13][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:21]=[CH:22][C:23]([O:26][C:27]([F:28])([F:30])[F:29])=[CH:24][CH:25]=4)[CH2:16][CH2:15]3)[CH2:31][CH2:32]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2
Reactant: NCCO
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1NCCO)CC2

Procedure:
The title compound was prepared in analogy to example 189 from 8-(2-chloro-pyridine-3-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 188) and ethanolamine. White gum. MS (ESI): 515.3 (MH+).
Reaction SMILES: [H-].[Na+].C1(C)C=CC=CC=1.[C:10]([NH2:16])(=[O:15])[CH2:11][C:12]([NH2:14])=[O:13].[F:17][C:18]([F:25])([F:24])[C:19](OCC)=O>C(O)CCC>[OH:13][C:12]1[CH:11]=[C:10]([OH:15])[N:16]=[C:19]([C:18]([F:25])([F:24])[F:17])[N:14]=1
Reactant: NC(=O)CC(N)=O
Reactant: CCOC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: Oc1cc(O)nc(C(F)(F)F)n1
Reaction time: 16 h
Yield: 44.5 %

Procedure:
Sodium hydride (900 g, 57.5% dispersion in mineral oil; 518 g active NaH; 22.5M) was stirred with 7.5 L toluene in a 22 L round-bottomed flask. Butanol was added over 5 hr. so that the pot temperature was maintained at 40°. The mixture was stirred an additional 16 hr. Malonamide (765 g; 7.5 M) was added, followed by ethyl trifluoroacetate (1065 g; 7.5 M). The ensuing reaction was exothermic; the mixture was then heated on a steam-bath for 3.5 hrs. It was then stirred at 23°-25° for an additional 16 hrs. The mixture was extracted with water (1×4 L and 1×2 L). The combined aqueous extracts were treated with activated charcoal and filtered. The filtrate was maintained at 10°-15° as it was acidified to pH 1-2 with 37% hydrochloric acid. The mixture was chilled to 5°. The solid was isolated by filtration and dried at 50° in vacuo to give 600 g (44.4% yield) VI m.p. 255°-256° (Lit. 265°).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14](=[O:32])[NH:15][C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].F[C:35]1[CH:36]=[CH:37][C:38]([N+:42]([O-:44])=[O:43])=[C:39]([NH2:41])[CH:40]=1>>[C:1]([O:5][C:6](=[O:33])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14](=[O:32])[NH:15][C:16]2[CH:17]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:19]=[C:20]([O:22][C:35]3[CH:36]=[CH:37][C:38]([N+:42]([O-:44])=[O:43])=[C:39]([NH2:41])[CH:40]=3)[CH:21]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)Nc2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)Nc2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc([N+](=O)[O-])c(N)c3)c2)CC1

Procedure:
Using {trans-4-[3-(4-cyano-phenoxy)-5-hydroxy-phenylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester (1.5 g, 5.29 mmol) and 5-fluoro-2-nitro-phenylamine (0.91 g, 5.82 mmol) following the procedure of Example 42(b) afforded 1.6 g of the required product 1H NMR (DMSO-d6): δ 1.45 (9H, s), 1.8 (4H, m), 2.5 (4H, m), 3.2 (1H, m), 6.48 (2H, m), 6.75 (1H, d), 7.24 (2H, m), 7.51 (4H, m), 7.78 (2H, d), 8.05 (1H, d), 8.38 (1H, d).
Reaction SMILES: Cl.[OH:2][N:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:6][N:5]=[C:4]1[Cl:15].[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19]>>[Cl:15][C:4]1[N:3]([O:2][C:18](=[O:19])[N:17]([CH3:16])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)=[CH:6][N:5]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Cc1ccc(-c2cnc(Cl)n2O)cc1
Agent: Cl
Product: Cc1ccc(-c2cnc(Cl)n2OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title compound was prepared from 1-hydroxy-2-chloro-5-(4-methylphenyl)imidazole, hydrochloride and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (80%, oil).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[Li]CCCC.CCCCCC.[Cl:23][C:24]1[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[CH:42][C:25]=1[O:26][C:27]1[CH:28]=[CH:29][C:30]([N+:39]([O-:41])=[O:40])=[C:31]([CH:38]=1)[O:32][CH:33]([CH3:37])[C:34](Cl)=[O:35].Cl>O1CCCC1>[Cl:23][C:24]1[CH:45]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:43]=[CH:42][C:25]=1[O:26][C:27]1[CH:28]=[CH:29][C:30]([N+:39]([O-:41])=[O:40])=[C:31]([CH:38]=1)[O:32][CH:33]([CH3:37])[C:34](=[O:35])[CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[C:10]#[N:11]
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)C(C#N)c1ccc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.93 g of 2,4-dichlorophenylacetonitrile in 30 ml of anhydrous tetrahydrofuran (hereinafter abbreviated as "THF") was cooled to -78° C. To this solution was added 3.5 ml of a 1.6Mn BuLi-hexane solution. Then, a THF solution of 2.12 g of 2-[5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrophenoxy]propionic acid chloride was added thereto dropwise. The mixed solution was stirred for 30 minutes, then acidified with a 10% hydrochloric acid aqueous solution, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered and concentrated with a rotary evaporator.
Reaction SMILES: Br.[NH2:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH2:7][CH2:8]1)[CH2:5][CH2:4]2.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[F:27][C@@H:28]1[CH2:32][N:31]([C:33](=[O:45])[CH2:34]OS(C2C=CC=CC=2)(=O)=O)[C@H:30]([C:46]#[N:47])[CH2:29]1>O>[CH2:14]([O:13][C:11]([C:6]12[CH2:5][CH2:4][C:3]([NH:2][CH2:34][C:33]([N:31]3[CH2:32][C@@H:28]([F:27])[CH2:29][C@H:30]3[C:46]#[N:47])=[O:45])([CH2:10][CH2:9]1)[CH2:8][CH2:7]2)=[O:12])[CH3:15]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)COS(=O)(=O)c1ccccc1
Reactant: CCOC(=O)C12CCC(N)(CC1)CC2
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Reaction time: 1 h
Yield: 82.6 %

Procedure:
Ethyl 4-aminobicyclo[2.2.2]octane-1-carboxylate hydrobromide (612 mg), potassium carbonate (608 mg) and N,N-dimethylformamide (4 mL) were mixed together. To this mixture, (2S,4S)-4-fluoro-1-[2-(benzenesulfonyloxy)acetyl]pyrrolidine-2-carbonitrile (625 mg) was added at 40° C. and the mixture was further stirred for 1 hour. Subsequently, water (10 mL) was added and the resulting crystal was collected by filtration. This product was washed with water (5 mL) and dried at 50° C. under reduced pressure to give (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]ac etyl]-4-fluoropyrrolidine-2-carbonitrile as a colorless powder (581 mg, 83% yield). This compound was identical to the compound obtained in Example 7.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]3[N:15]=[C:14]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH:13]=[N:12][CH:11]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:22]CCl>>[Cl:22][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[C:8]([C:10]3[N:15]=[C:14]([N:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[CH:13]=[N:12][CH:11]=3)[CH:9]=2)[NH:1][CH:2]=1
Reactant: c1cc2cc(-c3cncc(N4CCOCC4)n3)cnc2[nH]1
Reactant: ClCCl
Product: Clc1c[nH]c2ncc(-c3cncc(N4CCOCC4)n3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 4-(6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yl)morpholine (148) (40 mg, 0.142 mmol, 1.0 eq) in dichloromethane (6 mL) was added n-chlorosuccinamide (38 mg, 0.283 mmol, 2.0 eq) and the resulting reaction mixture was stirred at room temperature overnight. After completion of the reaction the solvents were removed and extracted into CH2Cl2. The organic layer was separated and the aqueous phase was extracted with CH2Cl2 to retain the crude material. The combined organic layer was washed with brine solution and dried over sodium sulphate and the solvents were removed by rotary evaporator. The crude material was purified by flash column with 100-200 mesh silica gel employing 70% EtOAc/hexane eluents to obtain the pure off-white colored solid of 4-(6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yl)morpholine 149 (10 mg). 1H NMR (400 MHz, CDCl3) δ: 9.0 (s, 1H), 8.83 (s, 1H), 8.52 (s, 1H), 8.45 (s, 1H), 8.10 (s, 1H), 7.34 (d, J=2.31 Hz, 1H), 3.89 (m, 4H), 3.70 (m, 4H); MS m/z 315.9 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:10]=[N:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.C(OC([N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH:36]=[C:35]([NH2:37])[CH:34]=[N:33]2)[CH2:28][CH2:27]1)=O)(C)(C)C>COCCO>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[C:6]3[N:7]=[C:2]([NH:37][C:35]4[CH:34]=[N:33][N:32]([CH:29]5[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]5)[CH:36]=4)[N:3]=[CH:4][C:5]=3[N:10]=[N:9]2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-n2nnc3cnc(Cl)nc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(N)cn2)CC1
Solvent: COCCO
Product: COc1ccc(-n2nnc3cnc(Nc4cnn(C5CCNCC5)c4)nc32)cc1
Temperature: 25 °C

Procedure:
A solution of 183 mg (0.70 mmol) 5-chloro-3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (from example 2) and 186 mg (0.70 mmol) 4-(4-amino-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester in 1.8 ml 2-methoxy-ethanol is stirred for 4 hours at 100° C. The reaction mixture is cooled to room temperature, concentrated under vacuum and the residue is chromatographed on a silica gel column with dichloromethane/methanol as eluent giving two products: