Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:51])[NH:7][C@H:8]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=3)[CH2:19][CH2:18]2)=[CH:13][N:12]([CH2:32][C:33]2[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:36]=[CH:35][C:34]=2[F:43])[C:11]1=[O:44])([CH3:4])([CH3:3])[CH3:2].[N:52]([Sn](CCCC)(CCCC)CCCC)=[N+:53]=[N-:54]>C1(C)C=CC=CC=1.ClCCl>[C:1]([O:5][C:6](=[O:51])[NH:7][C@H:8]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[NH:54][N:53]=[N:52][N:31]=4)[CH:25]=3)[CH2:19][CH2:18]2)=[CH:13][N:12]([CH2:32][C:33]2[C:38]([C:39]([F:40])([F:41])[F:42])=[CH:37][CH:36]=[CH:35][C:34]=2[F:43])[C:11]1=[O:44])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(N2CCN(Cc3cccc(C#N)c3)CC2)cn(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(N2CCN(Cc3cccc(-c4nnn[nH]4)c3)CC2)cn(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
{(R)-2-[5-[4-(3-cyano-benzyl)-piperazin-1-yl]-3-(2-fluoro-6-trifluoromethyl-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (35 mg, 0.049 mmol), and azidotributyl tin (IV) (16 μl, 0.059 mmol) were dissolved at 120° C. for 10 hrs in toluene (1 mL) with stirring. The solution was cooled to room temperature, followed by the addition of azidotributyl tin (IV) (20 μl, 0.074 mmol) thereto and stirring at 120° C. for an additional 2 hrs. The solution was cooled to room temperature, diluted in dichloromethane, and washed with an aqueous saturated ammonium chloride solution and an aqueous saturated sodium chloride solution in the order. The organic layer thus formed was separated and concentrated, and the residue was purified using silica gel chromatography (eluent: dichloromethane/methanol, 6/1) and dried in a vacuum to afford 20 mg of the compound as a colorless oil (yield 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6](OCC)=[O:7].O.[NH2:24][NH2:25]>C(O)C>[Cl:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([NH:24][NH2:25])=[O:7]
Reactant: CCOC(=O)COc1ccc(C2=NNC(=O)NC2C)cc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC1NC(=O)NN=C1c1ccc(OCC(=O)NN)c(Cl)c1
Reaction time: 4 h
Yield: 76.3 %

Procedure:
A solution of 1.0 g of ethyl α-[2-chloro-4-(2,3,4,5-tetrahydro-5-methyl-3-oxo-1,2,4-triazin-6-yl)phenoxy]acetate (prepared as described in Example 5) and 0.39 g of 80% hydrazine hydrate in 10 ml of ethanol was stirred on an oil bath kept at 105° C. for 4 hours. The mixture was then cooled, after which the crystals which precipitated were collected by filtration and recrystallized from ethanol, to give 0.73 g of the title compound as white crystals melting at 252°-254° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.[NH2:8][C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[N:8][C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[CH2:11][N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: Nc1ccccc1CN1CCOCC1
Reactant: O=C1CCCCN1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: c1ccc(N=C2CCCCN2)c(CN2CCOCC2)c1

Procedure:
A mixture of 2-piperidone (3.6 g) in benzene (30 ml), 4-(2-aminobenzyl)morpholine (5.7 g) in benzene (20 ml) and phosphorus oxychloride (3.6 ml) was heated at 65°-70° C. for 48 hours to yield 4-[2-(2-piperidinylideneamino)benzyl]morpholine (m.p. 108°-110° C.) which was recrystallised from hexane.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH2:15][C:16]([NH:18][CH:19]([CH2:23][NH:24][C:25]([CH:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])[C:20](O)=[O:21])=[O:17])(=[O:13])=[O:12].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[O:42]1[CH2:43][CH2:44][N:39]([C:20]([CH:19]([NH:18][C:16](=[O:17])[CH2:15][NH:14][S:11]([C:2]2[CH:1]=[CH:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:3]=2)(=[O:12])=[O:13])[CH2:23][NH:24][C:25]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]3[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=3)[CH2:29][CH2:28]2)=[O:26])=[O:21])[CH2:40][CH2:41]1
Reactant: O=C(CNS(=O)(=O)c1ccc2ccccc2c1)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)O
Reactant: C1COCCN1
Product: O=C(CNS(=O)(=O)c1ccc2ccccc2c1)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCOCC1
Yield: 36 %

Procedure:
Using an analogous procedure to that described in Example 20, 2-[2-(2-naphthalenesulphonamido)acetamido]-3-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]propionic acid was reacted with morpholine to give N-{1-morpholinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]-ethyl}-2-(2-naphthalenesulphonamido)acetamide in 36% yield.
Reaction SMILES: O[C:2]1[C:3]2[N:13]=[CH:12][CH:11]=[CH:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.P(Cl)(Cl)([Cl:16])=O.C(#N)C>CN(C)C=O>[Cl:16][C:2]1[C:3]2[N:13]=[CH:12][CH:11]=[CH:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc(O)c2ncccc2n1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c2ncccc2n1
Reaction time: 0.17 h
Yield: 85.8 %

Procedure:
A mixture of 19.0 g (98 mmol) of 4-hydroxy-2-methylthiopyrido[3,2-d]pyrimidine, 36.5 mL (60 g, 390 mmol) of phosphorus oxychloride and 200 mL of acetonitrile was prepared and heated to reflux with stirring. Since not much appeared to happen, about 1 mL of N,N-dimethylformamide was added. The solids then all went into solution in about 10 min. After about 2 hours, the volatiles were removed by evaporation under reduced pressure and the residue was diluted with dichloromethane. The resulting mixture was carefully washed with water, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was diluted with hexane and the solids were recovered by filtration and dried to obtain 17.8 g of the title compound melting at 120°-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH3:9])=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:29]1[C:30]([CH3:36])=[CH:31][C:32]([Cl:35])=[N:33][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:29]1[CH:34]=[N:33][C:32]([Cl:35])=[CH:31][C:30]=1[CH3:36]
Reactant: Cc1cc(Cl)ncc1Br
Reactant: CN(C(=O)c1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1)c1ccccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc(Cl)ncc1-c1cc(C(=O)N(C)c2ccccc2O)ccc1Cl
Temperature: 100 °C
Yield: 119.2 %

Procedure:
A mixture of 4-chloro-N-(2-hydroxy-phenyl)-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (100 mg, 0.26 mmol, Step 8A), 5-bromo-2-chloro-4-methyl-pyridine (200 mg, 0.52 mmol), Pd(PPh3)4 (30 mg, 0.026 mmol), K2CO3 (180 mg, 1.3 mmol) in dioxane (2.5 mL), was heated at 100° C. for 12 hrs. The mixture was dried in vacuo in the presence of silica gel and directly chromatographed on silica gel (eluent: ethyl acetate/hexane (1/4 up to 2/3)) to yield 4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide (120 mg). MS [M+H]+: 387.0; tR=2.27 min. (method 1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].[OH:20][CH:21]([CH:24]1[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]1)[CH2:22][NH2:23]>O1CCOCC1>[OH:20][CH:21]([CH:24]1[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]1)[CH2:22][NH:23][C:13](=[O:15])[CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:16]([F:19])([F:18])[F:17])[CH:4]=1
Reactant: CC1(C)OCC(C(O)CN)O1
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Solvent: C1COCCO1
Product: CC1(C)OCC(C(O)CNC(=O)CS(=O)(=O)Nc2ccc(F)c(C(F)(F)F)c2)O1

Procedure:
Analogously to the instructions for Example 9(a), 2.21 g (7 mmol) of 2-[N-(4-fluoro-3-trifluoromethyl-phenyl)sulfamoyl] acetic acid in dioxane is reacted with 1.13 g (7 mmol) of 2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamine for about 1 hour at 90° C. After concentration by evaporation and crystallization from ethanol/ether, 2.87 g=92.3% of the theoretical yield is obtained as a crystallizate. Melting point 144°-146° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2([CH2:21][NH:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26]Cl)[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].O>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:28])[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCCl)NCC1(CCN2CCN(Cc3ccccc3)CC2)CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCCN1CC1(CCN2CCN(Cc3ccccc3)CC2)CCCC1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a stirred solution of N-[[1-[2-(4-benzyl-1-piperazinyl)ethyl]cyclopentyl]methyl]-4-chlorobutanamide (664 mg) in dimethylformamide(5.5 ml) was added sodium hydride(60% in oil, 98 mg) at room temperature and the mixture was stirred at 70° C. for 5 hours. After cooling down, water (3 ml) was added and the organic layers were extracted with ethyl acetate (15 ml). The extract was washed with brine (4 ml), dried over magnesium sulfate filtered and concentrated in vacuo. The residue was purified by column chromatography (NH2 gel, 230-400 mesh/20 g/hexane:ethyl acetate=2:1-1:2) to give a yellow oil (408 mg/67%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3].[C:22]([O:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:24])[CH3:23]>C(Cl)Cl.CN(C=O)C>[C:22]([O:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[Cl:11])=[CH:30][CH:29]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OCCc1ccccc1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)OCCc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
To a solution of commercially available 5-bromo-2-chlorobenzoic acid (5 g, 21.23 mmol) in 30 mL of anhydrous DCM was added a catalytic amount of DMF followed by oxalyl chloride (1.95 mL, 22.3 mmol) and stirred for 2 h at room temperature. A mixture of aluminum trichloride (3.68 g, 27.6 mmol) and phenethyl acetate (3.38 mL, 21.23 mmol) in 15 mL DCM was cooled in an ice-bath and the acid chloride was transferred to it using a canula. The mixture was stirred at room temperature for 4 h. The mixture was poured into 100 mL of ice-cold water and the organic layer was isolated. The aqueous solution was extracted with 25 mL DCM. The combined organic solution was washed with brine (25 mL) and dried (Na2SO4), filtered and evaporated. Purification on silica gel using an ISCO column with 5:1 hexane:EtOAc followed by 10:1 hexane:EtOAc gave intermediate BF (2.1 g, yield 26%). 1H NMR (300 MHz, CDCl3): δ 8.12 (d, J=2.4 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.59 (d, J=2.7 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.36 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 4.31 (t, J=6.9, 6.6 Hz, 2H), 3.01 (t, J=6.9, 6.6 Hz, 2H), 2.04 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4](=[S:7])[N:3]1[CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=1[CH:17]=O.N1CCCCC1>C(O)C>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=1/[CH:17]=[C:6]1/[C:2](=[O:1])[N:3]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:4](=[S:7])[S:5]/1
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: O=C(O)CCN1C(=O)CSC1=S
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(OC)c(/C=C2\SC(=S)N(CCC(=O)O)C2=O)c1
Yield: 87.4 %

Procedure:
3-(4-oxo-2-thioxothiazolidin-3-yl)propanoic acid (200 mg, 1 mmol), 2,5-dimethoxy benzaldehyde (168 mg, 1 mmol) and piperidine (0.3 mL) were combined in ethanol (3 mL) and irradiated in the microwave at 100° C. for 10 minutes. The reaction was cooled, the solid was collected by filtration, washed with ethyl acetate/hexanes (1/1) and recrystallized from ethanol to afford 85% yield of the title compound (309 mg, brown-orange solid). MS (M+H, 284); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 2.57 (t, 2H)), 3.74 (s, J=6.8 Hz, 3H), 3.84 (s, 3H), 4.19 (t, 2H), 6.90 (s, 1H), 7.10 (s, 2H), 7.86 (s, 1H).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:17])(=[O:16])[N:13]([CH3:15])[CH3:14])[CH:6]=1)=[O:4].[CH2:18]([NH:20][C:21]([NH:23][CH2:24][CH3:25])=[S:22])[CH3:19]>>[BrH:1].[CH2:24]([N:23]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:17])(=[O:16])[N:13]([CH3:15])[CH3:14])[CH:6]=2)([OH:4])[CH2:2][S:22][C:21]1=[N:20][CH2:18][CH3:19])[CH3:25]
Reactant: CCNC(=S)NCC
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Product: Br
Product: CCN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)N(C)C)c2)N1CC

Procedure:
6.8 g of 2-bromo-4'-chloro-3'-dimethylsulfamoylacetophenone and 2.7 g of 1,3-diethylthiourea were reacted as prescribed in Example 23. The solvent was decanted and the oily precipitate of the end product was crystallized under fresh acetone. Colorless solid body, decomposition beginning at 154° C, γ C=N 1610 cm-1.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:13])[C:4](=[O:12])[C@H:5]([CH2:7][S:8]([CH3:11])(=[O:10])=[O:9])[NH2:6].C(N(CC)CC)C.S=[C:22]1[CH2:26][S:25][C:24](=[O:27])[NH:23]1>C(O)C>[CH3:2][N:3]([CH3:13])[C:4](=[O:12])[C@H:5]([CH2:7][S:8]([CH3:11])(=[O:9])=[O:10])[NH:6][C:22]1[CH2:26][S:25][C:24](=[O:27])[N:23]=1
Reactant: CN(C)C(=O)[C@@H](N)CS(C)(=O)=O
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@H](CS(C)(=O)=O)NC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
To a solution of N,N-dimethyl-3-(methylsulfonyl)-L-alaninamide hydrochloride (923 mg) and triethylamine (1.07 mL) in ethanol (10 mL) was added 4-thioxothiazolidin-2-one (533 mg) at room temperature. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (150 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[F:38]C1C=CC=CC=1B(O)O>>[F:38][C:6]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[C:8]1[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=1[N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[N:21]([CH3:36])[CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=3)[N:24]=2)[CH2:16][CH2:15]1
Reactant: OB(O)c1ccccc1F
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccccc2F)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 2-fluorophenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=515, obsd.=515).
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:17]1([CH2:23][CH2:24][CH2:25][NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[C:1]1([O:7][C:8](=[O:9])[NH:26][CH2:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NCCCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NCCCc1ccccc1)Oc1ccccc1
Reaction time: 24 h

Procedure:
Chloroformic acid phenyl ester (3.29 g, 21.0 mmol.) and pyridine (1.74 g, 22.0 mmol.) were added to a solution of 3-phenylpropylamine (2.7 g, 20.0 mmol.) in abs. DCM (50 ml), and stirring was carried out for 24 h at RT. For working up, the mixture was washed in succession with water (2×20 ml), 1M HCl (2×20 ml) and 1N NaOH (2×20 ml) and then the organic phase was dried, filtered and concentrated. (3-Phenylpropyl)carbamic acid phenyl ester was obtained in a yield of 4.11 g by recrystallisation from EE/hexane (1:1) (white solid, m.p. 55–56° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2([CH3:13])[CH3:12])=[CH:5][CH:4]=1.C(O)(=[O:16])C>C(O)(=O)C.O.[O-2].[O-2].[O-2].[Cr+6]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6](=[CH:5][CH:4]=1)[C:7](=[O:16])[CH2:8][C:9]2([CH3:13])[CH3:12]
Reactant: CC(=O)O
Reactant: COc1ccc2c(c1)C(C)(C)CC2
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 6-methoxy-1,1-dimethyl-indan (1 g, 5.67 mmol) in acetic acid (5 mL) is cooled to 0° C. and treated with a solution of chromium trioxide (1.3 g, 13 mmol) in acetic acid/H2O (5 mL/4 mL). Then the reaction mixture is allowed to warm to ambient temperature and stirred for 3 h. The reaction mixture is diluted and extracted with ethyl acetate (3×20 mL). The combined organic phases are washed with saturated aqueous NaHCO3 and brine and dried over Na2SO4. Evaporation of solvent affords 5-methoxy-3,3-dimethyl-indan-1-one as a yellow oil: ESMS m/z 191.1 (M+H+).
Reaction SMILES: [N:1]([C@H:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)=[N+]=[N-].O.O.Cl[Sn]Cl>CO>[Br:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[C@H:4]([NH2:1])[CH2:5][CH2:6]2
Reactant: [N-]=[N+]=N[C@@H]1CCc2cc(Br)ccc21
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: N[C@@H]1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A solution of (R)-1-azido-5-bromo-indane (154 g, 0.645 mol) was dissolved in methanol (2.4 L) and SnCl2.2H2O (265 g, 1.18 mol) was added. The mixture was stirred at room temperature overnight (TLC indicated no starting material) and was concentrated to dryness. The resulting residue was treated with 2N aqueous NaOH (2.5 L) and EtOAc (1.5 L). The mixture was stirred for 1 hour and filtered through Celite® with the aid of EtOAc (3×250 ml). The organic solution was separated and the aqueous layer was extracted with EtOAc (3×2 L). The combined organic extracts were washed with 1 N HCl (2×2 L) followed by water (2 L). The pH of the combined aqueous layers was adjusted to 11 with cold saturated NaOH solution and the mixture was extracted with EtOAc (3×2 L). The combined organic extracts were dried over MgSO4, filtered and concentrated to give (87.5 g, 64.0%) (1R)-5-bromoindan-1-amine as a dark yellow oil which solidified upon refrigeration. MS (ES+) 213.9 (M+H)+. 1H NMR (CDCl3) δ 1.70-1.75 (m, 1H), 2.40-2.45 (m, 1H), 2.77-2.82 (m, 1H), 2.93-2.97 (m, 1H), 4.28-4.33 (m, 1H), 7.18-7.23 (m, 1H), 7.36-7.41 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([OH:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[C:3]1=[O:16].[H-].[Na+].[CH2:19](Br)[CH3:20].O>CN(C)C=O>[CH3:1][N:2]1[CH2:6][CH:5]([O:7][CH2:19][CH3:20])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[C:3]1=[O:16]
Reactant: CN1CC(O)N(c2ccc(Cl)c(Cl)c2)C1=O
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC1CN(C)C(=O)N1c1ccc(Cl)c(Cl)c1
Temperature: 10 °C
Yield: 82.1 %

Procedure:
Dissolved in 100 ml of dimethylformamide was 10.4 g (0.04 mole) of 1-methyl-3-(3,4-dichlorophenyl)-4-hydroxyimidazolidine-2-one. The solution was cooled to 10° C. and 2 g (0.04 mole) of sodium hydride was added to the solution with stirring. After the addition, the mixture was stirred for 30 minutes and 4.4 g of ethyl bromide was added dropwise. The mixture was stirred at room temperature for 2 hours and water was added to the reaction mixture. The mixture was extracted with chloroform and the chloroform extract was concentrated, giving 9.5 g of an oil in 82.1% yield.
Reaction SMILES: [NH2:1][C@@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[S:4][CH2:5][C:6]([CH:14]=[O:15])=[C:7]2[C:11]([OH:13])=[O:12].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[C:28]([NH:47][C:48]1[S:49][CH:50]=[C:51](/[C:53](=[N:57]/[O:58][CH3:59])/[C:54](Cl)=[O:55])[N:52]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>C(#N)C.C(Cl)Cl>[OH:15][CH:14]1[C:6]2[CH2:5][S:4][CH:3]3[CH:2]([NH:1][C:54](=[O:55])[C:53]([C:51]4[N:52]=[C:48]([NH:47][C:28]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[S:49][CH:50]=4)=[N:57][O:58][CH3:59])[C:9](=[O:10])[N:8]3[C:7]=2[C:11](=[O:13])[O:12]1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(C=O)CS[C@H]12
Reactant: CO/N=C(\C(=O)Cl)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CON=C(C(=O)NC1C(=O)N2C3=C(CSC12)C(O)OC3=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.17 h

Procedure:
10 g of 7-amino-3-formyl-3-cephem-4-carboxylic acid in 200 ml of acetonitrile: methylenchloride (1:1) are treated with 37.4 ml of N,O-bis(trimethylsilyl)acetamide at room temperature within ca. 5 minutes. After ca. 30 minutes the reaction mixture is cooled to −10° and 21 g of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetic acid chloride are added in 3 portions. The temperature raises to −5°. After ca. 45 minutes the reaction mixture is treated with 4 ml of water. The temperature raises to 20°. The reaction mixture is stirred for ca. 10 minutes and filtered. 15 g of active charcoal are added to this filtrate and stirring is continued for ca. 10 minutes. After filtration the solvent of the filtrate obtained is evaporated. The evaporation residue is treated with tert.butyl-methyl ether. A crystalline, almost colourless precipitate is obtained, filtered off and dried. Crystalline N-(1,4,5a,6-Tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazin-6-yl)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetic acid amide is obtained in form of a diastereomeric mixture in the ratio of ca. 1:1.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][C:8](OC)=O)=[CH:4][CH:3]=1.[Na].[C:15]([NH:18][NH2:19])([NH2:17])=[NH:16].Cl>CO>[NH2:17][C:15]1[N:16]=[C:8]([CH:7]=[CH:6][C:5]2[CH:12]=[CH:13][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:19][N:18]=1
Reactant: N=C(N)NN
Reactant: COC(=O)C=Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: Nc1n[nH]c(C=Cc2ccc(Cl)cc2)n1
Yield: 46 %

Procedure:
The synthesis method of Example 7-(2) was applied. The compound (9.66 g) obtained in (1) above, methanol (140 ml), metallic sodium (5.69 g) and aminoguanidine hydrochloride (27.3 g) were used as reagents to give 4.93 g of a pale-brown solid (yield 46%).