Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.[P:14](Cl)([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15]>O1CCCC1.CCCCC>[CH3:8][C:4]1[CH:3]=[C:2]([P:14]([O:19][CH2:20][CH3:21])(=[O:15])[O:16][CH2:17][CH3:18])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(Br)c1
Reactant: CCOP(=O)(Cl)OCC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCOP(=O)(OCC)c1cccc(C)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromotoluene (5 g) in tetrahydrofuran at −78° C. was added tert-butyllithium (35 ml of a 1.7 M solution in pentane). The mixture was stirred at −78° C. for 1 hour and diethl chlorophosphate (5.1 ml) was added. After 2 hours the mixture was warmed to 0° C., quenched with aqueous ammonium chloride and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. Purified by chromatography eluting with 40% ethyl acetate in isohexane. Yield 2.7 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17].CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[K+].[K+].Br[C:36]1[CH:37]=[CH:38][C:39]2[O:44][CH2:43][C:42]([C:45]([O:47][CH3:48])=[O:46])=[CH:41][C:40]=2[CH:49]=1>O1CCOCC1.[Cu]I.CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:36]3[CH:37]=[CH:38][C:39]4[O:44][CH2:43][C:42]([C:45]([O:47][CH3:48])=[O:46])=[CH:41][C:40]=4[CH:49]=3)[N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15]([O:16][CH3:17])=[O:18]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2OC1
Reactant: COC(=O)NCc1cc(-c2cc[nH]n2)ccc1Cl
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)NCc1cc(-c2ccn(-c3ccc4c(c3)C=C(C(=O)OC)CO4)n2)ccc1Cl
Temperature: 100 °C
Yield: 16 %

Procedure:
To a solution of methyl N-[[2-chloro-5-(1H-pyrazol-3-yl)phenyl]-methyl]carbamate (i.e. the product of Step B) (400 mg, 1.50 mmol) in dioxane (16 mL) was added trans-N,N′-dimethylcyclohexane-1,2-diamine (0.30 mmol, 43 mg) under a nitrogen atmosphere. Copper (I) iodide (57 mg, 0.30 mmol) and K2CO3 (1.24 g, 9.05 mmol) were added to the reaction mixture. Methyl 6-bromo-2H-1-benzopyran-3-carboxylate (607 mg, 2.26 mmol) was added to the reaction mixture last. The reaction mixture was heated at 100° C. under a nitrogen atmosphere overnight. After TLC analysis (10% MeOH/CHCl3) showed 80% conversion of the starting material, the reaction mixture was cooled and concentrated under vacuum. The crude residue was purified on a silica gel column with 1% MeOH/CHCl3 as eluent to give compound number 23, a compound of the present invention, (110 mg, 16% yield) as solid.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[CH3:22][N:23]([CH3:39])[C:24]1[N:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[CH2:4][CH2:5][CH2:6][C:2]=3[C:27]3[CH:28]=[N:29][C:24]([N:23]([CH3:22])[CH3:39])=[N:25][CH:26]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: CN(C)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
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: O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3cnc(N(C)C)nc3)CCC2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a degassed stirred solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), 2-(dimethylamino)pyrimidine-5-boronic acid pinacol ester (129 mg, 0.578 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-dimethoxyethane (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to yield 5-(2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)cyclopent-1-enyl)-N,N-dimethylpyrimidin-2-amine. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.8 (d, 2H), 7.3 (s, 1H), 6.98-7.1 (m, 2H), 4.7 (m, 1H), 4.38 (m, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 2.78-3.1 (m, 15H), 2.4 (s, 3H), 2.2 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C=O)C.[H-].[Na+].I[CH:15]1[CH2:21][C:20]([CH3:23])([CH3:22])[C:19]2[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:18]=2[NH:17][C:16]1=[O:31]>>[CH3:22][C:20]1([CH3:23])[C:19]2[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:18]=2[NH:17][C:16](=[O:31])[CH:15]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH2:21]1
Reactant: C1COCCN1
Reactant: CC1(C)CC(I)C(=O)Nc2cc([N+](=O)[O-])ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(N2CCOCC2)C(=O)Nc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Morpholine (0.0726 mL, 0.000833 mol) was dissolved in DMF (45 mL, 0.58 mol) and cooled to 0° C., and to this solution was added Sodium hydride, 60% disp. in mineral oil (40.0 mg). This mixture was allowed to stir for 30 minutes, followed by the addition of 3-Iodo-5,5-dimethyl-8-nitro-1,3,4,5-tetrahydro-1-benzazepin-2-one (300 mg, 0.0008 mol). The reaction was allowed to warm to rt for 16 h. The reaction was quenched by the addition of ice & water, partitioned between water and EtOAc, extracted 3× with 30 mL portions of EtOAc, was dried over MgSO4, filtered, and concentrated under reduced pressure. (87 mg, 30%). LCMS 320 (M+H)
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C[O:15][C:16](=[O:45])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32]C3C=CC(C(F)(F)F)=CC=3Br)[CH:27]=2)=[CH:21][C:20]=1[CH3:44]>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([O:32][C:28]2[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=2)[O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][C:16]([OH:45])=[O:15])=[C:20]([CH3:44])[CH:21]=2)=[C:5]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)[CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3-c3ccc(C(F)(F)F)cc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 89 by using 4-trifluoromethylphenyl boronic acid and 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford about 99 mg (62%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C30H22O4F6 560, found 561 (M+1, 100%).
Reaction SMILES: [CH2:1]([C:7]1[S:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:15]([C:26]1[CH:27]=[N:28][C:29]([C:32]2[CH:37]=[CH:36][C:35](O)=[C:34]([F:39])[CH:33]=2)=[N:30][CH:31]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.N1(C2C=CC=CN=2)CCCC1>[CH2:1]([C:7]1[S:11][C:10]([C:12]([O:14][C:35]2[CH:36]=[CH:37][C:32]([C:29]3[N:30]=[CH:31][C:26]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:27][N:28]=3)=[CH:33][C:34]=2[F:39])=[O:13])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(C(=O)O)s1
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(O)c(F)c2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1ccc(N2CCCC2)nc1
Solvent: ClCCl
Product: CCCCCCCCCCCc1cnc(-c2ccc(OC(=O)c3ccc(CCCCCC)s3)c(F)c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
1.0 g (4.72×10-3 mol) of 5-hexylthiophene-2-carboxylic acid, 1.62 g (4.72×10-3 mol) 4-(5-undecyl-2-pyrimidinyl)-2-fluorophenol, N,N'-dicyclohexylcarbodiimide (DCC) and 0.03 g of pyrrolidinopyridine were dissolved in 30 ml of dichloromethane, followed by stirring overnight at room temperature. After the reaction, the insoluble matter was filtered off, followed by distilling-off of the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (ethanol/ethyl acetate) to obtain 1.86 g of a pure product (Yield: 3.2%) ##STR84##
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][CH2:23][CH:24]=[CH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1>[Pd].O1CCCC1>[CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(OCC=Cc3ccccc3)CC1)O2
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(OCCCc3ccccc3)CC1)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
A suspension of 2,3-dihydro-2,4,6,7-tetramethyl-2-[[4-[(3-phenyl-2-propenyl)oxy]-1-piperidinyl]methyl]-5-benzofuranamine (1.2 g) and 5% palladium on carbon (0.23 g) in tetrahydrofuran (10 mL) was stirred under hydrogen atmosphere at room temperature for 1 hour. The catalyst was then filtered off and the filtrate was concentrated under reduced pressure. The residue was crystallized from hexane to provide 0.36 g of the title compound. Yield 31%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8](O)=[O:9])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)O)nn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ccc(CO)nn1

Procedure:
6-Amino-3-pyridazinecarboxylic acid is converted to the ethyl ester and the ester is reduced with lithium aluminium hydride in tetrahydrofuran to give 6-amino-3-hydroxymethylpyridazine.
Reaction SMILES: C(C1CCC([N:11]([CH2:26][C:27]2[CH:44]=[CH:43][C:30]([C:31]([CH:33]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])[CH:34]3[CH2:36][CH2:35]3)=[O:32])=[CH:29][CH:28]=2)[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[O:13])CC1)(C)(C)C.[C:45](O)([C:47](F)(F)F)=O>ClCCl>[C:27]([CH:45]1[CH2:47][CH2:17][CH:16]([CH:26]([NH:11][C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=2)=[O:13])[C:27]2[CH:44]=[CH:43][C:30]([C:31]([CH:33]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])[CH:34]3[CH2:35][CH2:36]3)=[O:32])=[CH:29][CH:28]=2)[CH2:15][CH2:20]1)([CH3:44])([CH3:28])[CH3:26]
Reactant: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)C(NCCC(=O)O)C3CC3)cc2)C(=O)Nc2ccc(OC(F)(F)F)cc2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C1CCC(C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)c2ccc(C(=O)C(NCCC(=O)O)C3CC3)cc2)CC1
Reaction time: 0.08 h

Procedure:
The above resin bound 3-({4-[1-(4-tert-butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)-ureidomethyl]benzoyl}cyclopropylmethyl)aminopropionic acid (50 mg) was treated with 1 mL 5% TFA in dichloromethane for 1 hour at 25° C. The product was filtered off and the resin was washed with 1 mL dichloromethane. The combined extracts were concentrated in vacuo. The residue was dissolved in 50 μL DMSO+500 μL acetonitrile and purified by preparative HPLC using a Supelcosil ABZ+25 cm×10 mm 5μ column. The starting eluent composition was 5% acetonitrile in water changing over 30 min to 90% acetonitrile in water which was then kept constant for 5 min before going back to the starting composition over 10 min. The flow rate was kept constant at 8 mL/min collecting one fraction per minute. The process was monitored using an UV detector operating at 214 nm. The fractions containing the desired product were combined and evaporated in vacuo to afford the title compound.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:58])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:45]2)[CH:7]([CH3:59])[CH2:6][CH2:5][C:4]1=[O:60])[CH3:2].[C:61]([O:64][CH2:65][C:66](Cl)=[O:67])(=[O:63])[CH3:62]>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:58])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][C:66](=[O:67])[CH2:65][O:64][C:61](=[O:63])[CH3:62])[CH:46]([O:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:45]2)[CH:7]([CH3:59])[CH2:6][CH2:5][C:4]1=[O:60])[CH3:2]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N)C(Oc4ccccc4)C3)C(C)CCC1=O)C(C)CC2OC
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(NC(=O)COC(C)=O)C(Oc4ccccc4)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 17-ethyl-1-hydroxy-12-[2'-(4"-amino-3"-phenoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (42 mg) in dry methylene chloride (0.4 ml) is cooled to 0° C. To this solution is added a solution of acetoxyacetyl chloride (9 mg) in methylene chloride (0.5 ml). The reaction mixture is stirred at 0° C. for 30 minutes, and quenched with a drop of methanol. Purification by preparative tlc on silica gel gives the title compound.
Reaction SMILES: Cl[C:2]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:18])=[N:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].ClC(Cl)Cl.[C-:23]#[N:24].[K+]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[C:2](=[N:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])[C:23]#[N:24]
Reactant: Cc1ccccc1N=C(Cl)c1c(Cl)cccc1Cl
Reactant: [C-]#N
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1N=C(C#N)c1c(Cl)cccc1Cl
Reaction time: 0.5 h

Procedure:
To a stirred solution of 7.45 parts of N-[chloro(2,6-dichlorophenyl)methylene]-2-methylbenzenamine in 150 parts of trichloromethane is added a solution of 4.88 parts of potassium cyanide and 8.5 parts of N,N,N-triethylbenzenemethanaminium chloride in 8 parts of water while stirring vigorously. Stirring is continued for 30 minutes at room temperature. The organic phase is separated, washed twice with water, dried, filtered and evaporated. The residue is dissolved in petroleumether and the solution is decanted from some insoluble tar. The petroleumether is evaporated in vacuo. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 17.5 parts of petroleumether, yielding 2.8 parts of 2,6-dichloro-α-[(2-methylphenyl)imino]benzeneacetonitrile; mp. 55° C.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.S(O[O-])([O-])(=O)=O.[NH4+].[NH4+].[C:22](#N)[CH3:23]>O.C(OCC)C.[N+]([O-])([O-])=O.[Ag+]>[OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[C:11]=1[C:22]1([CH3:23])[CH2:10][CH2:11][CH2:2][CH2:3]1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC#N
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: [Ag+]
Agent: O=S(=O)([O-])O[O-]
Agent: O=[N+]([O-])[O-]
Solvent: CCOCC
Solvent: O
Product: CC1(C2=C(O)C(=O)c3ccccc3C2=O)CCCC1
Temperature: 20 °C

Procedure:
A 50% excess of this acid was added to a stirred solution of 2-hydroxynaphthalene-1,4-dione (1.00 g, 5.7 mmol), and silver nitrate (600 mg) in a mixture of acetonitrile (20 ml) and water (20 ml) at 65° C. and a solution of ammonium peroxysulphate (1.96 g, 8.6 mmol) in water (10 ml) was slowly added to that over a period of 15 minutes. The mixture was heated for a further hour before cooling to room temperature (about 20° C.) and diluting with diethyl ether (50 ml). The organic phase was separated and washed successively with 25 water, dilute aqueous sodium hydrogen carbonate solution, water and saturated sodium chloride solution before drying over magnesium sulphate as set out in Example 3. Filtration and evaporation of the solvent under reduced pressure followed by silica gel column chromatography using 2:1 petrol:diethyl ether as eluant gave 2-hydroxy-3-(1-methylcyclopentyl)naphthalene-1,4-dione (mp 116-118° C.).
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)O)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:20][S:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:31]=1[NH:30][CH:29]=[CH:28]2>ClCCl>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH:4]([CH:1]2[CH2:3][CH2:2]2)[C:28]2[C:27]3[C:31](=[C:23]([CH2:22][S:21][CH3:20])[CH:24]=[CH:25][CH:26]=3)[NH:30][CH:29]=2)=[CH:7][CH:8]=1
Reactant: OC(c1ccc(Cl)cc1)C1CC1
Reactant: CSCc1cccc2cc[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
515 mg (2.82 mmol) of the compound from Example 153A and 0.26 ml (3.39 mmol) of trifluoroacetic acid were added to 500 mg (2.82 mmol) of the compound from Example 8A in 20 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min, the solvent was removed in vacuo, and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 500 mg (50% of theory) of the title compound were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([C:22]([F:25])([F:24])[F:23])=[C:10]2[C:26](O)=[O:27])=[C:5]([O:29][CH3:30])[CH:4]=1)#[N:2].C(N1C=CN=C1)([N:33]1C=CN=C1)=O.N>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([C:22]([F:23])([F:24])[F:25])=[C:10]2[C:26]([NH2:33])=[O:27])=[C:5]([O:29][CH3:30])[CH:4]=1)#[N:2]
Reactant: CCOc1nccc2c1C(c1ccc(C#N)cc1OC)C(C(=O)O)=C(C(F)(F)F)N2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CCOC(C)=O
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1OC)C(C(N)=O)=C(C(F)(F)F)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
180 mg (0.429 mmol) of the compound from Example 38A are introduced into 5 ml of ethyl acetate and, after addition of 87.0 mg (0.537 mmol) of 1,1′-carbonyldiimidazole, stirred at room temperature for two hours. Complete conversion is established by a TLC check. The volatile components are removed in a rotary evaporator, and the residue is taken up in 4 ml of DMF. Then 597 μl of ammonia (28% by weight solution in water, 4.29 mmol) are added, and the reaction mixture is heated at 100° C. in a closed vessel for three hours. After cooling, the solvent is removed under reduced pressure, and the residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 10 mg (5% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:39][CH2:38][CH2:37][CH:36]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])[CH2:35]3)(=[O:32])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC1CCCN(S(=O)(=O)c2ccccc2Br)C1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CC(C)(C)OC(=O)NC1CCCN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)C1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and racemic tert-butyl (1-((2-bromophenyl)sulfonyl)piperidin-3-yl)carbamate. MS (ESI): mass calcd. for C26H30FN5O4S, 527.20; m/z found, 528.3 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.34 (d, J=9.1, 2H), 8.10-8.07 (m, 1H), 8.00 (m, 1H), 7.73-7.68 (m, 1H), 7.64-7.59 (m, 1H), 7.44-7.40 (m, 1H), 7.35-7.29 (m, 2H), 3.30-3.20 (m, 2H), 3.15-3.06 (m, 1H), 2.51-2.40 (m, 1H), 2.30-2.21 (m, 1H), 1.79-1.70 (m, 1H), 1.65-1.56 (m, 1H), 1.39-1.28 (m, 10H), 1.26-1.14 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][CH2:12][OH:13])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1O)([O-:16])=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N+:14]([O-:16])=[O:15])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: OCCCNc1nc(Cl)ncc1Br
Reactant: O=[N+]([O-])c1ccccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1OCCCNc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1.06 g (4.0 mmol) of 3-(5-bromo-2-chloro-pyrimidin-4-ylamino)-propan-1-ol, 0.65 g (4.8 mmol) of 2-nitro-phenol and 1.25 g (4.8 mmol) of triphenylphosphine in 30 ml of THF is mixed under argon at 0° C. with 0.8 ml of DEAD. The reaction mixture is heated to room temperature while being stirred. After 20 hours, the batch is spun in, and the residue is purified by chromatography (hexane/ethyl acetate 3:1, Flashmaster II). 1.15 g (3.0 mmol, corresponding to 74% of theory) of the product is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[N:8][CH:9]=1)(=[O:3])[CH3:2].[Br:15][Si](C)(C)C.O.BrN1C(=O)CCC1=O>ClCCl.C(N(CC)CC)C>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[N:8][CH:9]=1)=[O:3]
Reactant: C[Si](C)(C)Br
Reactant: CC(=O)c1ccc(-n2ccnc2)nc1
Agent: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)c1ccc(-n2ccnc2)nc1
Temperature: 25 °C
Yield: 19.7 %

Procedure:
87 mg (corresponding to 0.462 mmol) of 5-acetyl-2-(1H-imidazole-1-yl)pyridine was dissolved in 3.0 mL of dichloromethane and 193 μL of triethylamine, and then 120 μL (corresponding to 0.924 mmol) of bromotrimethylsilane was dropped under ice cooling. The resulting solution was stirred over night at room temperature under argon gas atmosphere, and then the reaction solution was supplemented with water and extracted 3 times with dichloromethane. The combined dichloromethane layer was washed with water and a saturated saline solution, and dried over magnesium sulfate. The solvent was distilled off, the resulting residue was dissolved in 3.0 mL of tetrahydrofuran, and 82.2 mg (corresponding to 0.462 mmol) of N-bromosuccinimide was added thereto under ice cooling. The resulting solution was stirred at room temperature for 30 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by flash silica gel column chromatography (elution solvent: dichloromethane/ethyl acetate=2/1), to obtain 24.3 mg (corresponding to 0.091 mmol) of 5-(2-bromoacetyl)-2-(1H-imidazole-1-yl)pyridine (FIG. 3, step 2).