Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH2:30]([O:37][CH2:38][C@H:39]([NH:41][CH:42]([CH3:44])[CH3:43])[CH3:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][CH2:38][C@H:39]([N:41]([CH:42]([CH3:44])[CH3:43])[C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:17]([C:8]2[C:7]3[CH:26]=[C:27]([O:28][CH3:29])[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=3[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][N:13]([CH3:16])[CH2:14]3)[N:9]=2)=[CH:18][CH:19]=1)[CH3:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Reactant: CC(C)N[C@H](C)COCc1ccccc1
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)[C@H](C)COCc3ccccc3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)benzoic acid and ((R)-2-benzyloxy-1-methyl-ethyl)-isopropyl-amine as described for example 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[N:10]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Reactant: CC(C)(C)C(=O)Cl
Product: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)C(C)(C)C)c2ccccc21

Procedure:
In an analogous manner to that described in Example 103b), the acylation of (S)-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester with pivaloyl chloride yielded the title compound as a white solid; MS: m/e=376 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[C:15]([CH3:27])[C:10]=1[C:11]([NH:13][NH2:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:28][C:29]1[CH:30]=[C:31]([CH:37]=[CH:38][CH:39]=1)[CH:32]([OH:36])[C:33](O)=[O:34]>>[OH:36][CH:32]([C:31]1[CH:37]=[CH:38][CH:39]=[C:29]([OH:28])[CH:30]=1)[C:33]([NH:14][NH:13][C:11](=[O:12])[C:10]1[C:15]([CH3:27])=[CH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:34]
Reactant: O=C(O)C(O)c1cccc(O)c1
Reactant: Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1C(=O)NN
Product: Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1C(=O)NNC(=O)C(O)c1cccc(O)c1
Yield: 47 %

Procedure:
The substance is prepared analogously to Example 1 from 2,4-dibenzyloxy-6-methylbenzohydrazide and 3-hydroxymandelic acid in a yield of 47%, m.p. 181-1820 (from Me2COHoEt2O).
Reaction SMILES: N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:22][C:23]1([CH3:38])[C@@H:25](/[CH:26]=[C:27](\[Br:34])/[C:28]([O:30][CH2:31][CH2:32][CH3:33])=[O:29])[C@H:24]1[C:35]([OH:37])=[O:36].[C:39]([C@@H:41](O)[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:43]=1)#[N:40]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:38][C:23]1([CH3:22])[C@@H:25](/[CH:26]=[C:27](\[Br:34])/[C:28]([O:30][CH2:31][CH2:32][CH3:33])=[O:29])[C@H:24]1[C:35]([O:37][C@H:41]([C:39]#[N:40])[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:43]=1)=[O:36]
Reactant: CCCOC(=O)/C(Br)=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCOC(=O)/C(Br)=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Reaction time: 0.25 h
Yield: 87.5 %

Procedure:
0.9 ml of pyridine and 2.1 g of dicyclohexylcarbodiimide were added to a solution of 2.9 g of the product of Step B in 40 ml of methylene chloride and the mixture was stirred for 15 minutes. A solution of 2.5 g of (S)α-cyano-3-phenoxy-benzyl alcohol in 15 ml of methylene chloride and then 25 mg of 4-dimethylamino-pyridine were added to the reaction mixture which was stirred for 2 hours and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 9-1 cyclohexane-ethyl acetate mixture yielded 4.26 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(Z)-[2-bromo-2-propoxycarbonyl-ethenyl]-cyclopropane-1-carboxylate melting at 64° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[N:13][O:14][CH:15]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:31]=2[CH:32]=[N:33][NH:34]3)O1>>[NH:34]1[C:35]2[C:31](=[C:30]([C:2]3[N:3]=[C:4]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[C:5]4[S:10][C:9]([C:11]5[CH:12]=[N:13][O:14][CH:15]=5)=[CH:8][C:6]=4[N:7]=3)[CH:38]=[CH:37][CH:36]=2)[CH:32]=[N:33]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2sc(-c3cnoc3)cc2n1
Product: c1cc(-c2nc(N3CCOCC3)c3sc(-c4cnoc4)cc3n2)c2cn[nH]c2c1

Procedure:
2-Chloro-6-(isoxazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine (85 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 4.3 mg of 328. MS (Q1) 405.1 (M)+
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[C:13]([Cl:19])=[CH:12][C:11]=2[CH:20]([NH2:22])[CH3:21])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Br[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][NH:28]2>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[C:13]([Cl:19])=[CH:12][C:11]=2[CH:20]([NH:22][C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[CH:27][NH:28]3)[CH3:21])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2c(C(C)N)cc(Cl)c3cncn23)CC1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCO
Product: CC(=O)N1CCN(c2c(C(C)Nc3ncnc4[nH]cnc34)cc(Cl)c3cncn23)CC1
Temperature: 110 °C
Yield: 43.5 %

Procedure:
A mixture of 1-[5-(4-acetylpiperazin-1-yl)-8-chloroimidazo[1,5-a]pyridin-6-yl]ethanamine (11.2 mg, 0.035 mmol), 6-bromo-9H-purine (14 mg, 0.070 mmol) and IV, N-diisopropylethylamine (18 μL, 0.10 mmol) in ethanol (0.93 mL) was heated to 110° C. overnight. Purification by preparative LCMS (pH 10) gave the desired compound (6.7 mg, 44%). LCMS calculated for C20H23ClN9O (M+H)+: m/z=440.2. found: 439.9. 1H NMR (300 MHz, DMSO-d6): δ 8.52 (s, 1H), 8.17 (m, 3H), 7.42 (s, 1H), 7.37 (s, 1H), 5.90 (s, 1H), 3.80 (m, 2H), 3.65 (m, 2H), 3.50 (m, 1H), 3.40 (m, 2H), 3.20 (m, 2H), 2.09 (s, 3H), 1.52, (m, 3H).
Reaction SMILES: [CH:1]1([Sn](CCCC)(CCCC)CCCC)[CH2:3][CH2:2]1.C([Li])CCC.[Cl:22][C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1COCC1.[Cu]I>[CH:1]1([C:25]([C:24]2[C:23]([Cl:22])=[N:31][CH:30]=[CH:29][CH:28]=2)=[O:26])[CH2:3][CH2:2]1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)C1CC1
Agent: [Cu]I
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1cccnc1Cl)C1CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A mixture of cyclopropyltributyltin (0.5 g, 1.51 mmol) in 3 mL of THF was cooled to -78° C. and then n-butyllithium (0.604 mL, 2.5M in hexanes, 1.51 mmol) was added. The mixture was stirred at 0° C. for 0.5 hours. A mixture of copper(I) iodide (0.142 g, 0.75 mmol) in THF was cooled to -40° C. and the mixture containing the cyclopropyltributyltin was added. The mixture was stirred for 45 minutes and then 2-chloronicotinic acid chloride (0.265 g, 1.51 mmol) was added dropwise. The mixture was stirred at -40° C. for 1.5 hours and allowed to warm to room temperature. The mixture was quenched with water, diluted with methylene chloride, filtered and the aqueous layer was extracted with methylene chloride (2×30 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified on silica gel by flash chromatography eluting with hexanes/ethyl acetate (85:15) to give 2-chloro-3-pyridyl cyclopropyl ketone (0.15 g, 0.83 mmol) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH:4]=O.[CH3:11][C:12]([CH3:14])=[O:13].[OH-].[Ca+2].[OH-]>O>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH:4]=[CH:11][C:12](=[O:13])[CH3:14]
Reactant: Cc1cccc(C)c1C=O
Reactant: CC(C)=O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1c(C)cccc1C
Yield: 90 %

Procedure:
13,4 g (0,1 mol) of 2,6-dimethylbenzaldehyde, 100 ml of acetone, 100 ml of water and 2 g of calcium hydroxide are mixed together and refluxed for about 20-25 h with agitation. The precipitate is filtered off from the cold reaction mixture. 1 l of ice water is added to the filtrate with agitation. The product is crystallized at a yield of about 90%. M.p. of the recrystallized product: 34°-35° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][N:8]=[N+:9]=[N-:10])=[CH:5][CH:4]=1.C(Cl)[Cl:14]>>[Cl:14][CH2:1][S:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][N:8]=[N+:9]=[N-:10])=[CH:5][CH:4]=1
Reactant: ClCCl
Reactant: CSc1ccc(CN=[N+]=[N-])cc1
Product: [N-]=[N+]=NCc1ccc(SCCl)cc1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-(methylthio)benzylazide (0.359 g, 2 mmol) in CH2Cl2 was cooled in ice and treated slowly with SO2Cl2 (0.297 g, 2.2 mmol). The reaction mixture was stirred at 5° C. for 1.5 h and then evaporated to dryness. The crude compound was obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12](=O)[CH3:13].[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>>[F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]([NH:21][S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])[CH3:13]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cccc(C(F)(F)F)c1F
Product: CC(N[S@](=O)C(C)(C)C)c1cccc(C(F)(F)F)c1F
Yield: 56 %

Procedure:
The title compound is prepared in 56% yield (511 mg, a white solid) from 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethanone (600 mg, 2.91 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide (529 mg, 4.37 mmol) by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][N:8]([CH:13]([C:15]3[C:16]([O:37][CH2:38][CH3:39])=[C:17]([CH:23]4[CH2:26][N:25](C(OCC5C=CC=CC=5)=O)[CH2:24]4)[C:18]([CH3:22])=[C:19]([Cl:21])[CH:20]=3)[CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.O>[Pd].CO>[NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][N:8]([CH:13]([C:15]3[CH:20]=[C:19]([Cl:21])[C:18]([CH3:22])=[C:17]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:16]=3[O:37][CH2:38][CH3:39])[CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCOc1c(C(C)n2ccc(=O)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CCOc1c(C(C)n2ccc(=O)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Reaction time: 2 h
Yield: 40.3 %

Procedure:
To a mixture of benzyl 3-{3-[1-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidine-1-carboxylate (23 mg, 0.042 mmol) and 5% palladium on carbon (10 mg) in methanol (1.6 mL) was added 0.25 M hydrogen chloride in water (0.42 mL, 0.10 mmol). The suspension was hydrogenated under balloon pressure of H2 at room temperature for 2 hours. After filtered off the catalyst, the filtrate was neutralized with sat. NaHCO3 solution, extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give 4-amino-8-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-methylphenyl)ethyl]pyrido[2,3-d]pyrimidin-5(8H)-one (7 mg, 40%). To a mixture of the crude amine in acetonitrile (0.1 mL)/methanol (0.1 mL)/tetrahydrofuran (0.1 mL) was added N,N-diisopropylethylamine (0.02 mL, 0.1 mmol), followed by acetone (0.03 mL, 0.4 mmol). The mixture was stirred for 30 minutes before the addition of sodium triacetoxyborohydride (0.044 g, 0.21 mmol). The reaction was stirred at room temperature for 4 hours, then quenched with water and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product as TFA salt. The product was isolated as a racemic mixture. LCMS calculated for C24H31ClN5O2 (M+H)+: m/z=456.2; Found: 456.1.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:36][CH2:37][CH3:38].O>CN(C=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH2:36][CH2:37][CH3:38])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)sc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41 and potassium carbonate (152 mg) are suspended in DMF (10 mL) and to the mixture is added 1-iodopropane (107 μL). The reaction mixture is allowed to stir at room temperature for 4 h. Additional 1-iodopropane (107 μL) is added and the mixture is heated to 60° C. for 2 h. The mixture is allowed to cool to room temperature and stand for 18 h. The resulting suspension is poured into water (25 mL), filtered, and washed with water (5 mL) followed by diethyl ether (5 mL). The resulting crude solid is purified by recrystallization from ethanol to afford 335 mg (73%) of the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](=O)[CH2:19][C:20](OC)=[O:21]>C(O)(=O)C>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]1[NH:12][C:10]2[N:9]([N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)[C:20](=[O:21])[CH:19]=1
Reactant: COC(=O)CC(=O)c1ccco1
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Solvent: CC(=O)O
Product: O=c1cc(-c2ccco2)[nH]c2cc(-c3ccccc3)nn12
Temperature: 25 °C
Yield: 64.6 %

Procedure:
A mixture of 3-phenyl-1H-pyrazol-5-amine (1: 0.318 g, 2.0 mmol, 1.0 eq) and methyl 3-(furan-2-yl)-3-oxopropanoate (0.370 g, 2.2 mmol, 1.10 eq) was heated in acetic acid (2.0 mL) at 100° C. for 4 hr. After cooling down to rt, the precipitate was collected by filtration. The precipitate was rinsed with EtOH (15 mL) and dried under air to afford 5-(furan-2-yl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (0.358 g, 65%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.06 (m, 1H), 8.00 (m, 1H), 7.98 (m, 1H), 7.51-7.47 (m, 3H), 7.44-7.42 (m, 1H), 6.81 (dd, J=3.7, 1.8 Hz, 1H), 6.64 (s, 1H), 6.15 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][C:12]([OH:28])=[C:13]([C:24]([O:26]C)=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][C:12]([OH:28])=[C:13]([C:24]([OH:26])=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2nc(N3CCC[C@@H]3C)c(-c3ccc(F)cc3)nc2cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)c(O)cc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a solution of (S)-methyl 2-(4-fluorophenyl)-7-hydroxy-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (150 mg, 0.39 mmol) in methanol (30 ml) and water (1 ml) was added sodium hydroxide (19.5 mg, 0.49 mmol), and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 mL), and adjusted to pH 5 with hydrochloric acid (3N) to give the precipitate, which was collected by filtration to afford (S)-2-(4-fluorophenyl)-7-hydroxy-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a light yellow solid (100 mg, 69%).
Reaction SMILES: [CH2:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH3:11])[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:12][O:13][CH2:14][CH2:15][O:16][C:17](=[O:32])[C:18](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N+:29]([O-:31])=[O:30])[C:19]([CH3:21])=O>>[CH3:12][O:13][CH2:14][CH2:15][O:16][C:17]([C:18]1[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])[C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][N:7]([CH3:11])[C:8]=2[NH:10][C:19]=1[CH3:21])=[O:32]
Reactant: CCCCc1cc(N)n(C)n1
Reactant: COCCOC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(C)=O
Product: CCCCc1nn(C)c2c1C(c1ccccc1[N+](=O)[O-])C(C(=O)OCCOC)=C(C)N2

Procedure:
Starting from 3-butyl-1-methyl-5-pyrazolamine and (2-methoxyethyl)-2-(2-nitrobenzyliden)acetoacetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH:12]1(O)[CH2:16][CH2:15][CH2:14][CH2:13]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Reactant: OC1CCCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Br)ccc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a mixture of 4-bromo-2-nitrophenol (1.0 g, 4.6 mmol), cyclopentanol (600 mg, 7.0 mmol) and Ph3P (1.47 g, 5.6 mmol) in THF (50 mL) at 0° C. was portion-wise added diisopropylazodicarboxylate (1.52 g, 7.5 mmol) in THF (10 mL) and the resulting mixture was left to stir overnight at ambient temperature. Solvent removal and purification by chromatography on silica gel afforded the sub-title compound (1.24 g, 94%).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]1([CH3:22])[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1>>[CH3:22][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: Cc1cccc(C=O)c1
Product: Cc1cccc(CN2CCN(c3cc(=O)[nH]cn3)CC2)c1

Procedure:
6-[4-(3-Methyl-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and m-tolualdehyde. Mass spectrum (ES) MH+=285.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1F.[O:13]1[C:17]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([F:1])[C:3]=1[N:20]1[CH2:21][CH2:22][C:17]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:18][CH2:19]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(F)c(N2CCC3(CC2)OCCO3)c(F)c1
Temperature: 100 °C

Procedure:
A mixture of 1,2,3-trifluoro-5-nitrobenzene (4.0 mL, 34.3 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (6.59 mL, 51.4 mmol) and potassium carbonate (5.68 g, 41.1 mmol) in DMSO (35 mL) was heated at 100° C. for 3 hours and then cooled to room temperature. The mixture was partitioned between water and EtOAc, and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-20% EtOAc in hexanes to give a yellow oil.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].[OH-].[Na+].[C:9]([C:11](C#N)=[C:12]([C:15]#[N:16])[C:13]#[N:14])#[N:10]>O>[C:9]([C:11]1[C:12]([C:13]#[N:14])=[C:15]([NH2:16])[N:3]([C:4]([NH2:6])=[O:5])[N:2]=1)#[N:10]
Reactant: NNC(N)=O
Reactant: N#CC(C#N)=C(C#N)C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1nn(C(N)=O)c(N)c1C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.6 %

Procedure:
To a mixture of semicarbazide hydrochloride (11.2 g, 0.1 mol), water (200 ml) and sodium hydroxide (4.0 g, 0.1 mol) cooled in an ice-bath was added dropwise tetracyanoethylene (12.8 g, 0.1 mol). The reaction mixture was warmed to room temperature, stirred for 1.5 hours and then allowed to stand for 24 hours. The white precipitate which formed during the course of the reaction was collected by filtration and washed with water to afford 15.6 g (89%) of 3-cyano-4-cyano-5-amino-1H-pyrazole-1-carboxamide as a white solid, m.p. 225° C. (dec.) when dried at 85° C. in high vacuum.
Reaction SMILES: [ClH:1].CS[C:4]1[N:5]2[CH:17]=[CH:16][N:15]=[C:6]2[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[OH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O)CCCC>>[ClH:1].[ClH:1].[OH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:4]2[N:5]3[CH:17]=[CH:16][N:15]=[C:6]3[S:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH2:23][CH2:22]1
Reactant: CSC1=Nc2ccccc2Sc2nccn21
Reactant: OCCN1CCNCC1
Agent: Cl
Solvent: CCCCCO
Product: OCCN1CCN(C2=Nc3ccccc3Sc3nccn32)CC1

Procedure:
A mixture of 5 g of 5-methylthio-imidazo[2,1-b][1,3,5]benzothiadiazepine hydrochloride, 2.86 g of N-β-hydroxyethylpiperazine, and 175 ml of amyl alcohol is refluxed under nitrogen for 48 hrs. with stirring. The solvent is removed under vacuum, the residue is triturated with methylene chloride, washed with 2 N sodium hydroxide solution, dried over MgSO4, and evaporated to dryness. The residue is dissolved in 5 ml of methanol and treated with 2 N ethereal hydrochloric acid solutions to give 5-(4-β-hydroxyethylpiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine dihydrochloride melting at 212°-214°.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22](O)=[O:23].[C:25]1([CH2:31][CH:32]([NH2:38])[C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([CH2:31][CH:32]([NH:38][C:22]([C@H:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:15]([CH2:14][CH2:13][C@:11]23[CH3:12])[C@:16]2([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]2)=[CH:4][CH2:5]4)=[O:23])[C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: NC(Cc1ccccc1)c1cccs1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)NC(Cc4ccccc4)c4cccs4)[C@@]3(C)CC[C@@H]12
Yield: 48 %

Procedure:
The title compound was prepared in a yield of 48% in a similar manner to that described in Example 1 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and 2-phenyl-1-(2-thienyl)ethylamine.
Reaction SMILES: [NH2:1][C:2]([CH:17]([F:19])[F:18])([CH2:6][CH2:7][CH2:8][NH:9]C(OC(C)(C)C)=O)[C:3]([OH:5])=[O:4].[C:20](Cl)(=[O:22])[CH3:21].Cl>[OH-].[Na+]>[C:20]([NH:1][C:2]([CH:17]([F:18])[F:19])([CH2:6][CH2:7][CH2:8][NH2:9])[C:3]([OH:5])=[O:4])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCC(N)(C(=O)O)C(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)NC(CCCN)(C(=O)O)C(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2.9 g of 2-amino-5-tert-butoxycarbonylamino-2-difluoromethylpentanoic acid in 10.5 ml of 1 M sodium hydroxide is added at 0° C. simultaneously 0.19 g of acetylchloride and 5 ml of 2 M aqueous sodium hydroxide. The reaction mixture is stirred for 3 hours at room temperature. The alkaline aqueous solution is then adjusted to a pH of 2 with hydrochloric acid and extracted with ethylacetate. After usual work-up the solvent is evaporated and the residue taken up in trifluoroacetic acid. After concentration and purification by ion exchange chromatography on a resin 5-amino-2-acetylamino-2-difluoromethylpentanoic acid is obtained.