Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][CH:32]=1)[C:9]([C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[C:14]([C:25]([O:27]CC)=[O:26])=[CH:13][N:12]=1)=[O:10])[CH2:2][CH2:3][CH3:4]>C(O)C.C1COCC1.[OH-].[Na+]>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][CH:32]=1)[C:9]([C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[C:14]([C:25]([OH:27])=[O:26])=[CH:13][N:12]=1)=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(C(=O)c2ncc(C(=O)OCC)c3cc(OC)c(OC)cc23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCOc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OC)c(OC)cc23)c1
Yield: 96 %

Procedure:
The above intermediate, 1-(3-butoxybenzoyl)-6,7-dimethoxy-4-ethoxycarbonyl-isoquinoline (390 mg, 0.89 mmol) was dissolved in a solution of ethanol (10 ml), THF (5 ml) and 4N sodium hydroxide (1 ml). The mixture was refluxed until all starting material was consumed. Solvents were evaporated and 25 ml of water was added. The solution was washed with ethyl ether (2×10 ml). The aqueous phase was neutralized by the addition of 4 ml of 1.0 N hydrochloric acid. The milky mixture was extracted with two 25 ml portions of ethyl acetate. The organic layer was washed with brine. The organic extracts were dried over sodium sulfate, filtered and evaporated to give 350 mg of yellow solid which was stirred in 25 ml of ethyl ether. The solid was filtered and washed with cold ethyl ether to produce 310 mg of the carboxylic acid as a yellow solid 1-(3-Butoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid.
Reaction SMILES: [Li+].[OH-].[NH2:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([CH2:14][C@@H:15]([O:35][C:36]([N:38]2[CH2:43][CH2:42][CH:41]([N:44]3[CH2:50][CH2:49][C:48]4[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=4[NH:46][C:45]3=[O:55])[CH2:40][CH2:39]2)=[O:37])[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]([O:32]CC)=[O:31])[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)=[O:17])=[CH:6][C:5]=1[Cl:56].Cl>O.C1COCC1>[NH2:3][C:4]1[C:9]([C:10]([F:12])([F:11])[F:13])=[CH:8][C:7]([CH2:14][C@@H:15]([O:35][C:36]([N:38]2[CH2:39][CH2:40][CH:41]([N:44]3[CH2:50][CH2:49][C:48]4[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=4[NH:46][C:45]3=[O:55])[CH2:42][CH2:43]2)=[O:37])[C:16]([N:18]2[CH2:19][CH2:20][CH:21]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]3)[CH2:22][CH2:23]2)=[O:17])=[CH:6][C:5]=1[Cl:56]
Reactant: CCOC(=O)C1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC(C(=O)O)CC3)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 7.2 mg (0.3 mmol) LiOH in 1 mL water was added to a solution of 140 mg (0.18 mmol) ethyl 1′-{(R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-4-carboxylate in 1 mL THF and the reaction mixture was stirred for 3 h at RT. 1 mL HCl (1 M) was added and the crude product was purified by HPLC. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:22][C:16]3([CH3:23])[CH2:17][C:18]([OH:21])([CH2:20][C:14]([CH3:24])([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:22][C:16]3([CH3:23])[CH2:17][C:18]([O:21][C:29]([CH2:28][CH2:27][CH2:26][Br:25])=[O:30])([CH2:20][C:14]([CH3:24])([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC12CC3(C)CC(O)(C1)CC(NC(=O)OCc1ccccc1)(C2)C3
Reactant: O=C(Cl)CCCBr
Solvent: CN(C)C=O
Product: CC12CC3(C)CC(NC(=O)OCc4ccccc4)(C1)CC(OC(=O)CCCBr)(C2)C3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(benzyloxy-carbonyl)amino-3,5-dimethyl-7-hydroxyadamantane (100 mg) in DMF (0.4 mL) was added 4-bromobutyryl chloride (0.3 mL). The reaction mixture was stirred for 2 h at room temperature. The mixture was purified by thin layer chromatography eluting with ethyl acetate and hexane (½, v/v) to afford an oily product. 1H NMR (DMSO-d6, ppm): 7.38-7.29 (m, 5 H, C6H5), 7.12 (brs, 1 H, NH), 4.95 (s, 2 H, OCH2), 3.53-3.49 (t, 2 H, J=6.6 Hz, COCH2), 2.36-2.32 (t, 2 H, J=7.7 Hz, CH2Br), 2.10 (s, 2 H), 2.00-1.96 (m, 2 H, CHCH2CH2), 1.66 (s, 4 H), 1.59-1.41 (dd, 4 H, J=11.5, 51.7 Hz), 1.08-1.07 (d, 2 H, J=3.8 Hz), 0.87 (s, 6 H, 2×CH3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:14][C@H:15]([C:17]([NH:19][CH:20]1[C:26](=[O:27])[N:25]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[N:22]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:21]1=[O:40])=[O:18])[CH3:16]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:14][C@H:15]([C:17]([NH:19][CH:20]2[C:21](=[O:40])[N:22]([CH2:36][CH:37]([CH3:38])[CH3:39])[C:23]3[CH:35]=[CH:34][CH:33]=[CH:32][C:24]=3[N:25]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:26]2=[O:27])=[O:18])[CH3:16])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CC(C)CN1C(=O)C(NC(=O)[C@H](C)N)C(=O)N(CC(C)C)c2ccccc21
Agent: Cl
Product: CC(C)CN1C(=O)C(NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)C(=O)N(CC(C)C)c2ccccc21

Procedure:
Following General Procedure I above using 3,5-difluorophenylacetic acid (Lancaster) and 3-(L-alaninyl)amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-S), the title compound was prepared as a white solid (melting point=197-198° C.). Purification was by flash chromatography eluting with CH2Cl2/EtOAc (2:1 gradient to 3:4). Rf=0.23 (CH2Cl2/EtOAc, 1:1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:12][CH:11]3[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH:10]3[CH2:9]2)[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:9][CH:10]3[CH:11]([CH2:13][NH:14][CH2:15]3)[CH2:12]2)[N:3]=1
Reactant: Cc1ncnc(N2CC3CN(C(=O)OC(C)(C)C)CC3C2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncnc(N2CC3CNCC3C2)n1

Procedure:
tert-Butyl 5-(4-methyl-1,3,5-triazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (43 mg, 0.142 mmol), DCM (1.4 mL) and TFA (0.71 mL) were stirred at room temperature for 2 h. The mixture was concentrated in vacuo and taken on to the next step without further purification.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[CH3:14])([CH3:3])[CH3:2].Cl.[NH2:16][OH:17].C([O-])([O-])=O.[Na+].[Na+]>CCO.CCOC(C)=O>[CH:1]([O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([CH:9]=[N:16][OH:17])=[CH:7][C:6]=1[CH3:14])([CH3:3])[CH3:2]
Reactant: Cc1cc(C=O)cc(C)c1OC(C)C
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C=NO)cc(C)c1OC(C)C

Procedure:
4-(Isopropoxy)-3,5-dimethylbenzaldehyde (1.98 g, 10.3 mmol) in EtOH (60 mL) was heated to 60° C. with hydroxylamine hydrochloride (2.4 M aq. solution, 5.2 mL, 1.2 eq.) and Na2CO3 (1.2 M solution, 5.2 mL, 0.6 eq.) at room temperature for 2 hours. The reaction was transferred to a separatory funnel, diluted with EtOAc; the organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated to yield 710 mg (3.24 mmol) of 4-(isopropoxy)-3,5-dimethylbenzaldehyde oxime as a light yellow oil. 1H-NMR (500 MHz, CDCl3): 8.10 (s, 1H), 7.23 (s, 2H), 4.29-4.18 (m, 1H), 2.29 (s, 6H), 1.29 (d, 6H).
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:27]2([CH2:32][NH2:33])[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:33][CH2:32][C:27]2([C:21]3[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:19]([O:18][CH3:17])[CH:20]=3)[CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:14])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C2(CNC(=O)c3ccc(Cc4ccccc4)cc3)CCCC2)cc1OC
Reaction time: 16 h
Yield: 56.1 %

Procedure:
4-Benzyl-benzoic acid (21.2 mg, 0.100 mmol) and C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (23.5 g, 0.100 mmol) were dissolved in acetonitrile (1 mL) containing triethylamine (41.8 μL, 0.300 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (38.0 mg, 0.100 mmol) was added and the solution was allowed to stir for 16 hours. The mixture was then purified by reverse phase preparative liquid chromatography to yield the pure product (24.1 mg, 0.0561 mmol, 56.1%) ESI-MS m/z calc. 429.2, found 430.4 (M+1)+. Retention time of 3.75 minutes.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@@H:2]1[CH2:3][OH:4].N[CH2:9][C@@H:10]1CC[CH2:12][N:11]1CC.C(=O)C>>[CH3:12][NH:11][CH2:10][CH2:9][N:1]1[CH2:7][CH2:6][CH2:5][C@@H:2]1[CH2:3][OH:4]
Reactant: OC[C@H]1CCCN1
Reactant: CCN1CCC[C@H]1CN
Agent: CC=O
Product: CNCCN1CCC[C@@H]1CO

Procedure:
By using D-prolinol (500 mg) as a starting material, the title compound (0.17 g) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 39, (2).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:16]([C:20]#[N:21])=[CH:17][NH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][C:29](F)=[CH:28][C:27]=1[O:33][CH2:34][O:35][CH3:36])[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:22]([O:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][C:29]([N:18]2[CH:19]=[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:16]([C:20]#[N:21])=[CH:17]2)=[CH:28][C:27]=1[O:33][CH2:34][O:35][CH3:36])[CH3:23]
Reactant: N#Cc1c[nH]cc1-c1ccccc1OCc1ccccc1
Reactant: CCOC(=O)c1ccc(F)cc1OCOC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3OCc3ccccc3)c2)cc1OCOC
Temperature: 65 °C
Reaction time: 15 h
Yield: 87.2 %

Procedure:
To a solution of 4-(2-benzyloxyphenyl)-1H-pyrrole-3-carbonitrile (1.5 g), 4-fluoro-2-methoxymethoxybenzoic acid ethyl ester (1.4 g) in N,N-dimethylformamide (25 mL) was added cesium carbonate, and this mixture was stirred at 65° C. for 15 hours. This reaction mixture was poured into water, the precipitated solid was collected by filtration, and washed with water and n-hexane, dried under reduced pressure at 50° C. to give the title compound (2.3 g).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]#[N:7])[CH:3]=[N:2]1.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.CC(C)([O-])C.[K+]>C1COCC1>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:1]2[CH:5]=[C:4]([C:6]#[N:7])[CH:3]=[N:2]2)=[CH:12][CH:11]=1
Reactant: COc1ccc(CBr)cc1
Reactant: N#Cc1cn[nH]c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(C#N)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., 1 g (10.7 mmol) of 1H-pyrazole-4-carbonitrile and 2.4 g (11.8 mmol) of 4-methoxybenzyl bromide were initially charged in 22 ml of THF. 1.3 g (11.8 mmol) of potassium tert-butoxide were added a little at a time, and the reaction was stirred at RT overnight. The precipitated solid was then filtered off, and the mother liquor was freed from the solvent on a rotary evaporator. The residue was dissolved in ethyl acetate and the solution was washed with water and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated. This gave 2 g (87% of theory) of the title compound, which was used without further purification for the subsequent step.
Reaction SMILES: [C:1]12([CH2:11]O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:13][C:14]1[C:18]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)=[C:17]([CH3:28])[NH:16][N:15]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH3:13][C:14]1[C:18]([B:19]2[O:23][C:22]([CH3:24])([CH3:25])[C:21]([CH3:27])([CH3:26])[O:20]2)=[C:17]([CH3:28])[N:16]([CH2:11][C:1]23[CH2:10][CH:5]4[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]4)[CH2:8]2)[CH2:2]3)[N:15]=1
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1nn(CC23CC4CC(CC(C4)C2)C3)c(C)c1B1OC(C)(C)C(C)(C)O1
Reaction time: 8 h

Procedure:
To a solution of 1-adamantanemethanol (0.090 g), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.160 g) and cyanomethylenetributylphosphorane (0.215 g) were added and stirred together in toluene (2 mL) at room temperature. After stirring overnight the reaction was loaded directly onto silica gel and eluted using a gradient of 2% to 20% ethyl acetate/hexanes to provide the title compound.
Reaction SMILES: [OH:1][CH:2]([CH:4]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=O)[CH3:3].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[NH2:46][CH:47]([C:49]1[C:50](=[O:64])[NH:51][C:52]([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][CH:57]=2)=[N:53][N:54]=1)[CH3:48]>>[OH:1][CH:2]([CH:4]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([NH:46][CH:47]([C:49]1[C:50](=[O:64])[NH:51][C:52]([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][CH:57]=2)=[N:53][N:54]=1)[CH3:48])=[O:7])[CH3:3]
Reactant: CC(O)C(CCCc1ccccc1)C(=O)O
Reactant: COc1ccc(Cc2nnc(C(C)N)c(=O)[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: COc1ccc(Cc2nnc(C(C)NC(=O)C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)cc1

Procedure:
1.02 g (4.61 mmol) of 2-(1-hydroxyethyl)-5-phenylpentanoic acid are reacted analogously to Example 39A with 620 mg (4.61 mmol) of 1-hydroxy-1H-benzotriazole, 930 mg (9.22 mmol) of 4-methylmorpholine, 880 mg (4.61 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 1.00 g (3.84 mmol) of 6-(1-aminoethyl)-3-(4-methoxybenzyl)-1,2,4-triazin-5(4H)-one to give 2-(1-hydroxyethyl)-N-{1-[3-(4-methoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-5-phenylpentanamide.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH3:8][C:9]([C:11]([CH3:13])=[CH2:12])=[CH2:10]>C1(C)C=CC=CC=1>[CH3:8][C:9]1[CH2:10][C@H:2]2[C:1]([O:6][C:4](=[O:5])[C@H:3]2[CH2:12][C:11]=1[CH3:13])=[O:7]
Reactant: O=C1C=CC(=O)O1
Reactant: C=C(C)C(=C)C
Solvent: Cc1ccccc1
Product: CC1=C(C)C[C@H]2C(=O)OC(=O)[C@H]2C1
Yield: 92 %

Procedure:
Maleic anhydride (9.8 g, 0.10 mol) and 2,3-dimethylbutadiene (9.84 g, 0.12 mol) were mixed in toluene (50 ml) for 24 h at 50° C. The solution was allowed to cool, the solvent removed in vacuo and the residue recrystallised from petroleum ether (40° C.-60° C.) to yield the title compound in 92% yield. N.m.r: δH (90 MHz, CDCl3) 2.60 (m,2H), 2.14 (m,4H), 1.74 (s,6H).
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[CH3:18][CH:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O>[N:1]1([CH:6]([CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:18])[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(Cl)c1ccccc1
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1ccccc1)C(C(=O)c1ccc(Cl)cc1)n1cncn1

Procedure:
2-(1,2,4-Triazol-1-yl)-4'-chloroacetophenone (0.01 mol) was dissolved in dimethylformamide (5.0 ml) at room temperature and treated with sodium hydride (0.01 mol). When the reaction was complete (3 hours), the mixture was cooled to 0° and α-methylbenzyl chloride (0.01 mol) was added dropwise with stirring. After stirring at room temperature for 20 hours, the mixture was poured into water and the product filtered off. Recrystallisation from chloroform/petroleum ether (60°-80°) gave the title compound as a colourless crystalline solid, m.p. 163°-5°.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[F:9][C:10]([F:28])([F:27])[C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][N:15]1[CH2:19][CH:18]2[C:20](=O)[CH2:21][CH2:22][CH:17]2[CH2:16]1>O.C(O)C>[F:9][C:10]([F:28])([F:27])[C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][N:15]1[CH2:19][CH:18]2/[C:20](=[N:2]/[OH:3])/[CH2:21][CH2:22][CH:17]2[CH2:16]1
Reactant: O=C1CCC2CN(Cc3cccc(C(F)(F)F)c3)CC12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O/N=C1\CCC2CN(Cc3cccc(C(F)(F)F)c3)CC12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydroxylamine hydrochloride (3.47 g, 50.0 mmol) and sodium acetate (4.27 g, 52.0 mmol) were dissolved in 15 mL of water and added to a solution of 2-(3-(trifluoromethyl)benzyl)hexahydrocyclopenta[c]pyrrol-4(5H)-one (11.33 g, 40 mmol) from Step C in ethanol (80 mL). The reaction was brought to reflux for 5 minutes and allowed to cool to 70° C. After 1 hour, the reaction mixture was cooled, and the solvent was removed in vacuo to give (E)-2-(3-(trifluoromethyl)benzyl)hexahydrocyclopenta[c]pyrrol-4(5H)-one oxime which was used without additional purification in the next step.
Reaction SMILES: [N:1]([CH:4]([C:11]1([CH2:15][F:16])[CH2:14][O:13][CH2:12]1)[C:5]1[O:6][C:7]([CH3:10])=[CH:8][CH:9]=1)=[N+]=[N-].[H][H]>C(O)C.[Pd]>[CH3:10][C:7]1[O:6][C:5]([CH:4]([NH2:1])[C:11]2([CH2:15][F:16])[CH2:12][O:13][CH2:14]2)=[CH:9][CH:8]=1
Reactant: [H][H]
Reactant: Cc1ccc(C(N=[N+]=[N-])C2(CF)COC2)o1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C(N)C2(CF)COC2)o1
Yield: 100.4 %

Procedure:
A solution of 2.25 g (10 mmol, 1 eq) of 2-[azido-(3-fluoromethyloxetan-3-yl)methyl]-5-methylfuran in 40 ml of ethanol in the presence of 378 mg (17% by weight) of palladium on carbon at 10% was stirred at hydrogen atmospheric pressure for two and a half hours. The reaction medium was filtered and the filtrate was evaporated. 2.0 g of C-(5-methylfuran-2-yl)-C-(3-fluoromethyloxetan-3-yl)methylamine were obtained in the form of a grayish oil. Yield=100%. TLC SiO2/Heptane:EtOAc (70/30), developing with KMnO4.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[CH2:20]Br>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH2:20][C:19]2[CH:22]=[CH:23][C:24]([N+:25]([O-:27])=[O:26])=[C:17]([F:16])[CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1F
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: N#Cc1ccc(N(Cc2ccc([N+](=O)[O-])c(F)c2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl) amino]pyrimidine and 3-fluoro-4-nitrobenzyl bromide
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:48])/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)([C:26](=[O:38])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[CH3:25])=[CH:20][CH:19]=1)(C)(C)C.Cl>CO>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:48])/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)([C:26](=[O:38])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][CH:29]=2)[CH3:25])=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccc(C(C)(NCCN2CCOCC2)C(=O)Nc2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: CO
Product: CC(NCCN1CCOCC1)(C(=O)Nc1ccc(C(F)(F)F)cc1)c1ccc(/C=C/C(=O)Nc2ccccc2N)cc1
Yield: 13 %

Procedure:
(E)-[2-(3-{4-[1-(2-Morpholin-4-yl-ethylamino)-1-(4-trifluoromethyl-phenylcarbamoyl)-ethyl]-phenyl}-acryloylamino)-phenyl]-carbamic acid tert-butyl ester (crude material from Example 24) was treated with 1.25M HCl in methanol (2.8 mL) at room temperature for 2 hours. The reaction was quenched slowly with solid sodium bicarbonate until the pH was 6-7. The mixture was diluted in acetonitrile with a small amount of dimethylsulfoxide, passed through a 40 μm pipette filter, and then purified by preparative HPLC to obtain the desired product (35 mg, 13%). MS: calc'd 582 (MH+), exp 582 (MH+). 1H NMR (d6-DMSO, 400 MHz) δ 10.5 (broad s, 1H), 9.39 (s, 1H), 7.88 (d, 2H, J=8.8 Hz), 7.68 (d, 2H, J=8.8 Hz), 7.62 (d, 2H, J=8.4 Hz), 7.57 (d, 2H, J=8.4 Hz), 7.54 (d, 1H, J=15.6 Hz), 7.35 (d, 1H, J=7.6 Hz), 6.92 (t, 1H, J=7.6 Hz), 6.90 (d, 1H, J=15.6 Hz), 6.75 (dd, 1H, J=8.0 Hz, 1.2 Hz), 6.57 (td, 1H, J=8.0 Hz, 1.2 Hz), 4.93 (s, 2H), 3.53 (m, 4H), 3.33 (m, 2H, overlapped with DMSO solvent residual peak), 2.55 (m, 2H), 2.30 (m, 4H), 1.65 (s, 3H).
Reaction SMILES: [ClH:1].[CH2:2]([CH:9]1[CH:14]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:12][NH:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N.[CH2:20]=O.Cl>C(O)=O>[ClH:1].[CH2:2]([CH:9]1[CH:14]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:12][N:11]([CH3:20])[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C=O
Reactant: O=C(O)CC1CCNCC1Cc1ccccc1
Agent: Cl
Agent: N
Solvent: O=CO
Product: CN1CCC(CC(=O)O)C(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
A mixture of 95 g of 3-benzyl-4-piperidine-acetic acid hydrochloride (isomeric mixture), 30 ml of concentrated ammonia solution, 900 ml of 33% formaldehyde solution and 140 ml of 90% formic acid is heated for 18 hours at boiling temperature. After cooling to room temperature and adding 120 ml of concentrated hydrochloric acid, the mixture is evaporated to dryness under reduced pressure and the residue is dried under high vacuum for 5 hours at 100°. The crude 3-benzyl-1-methyl-4-piperidine-acetic acid hydrochloride (isomeric mixture) obtained is further reacted without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[O:13].C(CN)O>O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[C:17]1[NH:11][C:12](=[O:13])[NH:14][C:15]1=[O:16]
Reactant: COc1ccccc1C=O
Reactant: O=C1CNC(=O)N1
Solvent: O
Solvent: NCCO
Product: COc1ccccc1C=C1NC(=O)NC1=O
Reaction time: 4 h
Yield: 90.5 %

Procedure:
A mixture of o-methoxybenzaldehyde (2.00 g., 14.7 moles) and hydantoin (1.47 g., 1 molar ratio) in water (12ml) was heated to 70°; monoethanolamine (1.35 g., 1.5 molar ratio) was then added. The mixture was heated in an oil bath (90°-92° ) and stirred magnetically for 4 hours. Usual workup gave the title compound as an orange solid (2.90 g.), m.p. 174°-179°.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:12])=[N:4][C:5](S(C)=O)=[N:6][C:7]=1[Cl:8].[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[N:14]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[C:3]([NH2:12])=[N:4][C:5]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[N:14]2)=[N:6][C:7]=1[Cl:8]
Reactant: CS(=O)c1nc(N)c(Br)c(Cl)n1
Reactant: c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1nc(-n2ncc3ccccc32)nc(Cl)c1Br
Temperature: 0 °C

Procedure:
To a vigorously stirring suspension of 2 g (7.4 mmol) of 5-bromo-6-chloro-2-(methylsulfinyl)pyrimidine-4-amine (intermediate 3) in 40 ml of DMF, 0.87 g (7.4 mmol) indazole and 1.4 g (4.4 mmol) of cesium carbonate were added. The reaction mixture was stirred at room temperature for 20 minutes. The solution was poured onto 200 ml of ice-water. The resulting precipitate was filtered, washed with cold water and dried. The desired product is obtained as a white solid 1.31 g (54.6%)