Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:9]=2)=[CH:5][CH:4]=1)#[N:2].[C:27]([O:31][C:32](=[O:42])[NH:33][CH2:34][CH2:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:42])[NH:33][CH2:34][CH2:35][CH:36]1[CH2:37][CH2:38][N:39]([C:12]([C:11]2[C:10]([O:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[N:9][C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:26][CH:25]=3)=[CH:16][CH:15]=2)=[O:13])[CH2:40][CH2:41]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Reactant: N#Cc1ccc(Oc2ccc(C(=O)O)c(Oc3ccc(F)cc3)n2)cc1
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(F)cc2)CC1
Yield: 78.2 %

Procedure:
6-(4-cyano phenoxy)-2-(4-fluoro phenoxy)nicotinic acid (0.2 g, 0.57 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.13 g, 0.57 mmol) were coupled using the procedure of Example 5(c) to afford 0.25 g of the required product. Percentage purity: LCMS (−ve mode): 67.5%.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[C:13]([CH:18]=1)[C:14]([NH:16][CH3:17])=[O:15].C=O.[C:24]([BH3-])#N>C(#N)C.C(O)(=O)C>[CH3:17][NH:16][C:14](=[O:15])[C:13]1[CH:18]=[C:9]([N:2]2[CH2:3][CH:4]3[CH:5]([CH2:6][N:7]([CH3:24])[CH2:8]3)[CH2:1]2)[CH:10]=[CH:11][C:12]=1[N+:19]([O-:21])=[O:20]
Reactant: CNC(=O)c1cc(N2CC3CNCC3C2)ccc1[N+](=O)[O-]
Reactant: [BH3-]C#N
Agent: C=O
Solvent: CC(=O)O
Solvent: CC#N
Product: CNC(=O)c1cc(N2CC3CN(C)CC3C2)ccc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 48.3 %

Procedure:
5-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-methyl-2-nitrobenzamide (1.78 g, 6.13 mmol) (Intermediate 10B) was dissolved in acetonitrile (45 mL) before addition of formaldehyde (0.6 g, 7.36 mmol) and MP-cyanoborohydride (3.6 g, 9.25 mmol) followed by 6 drops of acetic acid. The resulting mixture was split into 3 microwave vials and heated at 130° C. for 20 minutes. The reaction mixture was filtered and concentrated. The resultant crude material was purified by a 50 g silica column in 100% dichloromethane, 20% methanol in dichloromethane, 100% methanol (Biotage Snap cartridge). Fractions of the product were combined and reduced to dryness under reduced pressure to afford N-methyl-5-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-nitrobenzamide (900 mg, 2.96 mmol).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:22](O)(=[O:26])[CH2:23][CH2:24][CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:22]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)(=[O:13])=[O:14])[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:26])[CH2:23][CH2:24][CH3:25]
Reactant: Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Reactant: CCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Temperature: 60 °C
Reaction time: 8 h
Yield: 129.9 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-aminobenzothiazol-6-yl ester (intermediate 16) (359 mg, 1.107 mmol), butyric acid (146 mg, 1.66 mmol), HATU (631 mg, 1.66 mmol) and N,N-diisopropylethylamine (0.286 ml, 1.66 mmol) in 5.5 ml of dimethylformamide in a 20 ml round-bottomed flask, equipped with a magnetic bar, is stirred for 8 hours at 60° C. and then left overnight at room temperature. The reaction medium is extracted with ethyl acetate and washed with water and then with 0.1 N hydrochloric acid solution. The organic phase is dried over magnesium sulfate, filtered and then evaporated to dryness. The residue obtained (567 mg of pale yellow solid) is purified by chromatography on a 40 g Biotage silica cartridge, eluting with a 9/1 toluene/isopropanol mixture. After evaporating off the solvent, 239 mg of 4-fluorobenzenesulfonic acid 2-butyrylaminobenzothiazol-6-yl ester are obtained (white solid) in a yield of 55%.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9](Cl)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([CH3:30])[C:22]=1[S:23]([CH2:26][N+:27]([O-:29])=[O:28])(=[O:25])=[O:24])[NH2:19].C(=O)([O-])[O-].[Ca+2].O>O1CCCC1>[CH3:30][C:21]1[CH:20]=[C:18]([NH:19][S:9]([C:8]2[CH:13]=[CH:14][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)(=[O:11])=[O:10])[CH:17]=[C:16]([CH3:15])[C:22]=1[S:23]([CH2:26][N+:27]([O-:29])=[O:28])(=[O:25])=[O:24]
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(C)c(S(=O)(=O)C[N+](=O)[O-])c(C)c2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 7.2 %

Procedure:
2.9 g (12.4 mmol) of N-acetylsulphanilyl chloride are added portionwise to a mixture, maintained under a nitrogen atmosphere, of 2.0 g (8.19 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline and 1.6 g (16.0 mmol) of calcium carbonate in 40 ml of anhydrous tetrahydrofuran. The reaction medium is stirred for 6 h at room temperature and is then refluxed for 2 h, after which it is poured into 200 ml of water. The mixture is extracted 3 times with methylene chloride. The combined organic extracts are washed with water, dried over sodium sulphate and concentrated to dryness under reduced pressure. The oily residue obtained is crystallized by trituration from a mixture of hexane and ethyl acetate. These crystals are washed with a mixture of methylene chloride and methanol at room temperature and then with a mixture of hexane and ethyl acetate at reflux, and finally with ethanol at room temperature, to give 0.26 g (7.2%) of N-[4-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenylsulphamoyl]phenyl]acetamide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[O:10]([CH3:12])[Na]>CO>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:10][CH3:12])[N:3]=1
Reactant: CO[Na]
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CO
Product: COc1cc(Cl)nc(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
16.4 g 2-amino-4,6-dichloropyrimidine (purchased from Aldrich Chemical Co., Milwaukee, WI 53201) was added to 200 ml of CH3OH. The mixture was cooled to 10° with an ice bath and 5.4 g of NaOCH3 was added in portions while maintaining the temperature. The reaction mixture was allowed to warm to ambient temperature and then heated to reflux for two hours. The reaction mixture was then allowed to cool to ambient temperature and it was stirred overnight. A yellow solid was filtered and recrystallized from butyl chloride. The resulting solid was chromatographed on a dry column of silica, and eluted with 40% EtOAchexane. The resulting yellow solid was further purified by recrystallization from butyl chloride. 9.4 g of product with m.p. 163°-166° was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][CH:11]=[CH:10][C:9]=2[OH:16])(=[O:4])[CH2:2][CH3:3].[CH3:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>O1CCOCC1>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=1[CH3:17])=[CH:12][CH:11]=[CH:10][C:9]=2[OH:16])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)c1cnc2c(O)cccc2c1Cl
Reactant: Cc1ccccc1N
Solvent: C1COCCO1
Product: CCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Reaction time: 8 h

Procedure:
Impure 3-propanoyl-4-chloro-8-hydroxyquinoline (86 g) and 2-methylaniline (10.7 ml) in dioxan (200 ml) were warmed over a steam bath for 30 minutes, then left to stand overnight. After evaporation of the dioxan, dichloromethane and aqueous sodium bicarbonate were added, the organic layer washed with water and brine, dried and evaporated to a yellow solid. Recrystallization from methanol gave 3-propanoyl-4-(2-methylphenylamino)-8-hydroxyquinoline (11.6 g), m.p. 125°-128°.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:9].[CH3:10][C:11]1[CH:16]=[CH:15][N+:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=1>C(O)C>[I-:9].[CH2:13]([N:14]([C:5]1[CH:6]=[CH:7][C:2](/[CH:1]=[CH:10]/[C:11]2[CH:16]=[CH:15][N+:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=2)=[CH:3][CH:4]=1)[CH2:17][CH2:18][OH:19])[CH3:12]
Reactant: O=Cc1ccccc1
Reactant: Cc1cc[n+](CCO)cc1
Agent: [I-]
Solvent: CCO
Product: CCN(CCO)c1ccc(/C=C/c2cc[n+](CCO)cc2)cc1
Yield: 67 %

Procedure:
Following the procedure of Example 6, equimolar amounts of 4-N-ethyl-N-hydroxyethylamino)benzaldehyde, prepared according to Example 2, and 4-methyl-N-(2-hydroxyethyl)pyridinium iodide, prepared according to Example 4, were reacted in ethanol at reflux, overnight. Upon cooling, dye3 precipitated as a red solid and was collected by filtration, washed, and dried. Yield: 67%. 1H-NMR (DMSO)-d6): δ 1.0 (t, 3H), 3.3 (q, 2H), 3.40 (q, 2H), 3.50 (t, 2H), 3.80 (q, 2H), 4.40 (t, 2H), 4.70 (t, 1H), 5.2 (t, 1H), 6.7 (d, 2H), 7.1 (d, 1H), 7.80 (d, 2H), 7.90 (d, 1H), 8.10 (d, 2H), 8.70 (d, 2H) ppm. The elements analy. calcd. for C19H25IN2O2: C, 51.8; H, 5.7; N, 6.4; Found: C, 51.5; H, 5.7; N, 7.1. Td 270° C.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[N:14]([N:18]=[C:19]([NH2:21])[N:20]=3)[CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].Br[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:13]3[N:14]([N:18]=[C:19]([NH:21][C:23]4[CH:24]=[CH:25][C:26]([N:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[CH:27][CH:28]=4)[N:20]=3)[CH:15]=[CH:16][CH:17]=2)=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Reactant: CS(=O)(=O)Cc1ccc(-c2cccn3nc(N)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5ccc(CS(C)(=O)=O)cc5)cccn4n3)cc2)CC1

Procedure:
[8-(4-Methanesulfonylmethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonylmethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (50.0 mg, 0.165 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (51.0 mg, 0.200 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (20.0 mg, 0.0366 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow foam (0.009 g, 11%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.44-8.40 (m, 1H), 8.08 (d, J=8.1 Hz, 2H), 7.60-7.54 (m, 3H), 7.51-7.46 (m, 2H), 7.00-6.93 (m, 3H), 6.70 (s, 1H), 4.32 (s, 2H), 3.21-3.14 (m, 4H), 2.83 (s, 3H), 2.66-2.56 (m, 4H), 2.37 (s, 3H). MS=477 (MH)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH:11]2[CH:6]([CH2:7][CH2:8][CH:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:10]2)[NH:5][C:4]1=O.[BH4-].[Li+]>C1COCC1.C1(C)C=CC=CC=1>[OH:1][CH2:2][CH:3]1[CH2:12][CH:11]2[CH:6]([CH2:7][CH2:8][CH:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:10]2)[NH:5][CH2:4]1
Reactant: COc1ccc(CC2CCC3NC(=O)C(CO)CC3C2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(CC2CCC3NCC(CO)CC3C2)cc1

Procedure:
In a manner analogous to Example 1, (±)-(3RS,4aRS,6SR,8aSR)-3,4,4a,5,6,7,8,8a-octahydro-3-hydroxymethyl-6-((4-methoxyphenyl)methyl)quinolin-2[1H]-one (prepared according to step a)) was reduced by heating at 100° C. in the presence of lithium borohydride solution in THF/toluene to give the title compound, mg. 282°-4° C. (HCl, hemihydrate salt).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH2:11])[CH:3]=1.[CH3:12][Si](C=[N+]=[N-])(C)C>O1CCCC1.CO>[CH3:12][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[NH2:11]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)cc1N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.), stirred solution of 4-fluoro-2-aminobenzoic acid (2.68 g; 17.3 mmol) in dry tetrahydrofuran (60 mL) and MeOH (10 mL) was added a solution of trimethylsilyldiazomethane in hexanes (12 mL of 2.0 N; 24 mmol) via syringe over 20 minutes under nitrogen atmosphere. The resulting solution was allowed to warm to room temperature and stirred for 2 hours then concentrated in vacuo to provide the ester a light yellow solid (˜100%).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]3)=[O:14])[N:10]=[C:9]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:8]=2)=[CH:4][CH:3]=1.[CH3:30][C:31]([CH3:33])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([NH:21][CH:31]([CH3:33])[CH3:30])[CH2:19][CH2:20]3)=[O:14])[N:10]=[C:9]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[CH:8]=2)=[CH:28][CH:29]=1
Reactant: NC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)NC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.4 %

Procedure:
To a solution of 1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-amine (0.3 g, 0.76 mmol) in CH2Cl2 (5 mL) was added acetone (56 μL, 0.76 mmol) and the solution was stirred for 15 minutes at room temperature. This was followed by the addition of NaBH(OAc)3 (0.242 g, 1.14 mmol) and the reaction mixture was stirred overnight at room temperature. The mixture was diluted with CH2Cl2 (20 mL) and 2 M NaOH and the bi-phasic solution was stirred for 20 minutes. The mixture was extracted with CH2Cl2 (2×25 mL) and the combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (90:10:1 CH2Cl2/MeOH/NH4OH) to give the title compound as a white solid (0.19 g, 44%). 1H NMR (400 MHz, DMSO-D6) δ ppm 8.51 (d, 2 H), 7.66 (d, 2 H), 7.30 (t, 2 H), 7.14 (t, 2 H), 6.51 (s, 1 H), 5.13-5.20 (m, 2 H), 4.07-4.16 (m, 1 H), 3.93 (s, 2 H), 3.77-3.87 (m, 1 H), 3.04-3.14 (m, 1 H), 2.83-2.93 (m, 1 H), 2.69-2.79 (m, 2 H), 1.72-1.86 (m, 5H); m/z (APCI+) for C25H30N5OF 436.1 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1N=C(C(O)=O)C=C(CCC)N=1.[CH2:15]([C:19]1[N:24]=[C:23](S(C)(=O)=O)[N:22]=[C:21]([C:29]([OH:31])=[O:30])[CH:20]=1)[CH:16]([CH3:18])[CH3:17].CNC>>[CH3:1][N:2]([CH3:3])[C:23]1[N:22]=[C:21]([C:29]([OH:31])=[O:30])[CH:20]=[C:19]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:24]=1
Reactant: CCCc1cc(C(=O)O)nc(NC)n1
Reactant: CC(C)Cc1cc(C(=O)O)nc(S(C)(=O)=O)n1
Agent: CNC
Product: CC(C)Cc1cc(C(=O)O)nc(N(C)C)n1

Procedure:
The title compound is obtained as a beige solid (132 mg) in analogy to 2-methylamino-6-propyl-pyrimidine-4-carboxylic acid starting from 6-isobutyl-2-methanesulfonyl-pyrimidine-4-carboxylic acid and 40% aq. dimethylamine; LC-MS: tR=0.78 min, [M+H]+=224.03.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][C:5]([C:7]1[N:8]=[CH:9][NH:10][C:11]=1[NH2:12])=[O:6].[CH:13](OCC)(OCC)OCC>C(O)C>[ClH:1].[N:8]1[C:7]2[C:5](=[O:6])[CH2:4][NH:3][CH:13]=[N:12][C:11]=2[NH:10][CH:9]=1
Reactant: NCC(=O)c1nc[nH]c1N
Reactant: CCOC(OCC)OCC
Agent: Cl
Solvent: CCO
Product: O=C1CNC=Nc2[nH]cnc21

Procedure:
A mixture of 285 mg. of 2-amino-1-(5-amino-1H-imidazol-4-yl)ethanone dihydrochloride (Example 1), 200 ml. of absolute ethanol and 10 ml. of triethyl orthoformate is stirred and heated at reflux for 1 hour, then cooled and evaporated at reduced pressure. The residue of 6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one monohydrochloride, which crystallizes on standing, is collected by filtration, washed with ethanol, then with ether, and dried at reduced pressure; m.p. above 250° C. dec.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](Cl)[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]([CH2:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)[CH3:29].[OH-].[Na+]>CN(C=O)C.CO>[CH3:29][N:28]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([NH:35]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:36][CH:37]=1)[CH3:27]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: COc1ccc(C(Cl)=C2C(=O)N(C(C)=O)c3ccc([N+](=O)[O-])cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(/C(Nc2ccc(CN(C)C)cc2)=C2/C(=O)Nc3ccc([N+](=O)[O-])cc32)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(4-methoxyphenyl)-methylidene)-5-nitro-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C@H:13]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.[Cl:33][CH2:34][C:35](=N)OCC.C(=O)(O)[O-].[Na+].C(Cl)(Cl)Cl>ClCCCl>[Si:25]([O:24][CH2:23][C@@H:13]([N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:35]1[CH2:34][Cl:33])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c(N)cnc2ccccc12
Reactant: CCOC(=N)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC[C@@H](CO[Si](C)(C)C(C)(C)C)n1c(CCl)nc2cnc3ccccc3c21
Temperature: 65 °C
Yield: 61 %

Procedure:
tert-Butyl (2S)-2-[(3-aminoquinolin-4-yl)amino]-3-{[tert-butyl(dimethyl)silyl]oxy}propylcarbamate (4.51 g, 10.1 mmol) was dissolved in 80 mL of anhydrous 1,2-dichloroethane and the solution was stirred under N2. Ethyl 2-chloroethanimidoate hydrochloride (2.39 g, 15.1 mmol) was then added and the reaction mixture was heated to 65° C. After stirring overnight, the reaction mixture was cooled and treated with 100 mL of saturated sodium bicarbonate (NaHCO3) solution and 100 mL of CHCl3. The layers were separated and the organic portion was washed successively with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 50% ethyl acetate/hexanes) gave tert-butyl (2S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate (3.11 g) as a golden foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14](I)=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]#[CH:27]>C(NCC)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]#[C:27][C:14]1[N:13]=[CH:12][N:11]2[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:18][C:6]=3[C:7](=[O:17])[N:8]([CH3:16])[CH2:9][C:10]=12
Reactant: CN1Cc2c(I)ncn2-c2ccc(F)cc2C1=O
Reactant: C#Cc1ccccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCNCC
Product: CN1Cc2c(C#Cc3ccccc3Cl)ncn2-c2ccc(F)cc2C1=O

Procedure:
3.6 g (10 mmol) of 8-fluoro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at room temperature overnight with 1.5 g (11 mmol) of o-chlorophenylacetylene, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 15 mg of copper(I) iodide in 20 ml of diethylamine. The reaction mixture was diluted with 175 ml of methylene chloride and washed three times with water. After drying and evaporation of the solution the residue was chromatographed on silica gel while eluting with methylene chloride/methanol (99:1). By recrystallization of the evaporated eluate there was obtained 3-[(o-chlorophenyl)ethynyl]-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 259°-261°.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[CH2:8]([O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)[CH3:9].Cl>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:8]([O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([C:11]2[O:10][C:7]3[CH:6]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:12]=2)=[CH:14][CH:13]=1)[CH3:9]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cc3ccccc3o2)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
The compound prepared in Reference Example 1 (2.64 g), dichlorobis(triphenylphosphine)palladium (II) [PdCl2(PPh3)2] (0.635 g) and triethylamine (10 ml) were added to a solution of 4-iodobenzoic acid ethyl ester (5 g) in dimethylformamide (10 ml). The mixture was stirred at 80° C. for 6 hours. To the reaction mixture, 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated. The precipitated crystals was washed with hexane/diethyl ether and dried to give the title compound (3.6 g) having the following physical data.
Reaction SMILES: [CH:1]1([CH:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([OH:23])[CH:16]=2)[CH:5]2C(=O)OC(C)(C)[O:7][C:6]2=[O:14])[CH2:3][CH2:2]1.O>CN(C=O)C>[CH:1]1([CH:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([OH:23])[CH:16]=2)[CH2:5][C:6]([OH:14])=[O:7])[CH2:3][CH2:2]1
Reactant: COc1ccc(C(C2CC2)C2C(=O)OC(C)(C)OC2=O)cc1O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(CC(=O)O)C2CC2)cc1O
Temperature: 90 °C
Reaction time: 15 h
Yield: 75.3 %

Procedure:
To a solution of 5-(cyclopropyl(3-hydroxy-4-methoxyphenyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.70 g) in DMF (20 mL) was added water (2.0 mL), and the mixture was stirred at 90° C. for 15 hr. The reaction mixture was cooled to room temperature, and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.50 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2=[N:8][C:9]([OH:13])=[C:10]([CH3:12])[N:11]=[C:6]2[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:13][C:9]1[N:8]=[C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][C:6]2=[N:11][C:10]=1[CH3:12])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc2ccnc(Cl)c2nc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc2ccnc(Cl)c2nc1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
A solution of 5-chloro-2-methylpyrido[3,4-b]pyrazin-3-ol (1.88 g, 9.61 mmol) in DCM (30 mL) at 0° C. was treated with DIEA (3.34 mL, 19.22 mmol) followed by methanesulfonyl chloride (1.11 mL, 14.42 mmol) (Sigma Aldich). The reaction mixture was warmed to RT and stiffed for 1 h. The mixture was diluted with DCM and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on a silica gel column (10-35% EtOAc in Hexanes) to give 5-chloro-2-methylpyrido[3,4-b]pyrazin-3-yl methanesulfonate (1.68 g, 6.14 mmol, 64% yield) as a brown solid. MS (ESI, pos. ion) m/z: 274.0 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm 8.59 (1H, d, J=5.7 Hz), 7.85 (1H, d, J=5.7 Hz), 3.83 (3H, s), 2.85 (3H, s).