Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[CH:14]=[C:13]([C:15]([O:17]C)=[O:16])[N:12]=[CH:11][N:10]3[CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[O-].[K+]>C1COCC1>[C:1]1([C:7]2[N:8]=[C:9]3[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[N:12]=[CH:11][N:10]3[CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc2nc(-c3ccccc3)cn2cn1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)c1cc2nc(-c3ccccc3)cn2cn1
Reaction time: 0.5 h

Procedure:
A 100 mL round bottom flask was charged with methyl 2-phenylimidazo[1,2-c]pyrimidine-7-carboxylate (500 mg, 1.97 mmol) and dissolved in THF (19.70 mL) using sonication. To that stirring solution was added potassium trimethylsilanolate (760 mg, 5.92 mmol). After 30 minutes, TLC showed complete consumption of the starting material. LCMS showed complete consumption of starting material and the formation of a large, more polar peak consistent with the desired product by mass (m/z=240 [M+H]+/Methanol/Water/Ammonium Acetate Phenomenex Luna C18, 30×2 mm, 3μ ES+/−). The mixture was quenched using 10 mL of 4.0M HCl in dioxane. The now yellow slurry was concentrated under reduced pressure. To remove any residual water, 50 mL of acetonitrile was added and the solution was concentrated under reduced pressure. The resulting yellow solid was taken on without any further characterization or purification. Mass found 240 [M+H]+.
Reaction SMILES: [Cl:1][N:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([NH:9][C:10]2[CH:11]=[C:12]([S:37]([OH:40])(=[O:39])=[O:38])[C:13]([CH:16]=[CH:17][C:18]3[C:19]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:20][C:21]([NH:24][C:25]4[NH:30][N:29]([Cl:31])[N:28]=[C:27](Cl)[CH:26]=4)=[CH:22][CH:23]=3)=[CH:14][CH:15]=2)[NH:3]1.[NH2:41][C:42]1[CH:51]=[CH:50][C:49]2[C:48]([S:52]([OH:55])(=[O:54])=[O:53])=[CH:47][CH:46]=[CH:45][C:44]=2[C:43]=1[S:56]([OH:59])(=[O:58])=[O:57]>>[Cl:1][N:2]1[N:7]=[C:6]([NH:41][C:42]2[CH:51]=[CH:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][C:48]=3[S:52]([OH:55])(=[O:54])=[O:53])[C:43]=2[S:56]([OH:59])(=[O:58])=[O:57])[CH:5]=[C:4]([NH:9][C:10]2[CH:11]=[C:12]([S:37]([OH:40])(=[O:39])=[O:38])[C:13]([CH:16]=[CH:17][C:18]3[C:19]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:20][C:21]([NH:24][C:25]4[NH:30][N:29]([Cl:31])[N:28]=[C:27]([NH:41][C:42]5[CH:51]=[CH:50][C:49]6[C:44](=[CH:45][CH:46]=[CH:47][C:48]=6[S:52]([OH:55])(=[O:54])=[O:53])[C:43]=5[S:56]([OH:59])(=[O:58])=[O:57])[CH:26]=4)=[CH:22][CH:23]=3)=[CH:14][CH:15]=2)[NH:3]1
Reactant: Nc1ccc2c(S(=O)(=O)O)cccc2c1S(=O)(=O)O
Reactant: O=S(=O)(O)c1cc(NC2=CC(Cl)=NN(Cl)N2)ccc1C=Cc1ccc(NC2=CC(Cl)=NN(Cl)N2)cc1S(=O)(=O)O
Product: O=S(=O)(O)c1cc(NC2=CC(Nc3ccc4c(S(=O)(=O)O)cccc4c3S(=O)(=O)O)=NN(Cl)N2)ccc1C=Cc1ccc(NC2=CC(Nc3ccc4c(S(=O)(=O)O)cccc4c3S(=O)(=O)O)=NN(Cl)N2)cc1S(=O)(=O)O

Procedure:
4,4′-Bis-(2,4-dichlorotriazin-6-ylamino)-stilbene-2,2′-disulfonic acid was reacted with 2-aminonaphthalene-1,5-disulfonic acid in a similar manner to Example 5.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[S:24][CH:25]=1.O>CN(C=O)C>[F:38][C:35]([F:36])([F:37])[O:34][C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[S:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: Oc1ccc(COCCn2ccnn2)cc1
Reactant: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)cs2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(/C=C/c2nc(COc3ccc(COCCn4ccnn4)cc3)cs2)cc1
Reaction time: 0.25 h

Procedure:
182 mg (7.00 mmol) 95% Sodium hydride were given to a solution of 1.50 g (7.00 mmol) 4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenol in 7.0 ml DMF and stirred for 15 min. 2.06 g (7.00 mmol) 4-Chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-thiazole were added and stirring continued at r.t. overnight. After addition of 20 ml water the resulting precipitate was washed twice with 10 ml water, then with n-heptane and finally a little amount of diethyl ether and dried at 45° C. in vacuum. Yield 2.4 g.
Reaction SMILES: [O:1]1[CH2:4][C:3](=[O:5])[CH2:2]1.[CH2:6]([Li])[CH2:7][CH2:8][CH3:9].CCCCCC>C1COCC1>[CH2:6]([C:3]1([OH:5])[CH2:4][O:1][CH2:2]1)[CH2:7][CH2:8][CH3:9]
Reactant: [Li]CCCC
Reactant: O=C1COC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC1(O)COC1

Procedure:
To a stirred solution of 3-oxetanone (0.5 g, 6.93 mmol) in dry THF (6 mL), at −78° C., under argon atmosphere, 2.5M solution of butyl lithium (BuLi) in hexane (3.05 mL, 7.62 mmol) was added dropwise over 10 min. The reaction was left to react 3 h at −78° C., then quenched with water and concentrated to dryness. The crude mixture was dissolved in CH2Cl2 and dried over Na2SO4. The organic solution was filtered and concentrated to dryness to afford a pale yellow oil (0.505 g). The crude product was purified by column chromatography using a Teledyne ISCO apparatus, eluting with Cy/TBME (from 100:0 to 70:30) affording the title compound (0.45 g, 50%) as transparent oil. 1H NMR (CDCl3): δ 0.90-1.04 (m, 3H), 1.36-1.47 (m, 4H), 1.79-1.93 (m, 2H), 4.53 (d, J=7.1, 2H), 4.59 (d, J=6.9, 2H).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:13]=[C:12]2[C:7]=1[C@@H:8]1[CH:26]=[C:25]([CH3:27])[CH2:24][CH2:23][C@H:9]1[C:10]([CH3:22])([CH3:21])[O:11]2)CCC.[B-](F)(F)(F)[F:37].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC(C)=O.C(S([O-])(=O)=O)(F)(F)F.[Ag+]>[F:37][C:6]1[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:13]=[C:12]2[C:7]=1[C@@H:8]1[CH:26]=[C:25]([CH3:27])[CH2:24][CH2:23][C@H:9]1[C:10]([CH3:22])([CH3:21])[O:11]2
Reactant: CCCCCc1cc2c(c([Sn](CCCC)(CCCC)CCCC)c1)[C@@H]1C=C(C)CC[C@H]1C(C)(C)O2
Reactant: F[B-](F)(F)F
Agent: [Ag+]
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC(C)=O
Product: CCCCCc1cc(F)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Tributyl((6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl)stannane (S29) (100 mg, 0.17 mmol, 1 eq.) will be dissolved in acetone (3.5 ml), and AgOTf (87.4 mg, 0.34 mmol, 2 eq.) and Selectfluor (71 mg, 0.20 mmol, 1.2 eq.) will be added at room temperature. The mixture will be stirred for 20 min at room temperature and subsequently concentrated under reduced pressure. The concentrate will be subjected to column chromatography (EtOAc-Hex; 0:100 to 5:95) to give 19.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH2:14]([CH2:16][NH2:17])[OH:15]>>[Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([F:12])=[C:6]([S:8]([NH:17][CH2:16][CH2:14][OH:15])(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Br)c(F)cc1F
Reactant: NCCO
Product: O=S(=O)(NCCO)c1cc(Br)c(F)cc1F
Yield: 98.6 %

Procedure:
Prepared by general procedure III from 5-bromo-2,4-difluorobenzene sulfonyl chloride (1.0 g, 3.4 mmol) and ethanolamine (231 mg, 3.77 mmol) to give the title compound (1.06 g, 100%) as an off-white solid. MS (ISP) 315.8 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[O:12]([NH2:14])[CH3:13]>>[CH3:13][O:12][N:14]=[CH:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[Cl:1]
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: CON
Agent: Cl
Product: CON=Cc1ccc(F)cc1Cl
Yield: 93 %

Procedure:
Reaction of 2-chloro-4-fluoro-benzaldehyde with methoxylamine hydrochloride as described in the preparation of compound 1-A gave the title oxime ether as a clear oil (93% yield). 1HNMR indicated a 9:1 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 3.99 (3H, s, OCH3), 6.99 (1H, m, aromatic), 7.12 (1H, m, aromatic), 7.87 (1H, m, aromatic), 8.41 (1H, s, CH).
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8]C(=O)OCC1C=CC=CC=1.[ClH:20]>>[ClH:20].[F:1][C:2]1([F:19])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8]
Reactant: O=C(NC1CCCCC1(F)F)OCc1ccccc1
Agent: Cl
Product: NC1CCCCC1(F)F

Procedure:
A solution of benzyl 2,2-difluorocyclohexylcarbamate (38 mg, 0.14 mmol) in 6 N HCl (2 mL) was heated at 100° C. for 2 h. The cooled reaction mixture was extracted with ether (3×1 mL) and the combined organic layers were concentrated to give 2,2-difluorocyclohexanamine hydrochloride as a light brown solid (23 mg, 96% crude).
Reaction SMILES: [C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1>C(OCC)C>[C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:6][C:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=1)=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CC(C)(C)N(N)C(=O)c1ccccc1
Solvent: CCOCC
Product: Cc1ccc(NC(=O)NN(C(=O)c2ccccc2)C(C)(C)C)cc1
Yield: 36.9 %

Procedure:
N't-butyl-N'-benzoylhydrazine (0.8 g) and p-methylphenylisocyanate (0.9 g) were stirred in diethylether (10 ml) at 23° C. for 15 hours. The reaction mixture was diluted with ether and filtered to afford 0.5 g of solid product: m.p. 208-210° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[O:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:37]=[CH:36][C:23]3[NH:24][C:25]([C:27]4[CH:35]=[CH:34][C:30]([C:31]([O-])=[O:32])=[CH:29][CH:28]=4)=[N:26][C:22]=3[CH:21]=2)[CH2:16][CH2:15]1>>[O:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:37]=[CH:36][C:23]3[NH:24][C:25]([C:27]4[CH:35]=[CH:34][C:30]([C:31]([NH:11][C:10]5[CH:9]=[CH:8][C:7]([N:4]6[CH2:5][CH2:6][O:1][CH2:2][CH2:3]6)=[CH:13][CH:12]=5)=[O:32])=[CH:29][CH:28]=4)=[N:26][C:22]=3[CH:21]=2)[CH2:16][CH2:15]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=C([O-])c1ccc(-c2nc3cc(N4CCOCC4)ccc3[nH]2)cc1
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc(-c2nc3cc(N4CCOCC4)ccc3[nH]2)cc1

Procedure:
Compound 457 was prepared from 4-morpholinoaniline and 4-(5-morpholino-1H-benzimidazol-2-yl)benzoate by standard conditions. [M+H]+ calcd for C28H29N5O3: 484.23; found: 484.01.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][S:28][CH3:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][S:28][CH3:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CSCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CSCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2.3 h
Yield: 48.4 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-methylthiomethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.22 g.), conc. hydrochloric acid (0.25 g.) and methanol (3.3 ml.) was stirred at room temperature for 2.3 hours. After concentrating the resultant solution in vacuo, the residue was poured into water, adjusted to pH 7 with 10% aqueous sodium hydroxide and washed with ethyl acetate. The aqueous solution was adjusted to pH 3 with 10% hydrochloric acid under ice cooling and stirred at the same temperature for 30 minutes. The precipitates were collected by filtration, washed with water and dried to give 7-[2-(2-aminothiazol-4-yl)-2-methylthiomethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.1 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:15](=O)[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3C2=O)=[C:4](C(=O)C2C=CC=CC=2)[CH:3]=1>C(O)C.[OH-].[Na+].Cl.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:8][CH2:9][CH2:10][N:11]=[C:15]([C:14]3[CH:13]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:7]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1CCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCCC2

Procedure:
A solution of 5.1 g (12.6 mmole) of 1-[4-chloro-2-benzoylphenyl]-3-phthalimidopropane in 100 ml of ethanol and 20 ml of 3N sodium hydroxide was refluxed for 2 hr. The solution was diluted with 60 ml of 3N hydrochloric acid and refluxed for 12 hr. The mixture was diluted with water and extracted with ether. The aqueous layer was separated, made alkaline with dilute sodium hydroxide, and extracted with methylene chloride. The methylene chloride extract was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was purified by plug filtration (silica gel, 10 g; eluent, methylene chloride) and the eluent was acidified with methanolic hydrogen chloride. The solution was concentrated at reduced pressure to dryness and the residue was crystallized from a mixture of isopropanol and ether to give a colorless solid, mp 234°-235° C. Recrystallization from a mixture of methylene chloride and ether gave colorless needles, mp 234°-235° C. dec.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:13])=[C:5]([CH3:12])[C:6]=1[C:7](OCC)=O.C=O>>[CH3:1][C:2]1[NH:3][C:4]([CH3:13])=[C:5]([CH3:12])[C:6]=1[CH3:7]
Reactant: CCOC(=O)c1c(C)[nH]c(C)c1C
Agent: C=O
Product: Cc1[nH]c(C)c(C)c1C

Procedure:
2,4,5-Trimethyl-3-carbethoxy-pyrrole was reductively alkylated using paraformaldehyde to yield tetramethyl pyrrole. ##STR82##
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([CH2:10][C:11](OC)=[O:12])[CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([CH2:10][CH2:11][OH:12])[CH2:2]1
Reactant: COC(=O)CC1CNc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC1CNc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Methyl (RS)-(2,3-Dihydro-1H-indol-3-yl)acetate (30.0 g, 0.16 mol) was dissolved in tetrahydrofuran (500 mL) and subsequently added to a suspension of lithium aluminium hydride (10.6 g, 0.28 mol) in tetrahydrofuran (500 mL) over a period of 75 min at 33-39° C. The reaction was quenched by sequential addition of water (20 mL), 15% NaOH (10 mL) and water (50 mL), and then MgSO4. The mixture was stirred at room temperature for 1 h, filtered and concentrated in vacuo to give the title compound (24.2 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:4][CH:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(O)C>[C:22]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:4][CH:3]=1)(=[O:24])[CH3:23].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc(S(=O)(=O)O)c2ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
12 g (0.05 mole) of 1-amino-4-naphthalenesulphonic acid, 7.2 ml of pyridine and 15 ml of acetic anhydride are placed in a flask provided with a stirrer and heater. The mixture is heated until the solution is clear, at which point 10 ml of absolute ethanol is added and the mixture is allowed to cool, first to ambient temperature and then in a refrigerator to 3° C. for 3 hours. The precipitate obtained is collected in a filter and is recrystallized in ethanol to give 11 g (Yield 59.4%) of pyridine N-acetyl-1-aminonaphthalene-4-sulphonate, having a m.p. of 172°-175° C. and whose IR spectrum (KBr) has the following bands: 3,400; 3,220; 1,640; 1,525; 1,370; 1,325; 1,200; 1,030; 850; 675; 635.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16](=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH:28]1([NH2:31])[CH2:30][CH2:29]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([NH:31][CH:28]3[CH2:30][CH2:29]3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]c3cc(Cl)ccc23)CC1
Reactant: NC1CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(c2cc(NC3CC3)nc3cc(Cl)ccc23)CC1
Yield: 46.5 %

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloroquinol-2-one (150 mg, 0.4 mmol), sodium hydride (15 mg, 0.6 mmol), N-phenyl(trifluoromethylsulfon)imide (208 mg, 0.56 mmol), and cyclopropylamine (580 μL, 6.4 mmol) are treated according to method E yielding 75 mg of 4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-7-chloro-2-(cyclopropylamino)quinoline. 62 mg thereof are treated with TFA-CH2Cl2 1:1 (0.6 mL) for 1 h and concentrated. The residue is converted into the title product with 4-fluorophenyl isocyanate (26 μL) and triethylamine (193 μL).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]2)[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:35][CH2:36][CH2:37][CH2:38]Br>C(O)C>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([N:27]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](N)CC2)nc1N
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](N3CCCC3)CC2)nc1N

Procedure:
To a stirred solution of trans-[4-amino-2-(4-amino-cyclohexylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (64 mg, 0.16 mmol, Example 120) and sodium carbonate (0.49 mmol, 52 mg) in ethanol (3 mL), 1,4-dibromobutane (22 uL, 0.16 mmol, Aldrich) was added and the mixture was stirred at reflux for 3 days. The solvent was removed under reduced pressure and the residue was purified by reversed phase HPLC to give a white solid. 30 mg, 43%. MS (ES) MH+=432.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]([CH2:30][S:31][C:32](=[O:34])[CH3:33])([CH3:29])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([N:14](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[C:11]([CH3:13])[CH:12]=1)[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4](=[O:35])[C:5]([CH2:30][S:31][C:32](=[O:34])[CH3:33])([CH3:29])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([NH2:14])=[C:11]([CH3:13])[CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(CSC(C)=O)Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(CSC(C)=O)Cc1cnc(N)c(C)c1
Reaction time: 1 h
Yield: 78.4 %

Procedure:
Crude 2-acetylsulfanylmethyl-3-(6-[N,N-bis(tert-butoxycarbonyl)amino]-5-methyl-pyridin-3-yl)-2-methyl-propionic acid ethyl ester (1.46 g) was dissolved in TFA (5 mL) and stirred for 60 min. Concentration under reduced pressure followed by chromathography (toluene/EtOAc, 1:1→1:10→0:1) gave slightly impure 2-acetylsulfanylmethyl-3-(6-amino-5-methyl-pyridin-3-yl)-2-methyl-propionic acid ethyl ester (696 mg, 84%)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-:3])=[O:2].[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>ClCCl>[CH3:23][S:24]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:6]=2)[CH2:11][CH2:12]1)(=[O:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1Nc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc([N+](=O)[O-])c(Nc3ccccc3)c2)CC1
Yield: 53.1 %

Procedure:
A solution of 2-nitro-N-phenyl-5-(piperazin-1-yl)benzenamine (0.30 g, 1.0 mmol), methanesulfonyl chloride (0.08 ml, 1.0 mmol) and triethylamine (0.32 ml, 4.0 mmol) in 20 ml dichloromethane was stirred at 0° C. for 2 hours. The mixture was washed with water (2×10 ml) and dried over anhydrous sodium sulfate before removing the solvents. 5-(4-methansulfonylpiperazin-1-yl)-2-nitro-N-phenylbenzenamine (0.20 g, 52%) was obtained by flash column chromatograph (30% ethyl acetate in hexanes). 1H NMR (500 MHz, DMSO-d6) δ (ppm) 2.90 (s, 3H), 3.20 (t, J=5.3 Hz, 4H), 3.42 (t, J=5.3 Hz, 4H), 6.46 (d, J=3.6, 1H), 6.62 (dd, J=3.6, 9.7 Hz, 1H), 7.21-7.46 (m, 5H), 8.05 (d, J=9.7 Hz, 1H), 9.74 (s, 1H). 13C NMR (125 MHz, DMSO-d6): δ (ppm) 34.2, 44.7, 45.9, 95.9, 106.6, 123.5, 124.8, 128.3, 129.6, 138.9, 144.3, 154.9.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](O)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1)#[N:2].P(Cl)(Cl)([Cl:20])=O.C(N(CC)CC)C>>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([Cl:20])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1)#[N:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1nc(O)c(-c2ccccc2)nc1C#N
Solvent: CCN(CC)CC
Product: N#Cc1nc(Cl)c(-c2ccccc2)nc1C#N
Reaction time: 1.5 h
Yield: 80.5 %

Procedure:
The 2,3-dicyano-5-hydroxy-6-phenylpyrazine (7.00 g; 0.0315 mole) was dissolved in 40.00 g (0.26 mole) of phosphorus oxychloride, and while the solution was cooled to 5° to 10° C., 3.53 g (0.035 mole) of triethylamine was added dropwise over the period of 20 minutes. After the addition, the mixture was stirred at 70° to 80° C. for 1.5 hours. The reaction mixture was worked up in the same way as in Example 3, and recrystallized from benzene to afford 6.10 g (yield 80%) of 2,3-dicyano-5-chloro-6-phenylpyrazine.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:35])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][C:29]([CH:32]=[N:33][CH3:34])=[CH:28][CH:27]=3)=[CH:4][C:3]=2[O:2]1.[BH3-]C#N.[Na+].C(O)(=O)C>CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:35])/[CH:24]=[CH:25]/[C:26]3[CH:27]=[CH:28][C:29]([CH2:32][NH:33][CH3:34])=[CH:30][CH:31]=3)=[CH:4][C:3]=2[O:2]1
Reactant: CN=Cc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Yield: 9.8 %

Procedure:
A solution of (E)-1-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-methyliminomethylphenyl)propene-1-one (0.46 g, 1.1 mmol), NaBH3CN (0.14 g, 2.3 mmol) and acetic acid (0.11 mL) in 20 mL of MeOH was stirred at rt for one hour. The reaction mixture was quenched with 50 mL of an aqueous saturated solution of NaHCO3. Extraction with 2×30 mL of DCM, washing with brine, drying over Na2SO4 and concentration in vacuo gave a residue that was purified via flash chromatography of silica gel using DCM:MeOH (97.3) as eluting solvent. Recrystallization from DCM:cyclohexane gave the title compound (0.05 g, 10%) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH2:12][C@@H:13]3[C:18]([CH3:20])([CH3:19])[C@:17]([CH3:21])([C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:16][CH2:15][N:14]3CC1C=CC=CC=1)=[O:5])[CH3:2]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH2:12][C@@H:13]3[C:18]([CH3:20])([CH3:19])[C@:17]([CH3:21])([C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:16][CH2:15][NH:14]3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc2c1C[C@H]1N(Cc3ccccc3)CC[C@]2(C)C1(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cccc2c1C[C@H]1NCC[C@]2(C)C1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pd(OH)2 (0.20 g) is added to a solution of (2R,6S)-3-benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-10-carboxylic acid ethyl ester (1.13 g) in ethanol (20 mL). The resulting mixture is stirred under hydrogen atmosphere (50 psi) at room temperature overnight. Then, the catalyst is separated by filtration and the filtrate is concentrated under reduced pressure to give the product.