Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9]([N:16]([CH2:21][C:22](O)=O)[CH2:17][C:18](O)=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)CO>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=[C:18]1[CH2:17][N:16]([CH2:21][C:22]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)CN(CC(=O)O)Cc1ccccc1
Reactant: Nc1ccccc1N
Solvent: OCCO
Product: c1ccc(CN(Cc2nc3ccccc3[nH]2)Cc2nc3ccccc3[nH]2)cc1

Procedure:
2d was synthesised by an analogous procedure to that described for 2a using o-phenylenediamine (2.41 g, 22.34 mmol) and benzyliminodiacetic acid (4.10 g, 11.17 mmol) in ethyleneglycol (10 ml) at 190° C. Yield 3.50 g (85%). 1H NMR (250.13 MHz, DMSO-d6, r.t.), δ 3.74 (s, 2H, CH2), 3.97 (s, 4H, NCH2), 7.19-7.58 (overlapping and broad m, 13H, ArH). 13C NMR (100.6 MHz, MeOH-d4, r.t.), δ 56.24 (NCH2), 62.34 (CH2), 102.03 (ArC), 126.94 (ArC), 132.37 (ArC), 133.38 (ArC), 134.23 (ArC), 142.70 (ArCq), 143.47 (ArCq), 157.41 (ArCq). +CI MS (m/z): 367 ([MH+]).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C@H:9]([NH:13][S@@](C(C)(C)C)=O)[CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[CH3:20].Cl>CO>[ClH:1].[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C@H:9]([NH2:13])[CH:10]([CH3:11])[CH3:12])=[CH:4][C:3]=1[CH3:20]
Reactant: Cc1cc([C@H](N[S@](=O)C(C)(C)C)C(C)C)cc(C)c1Cl
Agent: Cl
Solvent: CO
Product: Cc1cc([C@H](N)C(C)C)cc(C)c1Cl
Reaction time: 8 h

Procedure:
A solution of intermediate INT 61 (4.53 g, 14.34 mmol) in MeOH (75 mL) was treated with HCl (4 M in dioxane, 7.17 mL, 28.7 mmol) and stirred overnight. After evaporation of the solvents, a solid was obtained which was washed with Et2O. The solid was then dissolved in 10% sodium carbonate solution and extracted twice with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude amine was dissolved in Et2O and treated with an excess of an ethereal solution of HCl (2 M). The suspension was concentrated to yield the title compound.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[C:15]=1[F:22].[C:23](=[O:25])=[O:24]>C1COCC1>[Br:13][C:14]1[C:15]([F:22])=[C:16]([F:21])[C:17]([F:20])=[C:18]([CH:19]=1)[C:23]([OH:25])=[O:24]
Reactant: O=C=O
Reactant: Fc1ccc(Br)c(F)c1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c(F)c(F)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of diisopropylamine (10.14 g, 100.20 mmol) in THF (100 mL) was added n-BuLi (40.08 mL, 2.5 M in hexane, 100.20 mmol) at −78° C. under nitrogen atmosphere. The stirring was maintained at this temperature for 1 h. Then a solution of 1-bromo-2,3,4-trifluorobenzene (17.62 g, 83.50 mmol) in THF (120 mL) was added. After stirring for 1 h at −78° C., the mixture was transferred to a bottle with dry ice. The mixture was stirred overnight at room temperature. The reaction was quenched with 10% aqueous HCl and pH was adjusted to 1-2. The mixture was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the desired product (20.12 g, 94.5% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.95 (s, 1H), 7.97 (m, 1H).
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11]([N+]([O-])=O)=[N:10][C:9]=2[N:8]([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[ClH:23]>>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11]([Cl:23])=[N:10][C:9]=2[N:8]([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c2[nH]c([N+](=O)[O-])nc2n(CCCC)c1=O
Reactant: Cl
Product: CCCCn1c(=O)c2[nH]c(Cl)nc2n(CCCC)c1=O

Procedure:
1,3-Di-n-butyl-8-nitro xanthine (0.5 g, 0.0016 mol) was refluxed for 18 hours with concentrated hydrochloric acid (8 ml). The reaction mixture was extracted with dichloromethane (20 ml), the organic layer washed with water to neutrality and then dried over anhydrous sodium sulphate. The solvent was then removed by evaporation in vacuo and the residue was recrystallised from ethanol, to give the title compound, yield 0.38 g (73%), m.pt. 152° C.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][OH:12])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1>C(Cl)Cl.O=[Mn]=O>[O:1]1[C:10]2[CH:9]=[C:8]([CH:11]=[O:12])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: OCc1cc2c(cn1)OCCO2
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1cc2c(cn1)OCCO2
Yield: 60.6 %

Procedure:
A solution of 2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethanol (250 mg, 1.5 mmole) in CH2Cl2 (5 mL) was treated with MnO2 (650 mg, 7.5 mmole). After 3 days the mixture was filtered and the filtrate was concentrated to afford the title compound (150 mg, 61%) as a white solid: MS (APCI+) m/e 166 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:16][N:17]1[CH:21]=[N:20][C:19]([NH2:22])=[N:18]1>>[CH3:15][C:13]1[N:12]=[CH:11][N:10]([C:5]2[CH:4]=[CH:3][C:2]([NH:22][C:19]3[N:20]=[CH:21][N:17]([CH3:16])[N:18]=3)=[CH:9][C:6]=2[C:7]#[N:8])[CH:14]=1
Reactant: Cn1cnc(N)n1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3ncn(C)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-methyl-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a colorless solid (Yield=36%). MS ISP (m/e): 280.1 (100) [(M+H)+].
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:21][CH:20]=1)=[C:17]=[O:18].[Br-].[Mg+2].[Br-]>O1CCOCC1>[O:18]=[C:17]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:3][C@H:2]([CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])[O:1]1
Reactant: O=C=Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 120 °C
Yield: 95.1 %

Procedure:
(S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (4.04 g, 19.87 mmol, 1.15 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in 1,4-dioxane (70 mL) respectively, then heated to 120° C. and magnesium bromide (0.22 g, 1.21 mmol) was added. The mixture was reacted for 4 h, white solid was obtained by filtration (6.94 g, yield: 95.1%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][NH:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[CH:5][CH:4]=1.C=O.[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:9][CH2:10][CH2:11][N:12]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])[CH2:23][C:7]=2[CH:8]=1
Reactant: COc1ccc(SCCNC(=O)N2CCOCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: c1ccccc1
Product: COc1ccc2c(c1)CN(C(=O)N1CCOCC1)CCS2
Temperature: 72.5 °C
Reaction time: 14 h
Yield: 50 %

Procedure:
A mixture of compound 16 (100 mg), paraformaldehyde (110 mg), p-toluenesulfonic acid (60 mg) in benzene (5 mL) was stirred at 70-75° C. for 14 h. The reaction solution was filtrated, washed with sat. NaHCO3 and concentrated to give crude title product 17 in an estimated yield of ˜50% by TLC and NMR. Chromatography on SiO2 (CH2Cl2/EtOAc 10:1) provided pure sample for confirmation of the structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[C:5]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:4]=1.CO[C:31](OC)([N:33]([CH3:35])[CH3:34])[CH3:32]>O>[CH3:34][N:33]([CH3:35])[C:31]([CH3:32])=[CH:16][C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:7]2[CH:6]=[C:5]([NH:18][CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[N:4]=[C:3]([O:2][CH3:1])[N:8]=2)[CH:10]=1)=[O:17]
Reactant: COc1ccc(CCNc2cc(-c3cccc(C(C)=O)c3)nc(OC)n2)cc1
Reactant: COC(C)(OC)N(C)C
Solvent: O
Product: COc1ccc(CCNc2cc(-c3cccc(C(=O)C=C(C)N(C)C)c3)nc(OC)n2)cc1
Temperature: 90 °C

Procedure:
A mixture of 1-(3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-ethanone [125 mg, 0.33 mmol, Example 35(h)] and dimethylacetamide dimethylacetal (2 mL) in a round bottom flask is heated to 90° C. for 4 hours. The reaction mixture is treated with water (20 mL) and extracted three times with EtOAc (20 mL). The combined organics are dried over magnesium sulfate, filtered and concentrated by rotary evaporator to provide 3-dimethylamino-1-(3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-but-2-en-1-one [Intermediate (47)] in quantitative yield.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].Cl.[CH3:12][O:13][C:14](=[O:17])[CH2:15][NH2:16]>>[CH3:12][O:13][C:14](=[O:17])[CH2:15][NH:16][C:1](=[O:9])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(CCC)C(=O)Cl
Reactant: COC(=O)CN
Agent: Cl
Product: CCCC(CCC)C(=O)NCC(=O)OC

Procedure:
The title compound was prepared from valproyl chloride (19.34 g, 119 mmole) and glycine methyl ester hydrochloride (15.0 g, 119 mmole), according to the procedure described in Ex. 4.22 g (102 mmole, 86%) of an off-white solid, mp 68° C., was thus obtained.
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=O)[O:11][C:9](=[O:10])[C:8]2=[CH:14][CH:15]=1>C(O)C>[Br:4][C:5]1[CH:6]=[C:7]2[C:8](=[CH:14][CH:15]=1)[C:9](=[O:10])[N:3]=[N:2][C:12]2=[O:11]
Reactant: NN
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Solvent: O
Solvent: CCO
Product: O=C1N=NC(=O)c2cc(Br)ccc21

Procedure:
96.9 ml hydrazine monohydrate was added to a mixture of 20 g 4-bromophthalic anhydride and 400 ml ethanol, and the mixture was heated under reflex for 8 hr. After cooling, the resulting precipitates were collected by filtration to give 28 g of 6-bromo-1,4-phthalazinedione.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[O:5][N:4]=1.C[O:19][C:20](=[O:33])[CH2:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([SH:31])=[CH:25][C:24]=1[CH3:32]>>[CH3:30][O:29][C:27]1[C:26]([S:31][CH2:2][C:3]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[O:5][N:4]=2)=[CH:25][C:24]([CH3:32])=[C:23]([CH:28]=1)[O:22][CH2:21][C:20]([OH:33])=[O:19]
Reactant: COC(=O)COc1cc(OC)c(S)cc1C
Reactant: FC(F)(F)c1ccc(-c2cc(CCl)no2)cc1
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1cc(-c2ccc(C(F)(F)F)cc2)on1

Procedure:
The title compound was prepared in a manner analogous to Example 1F using 42C and 1D. MS m/z 468 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16]([O:27][CH3:28])=[C:17]2[CH:24]3[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:26][CH:18]2[CH2:19]4)[CH2:23]3)[CH:6]=[C:7]([NH:9]C(=O)C(F)(F)F)[CH:8]=1.O>CO>[NH2:9][C:7]1[CH:6]=[C:5]([C:16]([O:27][CH3:28])=[C:17]2[CH:18]3[CH2:26][CH:22]4[CH2:21][CH:20]([CH2:25][CH:24]2[CH2:23]4)[CH2:19]3)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COC(=C1C2CC3CC(C2)CC1C3)c1cc(NC(=O)C(F)(F)F)cc(OC)c1
Solvent: CO
Solvent: O
Product: COC(=C1C2CC3CC(C2)CC1C3)c1cc(N)cc(OC)c1

Procedure:
Trifluoroacetamide enol ether 31 is hydrolyzed at 60° C. with finely ground K2CO2 (3 eq) in MeOH containing trace water. Workup by partitioning the mixture with EtOAc/H2O, followed by silica gel chromatography provides enol ether aniline 32.
Reaction SMILES: CCN=C=NCCCN(C)C.[Cl:12][C:13]1[CH:21]=[N:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O.[NH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:38])([C:34]([F:37])([F:36])[F:35])[C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:25][C:24]=1[OH:39]>N1C=CC=CC=1>[Cl:12][C:13]1[CH:21]=[N:20][CH:19]=[CH:18][C:14]=1[C:15]([NH:22][C:23]1[CH:28]=[C:27]([C:29]([F:38])([C:30]([F:31])([F:32])[F:33])[C:34]([F:35])([F:36])[F:37])[CH:26]=[CH:25][C:24]=1[OH:39])=[O:17]
Reactant: O=C(O)c1ccncc1Cl
Reactant: Nc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1O)c1ccncc1Cl
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a mixture of 0.58 g of WSC and 5 ml of pyridine 5 ml, 0.48 g of 3-chloroisonicotinic acid was added. The reaction mixture was stirred at room temperature for 25 minutes. To the reaction mixture, 0.75 g of 2-amino-4-(heptafluoroisopropyl)phenol was added and was stirred while heating at 60° C. for three hours. The reaction mixture was cooled to room temperature, the 0.24 g of 3-chloroisonicotinic acid and 0.29 g of WSC was added and stirred while heating at 60° C. for 1.5 hours and then at 80° C. for 1.3 hours. The mixture reaction was cooled to room temperature, and then concentrated under reduced pressure. Then, water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.90 g of 3-chloro-N-[2-hydroxy-5-(heptafluoroisopropyl)phenyl]isonicotinamide.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:14]2[N:13]([CH3:15])[C:12](=[O:16])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5].Br[C:19]1[C:24]([N:25]([CH2:40][O:41][CH3:42])[S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=2)(=[O:28])=[O:27])=[CH:23][C:22]([Cl:43])=[CH:21][N:20]=1>>[Cl:43][C:22]1[CH:23]=[C:24]([N:25]([CH2:40][O:41][CH3:42])[S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([C:36]([F:38])([F:37])[F:39])[CH:30]=2)(=[O:28])=[O:27])[C:19]([C:4]([C:6]2[C:14]3[N:13]([CH3:15])[C:12](=[O:16])[NH:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)=[O:5])=[N:20][CH:21]=1
Reactant: CON(C)C(=O)c1cccc2[nH]c(=O)n(C)c12
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(C)c(C(F)(F)F)c1
Product: COCN(c1cc(Cl)cnc1C(=O)c1cccc2[nH]c(=O)n(C)c12)S(=O)(=O)c1ccc(C)c(C(F)(F)F)c1

Procedure:
N-[5-Chloro-2-(3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-4-methyl-3-trifluoromethyl-benzenesulfonamide was prepared from 3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-4-carboxylic acid methoxy-methyl-amide and N-(2-bromo-5-chloro-pyridin-3-yl)-N-methoxymethyl-4-methyl-3-trifluoromethyl-benzenesulfonamide according to previously described procedure in example 29, step 1. The product was purified by flash column chromatography on silica gel using ethyl acetate-hexane. MS m/z: 569.0 (M+H)+.
Reaction SMILES: C[O:2][CH:3](OC)[C@H:4]([CH:53]([CH3:55])[CH3:54])[NH:5][C:6](=[O:52])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:51])[C@H:13]([CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:50])[C:34]1[CH:39]=[CH:38][C:37]([C:40]([O:42]CC2C=CC=CC=2)=[O:41])=[CH:36][CH:35]=1)[NH:14][S:15]([C:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2)(=[O:17])=[O:16]>CN(C)C=O.C(=O)(O)[O-].[Na+].[Pd]>[C:18]12([S:15]([NH:14][C@H:13]([C:12]([N:8]3[CH2:9][CH2:10][CH2:11][C@H:7]3[C:6]([NH:5][C@H:4]([CH:3]=[O:2])[CH:53]([CH3:55])[CH3:54])=[O:52])=[O:51])[CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:50])[C:34]3[CH:39]=[CH:38][C:37]([C:40]([OH:42])=[O:41])=[CH:36][CH:35]=3)(=[O:16])=[O:17])[CH2:19][CH:20]3[CH2:21][CH:22]([CH2:23][CH:24]([CH2:26]3)[CH2:25]1)[CH2:27]2
Reactant: COC(OC)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCCNC(=O)c1ccc(C(=O)OCc2ccccc2)cc1)NS(=O)(=O)C12CC3CC(CC(C3)C1)C2)C(C)C
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[C@@H](C=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCCNC(=O)c1ccc(C(=O)O)cc1)NS(=O)(=O)C12CC3CC(CC(C3)C1)C2
Yield: 32.5 %

Procedure:
1.3 g (1.6 mmol) of Nα -(1-adamantylsulphonyl)-Nε -(4-benzyloxycarbonylbenzoyl)-L-lysyl-L-prolyl-L-valinal dimethyl acetal in 15 ml of dimethylformamide were hydrogenated in the presence of 5% palladium/carbon for 3 hours. The catalyst was removed by filtration and the filtrate was evaporated to give an oil. This oil was taken up in sodium bicarbonate solution, extracted with ethyl acetate, the aqueous phase was acidified to pH 2-3 with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was washed free from acid with water, dried over magnesium sulphate and evaporated to give a foam. This foam was chromatographed on 25 g of silica gel using dichloromethane/methanol/acetic acid (190:9:2) for the elution. Evaporation of the eluate and trituration of the residue with diethyl ether yielded 0.35 g (33%) of Nα -(1-adamantylsulphonyl)-Nε -(4-carboxybenzoyl)-L-lysyl-L-prolyl-L-valinal in the form of a solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31]([F:35])=[C:30]([OH:36])[CH:29]=[CH:28]2>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.CCOC(C)=O>[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31]([F:35])=[C:30]([O:36][C:2]1[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=1)[CH:29]=[CH:28]2
Reactant: COc1cc2c(Cl)ccnc2cc1OCCCN1CCOCC1
Reactant: Oc1ccc2cc(Br)ccc2c1F
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(Oc3ccc4cc(Br)ccc4c3F)ccnc2cc1OCCCN1CCOCC1
Temperature: 180 °C

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinoline (prepared as described in WO 03/33472) (0.465 mg, 1.93 mmol), 6-bromo-1-fluoro-naphthalen-2-ol (Example 3a) (0.65 mg, 1.93 mmol) and DMAP (0.235 mg, 1.93 mmol, Aldrich) in toluene (in a microwave tube) was heated in a microwave oven (Personal Chemistry, Emrys Optimizer) at 180° C. for 2 h. The mixture was cooled to RT and diluted with 30 mL of EtOAc. The solution was washed with brine (2×10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was further purified with silica gel column chromatography (40% to 100% EtOAc in hexanes) to give the title compound as an orange foam. MS (ESI, pos. ion) m/z: 541.1 (M+1). Mass Calc'd for C27H26BrFN2O4: 540.11.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[C:42]([CH2:49][O:50][Si:51]([CH:58]([CH3:60])[CH3:59])([CH:55]([CH3:57])[CH3:56])[CH:52]([CH3:54])[CH3:53])=[N:43][N:44]([CH2:46][CH2:47][OH:48])[CH:45]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:70][S:71](Cl)(=[O:73])=[O:72]>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[C:42]([CH2:49][O:50][Si:51]([CH:55]([CH3:57])[CH3:56])([CH:58]([CH3:60])[CH3:59])[CH:52]([CH3:53])[CH3:54])=[N:43][N:44]([CH2:46][CH2:47][O:48][S:71]([CH3:70])(=[O:73])=[O:72])[CH:45]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)[Si](OCc1nn(CCO)cc1-n1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCC[C@@H]4C)n3c2)c2ccccc21)(C(C)C)C(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[Si](OCc1nn(CCOS(C)(=O)=O)cc1-n1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCC[C@@H]4C)n3c2)c2ccccc21)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
A solution of Intermediate 74i (134 mg, 0.16 mmol) in DCM (1.6 mL) was treated with DIPEA (83 μL, 0.48 mmol) then cooled to 0° C. Methanesulfonyl chloride was added and the mixture was stirred at 0° C. for 5 min then at RT for 1 h. The mixture was diluted with DCM and a saturated aqueous sodium bicarbonate solution and the phases were separated. The aqueous layer was then extracted with DCM (2×). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-8% MeOH in DCM, to give the title compound (107 mg, 73%). LCMS (Method 3): Rt 5.06 min, m/z 917.4 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].[H-].[Na+].[Cl:16][C:17]1[N:18]=[C:19](Cl)[C:20]2[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:21]=2[N:22]=1>CN(C=O)C>[Cl:16][C:17]1[N:18]=[C:19]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[C:20]2[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:21]=2[N:22]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)nc(Cl)nc21
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nc2c1ccn2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42 %

Procedure:
To a solution of 1-amino-2-(isopropylsulphonyl)benzene (199 mg, 1 mmol) in 2 mL of DMF was added NaH (60% in oil, 44 mg, 1.1 mmol) in one portion at 0° C. After the reaction mixture was stirred for 20 min, 2,4-dichloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (317 mg, 1 mmol) was added at 0° C. The reaction mixture was then warmed up to room temperature and stirred for additional 2 h. The reaction was quenched with water. Extraction with EtOAc followed by silica gel column chromatography (20% EtOAc in heptane) gave the desired product (202 mg, 42% yield). MS/ES+: m/z=481.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17](F)=[CH:16][C:15]=1[Cl:21])=[O:13].C([O-])([O-])=O.[K+].[K+].O>CC(N(C)C)=O>[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:10][C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[CH:16][C:15]=1[Cl:21])(=[O:13])[CH3:11]
Reactant: CC(=O)c1ccc(F)cc1Cl
Reactant: N#Cc1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)c1ccc(Oc2ccc(C#N)c(Cl)c2)cc1Cl
Temperature: 130 °C

Procedure:
To a solution 2-chloro-4-hydroxybenzonitrile (CAS Reg. No. 3336-16-1, 1 g), 2-chloro-4-fluoroacetophenone (CAS Reg. No. 700-35-6, 1.12 g) in DMA (10 ml) was added K2CO3 (1.08 g). The mixture is heated to 110° C. for 2 h and at 130° C. for 1 h. Water was added and the mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, 0 to 30% EtOAc/heptane) to give the title compound (780 mg) as light yellow oil. MS (m/e)=306.0 [M+H+].