Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[N:19]3[C:20]4[N:12]([C:13](=[O:22])[NH:14][C:15](=[O:21])[C:16]=4[N:17]=[CH:18]3)[CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[N+:27]([C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1)([O-:29])=[O:28]>CN(C)C=O>[N+:27]([C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:14]2[C:15](=[O:21])[C:16]3[N:17]=[CH:18][N:19]4[C:9]([C:5]5[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=5)=[CH:10][CH2:11][N:12]([C:20]=34)[C:13]2=[O:22])=[CH:32][CH:31]=1)([O-:29])=[O:28]
Reactant: O=c1[nH]c(=O)n2c3c1ncn3C(c1cccc(C(F)(F)F)c1)=CC2
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2ncn3c2n(c(=O)n1Cc1ccc([N+](=O)[O-])cc1)CC=C3c1cccc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To a stirred suspension of 5.0 g of 4-[3-(trifluoromethyl)phenyl]-6H,8H-pyrimido[1,2,3-cd]purine-8,10-(9H)-dione (prepared as described in Example 41) in 50 ml of dry N,N-dimethylformamide at room temperature, under nitrogen, was added 800 mg of sodium hydride (60% dispersion in mineral oil). The mixture was stirred for 2 hours, then 3.3 g of p-nitrobenzyl bromide in 10 ml of N,N-dimethylformamide was added and the mixture was stirred at room temperature for 40 hours. The mixture was evaporated to dryness, then was treated with water. The solid formed was collected by filtration, washed with water and dried in vacuo. The solid was stirred with 200 ml of dichloromethane and filtered. The filtrate was passed through a short column of magnesium silicate and the eluate was evaporated in vacuo to give 4.34 g of the product of the example which was recrystallized from isopropyl alcohol/acetonitrile as a white solid, mp 230°-232° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13](=[O:37])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([C:29](=[O:36])[C:30]#[C:31][C:32]([OH:35])([CH3:34])[CH3:33])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2I)[CH:15]=1>>[CH3:11][O:12][C:13](=[O:37])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)/[C:30](=[C:31](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[C:32]([OH:35])([CH3:34])[CH3:33])/[C:29]2=[O:36])[CH:15]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#CC(C)(C)O)c2ccccc2I)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(/c3ccc(Cl)cc3)C(C)(C)O)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 84 starting from 4-chlorophenylboronic acid (commercially available) and 3-{[(4-hydroxy-4-methyl-pent-2-ynoyl)-(2-iodo-phenyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (400 MHz, DMSO-d6) δppm 1.30 (s, 6H) 3.83 (s, 3H) 5.14 (s, 2H) 5.43 (d, J=7.58 Hz, 1H) 6.68 (t, J=7.58 Hz, 1H) 7.01 (d, J=7.83 Hz, 1H) 7.12 (t, J=7.45 Hz, 1H) 7.27 (d, J=8.34 Hz, 2H) 7.51 (t, J=7.71 Hz, 1H) 7.58-7.65 (m, 4H) 7.87 (d, J=7.58 Hz, 1H) 7.97 (s, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1.F[C:16]1[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([C:28]([NH:30][C:31]2[CH:32]=[N:33][C:34]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:35][CH:36]=2)=[O:29])[CH:22]=1)=[O:19]>C1COCC1.C(Cl)Cl>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:18]([C:17]2[CH:44]=[C:45]([C:48]([F:51])([F:49])[F:50])[CH:46]=[CH:47][C:16]=2[O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH3:7])[CH2:9][CH2:10]2)=[O:19])=[CH:22][C:23]=1[C:28]([NH:30][C:31]1[CH:36]=[N:35][C:34]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N:33][CH:32]=1)=[O:29]
Reactant: Cc1ccc(NC(=O)c2cc(C(F)(F)F)ccc2F)cc1C(=O)Nc1cnc(Nc2ccccc2)nc1
Reactant: CN1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cc(C(F)(F)F)ccc2OC2CCN(C)CC2)cc1C(=O)Nc1cnc(Nc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of potassium t-butoxide (17 mg, 0.151 mmol) in THF (2 mL) was added 1-methylpiperidin-4-ol (15 mg, 0.130 mmol). The mixture was allowed to stir at rt for 15 min, at which time 2-fluoro-N-(4-methyl-3-(((2-(phenylamino)-5-pyrimidinyl)amino)carbonyl)phenyl)-5-(trifluoromethyl)benzamide 40 (55 mg, 0.108 mmol) was added. The reaction mixture was stirred at room temperature for 24 h, at which time the LCMS showed complete conversion. The reaction mixture was diluted with CH2Cl2, washed with water (3×20 mL), dried over Na2SO4 and concentrated. The crude residue was taken up in MeOH/DMSO and purified on the Shimadzu reversed phase HPLC with a 15-85% gradient. Pure fractions were combined, basified with saturated sodium bicarbonate and extracted with CH2Cl2 (4×20 mL). Combined organic extracts were dried over sodium sulfate and concentrated to afford 2-methyl-5-(((2-((1-methyl-4-piperidinyl)oxy)-5-(trifluoromethyl)phenyl)carbonyl)amino)-N-(2-(phenylamino)-5-pyrimidinyl)benzamide 41. MS m/z found 605.3 [MH+]; calc. for C32H31F3N6O3=604.24.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13]CC)=[O:12])=[CH:4][CH:3]=1.[OH-].[Na+].C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)CC(=O)Nc1ccc(Br)cc1
Reaction time: 24 h

Procedure:
The product of Step 1 (16.63 g) was dissolved in THF (150 mL) and 2N NaOH (145 mL) was added over 15 minutes. The reaction was stirred for 24 hours. The reaction mixture was concentrated to remove the THF. Diethyl ether (20 mL) was added and the layers were separated. The aqueous layer was acidified to pH=2.2 with 1N HCl which resulted in the precipitation of solids. Ethyl acetate was added until the solids were dissolved and the layers were separated. The organic extract was dried with sodium sulfate, filtered and concentrated to give 14.7 g of a cake.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([S:14][Si](C(C)C)(C(C)C)C(C)C)[CH:7]=1)[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl[CH2:45][C:46](=[O:48])[CH3:47]>C1COCC1>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([S:14][CH2:45][C:46](=[O:48])[CH3:47])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(S[Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: CC(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(OC)c(SCC(C)=O)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(4-Methoxy-3-triisopropylsilanylsulfanyl-phenyl)-acetic acid ethyl ester (2.5 g, 6.53 mmol) was dissolved in THF (40 mL) and cooled to 0° C. Tetrabutylammonium fluoride (6.6 mL, 1.0M in THF, 6.6 mmol) was added and the reaction stirred for 15 minutes, after which time analytical TLC indicated complete reaction. Chloroacetone (0.520 mL, 6.53 mmol) was then added and the reaction was allowed to warm to room temperature. When analytical TLC indicated the reaction was complete, it was submitted to standard workup procedures then purified via silica gel chromatography to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:22]2[CH2:24][CH2:23]2)=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[C:6]=2[C:18]([NH:20][CH3:21])=[O:19].[F:25][CH:26]([F:31])[S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([N:7]2[C:6]([C:18]([NH:20][CH3:21])=[O:19])=[C:5]3[C:9]([CH:10]=[C:2]([NH:1][S:27]([CH:26]([F:31])[F:25])(=[O:29])=[O:28])[C:3]([CH:22]4[CH2:24][CH2:23]4)=[CH:4]3)=[N:8]2)=[CH:16][CH:15]=1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N)cc2nn1-c1ccc(Br)cc1
Reactant: O=S(=O)(Cl)C(F)F
Solvent: c1ccncc1
Product: CNC(=O)c1c2cc(C3CC3)c(NS(=O)(=O)C(F)F)cc2nn1-c1ccc(Br)cc1
Reaction time: 72 h
Yield: 69 %

Procedure:
Compound (47) was prepared by the following method: To a suspension of 6-amino-2-(4-bromophenyl)-5-cyclopropyl-N-methyl-2H-indazole-3-carboxamide (20 mg, 0.052 mmol) in neat pyridine (1 mL) at 0° C. was added difluoromethanesulfonyl chloride (60 μL). After 3 d, the reaction was quenched with saturated aqueous ammonium chloride (1 mL) and then extracted with ethyl acetate (3×2 mL). The combined organics were washed with 1M aqueous citric acid (2 mL), brine (2 mL) then dried (MgSO4) and concentrated to dryness to afford crude 2-(4-Bromophenyl)-5-cyclopropyl-6-{[(difluoromethyl)sulfonyl]amino}-N-methyl-2H-indazole-3-carboxamide (18 mg, 69%) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C@H:6]([N:13]1[CH:17]=[C:16]([CH:18]=[O:19])[NH:15][C:14]1=[S:20])[CH2:7]2.[CH3:21][Mg]Cl.S(=O)(=O)(O)O>>[OH:19][CH:18]([C:16]1[NH:15][C:14](=[S:20])[N:13]([C@H:6]2[CH2:5][CH2:4][C:3]3[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=3[F:1])[CH2:7]2)[CH:17]=1)[CH3:21]
Reactant: C[Mg]Cl
Reactant: O=Cc1cn([C@H]2CCc3c(F)cc(F)cc3C2)c(=S)[nH]1
Agent: O=S(=O)(O)O
Product: CC(O)c1cn([C@H]2CCc3c(F)cc(F)cc3C2)c(=S)[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
A mixture of (S)-3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-5-carbaldehyde (178 mg, 0.6 mmol), prepared as in Example 22, and methylmagnesium chloride (3M, 0.4 mL, 1.2 mmol) was stirred at approximately 0° C. for 1 hour and at approximately 25° for an additional 1 hour. The mixture was treated with 5 mL of dilute sulfuric acid and extracted with ethyl acetate (2×). The combined extracts were dried (MgSO4) and concentrated and the residue was purified by flash chromatography on silica gel eluting with methylene chloride/methanol (98:2). The purified residue was further purified by preparative thin layer chromatography on silica gel eluting with methylene chloride/methanol (95:5) to give (S)-4-(1-hydroxy)ethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (22 mg, 0.1 mmol), m.p. 210°-211° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([OH:48])(=[O:47])[CH2:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45]>CC(OC)(C)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([O-:48])(=[O:47])[CH2:41][CH2:42][CH2:43][C:44]([O-:46])=[O:45]
Reactant: O=C(O)CCCC(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Solvent: COC(C)(C)C
Product: O=C([O-])CCCC(=O)[O-]
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Nilotinib base (0.300 g, 0.57 mmol) was dissolved in TFE (2 mL) at 40° C. to obtain a mixture. The mixture was stirred and added to a solution of glutaric acid (0.037 g, 0.28 mmol) in TFE (1 mL) at 40° C. The resulting clear solution was stirred for about 4 h at 40° C. and the solution was subsequently cooled to 5° C. The mixture was kept at 5° C. overnight and then MTBE (1.5 v/v) was added to the mixture at room temperature leading to precipitation. The precipitate was filtered and the filter cake was dried at 40° C. in a vacuum oven overnight to give Nilotinib glutarate form II.
Reaction SMILES: [C:1]([C:3]1[O:7][C:6]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:5]=2[C:4]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:2].B#B.Cl>O1CCCC1>[ClH:12].[NH2:2][CH2:1][C:3]1[O:7][C:6]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:5]=2[C:4]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#Cc1oc2ccc(Cl)cc2c1-c1ccccc1
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Product: NCc1oc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
Treat 2.0 g. of 2-cyano-5-chloro-3-phenylbenzo[b]furan (0.008 mole) in 30 ml. of tetrahydrofuran with 18 ml. of diborane in tetrahydrofuran (1 M solution) and reflux for 2 hours. Cool, add 10 ml. of 10% hydrochloric acid and reflux for 1/2 hour. Evaporate the solution to dryness and dissolve the residue in 50 ml. of ethanol. Add 30 ml. of ethanol saturated with hydrogen chloride. Dry the precipitate obtained to yield the title compound; m.p. 254°-256°.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:6]=1)=[NH:4].[S:25]([C:29]1[S:30][C:31]([C:34](O)=O)=[CH:32][CH:33]=1)(=[O:28])(=[O:27])[NH2:26]>>[F:14][C:11]([F:12])([F:13])[C:9]1[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=2)[N:6]=[C:5]([C:3]2[N:4]=[C:34]([C:31]3[S:30][C:29]([S:25]([NH2:26])(=[O:28])=[O:27])=[CH:33][CH:32]=3)[O:1][N:2]=2)[N:10]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)s1
Reactant: N=C(NO)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Product: NS(=O)(=O)c1ccc(-c2nc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)no2)s1

Procedure:
The title compound was prepared from N-hydroxy-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine-2-carboxamidine (example C.2) (0.176 g, 0.5 mmol) and commercially available 2-sulfamoyl-thiophene-5-carboxylic acid [CAS-No. 7353-87-9] (0.104 g, 0.5 mmol) according to the general procedure V. Obtained as a light yellow solid (0.12 g, 46%). MS (ISN) 520.1[(M−H)−]; mp 258.5° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][CH:4]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=1)[NH:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([CH3:16])[CH:10]=2.Cl.[CH3:28][O:29][C:30](=[O:34])[CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CCOC(C)=O>[CH3:28][O:29][C:30](=[O:34])[CH2:31][CH2:32][NH:33][C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([CH:4]([NH:5][C:6]2[CH:7]=[N:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[C:11]([CH3:16])[CH:10]=3)[CH2:3][CH:2]([CH3:26])[CH3:1])=[CH:25][CH:24]=1
Reactant: Cc1ccc2cc(NC(CC(C)C)c3ccc(C(=O)O)cc3)cnc2c1
Reactant: COC(=O)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Nc2cnc3cc(C)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
To a solution of 4-[3-Methyl-1-(7-methyl-quinolin-3-ylamino)-butyl]-benzoic acid (44 mg, 0.13 mM) in DCM (1 mL) was added TEA (63.6 mg, 0.629 mM) and followed by 3-amino-propionic acid methyl ester hydrochloric acid (6) (26.4 mg, 0.189 mM) and then HBTU (57.3 mg, 0.151 mM). The reaction was stirred at RT for 16 h. The reaction mixture was diluted with EtOAc (5 mL) and washed with water (2×2 mL). The organic layer was separated, dried over Na2SO4 and concentrated. The crude material was separated by a 12 g silica gel column with 10-100% EtOAc in heptane to afford desired product (49 mg, 90%). 1H NMR (500 MHz, CDCl3) δ ppm 0.98 (d, J=6.10 Hz, 3 H) 1.04 (d, J=6.34 Hz, 3 H) 1.61-1.70 (m, 1 H) 1.71-1.86 (m, 2 H) 2.66 (t, 2 H) 2.82 (s, 3 H) 3.68-3.76 (m, 5 H) 4.36 (d, J=4.88 Hz, 1 H) 4.44-4.54 (m, 1 H) 6.73 (d, J=2.20 Hz, 1 H) 6.80 (t, J=5.49 Hz, 1 H) 7.20 (d, J=8.29 Hz, 1 H) 7.35 (d, J=8.54 Hz, 1 H) 7.45 (d, J=8.29 Hz, 2 H) 7.67 (s, 1 H) 7.75 (d, 2 H) 8.45 (d, J=2.44 Hz, 1 H). LC-MS: 434.2 (M+1).
Reaction SMILES: BrC1C=CC(C(N2CCN(C3C(C)=CC(C)=CN=3)CC2)=O)=CC=1F.COC1C=CC(CN2CC(C)NC2=O)=CC=1.[CH3:41][C:42]1[C:43]([N:49]2[CH2:54][CH2:53][N:52]([C:55]([C:57]3[CH:62]=[CH:61][C:60]([N:63]4[CH:67]([CH3:68])[CH2:66][N:65](CC5C=CC(OC)=CC=5)[C:64]4=[O:78])=[C:59]([F:79])[CH:58]=3)=[O:56])[CH2:51][CH2:50]2)=[N:44][CH:45]=[C:46]([CH3:48])[CH:47]=1>>[CH3:41][C:42]1[C:43]([N:49]2[CH2:50][CH2:51][N:52]([C:55]([C:57]3[CH:62]=[CH:61][C:60]([N:63]4[CH:67]([CH3:68])[CH2:66][NH:65][C:64]4=[O:78])=[C:59]([F:79])[CH:58]=3)=[O:56])[CH2:53][CH2:54]2)=[N:44][CH:45]=[C:46]([CH3:48])[CH:47]=1
Reactant: COc1ccc(CN2CC(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cc3F)C2=O)cc1
Agent: COc1ccc(CN2CC(C)NC2=O)cc1
Agent: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NCC4C)c(F)c3)CC2)c(C)c1

Procedure:
Using (4-bromo-3-fluorophenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (157 mg) described in Preparation Example 125 and 1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (106 mg) described in Preparation Example 52 and by the reaction and treatment in the same manner as in Example 506, the title compound (86 mg) was obtained via 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-2-fluorophenyl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one.
Reaction SMILES: O[C@@H:2]1[CH2:11][C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[C@@H:5]([C:12]([O:14][CH3:15])=[O:13])[C:4]([CH3:16])=[CH:3]1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.[OH-].[Na+]>ClCCl>[CH3:16][C:4]1[CH:5]([C:12]([O:14][CH3:15])=[O:13])[C:6]2([CH2:11][CH2:2][CH:3]=1)[CH2:10][CH2:9][CH2:8][CH2:7]2
Reactant: COC(=O)[C@H]1C(C)=C[C@H](O)CC12CCCC2
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C1C(C)=CCCC12CCCC2
Reaction time: 0.75 h
Yield: 90 %

Procedure:
At −30° C., a solution of crude trans-methyl 9-hydroxy-7-methylspiro[4.5]dec-7-ene-6-carboxylate (1.1 g, 4.9 mmol, prepared as described in the Example 23) in dichloromethane (10 ml) was treated with triethylsilane (4.0 ml, 24.5 mmol) and with BF3.OEt2 (0.92 ml, 7.4 mmol). The resulting mixture was stirred for 45 min. while allowing the temperature to reach 0° C., poured into cold 2N aqueous NaOH (50 ml), and extracted twice with MTBE (25 ml). The combined organic phases were washed with water (25 ml), with a saturated aqueous solution of NaCl (25 ml), dried (MgSO4), and concentrated. FC (55 g SiO2, hexane/MTBE 40:1) of the crude product (1 g) gave methyl 7-methylspiro[4.5]dec-7-ene-6-carboxylate (0.92 g, 90%). Boiling point: 98° C. (0.07 mbar).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:9]#[N:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)[OH:21].[OH-].[Na+]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([CH3:11])[C:9]([NH2:10])=[O:21])=[CH:18][CH:19]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: CC(C#N)(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C(N)=O)(c1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
) A mixture of 0.020 mol of p-nitro-α-phenylhydratroponitrile and 28 ml of concentrated sulfuric acid solution (90%) is heated in a water-bath for 3.5 hours. The reaction mixture is poured onto crushed ice, neutralized with a sodium hydroxide solution and the product is extracted with chloroform. The organic layer is washed with water, dried and evaporated in vacuo and the residue is crystallized from either, yielding 2.4 grams of p-nitro-α-phenylhydratropamide. (interm. 7)
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](OCC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O.[NH2:24][NH2:25]>C(O)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH:24][NH2:25])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Reactant: NN
Solvent: CCO
Solvent: O
Product: CN1Cc2c(C(=O)NN)ncn2-c2cccc(Cl)c2C1=O
Yield: 108.5 %

Procedure:
50 g (156.4 mmol) of ethyl 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate were stirred at boiling temperature for 6 hours with 90 ml (1.85 mol) of hydrazine hydrate in 500 ml of ethanol. By cooling to -10°, filtering the suspension under suction and drying the crystallizate there were obtained 51.9 g (100%) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid hydrazide of m.p. 287°.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6]([O-:10])(=[O:9])(=[O:8])=[O:7].[CH3:11][N:12]([C+:14]([N:16]([CH3:18])[CH3:17])Cl)[CH3:13]>O>[Cl:6]([O-:10])(=[O:9])(=[O:8])=[O:7].[CH3:11][N:12]([CH3:13])[C:14]([N:16]([CH3:18])[CH3:17])=[N+:3]([CH2:4][CH3:5])[CH2:1][CH3:2]
Reactant: CCNCC
Reactant: CN(C)[C+](Cl)N(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Product: CC[N+](CC)=C(N(C)C)N(C)C

Procedure:
3.42 g (46.8 mmol) of diethylamine are added with stirring and ice-cooling to 5.00 g (21.3 mmol) of bis(dimethylamino)chlorocarbenium perchlorate. The reaction mixture is subsequently stirred for 1 hour at room temperature and subsequently added to 20 ml of water. The organic phase is separated off and washed with 20 ml of water. The liquid is subsequently dried at 50° C. under reduced pressure (7.0 Pa), giving 5.17 g of N,N,N′,N′-tetramethyl-N″,N″-diethylguanidinium perchlorate, corresponding to a yield of 89.6%.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:4]=1.C[O:16][C:17](=[O:30])[CH2:18][O:19][C:20]1[CH:28]=[CH:27][C:26]([SH:29])=[C:25]2[C:21]=1[CH2:22][CH2:23][CH2:24]2>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[C:3]([CH2:2][S:29][C:26]3[CH:27]=[CH:28][C:20]([O:19][CH2:18][C:17]([OH:30])=[O:16])=[C:21]4[C:25]=3[CH2:24][CH2:23][CH2:22]4)[O:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: ClCc1cc(-c2ccc(Cl)cc2)no1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Product: O=C(O)COc1ccc(SCc2cc(-c3ccc(Cl)cc3)no2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 5-chloromethyl-3-(4-chloro-phenyl)-isoxazole and 12C. mp 92-94° C.; MS m/z 430 (M+1).
Reaction SMILES: [F:1][C:2]1([C:9]([OH:11])=[O:10])[CH:7]2[CH:3]1[CH2:4][CH2:5][C:6]2=[O:8].C(=O)([O-])O.[Na+].[CH2:17](I)[CH3:18].Cl>CN(C)C=O>[F:1][C:2]1([C:9]([O:11][CH2:17][CH3:18])=[O:10])[CH:7]2[CH:3]1[CH2:4][CH2:5][C:6]2=[O:8]
Reactant: O=C1CCC2C1C2(F)C(=O)O
Reactant: CCI
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(F)C2CCC(=O)C21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
(1RS,5RS,6RS)-6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylic acid in an amount of 1.0 g was dissolved in 5.0 mL of N,N-dimethylformamide, and 0.58 g of sodium hydrogencarbonate and 1.5 mL of ethyl iodide were added thereto. The mixture was stirred overnight at 50° C. The reaction mixture was poured into 1M hydrochloric acid, followed by extractions with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200 (produced by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=8:1), thereby yielding 1.1 g of (1RS,5RS,6RS)ethyl 6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH:20]([NH:23]C(=O)C)[CH2:19]3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19]3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)NC1CCN(CCOc2cc(C)n(-c3ccc(Cl)c(Cl)c3)n2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(OCCN2CCC(N)C2)nn1-c1ccc(Cl)c(Cl)c1
Yield: 90.1 %

Procedure:
A solution of N-(1-(2-(1-(3,4-dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy)ethyl)pyrrolidin-3-yl)acetamide (0.1 g, 0.25 mmol) in water (2 ml) and 6N aqueous solution of HCl (2 ml) was refluxed for 5 hrs. The mixture was basified with 20% aqueous solution of NaOH and extracted with dichloromethane. The combined organic solutions was washed with water, dried over Na2SO4, filtered and evaporated to dryness yielding 80 mg of 1-{2-[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazol-3-yloxy]ethyl}pyrrolidin-3-amine as an oil