Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:10])=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[C:11]([Cu])#[N:12]>CN1C(=O)CCC1.[Cu]I>[NH2:7][C:6]1[C:5]([CH3:9])=[CH:4][C:3]([F:10])=[C:2]([CH:8]=1)[C:11]#[N:12]
Reactant: Cc1cc(F)c(Br)cc1N
Reactant: N#C[Cu]
Agent: [Cu]I
Solvent: CN1CCCC1=O
Product: Cc1cc(F)c(C#N)cc1N
Temperature: 195 °C
Yield: 36 %

Procedure:
A mixture of 5-bromo-4-fluoro-2-methylaniline (2.04 g, 10.0 mmol), CuCN (889 mg, 10.0 mmol) and CuI (1.9 g, 10.0 mmol) in NMP was purged with N2 for 5 minutes and then sealed and heated at 195° C. for 30 minutes under microwave condition. The mixture was subjected to standard aqueous workup to give a residue which was purified by silica chromatography to yield 5-amino-2-fluoro-4-methylbenzonitrile (51) (540 mg, 36% yield). MS m/z 151.0 (M+1)+.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.Cl.O>CO.[OH-].[Na+]>[NH2:24][C:23]1[C:18]([N:15]2[CH2:14][CH2:13][N:12]([C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[CH:5][N:6]=3)=[O:11])[CH2:17][CH2:16]2)=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3N)CC2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
6-[1-(3-Amino-2-pyridyl)piperazin-4-yl-carbonyl]nicotinic acid methyl ester (3 g) was dissolved in methanol (25 ml) and with the addition of aqueous 1N-sodium hydroxide (20 ml), the mixture was stirred at 25° C. for 2 hours. With the slow addition of 3N-hydrochloric acid for neuturalization (pH=˜5), water (25 ml) was slowly added to the mixture for precipitate. After a 1-hour stirring, the precipitate was filtered, washed with water and dried to give a desired compound of 2.53 g (yield: 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10]C)[CH:3]=1.B(Br)(Br)Br.C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)cc(OC)c1
Agent: BrB(Br)Br
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(O)cc(Cl)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 32.2 %

Procedure:
1-Chloro-3,5-dimethoxy-benzene (1.72 g, 10 mmol) in 10 mL of CH2Cl2 was cooled to −78° C., followed by 1.0 M BBr3 in toluene (10 mL, 10 mmol) added dropwise. The solution was stirred at −78° C. for 1 hour, and then allowed to warmed to room temperature over 2 hours. The reaction was quenched with water, and the aqueous layer was extracted with additional CH2Cl2. The combined organic layers were washed with brine, dried, and concentrated under pressure. The residue was purified by silica gel column chromatography eluting with 1:1 EtOAc/Hexanes to give 0.51 g of the title compound. MS (APCI) m/e 159 (M+H)+, 1H NMR (500 MHz, DMSO-d6): □ 9.88 (s, 1H), 6.43 (m, 1H), 6.39 (m, 1H), 6.28 (m, 1H), 3.70 (s, 3H).
Reaction SMILES: [CH:1]([C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[O:4])=[CH2:2].[CH2:12]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH:1]([C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:31]([C:28]2[CH:27]=[CH:26][C:25]([C:22]3[CH:23]=[CH:24][C:19]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:20][CH:21]=3)=[CH:30][CH:29]=2)=[O:32])=[CH:9][CH:10]=1)=[O:4])=[CH2:2]
Reactant: CCCCCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: C=CC(=O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C=CC(=O)c1ccc(OC(=O)c2ccc(-c3ccc(CCCCCCC)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.3 %

Procedure:
A mixture of 4-hydroxyphenyl vinyl ketone (c) (1 g), 4′-heptyl-1,1′-biphenyl-4-carboxylic acid (1.8 g), DCC (1.9 g) DMAP (0.1 g) and methylene chloride (30 mL) was stirred at room temperature for 12 hours. The white solid precipitated was filtrated out, and the solvent was evaporated away from the filtrate. The residue was dissolved in ethyl acetate, and washed with aqueous 2 M NaOH solution and then with water. The solvent was evaporated away, and the residue was purified through column chromatography (eluent: toluene) and then through recrystallization (ethanol) to obtain 0.5 g of colorless crystals, compound (1-13-8). The NMR and MS spectra of the compound well support the structure thereof.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([F:28])[CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[C:21]([F:28])[CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cc(-c2ccc(Cl)cc2F)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, light brown solid (65 mg, 77%), MS (ISP) m/z=340.3 [(M+H)+], mp 278° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-chloro-2-fluoro-phenylboronic acid (56.7 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24](=[O:26])[CH3:25])=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1.FC(F)(F)S(O[Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[C:40]([Si:37]([CH3:39])([CH3:38])[O:26][C:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[CH:15]=[CH:14][C:12]2[NH:13][C:9]([CH2:8][O:7][C:6]3[CH:27]=[CH:28][C:3]([C:2]([F:1])([F:29])[F:30])=[CH:4][CH:5]=3)=[N:10][C:11]=2[CH:17]=1)=[CH2:25])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C(C)(C)C)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 1-{2-[2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazol-5-yl]-phenyl}-ethanone (0.215 g, 0.524 mmol) in CH2Cl2 (8 mL) at 0° C. was added tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) (0.304 g, 1.15 mmol) and triethylamine (0.29 mL, 2.10 mmol). After stirring 2 h, the reaction mixture was concentrated, and the residue was purified by chromatography (silica, hexanes: EtOAc, 2:1) to afford the title compound as a yellow oil (0.242 g, 88%).
Reaction SMILES: [S:1]([N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Cl:16][S:17](O)(=[O:19])=[O:18]>C(#N)C>[S:1]([N:11]1[CH:15]=[CH:14][C:13]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)n2cccc2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2ccc(S(=O)(=O)Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
To a stirred solution of compound 27a (5.0 g, 22.6 mmol) in ACN (50 mL) was carefully added ClSO3H (15.8 g, 136 mmol) and the solution was stirred at rt overnight, poured on ice-water and extracted with CHCl3 twice. The combined organic layers were washed with aq. NaHCO3 and brine (3×), concentrated and purified by CC (PE/EA=50/1) to give compound 27b (1.45 g, 20%) as a solid.
Reaction SMILES: O=C1CCC(=O)N1OC(=O)CCC(NC[CH:16]1[O:20][C:19]2[CH:21]=[CH:22][C:23]([CH2:25][CH:26]([N:28](CC)[C:29](=O)[C:30](F)(F)F)[CH3:27])=[CH:24][C:18]=2[O:17]1)=O>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>[CH3:30][CH2:29][NH:28][CH:26]([CH2:25][C:23]1[CH:22]=[CH:21][C:19]2[O:20][CH2:16][O:17][C:18]=2[CH:24]=1)[CH3:27]
Reactant: CCN(C(=O)C(F)(F)F)C(C)Cc1ccc2c(c1)OC(CNC(=O)CCC(=O)ON1C(=O)CCC1=O)O2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNC(C)Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
MDEA-BSA conjugate 36 was synthesized as described in copending, commonly assigned U.S. Ser. No. 10/622,254 filed contemporaneously herewith. A solution of 500 mg of bovine serum albumin (BSA) in 6.7 mL of 50 mM potassium phosphate (pH 7.5) was cooled in an ice-bath. To the solution was added 8.5 mL of DM50 dropwise, and the reaction mixture was maintained below room temperature. To the protein solution was added a solution of 12 mg (0.022 mmol) of N-(5-{2-[ethyl-(2,2,2-trifluoro-acetyl)-amino]-propyl}-benzo[1,3]dioxol-2-ylmethyl)-succinamic acid 2,5-dioxo-pyrrolidin-1-yl ester (compound 2L in U.S. Ser. No. 10/622,254) in 1.5 mL of anhydrous DMF dropwise. The reaction mixture was allowed to stir at room temperature 48 hours. The resulting conjugate was placed in a dialysis tube (10,000 MW cut-off) and was dialyzed in 1 L of 70% DMSO in 50 mM potassium phosphate (pH 7.5, 3 changes, at least 3 hours each), 1 L of 50% DMSO in 50 mM potassium phosphate (at least 3 hours), 1 L of 30% DMSO in 50 mM potassium phosphate (at least 3 hours), 1 L of 10% DMSO in 50 mM potassium phosphate (at least 3 hours) at room temperature. The trifluoroacetamido group of the conjugate was deprotected by dialysis of the resulting conjugate against 10% ammonium hydroxide for 3 days (1 L each for approximately 24 hours each), followed by 6 changes with 50 mM potassium phosphate (pH 7.5) at 4° C. (1 L each). The protein concentration was determined to be 7.12 mg/mL using BioRad Coomassie blue protein assay (Bradford, M., Anal. Biochem. 72:248, 1976). A total of 45 mL of the conjugate was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[F:31].[CH3:32][O:33][C:34]1[CH:35]=[C:36]([N:40]=[C:41]=[O:42])[CH:37]=[CH:38][CH:39]=1>N1C=CC=CC=1>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:41]([NH:40][C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([O:33][CH3:32])[CH:35]=4)=[O:42])=[C:3]([F:31])[CH:4]=3)[C:16]=12
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(N)c(F)c4)c4c(N)ncnc43)CC2)CC1
Reactant: COc1cccc(N=C=O)c1
Solvent: c1ccncc1
Product: COc1cccc(NC(=O)Nc2ccc(-c3nn([C@H]4CC[C@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2F)c1
Reaction time: 19 h

Procedure:
trans-3-(4-Amino-3-fluorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (77 mg, 0.182 mmol) was suspended in pyridine (1 mL). A solution of 3-methoxyphenylisocyanate (30 mg, 0.200 mmol) in pyridine (1 mL) was added to the reaction mixture and stirring was continued for 19 hours. The reaction mixture was concentrated under reduced pressure to yield the crude product as a pale yellow oil (149 mg). The crude material was purified on RP-HPLC (Waters PrepLC 4000, flow rate: 10 mL/min. λ=254 nm Gradient: 10% to 30% acetonitrile/0.1M aqueous ammonium acetate gradient over 40 minutes; Deltapak C18, 300A, 15 μm, 40×100 mm column) to afford trans-N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-N′-(3-methoxyphenyl)urea as a white solid (76 mg, 0.133 mmol). HPLC-RT: 12.33 min. (flow rate: 1 mL/min λ=254 nm Gradient: 5% to 85% acetonitrile/0.1M aqueous ammonium acetate gradient over 20 min.; Deltapak C18, 300A, 5 μm, 150×3.9 mm column); m/z (MH+)=574.2.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:15][CH2:16][C:17]1[C:18]([F:34])=[C:19]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=2)[C:28]#[N:29])[C:20]([Cl:23])=[CH:21][CH:22]=1.[NH:35]1[CH:39]=[N:38][C:37]([C:40](O)=[O:41])=[N:36]1>CN(C=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][NH:15][C:40]([C:37]2[N:38]=[CH:39][NH:35][N:36]=2)=[O:41])=[C:18]([F:34])[C:19]=1[O:24][C:25]1[CH:26]=[C:27]([C:28]#[N:29])[CH:30]=[C:31]([Cl:33])[CH:32]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: O=C(O)c1nc[nH]n1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3nc[nH]n3)c2F)c1
Yield: 39.1 %

Procedure:
The title compound was prepared in a similar manner to that described herein using EDC (0.068 g, 0.354 mmol), HOBT (0.048 g, 0.354 mmol), 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.100 g, 0.321 mmol) and 1H-1,2,4-triazole-3-carboxylic acid (0.036 g, 0.321 mmol) in DMF (2 mL) to give title compound (0.051 g, 39%) as a white solid. 1H NMR (400 MHz, DMSO-d6) (95° C.) δ ppm 14.24 (br. s., 1H), 8.60 (br. s., 1H), 7.72 (s, 1H), 7.33-7.49 (m, 5H), 4.55 (d, 2H). ES MS: m/z 406 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.[S:28]1[CH:32]=[CH:31][N:30]=[C:29]1[S:33](Cl)(=[O:35])=[O:34]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[S:33]([C:29]2[S:28][CH:32]=[CH:31][N:30]=2)(=[O:35])=[O:34])[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1nccs1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3cnccn3)cc2)S(=O)(=O)c2nccs2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 1 from 3-{3-[(4-pyrazin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11a, and thiazole-2-sulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.61 (s, 1H), 8.50 (s, 1H), 7.96 (d, 1H), 7.88 (d, 2H), 7.60 (d, 1H), 7.26 (d, 2H), 7.13 (m, 1H), 7.04 (m, 1H), 6.95 (m, 1H), 6.91 (s, 1H), 4.54 (s, 2H), 4.48 (s, 2H), 3.64 (s, 3H), 2.81 (t, 2H), 2.52 (t, 2H); MS 509 (M+1).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].[N:19]#[C:20]Br.[OH-].[Na+]>CCO>[C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:20]1=[NH:19]
Reactant: Cc1ccccc1NCCNc1ccccc1C
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1N1CCN(c2ccccc2C)C1=N
Reaction time: 1 h
Yield: 92.6 %

Procedure:
N,N' Bistolyl ethylene diamine (105.8 mg, 0.44 mmol) was taken up in EtOH (3 mL) to provide a light purple solution. This solution was then placed in a one-necked round-bottom flask (25 mL) equipped with magnetic stirbar and reflux condenser. To this solution, cyanogen bromide (50 mg, 0.47 mmol) in ethanol (2 mL) was added in a single portion. The resultant reaction mixture was stirred for 1 h. It was noted that the solution turned clear. The solution was then brought to reflux and maintained at that temperature for 16 h. The reflux condenser was then removed, allowing the solvent to evaporate. The reaction mixture was then fused at 150° C. for 30 min to provide a brown solid. This solid was immediately taken up in ethanol (4 mL) and placed into a centrifuge tube. To this solution 1N NaOH was added (8 mL) to provide a "whispy" tan precipitate. After several failed attempts to pellet the precipitate, the solution was simply extracted with chloroform (20 mL). The chloroform was concentrated to dryness to provide a clear oil (108.1 mg, 92.6%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([CH3:23])([C@H:6]1[CH2:11][CH2:10][C@H:9](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:8][CH2:7]1)[CH3:5].[CH3:25][NH:26][CH3:27]>>[CH3:1][O:2][C:3](=[O:24])[C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([N:26]([CH3:27])[CH3:25])[CH2:8][CH2:7]1)([CH3:23])[CH3:5]
Reactant: CNC
Reactant: COC(=O)C(C)(C)[C@H]1CC[C@H](OS(=O)(=O)c2ccc(C)cc2)CC1
Product: COC(=O)C(C)(C)[C@H]1CC[C@@H](N(C)C)CC1
Temperature: 25 °C

Procedure:
A solution of 0.354 g of trans-2-methyl-2-[4-(toluene-4-sulfonyloxy)-cyclohexyl]-propionic acid methyl ester in 10 ml of 60% aqueous dimethylamine solution is heated to 110° C. for 48 hours. The reactions mixture is cooled to room temperature and extracted with dichloromethane (3×). The combined extracts are dried over sodium sulphate and concentrated. Flash chromatography (SiO2 60F) of the residue provides the title compound which is identified on the basis of its Rf-value.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:21](=[O:22])[C:20]([C:23]([O:25]CC)=O)=[CH:19][N:12]4[CH2:13][C:14](=O)[NH:15][C:16]([CH:17]=2)=[C:11]34)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>CO>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:34][C:23]([C:20]2[C:21](=[O:22])[C:10]3[C:11]4[N:12]([CH:19]=2)[CH2:13][C:14]([NH:34][CH2:33][C:32]2[CH:35]=[CH:36][C:29]([Cl:28])=[CH:30][CH:31]=2)=[N:15][C:16]=4[CH:17]=[C:8]([CH2:7][N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH:9]=3)=[O:25])=[CH:31][CH:30]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn2c3c(cc(CN4CCOCC4)cc3c1=O)NC(=O)C2
Solvent: CO
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c3c(cc(CN4CCOCC4)cc3c1=O)N=C(NCc1ccc(Cl)cc1)C2
Temperature: 180 °C

Procedure:
A mixture of ethyl 9-(4-morpholinylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxylate (Preparation 4, 280 mg) and 4-chlorobenzylamine (1 mL) is heated at 180° C. The solution is cooled, diluted with methanol (2 mL), and the precipitate is filtered off. The resulting solid is washed with methanol followed by ether and dried to give 117 mg of the title compound. Physical characteristics: 1H NMR (DMSO-d6) δ2.35, 3.49, 3.57, 4.56, 4.60, 5.08, 7.20, 7.34-7.40, 7.64, 8.21, 8.62, 10.6. Anal. Found: C, 62.90; H, 4.99; N, 11.81; Cl, 12.03.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11]C=O)=[CH:7][N:6]=1)=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:26]([O:31][CH3:32])([O:29][CH3:30])OC>CO>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11][CH:26]([O:29][CH3:30])[O:31][CH3:32])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(CC=O)cn1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)c1cnc(CC(OC)OC)cn1
Yield: 78.5 %

Procedure:
A mixture of 5-(2-oxo-ethyl)-pyrazine-2-carboxylic acid methyl ester (prepared as in Example 42, 330 mg, 1.83 mmol), p-toluenesulfonic acid monohydrate (35 mg, 0.184 mmol), trimethyl orthoformate (3 mL, 137 mmol), and methanol (10 mL) was heated under reflux for 90 min. The mixture was concentrated in vacuo to dryness, and the residue was further concentrated in vacuo to dryness from toluene (10 mL). The resulting residue was shaken with methylene chloride (25 mL) and a saturated aqueous sodium bicarbonate solution (10 mL). The aqueous phase was back-extracted with methylene chloride (10 mL). Each extract was washed with a saturated aqueous sodium chloride solution (5 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 5-(2,2-dimethoxy-ethyl)-pyrazine-2-carboxylic acid methyl ester (325 mg, 78%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([CH3:11])=[CH:7]2.C[Mg]Br.[Cl:15][C:16]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].[NH4+].[Cl-]>C1COCC1.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([CH3:11])=[C:7]2[C:18]([C:17]1[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:16]=1[Cl:15])=[O:19]
Reactant: Cc1cc2cccc(Br)c2[nH]1
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1[nH]c2c(Br)cccc2c1C(=O)c1cccc(Cl)c1Cl
Temperature: -10 °C

Procedure:
10.7 g of 7-bromo-2-methyl-1H-indole are placed in 100 ml of THF and the mixture is cooled to −10° C. 22 ml of 3M methylmagnesium bromide in ether are added at this temperature. The mixture is allowed to return to AT and is then cooled to −5° C. and 13.5 g of 2,3-dichlorobenzoyl chloride, dissolved in 80 ml of THF, are added dropwise. The medium is allowed to return to AT and is then poured onto a saturated NH4Cl solution. Extraction is carried out with ether and then the organic phase is washed with a 10% NaOH solution, water and a saturated NaCl solution. It is dried and evaporated and the residue is chromatographed on silica while eluting with an AcOEt/cyclohexane (10/90, v/v) mixture. The product obtained crystallizes from ether and 5 g of the expected compound are obtained.
Reaction SMILES: [I:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][CH:12]=1>CN(C1C=CN=CC=1)C.ClC1C=CC=CC=1Cl>[CH2:24]([O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:8][C:7]3[C:2]([I:1])=[N:3][C:4]([CH3:9])=[CH:5][CH:6]=3)=[CH:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1ccc(O)c(I)n1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2c(Oc3ccc(C)nc3I)ccnc2cc1OCc1ccccc1
Temperature: 125 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
2-Iodo-6-picolin-3-ol (10 g), 4-chloro-7-benzyloxy-6-methoxyquinoline (6.8 g), and 4-(N,N-dimethylamino)-pyridine (12.2 g) were dissolved in 1,2-dichlorobenzene (400 ml) to prepare a solution, and the mixture was stirred at 125° C. overnight. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. Water was added to the residue, the mixture was extracted with chloroform, and the chloroform layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography using chloroform-acetone to give 7-benzyloxy-4-(2-iodo-6-methyl-pyridin-3-yloxy)-6-methoxy-quinoline (5.2 g, yield 31%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[C:5](Cl)=[C:4]([Cl:16])[N:3]=1.CCN(C(C)C)C(C)C.ClC1C(NC2C=C(OC(C)C)NN=2)=NC([NH:33][C@H:34]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][N:37]=2)[CH3:35])=NC=1>CCO>[Cl:16][C:4]1[N:3]=[C:2]([NH:33][C@H:34]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][N:37]=2)[CH3:35])[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[CH:5]=1
Reactant: Cc1cc(Nc2nc(Cl)nc(Cl)c2Cl)n[nH]1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ncc2Cl)n[nH]1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc(Cl)nc(N[C@@H](C)c3ccc(F)cn3)n2)n[nH]1
Temperature: 140 °C
Yield: 26.7 %

Procedure:
To a solution of 2,5,6-trichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 39; 2.0 g, 8.2 mmol) in absolute EtOH (40 ml) were added DIEA (2.5 ml) and (15)-1-(5-fluoropyridin-2-yl)ethanamine (Method 6; 1.2 g, 8.2 mmol) and the resulting solution was heated to 140° C. for 12 hours. The mixture was partitioned between EtOAc and H2O, the organic layer was washed with brine and dried. The solvents were removed under reduced pressure to give an oil which was purified by Gilson (20-75% acetonitrile/H2O, 35 min) to give the titled compound as solid (762 mg). m/z: 383.