Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:43](COCC[Si](C)(C)C)[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([CH2:24][NH:25]C(=O)OCC4C5C=CC=CC=5C5C4=CC=CC=5)=[N:22][CH:23]=3)[C:15]=2[CH:14]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(N)CN>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:43][C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([CH2:24][NH2:25])=[N:22][CH:23]=3)[C:15]=2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(CNC(=O)OCC5c6ccccc6-c6ccccc65)n43)n1COCC[Si](C)(C)C)cn2C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: NCCN
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(CN)n43)[nH]1)cn2C
Temperature: 85 °C

Procedure:
To a round bottom flask was added (9H-fluoren-9-yl)methyl (7-(5-methoxy-1-methyl-1H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)methylcarbamate (0.300 g, 0.429 mmol, prepared using J.1 from Preparation #I.1 with 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)acetic acid and L.1 with mercury(II) trifluoroacetate), DMF (10 mL), TBAF (1.0 M in THF, 1.72 mL, 1.72 mmol) and ethylenediamine (0.870 mL, 12.9 mmol). The mixture was heated to about 85° C. for about 6 h. The mixture was cooled to rt and concentrated in vacuo. The crude material was purified by flash chromatography (120 g silica gel column, DCM/MeOH 1:0 to 10:1). The solid was purified by reverse phase preparatory HPLC (Table 2, Method e) to give fractions with the title compound. The fractions were combined and concentrated in vacuo until a precipitate formed. The solid was collected by vacuum filtration and then dried under reduced pressure at about 60° C. for about 16 h to give (7-(5-methoxy-1-methyl-1H-indol-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)methanamine (0.021 g, 14%): LC/MS (Table 2, Method a) Rt=1.53 min; MS m/z 347 (M+H)+. Syk IC50=B.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=2[F:24])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2cc(F)c(F)cc2F)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2cc(F)c(F)cc2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
2.09 g of 5-(4-chlorophenyl)-6-methyl-4-(2,4,5-trifluorophenyl)-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 2.10 g of 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(2,4,5-trifluorophenyl)pyridazine (hereinafter, referred to as compound (vii) of the present invention).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[Cl:17][S:18](O)(=[O:20])=[O:19]>>[Cl:17][S:18]([C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16])(=[O:20])=[O:19]
Reactant: COc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: O=S(=O)(O)Cl
Product: COc1ccc(-c2ccc(C#N)cc2)cc1S(=O)(=O)Cl

Procedure:
(The used starting compound is prepared by reacting 4'-cyano-4-methoxy-biphenyl with chloro sulfonic acid)
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:20]([CH2:29][CH3:30])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1.C(#N)C>[Pd].CO>[CH2:29]([C:20]1[N:21]([CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:13]2[C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:19]=1)[CH3:30]
Reactant: CCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC1CCOCC1
Agent: [Pd]
Solvent: CO
Solvent: CC#N
Product: CCc1nc2cnc3cc(O)ccc3c2n1CC1CCOCC1
Reaction time: 16 h
Yield: 94.6 %

Procedure:
7-(Benzyloxy)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (8.3 g, 20.7 mmol) was added to a Parr vessel containing 10% palladium on carbon (1.5 g) wetted with acetonitrile. Methanol (160 mL) was added and the vessel was placed on the hydrogenator. The vessel was degassed three times and charged with 50 psi (3.4×105 Pa) hydrogen. The vessel was allowed to shake for 16 hours, replenishing the hydrogen as needed. The catalyst was removed by filtration through glass fiber filter paper. The catalyst was washed with 3:1 chloroform/methanol. The filtrates were combined. Evaporation under reduced pressure afforded 6.1 g of 2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-ol as a gray solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([N+:14]([O-:16])=[O:15])=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1.O>N1CCCCC1>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH:23]=[CH:1][C:2]2[N:3]=[C:4]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:7]=2)=[CH:25][CH:26]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1nc(N2CCOCC2)c([N+](=O)[O-])c(N2CCOCC2)n1
Solvent: C1CCNCC1
Solvent: O
Product: COc1ccc(C=Cc2nc(N3CCOCC3)c([N+](=O)[O-])c(N3CCOCC3)n2)cc1
Yield: 34.3 %

Procedure:
The synthesis method shall be explained concretely, and in order, below. A solution of 2-methyl-4,6-dimorpholino-5-nitropyrimidine (1.13 g, 3.65 mmol) and p-anisaldehyde (3.50 ml, 29.3 mmol) in piperidine (5 ml) was agitated under heating for 4 hours at 130 degrees Celsius. Water was added, and extraction was carried out 2 times using ethyl acetate. After washing the organic layer with saturated saline, drying was done with MgSO4, and the solvent was distilled away under reduced pressure. Purification was done by silica gel chromatography (hexane:ethyl acetate=1:1), and 535 mg of 2-[2-(4-methoxyphenyl)vinyl]-4,6-dimorpholino-5-nitropyrimidine (yield 58%) was obtained. The NMR data for the obtained 2-[2-(4-methoxyphenyl)vinyl]-4,6-dimorpholino-5-nitropyrimidine is shown below.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].S(Cl)(Cl)=O.[CH3:17][CH2:18]O>>[CH2:17]([O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Br:1])[CH:3]=1)[CH3:18]
Reactant: O=C(O)Cc1ccc(O)c(Br)c1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-4-hydroxyphenylacetic acid (1.19 g, 5 mmol, 1 eq.) in EtOH (15 mL), thionyl chloride (0.73 mL, 10 mmol, 2 eq.) was added. The reaction mixture was stirred at r.t. during 1 h 30. The mixture was concentrated in vacuo. The residue was partitioned between DCM (50 mL) and sat. aq. NaHCO3 soln. (50 mL). The layers were separated and the aq. phase was extracted with DCM (2×50 mL). The comb. org. phases were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a pale yellow oil. The product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C[C:20]([N:22]([CH3:24])[CH3:23])=O>CN(C=O)C>[CH3:20][N:22]([CH3:24])/[CH:23]=[CH:1]/[C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC(=O)N(C)C
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1/C=C/N(C)C
Temperature: 100 °C
Yield: 25.4 %

Procedure:
A mixture of ethyl 2-methyl-3,5-dinitrobenzoate (35 g, 0.14 mol) and DMA (32 g, 0.27 mol) in DMF (200 mL) was heated at 100° C. for 5 h. The mixture was poured into ice-water and the precipitated solid was filtered and washed with water to give (E)-ethyl 2-(2-(dimethylamino)vinyl)-3,5-dinitrobenzoate (11 g, 48%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(Cl)CCl.[CH2:16]([C:21]12[CH2:28][CH2:27][C:24]([C:29](O)=[O:30])([CH2:25][CH2:26]1)[CH2:23][CH2:22]2)[CH2:17][CH2:18][CH2:19][CH3:20]>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:29]([C:24]23[CH2:25][CH2:26][C:21]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([CH2:28][CH2:27]2)[CH2:22][CH2:23]3)=[O:30])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCCCCC12CCC(C(=O)O)(CC1)CC2
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCCCC12CCC(C(=O)NS(=O)(=O)c3ccc(Cl)cc3)(CC1)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.42 g of 4-chlorophenylsulfonamide, 60 mg of DMAP and 0.42 g of EDC are added to a solution of 0.5 g of 4-pentyl-bicyclo[2.2.2]octane-1-carboxylic acid in 8 ml of DMF, the mixture obtained is stirred for ca. 16 h at RT and solvent from the mixture obtained is evaporated. The evaporation residue obtained is dissolved in EtAc and washed with 1 N HCl, saturated NaHCO3 solution and brine and the organic phase obtained is dried. Solvent of the organic phase obtained is evaporated and the evaporation residue obtained is subjected to chromatography. 4-Chloro-N-(4-pentyl- bicyclo[2.2.2]octane-1-carbonyl)-benzenesulfonamide is obtained in the form of a white powder;
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Br:26])=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=1)=[O:9].[NH3:37]>CN(C)C=O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Br:26])=[N:12][C:13]([NH2:37])=[N:14][CH:15]=1)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(S(C)(=O)=O)nc1-c1ccccc1Br
Reactant: N
Solvent: CN(C)C=O
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(N)nc1-c1ccccc1Br
Reaction time: 4 h
Yield: 77 %

Procedure:
To a solution of 0.42 g (0.7 mmol) 4-(2-bromo-phenyl)-2-methylsulfonyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide in 30 ml N,N-dimethylformamide a stream of NH3 was introduced during 10 Min. The reaction solution was stirred for 4 hrs. The solvent was evaporated and the residue distributed between 20 ml CH2Cl2 and 20 ml H2O. The aqueous phase was extracted twice with 30 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH 140:10:1) to give 0.29 g (77%) 2-amino-4-(2-bromo-phenyl)-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a white foam, MS (ISP): 535.1, 533.1 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Cl[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([CH2:19]Cl)[C:13]=1[OH:21].[Cl-].[Al+3].[Cl-].[Cl-].ClCCl>[N+](C1C=CC=CC=1)([O-])=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:9])=[C:7]([CH:8]=1)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([CH2:19][C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][C:6]=2[OH:9])[C:13]=1[OH:21])#[N:2]
Reactant: N#Cc1ccc(O)cc1
Reactant: Oc1c(CCl)cc(F)cc1CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=[N+]([O-])c1ccccc1
Product: N#Cc1ccc(O)c(Cc2cc(F)cc(Cc3cc(C#N)ccc3O)c2O)c1
Temperature: 0 °C
Reaction time: 14 h
Yield: 3 %

Procedure:
p-Cyanophenol (19.4 g) and 2,6-bis(chloromethyl)-4-fluorophenol (17.0 g) were dissolved in nitrobenzene (250 ml) at 20°. The solution was cooled to 10° and crushed aluminium chloride (anhydrous 65 g) was added in 5 g portions over two hours. During the addition the temperature was maintained at 10°-12°. Stirring was continued at 20° for 14 hrs. The viscous black mixture was poured onto a vigorously stirred mixture of ice (2 l) and dichloro methane (2 l). The organic solvent layer was dried, dichloro methane and nitrobenzene removed by vacuum distillation and the residual tar passed through a silica column. The product, 2,6-bis(5-cyano-2-hydroxybenzyl)-4-fluorophenol (mp 222°) was obtained in 3% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:25]([NH:24][C:21]3[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)=[O:26])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: COc1ccc(NC(=O)NC2CCCc3c2[nH]c2ccc(Br)cc32)cc1

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-(4-methoxyphenyl)urea was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 4-methoxyphenyl isocyanate in a similar manner as described above to give a gray solid (61% yield). 1H-NMR (DMSO-d6): δ 10.99 (s, 1H), 8.16 (s, 1H), 7.60 (d, 1H), 7.38-7.27 (m, 3H), 7.17 (dd, 1H), 6.87 (d, 2H), 6.52 (d, 1H), 5.01 (m, 1H), 3.73 (s, 3H), 2.67 (m, 2H), 2.04 (m, 1H), 1.94-1.76 (m, 3H); MS m/z 414 (M−1).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8](=[O:16])[NH:7][C:6]1=[O:17])([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:23]O>>[Cl:15][C:12]1[CH:13]=[C:14]2[C:9]([C:8](=[O:16])[NH:7][C:6](=[O:17])[N:5]2[CH2:4][C:1]([O:3][CH3:23])=[O:2])=[CH:10][CH:11]=1
Reactant: CO
Reactant: O=C(O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Agent: O=S(=O)(O)O
Product: COC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Yield: 86.5 %

Procedure:
To a suspension of 1-carboxymethyl-7-chloro-2,4(1H, 3H)-quinazolinedione (1) (5 g) in methanol (70 ml) was added concentrated sulfuric acid (1.92 g) at room temperature, and the reaction solution was refluxed for 20 hours. After the reaction solution was concentrated suitablely to half, water (20 ml) was added to adjust to pH 9 with 20% potassium carbonate solution (27 g). The resulting crystal was collected by filtration, washed with water and dried under vacuum to give 4.56 g of the desired compound (yield, 86.5%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=[O:10])=[C:4]([F:12])[CH:3]=1.S(Cl)([Cl:15])=O.CN(C=O)C>CC(=O)OCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:15])=[O:10])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cl)Cc1ccc(Br)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (0.1 g, 0.429 mmol) in sulfurous dichloride (5 mL, 0.429 mmol) was added DMF (3.32 μL, 0.043 mmol). The resulting mixture was stirred at 60° C. After 2 h, TLC analysis (PE/EA=1/1) showed the starting material had disappeared. The solvent was removed in vacuo to give 2-(4-bromo-2-fluorophenyl)acetyl chloride (110 mg, 0.416 mmol, 97% yield). A solution of 2-(4-bromo-2-fluorophenyl)acetyl chloride (110 mg, 0.437 mmol) in THF (5 mL) was added to ammonium hydroxide (10 mL, 257 mmol). The resulting mixture was stirred at 0° C. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The residue was dissolved in EA (50 mL) and washed with H2O (10 mL) and brine (10 mL). The organic layer was dried and concentrated to give a white solid of 2-(4-bromo-2-fluorophenyl)acetamide (100 mg, 0.280 mmol, 63.9% yield), which was used into the next step without further purification: 1H NMR (400 MHz, CD3OD) δ 7.32-7.30 (m, 2H), 7.24 (t, J=8.2 Hz, 1H), 3.54 (s, 2H); ES-LCMS m/z 232.0 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:13][C:12]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:11][CH:10]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:13][C:12]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:11][CH:10]=1
Reactant: COc1ccccc1-c1ccc(S(N)(=O)=O)s1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2ccccc2O)s1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
A 70 ml CH2Cl2 suspension of 5-(2-methoxyphenyl)thiophene-2-sulfonamide (1.0 g, 3.7 mmol) is stirred under N2 at −75° C. as boron tribromide (1.1 ml, 12 mmol) is syringed into the reaction mixture. The amber solution is stirred for 30 minutes at −75° C., then at 0° C. for 2-3 hours. The reaction is quenched with ice, extracted with CH2Cl2. The extracts are washed with brine, dried (Na2SO4), filtered, and the filtrate is concentrated. The residue is purified by chromatography (SiO2, ethyl acetate/hexane gradient) to give 720 mg of 5-(2-hydroxyphenyl)thiophene-2-sulfonamide (76%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH:11]2[CH2:13][CH2:12]2)[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)=[CH:22][CH:21]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:11]1([NH:10][C:6]2[C:7]([C:8]#[N:9])=[C:2]([N:29]3[CH2:28][CH:27]=[C:26]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)[CH2:31][CH2:30]3)[N:3]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:5]=2)[CH2:13][CH2:12]1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NC1CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NC2CC2)nc(NCCO)nc1N1CC=C(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-6-cyclopropylamino-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 44a) was treated with 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield 4-cyclopropylamino-6-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=395.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31].O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:7]1[C:6]2[CH:21]=[C:2]([NH:1][C:30](=[O:31])[N:29]([CH3:33])[CH3:28])[CH:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=1
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(N)ccc21
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)Nc1ccc2c(c1)C(c1ccccc1F)=NCC(=O)N2C
Temperature: 20 °C
Reaction time: 336 h

Procedure:
4.2 g (0.015 M) of 7-amino-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one are suspended in 60 ml of absolute methylene chloride, treated with 2.1 g of powdered potassium carbonate and 1.6 ml of dimethylcarbamoyl chloride and stirred at 20° C. for 14 days. The mixture is then poured on to a mixture of ice and water, extracted with methylene chloride and the organic phase is washed 2-3 times with water, dried and sodium sulphate, filtered and concentrated. The residue is purified on a 200 g silica gel column using ethyl acetate as the eluting agent and crystallised from ethanol/petroleum ether. There is obtained 3-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-1,1-dimethylurea which crystallises with 0.5 mol of ethanol and melts at 97° C. with decomposition.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5](O)=[O:6].C(OC(Cl)=O)C(C)C.C(N(CC)CC)C.[CH2:43]([NH:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60]>O1CCCC1>[CH2:62]([N:61]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[C:5](=[O:6])[CH2:4][CH2:3][CH:2]([CH:8]1[C:12]2([CH3:27])[CH:11]([CH:16]3[CH:15]([CH2:14][CH2:13]2)[C:20]2([CH3:26])[CH:19]([CH2:24][CH:23]([OH:25])[CH2:22][CH2:21]2)[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)[CH3:1])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)CCC(C)C1CCC2C3CCC4CC(O)CCC4(C)C3CCC12C
Yield: 93.8 %

Procedure:
Lithocholic acid (81) (7.1 g, 18.8 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL). Isobutylchloroformate (2.6 g, 2.6 mL, 18.8 mmol) was added followed by the addition of triethylamine (3.84 g, 5.3 mL, 38 mmol) and dioctadecylamine (9.8 g, 18.77 g). The reaction mixture was brought to ambient temperature and allowed to stir over night. The reaction mixture was concentrated under vacuum, and the residue was dissolved in dichloromethane (250 mL). The organic layer was washed with 5% sodium bicarbonate, 3% aqueous HCl and water. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure to afford amide 82 (15.5 g) in 93% yield. This was used as such for the next step.
Reaction SMILES: C([O:5][C:6]([CH:8]=[CH:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)=[O:7])(C)(C)C>C(Cl)Cl.O>[C:6]([CH:8]=[CH:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1ccc(C=CC(=O)OC(C)(C)C)cc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(C=CC(=O)O)cc1
Reaction time: 27 h
Yield: 95.1 %

Procedure:
To a stirred solution at room temperature of VI (745 mg, 2.84 mmol) in CH2Cl2 (10 ml) was added trifluoroacetc acid (6 ml, 95% in water). After 27 h, the reaction mixture was concentrated, and triturated in water. After 1 h, the suspension was filtered off, rinsed with H2O, and dried to afford the title compound VII (556 mg, 2.70 mmol, 95% yield) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ(ppm): AB system (δA=8.01, δB=7.88, J=8.1 Hz, 4H), 7.68 (d, J=15.8 Hz, 1H), 6.70 (d, J=16.3 Hz, 1H), 3.90 (s, 3H).
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[OH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].N1C=CN=C1>C(Cl)Cl>[Si:5]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: COC(=O)CCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)CCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
A solution of tert-butylchlorodimethylsilane (27.1 g, 179.79 mmol) in DCM (50 mL) was added dropwise to a stirred solution of methyl 5-hydroxypentanoate (CAS no. 14273-92-8, Huckstep, M.; Taylor, R. J. K.; Caton, M. P. L. Synthesis 1982, 10, 881) (19.8 g, 149.82 mmol) and 1H-imidazole (15.30 g, 224.73 mmol) in DCM (200 mL) at 5° C., over a period of 10 minutes under nitrogen. The resulting suspension was stirred at ambient temperature for 6 hours. The reaction mixture was diluted with DCM (250 mL), and washed sequentially with water (2×200 mL) and saturated brine (200 mL). The organic layer was dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting with 10 to 50% ethyl acetate in isohexane to afford the product (19.3 g, 52%).