Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](CCCC)(CCCC)CCCC)[S:10][C:3]=12.Br[C:25]1[N:29]([CH3:30])[CH:28]=[N:27][CH:26]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:25]3[N:29]([CH3:30])[CH:28]=[N:27][CH:26]=3)[S:10][C:3]=12
Reactant: Cn1cncc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1cncc1-c1cc2nccc(Cl)c2s1
Yield: 79.4 %

Procedure:
Nitrogen was bubbled through a mixture of the tin derivative 6 (7.19 g, 15.7 mmol) and 5-bromo-1-methyl-1H-imidazole (2.02 g, 12.5 mmol) [a) Begtrup, M.; Larsen, P.; Acta Chem. Scand. 44, 10; 1990; 1050-1057. b) Begtrup, M.; Bull. Soc. Chim. Belz.; 97; 8-9; 1988; 573-598. c) Begtrup, M.; Larsen, P.; Chem. Pharm. Bull. 42, 9; 1994; 1784-1790.] in toluene (20 mL) for 5 minutes. Pd(PPh3)4 (1.50 g, 1.30 mmol) was added and nitrogen was bubbled for additional 5 minutes. Finally, the mixture was refluxed under nitrogen overnight, the resultant yellow suspension was concentrated under reduced pressure and then purified with flash chromatography (eluent EtOAc/MeOH 90:10), to afford title compound 16 as a yellow solid (2.48 g, 79% yield). MS (m/z): 250.0 (M+H).
Reaction SMILES: COC[O:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[N:13][C:8]=2[S:7][C:6]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20]([Li])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1.CCCCCC>[CH3:21][C:20]([C:12]1[CH:11]=[CH:10][C:9]2[C:5]([OH:4])=[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:7][C:8]=2[N:13]=1)([CH3:23])[CH3:22]
Reactant: [Li]C(C)(C)C
Reactant: COCOc1c(-c2ccccc2)sc2ncccc12
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(O)c(-c3ccccc3)sc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of 2.72 g (10.0 mmol) of 3-methoxymethoxy-2-phenyl-7-azabenzothiophene in 20 mL of dry tetrahydrofuran was cooled to -78° C. To this was added 11 mL of a 1.0M solution of t-butyllithium in hexane and the solution was allowed to warm to room temperature. The solution was quenched with methanol and stirred in air for 60 minutes, then partitioned between ether and water. The aqueous layer was washed with two portions of ether and the combined extracts were washed with brine, dried, and concentrated to an oil. The oil was dissolved in 10 mL methanol and 10 mL of 2M HCl and stirred at room temperature for 24 hours. The solution was partitioned between ether and water and the ether layer dried and concentrated. Recrystallization from ether-hexane afforded 2.43 g (84%) of pale yellow needles, m.p. 181°-183° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[Cl:17][C:18]1[CH:19]=[C:20]([S:25](Cl)(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1[Cl:24]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:25]([C:20]1[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=1)(=[O:27])=[O:26])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 123 mg of 3,4-Dichloro-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.25 (d, 1H, J=8.8 Hz), 7.36–39 (m, 3H), 7.43–47 (m, 3H), 7.53 (dd, 1H, J=8.8 Hz, 2.4 Hz), 7.61 (m, 1H), 7.65 (m, 1H), 7.73 (d, 1H, J=8.8 Hz), 9.56 (s, 1H). MS: m/z 440.7 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[OH-].[Na+].[CH:13](O)=O>>[NH:10]1[C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=[CH:13]1
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1ccc2[nH]cnc2c1
Temperature: 100 °C
Yield: 82 %

Procedure:
3,4-Diaminobenzonitrile (1.0 g; 7.5 mmol) was dissolved in formic acid (3 mL) and heated at 100° C. for 1.5 hours. The mixture was cooled, neutralised with 10% sodium hydroxide and the resulting precipitate isolated by filtration and dried in vacuo to yield the title compound as a brown solid (890 mg; 82%). 1H NMR (DMSO-d6) δ 8.50 (1H, s), 8.19 (1H, s), 7.79 (1H, d, J=8.3 Hz), 7.62 (1H, dd, J=8.3, 1.54 Hz). LC/MS (Method C): 144 (M+H)'. HPLC (Method F) Rt=2.14 min (Purity: 99.4%).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19](=O)[CH2:20][C:21](OCC)=[O:22]>>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]1[CH:20]=[C:21]([OH:22])[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: CCOC(=O)CC(=O)Cc1ccccc1Cl
Product: N#Cc1ccnc(-n2nc(Cc3ccccc3Cl)cc2O)c1
Yield: 39 %

Procedure:
The title compound was prepared in 39% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 4-(2-chlorophenyl)-3-oxobutanoate according to the procedure for the preparation of Example 158, part A.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:13]3[CH:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:15][CH2:16][CH2:17][C:12]=3[NH:11][C:10]=2[CH:26]=1)=O)C.CC(C[AlH]CC(C)C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:18]([CH:14]1[C:13]2[C:9]3[CH:8]=[CH:7][C:6]([CH2:4][OH:3])=[CH:26][C:10]=3[NH:11][C:12]=2[CH2:17][CH2:16][CH2:15]1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCC1CCCc2[nH]c3cc(C(=O)OCC)ccc3c21
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCCCCC1CCCc2[nH]c3cc(CO)ccc3c21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 96.2 %

Procedure:
A solution of 30.4 g of 5,6,7,8-tetrahydro-9-octyl-9H-dibenzo[b,d]pyrrole-3-carboxylic acid ethyl ester from Example 9, in 300 ml of methylene chloride was treated with 124 ml of a 1.5M DIBAH solution in toluene at 0°-5° C. (ice-water bath) in approximately 20 minutes. After an additional 20 minutes stirring at the same temperature, the reaction mixture was cautiously poured into cold 2N-HCl ice and extracted with methylene chloride. The organic extracts were washed with water and brine, then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 28.3 g of a crude yellow oil. Purification of this material on a small silica gel pad (eluting system:hexane-ethyl acetate 1:1) produced 25.8 g (96.2%) of 5,6,7,8-tetrahydro-9-octyl-9H-dibenzo[b,d]pyrrole-3-methanol as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=2)=O)=[N:5][N:4]=[N:3]1.Cl.[NH2:21][OH:22]>N1C=CC=CC=1.C(OCC)(=O)C>[OH:22][N:21]=[C:7]([C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1
Reactant: Cn1nnnc1C(=O)c1cccc(OC(F)(F)F)c1
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cn1nnnc1C(=NO)c1cccc(OC(F)(F)F)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a stirred solution of (1-methyl-1H-tetrazol-5-yl)[3-(trifluoromethoxy)phenyl]methanone (5.12 g, 16.2 mmol) in dry pyridine (25 mL) was added hydroxylamine hydrochloride (2.81 g, 40.4 mmol). The mixture was stirred at 70° C. for 3 h, then left to stand overnight. After concentration of the reaction mixture in vacuo, the residue was diluted with ethyl acetate (100 mL) and washed with water (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL), the combined organic layers dried (MgSO4), concentrated in vacuo and dissolved in toluene. A crystalline precipitate appeared, which was filtered off to afford N-hydroxy-1-(1-methyl-1H-tetrazol-5-yl)-1-[3-(trifluoromethoxy)phenyl]methanimine as a white solid [4.33 g, yield 92%; HPLC/MS:m/z=288 (M+H); log P(HCOOH)=2.37].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:18]([NH2:20])=[CH:17][C:16]([CH3:21])=[N:15][C:14]=3[S:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:22][N:23]1[CH:27]=[C:26]([S:28](Cl)(=[O:30])=[O:29])[N:25]=[CH:24]1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][C:16]([CH3:21])=[CH:17][C:18]=3[NH:20][S:28]([C:26]3[N:25]=[CH:24][N:23]([CH3:22])[CH:27]=3)(=[O:30])=[O:29])[S:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2csc3nc(C)cc(N)c23)cc1OC
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2csc3nc(C)cc(NS(=O)(=O)c4cn(C)cn4)c23)cc1OC

Procedure:
Following general method outlined in Example 1, starting from 3-[3,4-bis(methyloxy)phenyl]-6-methylthieno[2,3-b]pyridin-4-amine (62 mg, 0.150 mmol) (Description 24) and 1-methyl-1H-imidazole-4-sulfonyl chloride (54.0 mg, 0.299 mmol), the title compound (26 mg) was isolated as a TFA salt. LCMS (B) m/z: 445 [M+1]+, Rt 2.41 min.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][CH2:30][O:31][C:24]=3[CH:23]=2)[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][CH2:30][O:31][C:24]=4[CH:23]=3)[C:11]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1nc(NCc2ccc3c(c2)OCCO3)c2cc([N+](=O)[O-])sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-nitro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-nitro-4-(3,4ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>C(O)C>[CH2:10]([N:9]([C:20]([NH:19][CH2:17][CH3:18])=[O:21])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN=C=O
Reactant: CC(C)(C)OC(=O)NNCc1ccccc1
Solvent: CCO
Product: CCNC(=O)N(Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a solution of N'-benzylhydrazinecarboxylic acid tert-butyl ester (2.5 g, 11.8 mmol) in 99% ethanol (40 ml) was added ethyl isocyanate (1.1 g, 15.2 mmol) and the mixture was stirred for 2 h. Then the mixture was concentrated in vacuo and chromatographed on silica (20 g) with petrol ether/ethyl acetate 3:2 to give 3.0 g of 2-benzyl-1-tert-butoxycarbonyl-4-ethylsemicarbazide.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18](OC3C(F)=C(F)C(F)=C(F)C=3F)=[O:19])=[C:14]([F:32])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].C[Si](C)(C)[O:35][NH2:36].C(OCC)C>O1CCCC1>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:36][OH:35])=[O:19])=[C:14]([F:32])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)ON
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c(F)c2)C(=O)O1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)NC[C@H]1CN(c2ccc(C(=O)NO)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
Prepared according to Method D of the General Procedures for Preparation of 5-(S)-(N-Acylaminomethyl)-3-[4′-(4″-(un)substituted amino)carbonyl-3′-fluorophenyl]oxazolidine-2-ones from 5-(S)-acetamidomethyl-3-[4′-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]-oxazolidine-2-one (0.046 g, 0.1 mmol) and O-trimethylsilylhydroxylamine (0.052 mL, ca. 0.5 mmol) in tetrahydrofuran (1 mL). The synthesis was performed for 2 h at r.t. Diethyl ether (4 mL) was added, the precipitated product washed with diethyl ether, tetrahydrofuran (2×0.5 mL), excess ether, and dried in vacuo. MS: 312 [M+H]+. Rt 2.8 min. 1H NMR.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:7])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: BrCc1ccccc1
Reactant: COc1cc(C(=O)O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OCc2ccccc2)ccc1Br
Reaction time: 0.17 h
Yield: 91 %

Procedure:
4-Bromo-3-methoxy-benzoic acid (1.50 g, 6.49 mmol), K2CO3 (2.69 g, 19.5 mmol), and DMF (10 mL) were combined and the mixture was allowed to stir for 10 minutes. Bromomethylbenzene (849 μL, 7.14 mmol) was added dropwise and the mixture was allowed to stir at rt for 1 h. The reaction mixture was quenched with brine and was extracted with EtOAc (3×). The organic layers were dried over sodium sulfate, filter and concentrated. The residue was purified using silica gel chromatography (5%-70% EtOAc in hexanes) to provide benzyl 4-bromo-3-methoxybenzoate (91%). ESI-MS m/z calc 320.0. found 321.0/323.0 (M+1)+. Retention time: 3.24 minutes (4 min run).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[H-].[Na+].CS(O[CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24])(=O)=O>C1COCC1.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH:7][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24]
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: COCCCCOS(C)(=O)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCCCNc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
5-Fluoro-2-nitroaniline (1.0 g) was dissolved in THF (20 ml), sodium hydride (60% in oil, 384 mg) was added, and the mixture was stirred at room temperature for 30 min. 4-Methoxybutyl methanesulfonate (1.28 g) was added, and the mixture was heated under reflux with stirring for 15 hr. The reaction mixture was cooled to room temperature and saturated brine was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (30:70) was concentrated under reduced pressure to give the object product (494 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:36](I)[CH3:37]>CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:14]4=[N:15][CH:16]=3)=[N:7][N:8]2[CH2:36][CH3:37])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)C)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
2-(6-Chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (120 mg, 247 μmol) was dissolved in DMF (1 mL) and cooled to 0° C. Sodium hydride (12.9 mg, 322 μmol) was added and the mixture was allowed to stir for 30 min at 0° C. Ethyl iodide (57.9 mg, 30.0 μL, 371 μmol) was added and the mixture was warmed to 20° C. After 15 h the mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica, 40 g Analogix pre-packed column, 20-50% ethyl acetate in hexanes, 15 minute gradient) to give 2-(6-chloro-1-ethyl-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (78 mg, 152 μmol, 61%) as a yellow powder. MS (M+Na)+=535; 1H NMR (CDCl3) δ: 9.26 (s, 1H), 8.44-8.49 (m, 1H), 8.39-8.42 (m, 1H), 8.20-8.28 (m, 1H), 7.47-7.56 (m, 1H), 7.23 (d, J=1.5 Hz, 1H), 5.67-5.77 (m, 2H), 4.43-4.59 (m, 1H), 4.13 (q, J=7.2 Hz, 1H), 3.52-3.67 (m, 1H), 1.57-1.65 (m, 4H), 1.42 (d, J=6.4 Hz, 4H), 0.88-1.01 (m, 2H)
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)(O)=O.[C:40]([NH:44][CH3:45])([CH3:43])([CH3:42])[CH3:41]>>[C:40]([N:44]([CH3:45])[CH2:1][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:38][CH:39]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: CNC(C)(C)C
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(CCN(C)C(C)(C)C)cc2)c1
Yield: 31.7 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and tert-butylmethylamine (14 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (4.8 mg) was obtained.
Reaction SMILES: C[Al](C)C.C1(C)C=CC=CC=1.[Cl-].[NH4+:13].[F:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[F:14][C:15]1[CH:22]=[CH:21][C:18]([C:19](=[NH:13])[NH2:20])=[CH:17][CH:16]=1
Reactant: [NH4+]
Reactant: N#Cc1ccc(F)cc1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: N=C(N)c1ccc(F)cc1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
4.12 mL (8.24 mmol) of trimethyl aluminum (2.0 M toluene solution) was dropwise added to a 10 mL of toluene containing 441 mg (8.24 mmol) of ammonium chloride at room temperature. After stirring for 1.5 hours, 1 g (8.25 mmol) of 4-fluorobenzonitrile was added thereto and the resulting mixture was heated to 85° C. for 9 hours. After completion of a reaction, the reaction solution was cooled, then poured into 100 mL of chloroform containing 500 g of silica gel and filtered off. The residue was washed with 100 mL of methanol and distillation was conducted to give 821 mg (5.9 mmol) of the title compound in a yield of 71%.
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H](CCO)C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.[CH2:31]=[C:32]1[CH:49]2[C@:44]([CH3:51])([CH2:45][CH2:46][C:47](=[O:50])[CH2:48]2)[C@@H:43]2[C@H:34]([C@H:35]3[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38](=[O:52])[CH2:37][CH2:36]3)[CH2:33]1>>[OH:2][CH2:1][CH2:31][C@@H:32]1[CH:49]2[C@:44]([CH3:51])([CH2:45][CH2:46][C:47](=[O:50])[CH2:48]2)[C@@H:43]2[C@H:34]([C@H:35]3[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38](=[O:52])[CH2:37][CH2:36]3)[CH2:33]1
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Reactant: C[C@]12CCCCC1[C@@H](CCO)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCC(=O)CC1[C@@H](CCO)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 100 %

Procedure:
The title compound II-an was prepared in 100% yield from 3,3:17,17-bis(ethylendioxy)-6α-(2-hydroxyethyl)androstane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.32 (1H, t), 3.39 (2H, m), 2.46-0.54 (23H, m), 0.98 (3H, s), 0.79 (3H, s).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:16])[C:10](=[O:15])[N:11]2[OH:14])=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>P([O-])(O)(O)=O.[K+].C(O)C>[CH2:17]([O:14][N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([C:1]([OH:3])=[O:2])[CH:13]=2)[NH:8][C:9](=[O:16])[C:10]1=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc2[nH]c(=O)c(=O)n(O)c2c1
Reactant: BrCc1ccccc1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1ccc2[nH]c(=O)c(=O)n(OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
7-Carboxy-1-hydroxyquinoxaline-2,3(1H,4H)-dione (2.22 g, 10 mmol) was dissolved in a mixture of 50 ml of 1M potassium dihydrogen phosphate buffer (pH 7.4) and 25 ml of ethanol by gently heating. To the cooled mixture was added 1.19 ml (10 mmol) of benzylbromide and the mixture was stirred overnight at room temperature. The precipitate was isolated by filtration and washed with ethanol. The crude product was triturated with 4M hydrochloric acid and washed with water and dried in vacuo to give 1.56 g (50%) of the title compound.1H-NMR (DMSO-d6): 5.22 (s, 2H, CH2), 7.2-7.9 (m, 8H, ArH), 12.35 (s, 1H, exchangeable), 13.05 (br.s, 1H, exchangeable).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[C:23]([C:24]([OH:26])=O)=[CH:22][N:21]=[CH:20][CH:19]=3)[C:11]3[CH2:16][O:15][CH2:14][C:12]=3[N:13]=2)[CH:7]=1.C[N:29](C=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[C:23]([C:24]([NH2:29])=[O:26])=[CH:22][N:21]=[CH:20][CH:19]=3)[C:11]3[CH2:16][O:15][CH2:14][C:12]=3[N:13]=2)[CH:7]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1COC2
Product: NC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1COC2
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-[2-(5-chloro-2-fluoro-phenyl)-5,7-dihydro-furo[3,4-d]pyrimidin-4-ylamino]-nicotinic acid (50 mg, 0.13 mmol, 1 eq) in DMF (2 ml) was added 1-1′-carbonyldiimidazole (50 mg, 0.31 mmol, 2.4 eq) and the reaction mixture was warmed to 70° C. for 2 h. The mixture was cooled to r.t. and NH3(g) was bubbled through for 10 min. The reaction mixture was stirred at r.t. for an additional 1 h. The reaction was concentrated in vacuo and the residue was triturated with water (2×5 ml). To the crude residue was added 1 N NaOH (5 ml) and the suspension was heated to 100° C. for 2 h. The reaction mixture was cooled to room temperature and neutralized with 1 N HCl and the solid was filtered to give 4-[2-(5-Chloro-2-fluoro-phenyl)-5,7-dihydro-furo[3,4-d]pyrimidin-4-ylamino]-nicotinic amide, compound of formula (34) (25 mg, 50%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3([CH3:17])[O:16][CH2:15][CH2:14][O:13]3)=[CH:8][C:7]=2[C:18]2[C:19]3[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:25]([CH3:35])=[C:24]([C:36]([OH:38])=O)[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:3][CH2:2]1.[NH2:39][C@H:40]1[CH2:45][CH2:44][C@H:43]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:42][CH2:41]1>>[C:49]([O:48][C:47](=[O:53])[NH:46][C@H:43]1[CH2:42][CH2:41][C@H:40]([NH:39][C:36]([C:24]2[C:20]3[N:21]=[CH:22][N:23]=[C:18]([C:7]4[CH:8]=[C:9]([C:12]5([CH3:17])[O:13][CH2:14][CH2:15][O:16]5)[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:19]=3[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:25]=2[CH3:35])=[O:38])[CH2:45][CH2:44]1)([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(C4(C)OCCO4)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c2ncnc(-c3cc(C4(C)OCCO4)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c13) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.