Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][N:14]([CH3:16])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[CH2:48][CH2:47][N:46]3[C:39](=[CH:40][C:41]4[CH2:42][C:43]([CH3:50])([CH3:49])[CH2:44][C:45]=43)[C:38]2=[O:51])=[N:24][CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1)(=[O:19])[CH3:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[CH2:48][CH2:47][N:46]3[C:39](=[CH:40][C:41]4[CH2:42][C:43]([CH3:50])([CH3:49])[CH2:44][C:45]=43)[C:38]2=[O:51])=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][N:14]([CH3:16])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: Cn1cnc(Nc2cc(Br)cn(C)c2=O)c1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cn(C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 90 °C
Yield: 94.3 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 268c (150 mg, 0.53 mmol), {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (80.4 mg, 0.21 mmol), Pd(dppf)Cl2 (17.2 mg, 0.021 mmol), K3PO4 (89 mg, 0.42 mmol), sodium acetate (57.1 mg, 0.42 mmol), water (0.2 mL), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90° C. for 2.5 hrs. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (30:1 to 20:1) to afford 268d (110 mg, 37.2%) as brown solid. MS-ESI: [M+H]+ 556.4.
Reaction SMILES: [CH:1]([Br:4])(Br)[Br:2].[CH2:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl>[Br:2][C:1]1([Br:4])[CH2:5][CH:6]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrC(Br)Br
Reactant: C=Cc1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Product: BrC1(Br)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.9 %

Procedure:
In a 1 liter 3-neck flask, bromoform (312 g, 1.23 mol) was added dropwise over 120 min to stirred solution of styrene (100 g, 0.96 mol), benzyltriethylammonium chloride (7 g, 0.031 mol) and powdered potassium hydroxide (80.6 g, 1.44 mol) in dichloromethane (480 mL) at 40° C. The mixture was stirred at 25° C. for 20 h. The reaction mixture was filtered through a short plug of silica and the filtrate was concentrated. The dark residue was distilled at 80° C. under reduced pressure (about 50 Pa) to give the desired product as pale yellow liquid (233 g, yield 88%, purity 98% by HPLC (UV)). 1H NMR (CDCl3, 400 MHz): δ 7.38˜7.42 (m, 3H), 7.29˜7.31 (m, 2H), 2.98˜3.03 (m, 1H), 2.15˜2.20 (m, 1H), 2.04˜2.08 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:18]([NH:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([N:25]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:15]([CH:13]1[CH2:12][CH2:11][C:10]2[C:3]3[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=3[S:8][C:9]=2[CH2:14]1)=[O:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN(C)CCNCc1ccccc1
Reactant: O=C(O)C1CCc2c(sc3ncnc(Cl)c23)C1
Product: CN(C)CCN(Cc1ccccc1)C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1

Procedure:
300 mg (1.12 mmol) (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 31b) were transformed in analogy to example 3 using N′-benzyl-N,N-dimethylethane-1,2-diamine to give after working up and purification 152 mg (32%) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH3:31])[C:26](=[O:32])[CH2:25][CH2:24]3)[CH:20]=1)=O)(C)(C)C.[ClH:33]>CO>[ClH:33].[CH3:31][N:27]1[C:28]2[C:23](=[CH:22][C:21]([C:19]3[CH:18]=[N:17][CH:16]=[C:15]([O:14][CH2:13][C@H:9]4[CH2:10][CH2:11][CH2:12][NH:8]4)[CH:20]=3)=[CH:30][CH:29]=2)[CH2:24][CH2:25][C:26]1=[O:32]
Reactant: CN1C(=O)CCc2cc(-c3cncc(OC[C@H]4CCCN4C(=O)OC(C)(C)C)c3)ccc21
Agent: Cl
Solvent: CO
Product: CN1C(=O)CCc2cc(-c3cncc(OC[C@H]4CCCN4)c3)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 42, reaction of (R)-2-[5-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-yloxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (example 147) with hydrogen chloride (in dixoane) in methanol gave the title compound as a yellow solid. MS: 338.2 (M+H+).
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:18](O)[CH2:19][Cl:20].O>C1(C)C=CC=CC=1.C(OC(C)C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:20][CH2:19][CH2:18][O:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCCl
Reactant: O=C1c2ccccc2C(O)N1c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(OCCCl)N1c1ccccc1
Yield: 73 %

Procedure:
3-(2-Chloroethoxy)-2-phenyl-isoindolin-1-one can be obtained by refluxing a solution of 3-hydroxy-2-phenyl-isoindolin-1-one (22.5 g.) and glycol monochlorohydrin (7.7 g.) in anhydrous toluene (200 cc.) in the presence of p-toluenesulphonic acid (0.5 g.) in a Dean-Stark apparatus. Heating is continued until all the water formed has been entrained azeotropically. The cooled reaction mixture is then washed with 2N sodium hydroxide solution (50 cc.) and then with water (2 × 50 cc.). The organic solution obtained is dried over sodium sulphate and concentrated to dryness under reduced pressure. The residue obtained is taken up in diisopropyl ether (50 cc.) and the insoluble product is filtered off and washed with diisopropyl ether (6 cc.). After drying, 3-(2-chloroethoxy)-2-phenyl-isoindolin-1-one (20.1 g.), which melts at 71° C., is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[CH:6][N+:5]([O-:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: [O-][n+]1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: [O-][n+]1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 80 °C
Yield: 34.5 %

Procedure:
4-Chloropyridine-N-oxide (3.0 g, 23 mmol), 4-trifluoromethylphenylboronic acid (6.57 g, 34.6 mmol), K2CO3 (4.8 g, 35 mmol) and PdCl2(dppf) (470 mg, 0.57 mmol) were stirred in DMSO (40 mL) under vacuum for 30 min. The flask was flushed with nitrogen and the mixture was heated to 80° C. for 10 min. Upon cooling, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried, concentrated and the residue was purified by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 80% methylene chloride over 30 min at 40 mL/min) to provide the title compound (1.90 g, 34%) as a tan solid: ESI MS m/z 240 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:22][NH2:23]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:23][CH2:22][C:21]2[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:19]([O:18][CH3:17])[CH:20]=2)[N:3]=1
Reactant: COc1cc(CN)cc(OC)c1OC
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: COc1cc(CNc2nc(Cl)nc3c2ncn3C2CCCC2)cc(OC)c1OC

Procedure:
2-Chloro-6-(3,4,5-trimethoxybenzylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3,4,5-trimethoxybenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19](O)=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:29]=[C:28]([CH2:30][NH2:31])[N:27]=[CH:26]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19]([NH:31][CH2:30][C:28]4[N:27]=[CH:26][N:25]([CH3:24])[CH:29]=4)=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:9]=[N:8]2)=[CH:22][CH:23]=1
Reactant: Cn1cnc(CN)c1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cn(C)cn1
Yield: 71 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,14-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with with (1-methyl-1H-imidazol-4-yl)methanamine, the title compound was obtained as a white solid in 71% yield: mp 225-226° C. (ethyl acetate/hexane): 1H NMR (300 MHz, CDCl3) δ 8.24 (s, 1H), 7.55 (s, 1H), 7.41-7.32 (m, 2H), 7.08-6.97 (m, 2H), 6.91 (s, 1H), 6.78 (t, J=5.3 Hz, 1H), 4.96 (s, 2H), 4.53 (d, J=5.3 Hz, 2H), 3.70 (s, 3H), 2.64 (s, 3H); MS (ES+) m/z 428.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:31]=[C:5]2[N:6]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:7]([CH3:20])=[C:8]([C:18]#[N:19])[C@@H:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.N1C=CC=CC=1.Cl[C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[O:40]>C1COCC1>[CH3:43][CH:42]([O:41][C:39](=[O:40])[NH:1][C:2]1[N:31]=[C:5]2[N:6]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=3)[C:7]([CH3:20])=[C:8]([C:18]#[N:19])[C@@H:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1)[CH3:44]
Reactant: CC(C)OC(=O)Cl
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)OC(C)C)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (25 mg, 59 μmol) was dissolved in a mixture of abs. THF (2.5 ml) and abs. pyridine (48 μl, 593 μmol, 10 eq.). At room temperature, isopropyl chloroformate (36 mg, 297 μmol, 5 eq.) was added and the mixture was heated at 80° C. for 12 h. Once HPLC analysis showed substantial conversion, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (23.2 mg, 77% of theory).
Reaction SMILES: [H-].[Na+].C(S)C.[Br:6][C:7]1[C:16]2[C:15]([CH3:18])([CH3:17])[CH2:14][CH:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:11]=2[CH:10]=[C:9]([C:22](=[O:24])[CH3:23])[C:8]=1[O:25]C.Cl>CCCCCC.CN(C)C=O>[Br:6][C:7]1[C:16]2[C:15]([CH3:18])([CH3:17])[CH2:14][CH:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:11]=2[CH:10]=[C:9]([C:22](=[O:24])[CH3:23])[C:8]=1[OH:25]
Reactant: COc1c(C(C)=O)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCS
Product: CC(=O)c1cc2c(c(Br)c1O)C(C)(C)CC=C2C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.07 g, 26.64 mmol) was rinsed with hexane and suspended in dry N,N-dimethylformamide (80 mL). To the suspension was added ethanethiol (1.9 mL, 26.6 mmol) and stirred at room temperature for 30 min, which resulted in the formation of a clear solution. A solution of 1-(4-bromo-8-isopropyl-3-methoxy-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)-ethanone (Compound A-103,2.6 g, 7.4 mmol) in N,N-dimethylformamide (10 mL) was added to the solution and the mixture was heated at 130° C. for 5 h. The mixture was cooled to room temperature, acidified with 10% HCl and extracted with diethyl ether. The combined ethereal layers were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 5% ethyl acetate in hexane) to yield the title compound as a brown oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:14])=O)[CH:11]=1)[N:8]=[CH:7][N:6]([C:15]1[CH:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][C:16]=1[CH3:25])[C:5]2=[O:26].[N:27]1C=CC=CC=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>O1CCOCC1>[NH2:27][C:12]([C:10]1[CH:11]=[C:2]([I:1])[CH:3]=[C:4]2[C:9]=1[N:8]=[CH:7][N:6]([C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][C:16]=1[CH3:25])[C:21]([O:23][CH3:24])=[O:22])[C:5]2=[O:26])=[O:14]
Reactant: COC(=O)c1ccc(C)c(-n2cnc3c(C(=O)O)cc(I)cc3c2=O)c1
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c(-n2cnc3c(C(N)=O)cc(I)cc3c2=O)c1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 6-iodo-3-[5-(methoxycarbonyl)-2-methylphenyl]-4-oxo-3,4-dihydroquinazoline-8-carboxylic acid (2.4 g) in 1,4-dioxane (50 ml) was added pyridine (0.42 ml), di-tert-butyl dicarbonate (1.47 g) and NH4HCO3 (0.53 g). The reaction mixture was stirred at 40° C. for 18 hours and concentrated. The resultant white solid was washed with methanol and dried to yield methyl 3-[8-(aminocarbonyl)-6-iodo-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoate as a white solid (2.28 g); NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 3.85 (s, 3H), 7.61 (d, 1H), 8.03 (m, 3H), 8.52 (s, 1H), 8.60 (m, 1H), 8.70 (m, 1H), 9.33 (s, 1H); Mass Spectrum: M+H+ 464.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH:19]=O)[CH:8]=[CH:9][CH:10]=1.[NH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][NH:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:8]=[CH:9][CH:10]=1
Reactant: NCCN1CCOCC1
Reactant: COC(=O)Cc1cccc(-c2c(C=O)cccc2OC)c1
Product: COC(=O)Cc1cccc(-c2c(CNCCN3CCOCC3)cccc2OC)c1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using the following starting materials: (2′-formyl-6′-methoxy-biphenyl-3-yl)-acetic acid methyl ester and 4-(2-aminoethyl)morpholine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11][N:31]2[CH2:30][CH2:29][N:28]([CH:27]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)[CH2:33][CH2:32]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: Fc1ccc(C(OCCN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c2ccc(F)cc2)cc1

Procedure:
A mixture containing 12.7 g of 2-[bis(4-fluorophenyl)methoxy]ethyl chloride, 8.6 g of 1-[bis(4-fluorophenyl)methyl]piperazine, 6.2 g of powdered anhydrous potassium carbonate and 0.5 g of potassium iodide in 90ml of methyl isobutyl ketone is refluxed for 20 hours while stirring. Aftercooling down, the mixture is evaporated under reduced pressure and water and ethyl ether are added to the residue. The ethereal phase is washed with water, dried over anhydrous magnesium sulfate and evaporated. The crude product is purified on a Kieselgel column by using a 2:1 mixture of benzene and chloroform as eluant. The appropriate fractions are combined, evaporated and the residue is recrystallized from ethanol to give the aimed compound, m.p.: 87°-88° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:5](=[O:12])[CH2:4][S:3]1.[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[C:23]([F:30])[C:24]([CH:28]=O)=[CH:25][CH:26]=3)[CH:21]=[N:20]2)=[C:16]([C:33]([F:36])([F:35])[F:34])[CH:15]=1>>[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[C:23]([F:30])[C:24](/[CH:28]=[C:4]4/[C:5](=[O:12])[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:2](=[O:1])[S:3]/4)=[CH:25][CH:26]=3)[CH:21]=[N:20]2)=[C:16]([C:33]([F:34])([F:35])[F:36])[CH:15]=1
Reactant: CS(=O)(=O)NN1C(=O)CSC1=O
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1F
Product: CS(=O)(=O)NN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2F)C1=O

Procedure:
N-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-4-fluoro-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methanesulfonamide was prepared from N-(2,4-dioxothiazolidin-3-yl)methanesulfonamide (from Example 360) and [4-chloro-2-(trifluoromethyl)benzyl]-4-fluoro-1H-indazol-5-carbaldehyde (from Example 347) following General Procedure E.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](OCC)(=[O:18])[CH3:17]>[I-].C([N+](CC)(CC)CC)C>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:17][CH2:16][OH:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CCOC(C)=O
Agent: CC[N+](CC)(CC)CC
Agent: [I-]
Product: OCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 140 °C
Reaction time: 26 h
Yield: 83 %

Procedure:
0.5 gram of dibenzylamine (2.5 mmol), 0.446 gram of ethylenecarbonate (5 mmol) and 0.215 gram of tetraethylammoniumiodide (083 mmol) were mixed together at room temperature. The solid mixture was then heated at 140° C. and the resulting suspension was stirred at this temperature for 26 hours. The reaction mixture was diluted with ethyl acetate and extracted with 10 mL of a 0.5M solution of sodium hydroxide. The aqueous phase was washed with ethyl acetate and the combined organic phases were washed twice with brine. The organic phase was dried on magnesium sulfate, filtered, concentrated under reduced pressure and purified by flash chromatography on silica gel (eluant: ethylacetate/hexane 1/2) to afford 0.5 gram of N,N-dibenzyl-2-aminoethanol (yield: 83%) as an oil.
Reaction SMILES: [Si]([O:8][C@@H:9]([C@H:11]1[C:14](=[O:15])[N:13]([C:16](=[P:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C@@H:12]1[CH2:49][C:50]([C:52]1[CH:64]=[CH:63][C:55]([C:56]([O:58]C(C)(C)C)=[O:57])=[CH:54][CH:53]=1)=[O:51])[CH3:10])(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>>[OH:8][C@@H:9]([C@H:11]1[C:14](=[O:15])[N:13]([C:16](=[P:30]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[C@@H:12]1[CH2:49][C:50]([C:52]1[CH:53]=[CH:54][C:55]([C:56]([OH:58])=[O:57])=[CH:63][CH:64]=1)=[O:51])[CH3:10]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1CC(=O)c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](O)[C@H]1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1CC(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To tert-butyl 4-({(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-ethyl)-1-[2-[(4-nitrobenzyl)oxy]-2-oxo-1-(triphenylphosphoranylidene)ethyl]-4-oxo-2-azetidinyl}acetyl)benzoate (2.703 g, 3.00 mmol) obtained in Step a) was added trifluoroacetic acid (9 ml) under ice-cooling and dissolved it, and the mixture was further stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was dissolved again in chloroform/toluene, and concentrated again under reduced pressure. To the residue was added hexane/diethyl ether, and the mixture was subjected to decantation (three times), and the resulting solid was collected by filtration, washed with hexane, and dried under reduced pressure to give 4-({(2R,3S)-3-[(1R)-1-hydroxyethyl]-1-[2-[(4-nitrobenzyl)oxy]-2-oxo-1-(triphenylphosphoranylidene)ethyl]-4-oxo-2-azetidinyl}acetyl)benzoic acid (2.187 g).
Reaction SMILES: [NH2:1][C:2]1([C:15]([OH:17])=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl.[CH2:19]([O:26][C:27](ON1C(=O)CCC1=O)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>[OH-].[Na+].COCCOC>[CH2:19]([O:26][C:27]([NH:1][C:2]1([C:15]([OH:17])=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(=O)O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(=O)O)CC1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
4-Amino-1-tert-butoxycarbonylpiperidine-4-carboxylic acid (18.0 g) was dissolved in 0.03M aqueous sodium hydroxide (750 mL), and 1,2-dimethoxyethane (100 mL). The pH was adjusted to 9.5 with dilute hydrochloric acid, and the suspension was added to an ice-cold solution of N-(benzyloxycarbonyloxy)succinimide (28.8 g) in 1,2-dimethoxyethane (100 mL). The pH was kept at 9.5 by addition of aq. sodium hydroxide, and the mixture was stirred at room temperature. More N-(benzyloxycarbonyloxy)succinimide (3 g) was added after 7 h, then stirring continued overnight. After evaporation to remove the 1,2-dimethoxyethane, the aqueus residue was extracted with ether then acidified to pH 4 and extracted with ethyl acetate. This extract was washed with dilute hydrochloric acid, water and brine, dried and evaporated. Trituration of the oily residue gave 4-benzyloxycarbonylamino-1-tert-butoxycarbonylpiperidine-4-carboxylic acid (23 g). This acid (9.62 g) was esterified by treatment with alkyl bromide (2.2 mL), potassium carbonate (7.04 g) and potassium iodide (catalytic) in acetone (100 mL) under reflux for 20 h. Evaporation, partitioning of the residue between dichloromethane and water and evaporation of the organic phase gave the alkyl ester (10.2 g). This was then treated with trifluoroacetic acid in dichloromethane (1.5 h, room temp.) to give, after basification of the triflate salt and extraction with dichloromethane/methanol, the piperidine free base (6.58 g).
Reaction SMILES: C[C:2]1[CH:7]=[C:6]([N:8](CC)CC)[CH:5]=[CH:4][C:3]=1[N:13]=[C:14]1[CH:23]=[CH:22][C:21](=[O:24])[C:20]2N=CC=C[C:15]1=2>O.C(O)C>[CH:23]1[C:14](=[N:13][C:3]2[CH:2]=[CH:7][C:6]([NH2:8])=[CH:5][CH:4]=2)[CH:15]=[CH:20][C:21](=[O:24])[CH:22]=1
Reactant: CCN(CC)c1ccc(N=C2C=CC(=O)c3ncccc32)c(C)c1
Solvent: O
Solvent: CCO
Product: Nc1ccc(N=C2C=CC(=O)C=C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Then, a solution prepared by dissolving 285.3 mg of Ni(ClO4)2.6H2O in 50 ml of water, was added under a nitrogen atmosphere to a solution prepared by dissolving 100 mg of 5-(2'-methyl-4'-diethylaminophenylimino)quinoline-8-one obtained above in 50 ml of 99% ethanol, and the mixture was stirred at room temperature for about 30 minutes. Formed precipitates were subjected to suction filtration, washed with water and dried to obtain a metal-containing indoaniline compound having the formula: ##STR9##