Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@H:7]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:9]([C:19](=[O:24])N(OC)C)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:1]1([C@H:7]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[C@H:9]([CH:19]=[O:24])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CON(C)C(=O)[C@@H]1C[C@@H](C2CCCCC2)CN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](C2CCCCC2)C[C@H]1C=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
(2S,4S)-tert-butyl 4-cyclohexyl-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (1.14 g, 3.35 mmol) was treated with THF (20 mL), cooled to 0° C. in an ice bath and then treated with lithium aluminum hydride (1.0M solution in THF, 3.35 mL, 3.35 mmol) slowly dropwise over 3 min. The solution was then stirred at 0° C. for 45 min. The reaction mixture was quenched with a solution of sodium potassium tartrate, stirred at room temperature for 20 min, then extracted with EtOAc (3×50 mL), washed with brine and dried over MgSO4, filtered and concentrated affording crude (2S,4S)-tert-butyl 4-cyclohexyl-2-formylpyrrolidine-1-carboxylate as a clear, viscous oil. MS (ESI) 304.1 [M+Na]. The crude material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH:23]=O)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:25]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][N:25]3[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=CCCN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Reactant: OC1CCNCC1
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCN2CCC(O)CC2)CC1

Procedure:
In analogy to examples 35-91, 3-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propionaldehyde (intermediate 2) was reacted with piperidine-4-ol to afford the title product as a white solid. MS: 454.4 (MH+, 2Cl).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([O:15][CH2:16][C:17]([OH:19])=O)=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:5]2[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3]1.CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:45][O:46][C:47]1[CH:55]=[CH:54][C:50]([C@@H:51]([NH2:53])[CH3:52])=[CH:49][CH:48]=1>CN(C=O)C>[CH3:45][O:46][C:47]1[CH:55]=[CH:54][C:50]([C@@H:51]([NH:53][C:17](=[O:19])[CH2:16][O:15][C:8]2[N:7]=[C:6]3[N:2]([CH3:1])[N:3]=[C:4]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:5]3=[C:10]([C:11]([F:13])([F:14])[F:12])[CH:9]=2)[CH3:52])=[CH:49][CH:48]=1
Reactant: Cn1nc(-c2ccccc2)c2c(C(F)(F)F)cc(OCC(=O)O)nc21
Reactant: COc1ccc([C@H](C)N)cc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc([C@H](C)NC(=O)COc2cc(C(F)(F)F)c3c(-c4ccccc4)nn(C)c3n2)cc1
Reaction time: 12 h
Yield: 63.2 %

Procedure:
A solution of (1-Methyl-3-phenyl-4-trifluoromethyl-1H-pyrazolo[3,4-b]pyridin-6-yloxy)-acetic acid (350 mg, 0.996 mmol), DIC (189 mg, 1.494 mmol) and HOBt (175 mg, 1.295 mmol) in DMF (10 ml) was stirred at rt for 10 min. (S)-(−)-4-methoxy-α-methyl benzyl amine (166 mg, 1.096 mmol) was added to the reaction mixture at rt and stirring was continued for 12 h at rt. After completion of the reaction, the reaction mixture was poured into rapidly stirred ice-cold water to obtain the crude product as a solid. The solid was collected by filtration and dried under vacuum. The product was further purified by flash column chromatography [(eluent: EtOAc/hexane (1:3)] to yield the title compound as a white solid (305 mg, 63%). [1H-NMR (CDCl3, 300 MHz) δ 7.58-7.39 (m, 5H), 7.32-7.21 (m, 2H), 6.99 (s, 1H), 6.85 (d, 2H), 6.51 (d, 1H), 5.31-5.22 (m, 1H), 5.0 (s, 2H), 4.05 (s, 3H), 3.8 (s, 3H), 1.52 (d, 3H); HPLC RtB=5.933 min. (98%); LCMS RtA=1.785, [M+H]+=485.1; Mp=172-174° C.]
Reaction SMILES: [CH2:1]([N:4]([CH2:26][CH2:27][CH3:28])[C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13](=S)[CH2:12][N:11]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-:24])=[O:23])[C:9]=2[CH:25]=1)[CH2:2][CH3:3].[CH:29]([NH:31][NH2:32])=O>C(O)C>[CH2:1]([N:4]([CH2:26][CH2:27][CH3:28])[C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[CH:29]=[N:31][N:32]=[C:13]3[CH2:12][N:11]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-:24])=[O:23])[C:9]=2[CH:25]=1)[CH2:2][CH3:3]
Reactant: NNC=O
Reactant: CCCN(CCC)c1ccc2c(c1)C(c1ccccc1[N+](=O)[O-])=NCC(=S)N2
Solvent: CCO
Product: CCCN(CCC)c1ccc2c(c1)C(c1ccccc1[N+](=O)[O-])=NCc1nncn1-2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 7-(dipropylamino)-1,3-dihydro-5-(o-nitrophenyl)-2H-1,4-benzodiazepine-2-thione is heated in ethanol with formic acid hydrazide and the resulting product heated to 250° C. to give 8-(dipropylamino)-6-(o-nitrophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Br:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([N+:26]([O-:28])=[O:27])[C:7](OS(C3C(C)=CC(C)=CC=3C)(=O)=O)=[CH:8][CH:9]=2)[O:4][C:3]=1[CH:29]([CH3:31])[CH3:30].[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([N+:26]([O-:28])=[O:27])[C:7]([NH:39][CH2:38][C:37]3[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)=[CH:8][CH:9]=2)[O:4][C:3]=1[CH:29]([CH3:30])[CH3:31]
Reactant: Cc1cc(C)c(S(=O)(=O)Oc2ccc3c(=O)c(Br)c(C(C)C)oc3c2[N+](=O)[O-])c(C)c1
Reactant: COc1ccc(CN)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2ccc3c(=O)c(Br)c(C(C)C)oc3c2[N+](=O)[O-])cc1
Temperature: 130 °C

Procedure:
To a solution of 2,4,6-trimethyl-benzenesulfonic acid 3-bromo-2-isopropyl-8-nitro-4-oxo-4H-chromen-7-yl ester (1.906 g, 3.5 mmol) in dry toluene (18 ml) in a 20 ml capacity microwave tube is added p-methoxybenzylamine (0.69 ml, 5.26 mmol). The mixture is heated at 130° C. under microwave irradiation for 90 minutes and then at 140° C. under microwave irradiation for a further 30 minutes. Water (40 ml) is added, and the mixture is extracted with ethyl acetate (3×100 ml). The ethyl acetate extracts are combined, washed with saturated brine (50 ml), dried (MgSO4), filtered and evaporated. The crude product is purified by chromatography on silica gel using cyclohexane-ethyl acetate (8:1) as eluant. The product-containing fractions are evaporated under reduced pressure, and the residue is triturated with diethyl ether to give a pale yellow solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[CH3:8][Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][O:12][CH2:13]Cl>CN(C)C=O>[CH3:8][Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][O:12][CH2:13][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccnc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 134.7 %

Procedure:
Under an argon atmosphere, a dimethylformamide (500 mL) suspension of sodium hydride (60%, 18.9 g) was ice-cooled and then imidazole (30.9 g) was added so as to prevent an inner temperature from rising to 5° C. or higher. The reaction solution was stirred at 0° C. for 45 minutes. To the reaction solution, 2-(trimethylsilyl)ethoxymethyl chloride (72.4 g) was added dropwise. The reaction solution was stirred at room temperature for 14 hours. To the reaction solution, ice water (200 mL) was added. The aqueous layer was extracted twice with a solution (n-hexane:ethyl acetate=1:1 (200 mL)). The combined organic layer was washed with saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing anhydrous magnesium sulfate by filtration, the filtrate was concentrated to obtain the title compound (116 g) having the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25](O)=[O:26])[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[CH3:35][N:36]([CH3:42])[CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[CH3:35][N:36]([CH3:42])[CH:37]1[CH2:41][CH2:40][N:39]([C:25]([C:21]2[CH:20]=[C:19]([C:12]3[CH:11]=[C:10]4[C:15]([CH2:16][CH:17]([CH3:18])[N:8]([C:6]5[CH:5]=[C:4]([N:28]6[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]6)[N:3]=[C:2]([NH2:1])[N:7]=5)[CH2:9]4)=[CH:14][CH:13]=3)[CH:24]=[CH:23][N:22]=2)=[O:26])[CH2:38]1
Reactant: CN(C)C1CCNC1
Reactant: CC1Cc2ccc(-c3ccnc(C(=O)O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CC1Cc2ccc(-c3ccnc(C(=O)N4CCC(N(C)C)C4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 61A starting from 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 61A, Step 2) and 3-(dimethylamino)pyrrolidine (TCI, Cat. No. D1859). LCMS (M+H)+: m/z=556.3.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[C:5]#[N:6].Cl.[NH2:15][OH:16].CCN(C(C)C)C(C)C>CCO>[OH:16][NH:15][C:5](=[NH:6])[C:4]1[CH:7]=[CH:8][C:9]([O:10][CH:11]([CH3:12])[CH3:13])=[C:2]([I:1])[CH:3]=1
Reactant: CC(C)Oc1ccc(C#N)cc1I
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(C(=N)NO)cc1I
Temperature: 50 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
A suspension of 3-iodo-4-isopropoxybenzonitrile (0.576 g; 2 mmol), HCl×NH2OH (0.276 g; 4 mmol) and DIPEA (0.69 ml; 4 mmol) in EtOH (50 ml) was stirred for 18 h at 50° C. The solvent was distilled off and the residue was diluted to 50 ml with EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was distilled off to give the title product (0.61 g; 95%), as colourless solid. 1H-NMR (CDCl3) 8.0 (d, 1H, J=2.22 Hz); 7.55 (dd, 1H, J=9.54, 2.28 Hz); 6.77 (d, 1H, J=8.7 Hz); 4.95 (b, 2H); 4.69-4.63 (m, 1H); 1.42 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[N:17][C:18]([NH:20][C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)=[N:19][C:12]=2[N:11]2[CH:30]=[CH:31][N:32]=[C:10]12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH3:65][N:66]([CH3:73])[CH:67]1[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]1>CN(C)C=O.C(OCC)(=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[N:17][C:18]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([N:70]4[CH2:71][CH2:72][CH:67]([N:66]([CH3:73])[CH3:65])[CH2:68][CH2:69]4)=[O:26])=[CH:28][CH:29]=3)=[N:19][C:12]=2[N:11]2[CH:30]=[CH:31][N:32]=[C:10]12
Reactant: CN(C)C1CCNCC1
Reactant: O=C(O)c1ccc(Nc2ncc3c(=O)n(-c4c(Cl)cccc4Cl)c4nccn4c3n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C1CCN(C(=O)c2ccc(Nc3ncc4c(=O)n(-c5c(Cl)cccc5Cl)c5nccn5c4n3)cc2)CC1
Reaction time: 8 h

Procedure:
To a solution of Example 237A (100 mg, 0.214 mmol) in 5 mL N,N-dimethylformamide was added 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (61.5 mg, 0.321 mmol), 1-hydroxybenzotriazole hydrate (49.2 mg, 0.321 mmol), diisopropylethylamine (0.075 ml, 0.428 mmol) followed by N,N-dimethylpiperidin-4-amine (0.036 ml, 0.257 mmol). The reaction mixture was held at room temperature overnight, and then diluted with ethyl acetate. The organics were washed with aqueous saturated NaHCO3, water, and brine, then dried over MgSO4, filtered, and concentrated. The compound was triturated from the crude reaction mixture to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 1.21-1.55 (m, 2H) 1.63-1.98 (m, 2H) 2.13-2.43 (m, 6H) 2.73-3.12 (m, 2H) 7.14 (d, J=1.59 Hz, 1H) 7.48 (d, J=8.73 Hz, 2H) 7.58-7.81 (m, 4H) 7.86-8.02 (m, 3H) 9.06-9.33 (m, 1H) 11.04 (s, 1H). MS (ESI+) m/z 477.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[OH-:12].[Na+]>O>[Cl:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[NH:6][CH:7]=[N:8][C:9]=2[N:10]=1
Reactant: [OH-]
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c(Cl)nc2nc[nH]c12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of compound 2,6-dichloro-7H-purine, 1 (60 g, 300 mL) and NaOH (30 g) in water was stirred at 100° C. for 5 h, then the reaction mixture was cooled to room temperature and was filtered. The solid was washed with ethyl acetate, then dissolved in water, treated with aq. HCl solution until pH was adjusted to 4. A precipitate formed overnight, the solid was filtered, was washed with a little water, and was dried to give 2.
Reaction SMILES: [O:1]=[C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][O:4][C:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7](=[O:15])[CH:6]=1.Br[CH2:23][C:24](=[CH2:30])[C:25](OCC)=[O:26]>O1CCCC1.[Zn].C1(C=CC(O)=CC=1)O>[CH2:23]=[C:24]1[C:25](=[O:26])[O:1][C:2]([CH2:3][O:4][C:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][C:7](=[O:15])[CH:6]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:30]1
Reactant: O=C(COc1cc(=O)oc2ccccc12)c1ccccc1
Reactant: C=C(CBr)C(=O)OCC
Agent: Oc1ccc(O)cc1
Agent: [Zn]
Solvent: C1CCOC1
Product: C=C1CC(COc2cc(=O)oc3ccccc23)(c2ccccc2)OC1=O
Temperature: 0 °C
Yield: 86.1 %

Procedure:
To a solution of 2a (0.84 g, 3 mmol) in dry tetrahydrofuran (60 ml) were added activated zinc powder (0.255 g, 3.9 mmol), hydroquinone (6 mg), and ethyl 2-(bromomethyl)acrylate (0.78 g, 4 mmol). The mixture was refluxed under nitrogen atmosphere for 18 h. (monitored by TLC). After cooling it was poured into an ice-cold 5% HCl solution (300 ml) and extracted with CH2Cl2 (75 ml×3). The dichloromethane extracts were combined and washed with saline, dried over Na2SO4, and then evaporated to give a residual solid which was crystallized from ethyl acetate to afford the title compound (0.90 g, 86.4%). mp: 212°-214° C.; IR(KBr) νmax : 1766, 1717, 1620; UV(CHCl3) νmax (log ε): 306 (3.89), 277 (4.10), 266 (4.14); 1H-NMR (CDCl3): δ3.33 (dt, 1H, 4'-H), 3.66 (dt, 1H, 4'-H), 4.26, 4.32 (two d, 2H, OCH2), 5.60 (s, 1H, 3-H), 5.79 (t, 1H, vinylic H), 6.42 (t, 1H, vinylic H), 7.20-7.61 (m, 9H, 5,6,7,8-H, and aromatic H). Anal. Calcd for C21H16O5 0.25H2O: C, 71.48; H, 4.71. Found: C, 71.37; H, 4.67.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH2:21][CH3:22].[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][CH2:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:29]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:30])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: O=C(Cl)N1CCOCC1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)N1CCOCC1
Yield: 47.1 %

Procedure:
Using the general method of Example 149, 1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.36 mmol) was reacted with 4-morpholinecarbonyl chloride (830 mg, 5.55 mmol) to provide 650 mg of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]morpholine-4-carboxamide as a white powder, m.p. 193.4-194.6° C. Analysis: Calculated for C22H30N6O2: %C, 64.37; %H, 7.37; %N, 20.47; Found: %C, 64.00; %H, 7.32; %N, 20.16.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:14]=[C:15](Cl)OC(Cl)(Cl)Cl>O1CCOCC1>[N+:11]([C:8]1[CH:7]=[C:3]2[C:4]([O:6][C:15](=[O:14])[NH:1][C:2]2=[CH:10][CH:9]=1)=[O:5])([O-:13])=[O:12]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(=O)o1

Procedure:
To the mixture of 37 g of 2-amino-5-nitrobenzoic acid in 500 mL of dioxane, under stirring 24.5 mL of diphosgene was added dropwise. The mixture was heated under reflux conditions for 6 hours then it was evaporated to dryness. The residue was suspended in 100 mL of diethyl ether and filtered off to give 41.4 g of the title product as HCl salt, m.p.: 256-259° C. LC-MS: MH+ 209; Ret. time: 5 minutes.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH2:6][CH2:7][CH2:8][CH:9]([N:10]=[C:11]=[S:12])[C:2]1=2.Cl.[CH3:14][O:15][NH:16][CH3:17]>>[CH3:17][N:16]([O:15][CH3:14])[C:11]([NH:10][CH:9]1[C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH2:6][CH2:7][CH2:8]1)=[S:12]
Reactant: CNOC
Reactant: S=C=NC1CCCc2ccsc21
Agent: Cl
Product: CON(C)C(=S)NC1CCCc2ccsc21

Procedure:
In the manner described in Example 5, 4,5,6,7-tetrahydrobenzo[b]thien-7-yl isothiocyanate is allowed to react with O,N-dimethylhydroxylamine hydrochloride to afford the title compound.
Reaction SMILES: [C:1]([N:4]1[C:8]2=[CH:9][CH:10]=[C:11](I)[C:12](=[O:13])[N:7]2[C@H:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C@@H:5]1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)(=[O:3])[CH3:2].[CH3:29][O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]>>[C:1]([N:4]1[C:8]2=[CH:9][CH:10]=[C:11]([C:34]3[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[C:36]([O:37][CH3:38])[CH:35]=3)[C:12](=[O:13])[N:7]2[C@H:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C@@H:5]1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(I)c(=O)n2[C@H](c2ccc(Cl)cc2)[C@@H]1c1ccc(Cl)cc1
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2ccc3n(c2=O)[C@H](c2ccc(Cl)cc2)[C@H](c2ccc(Cl)cc2)N3C(C)=O)cc1OC

Procedure:
rac-cis-1-Acetyl-2,3-bis-(4-chloro-phenyl)-6-(3,4-dimethoxy-phenyl)-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one was prepared according to general method D by reaction of rac-cis-1-acetyl-2,3-bis-(4-chloro-phenyl)-2,3-dihydro-6-iodo-1H-imidazo[1 2-a]pyridin-5-one with 3,4-dimethoxyphenylboronic acid The compound was isolated by preparative HPLC. The expected product was characterized by LC/MS (M+H) where the mass was observed as 535.16; the expected mass is 534.1. LC/MS indicated a purity of 100% as measured by UV 214 nM.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Br[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.C(C1C=C(NC2CCN(C(OC(C)(C)C)=O)CC2)C=CC=1)#N>>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([NH:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:17][CH:18]=1)#[N:21]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N#Cc1ccc(Br)cc1
Agent: CC(C)(C)OC(=O)N1CCC(Nc2cccc(C#N)c2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared from 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate and 4-bromobenzonitrile using a method similar to that described for D5 in Description 5.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6]N=O.CCCCCCC.[CH2:16]=[C:17]=[O:18].[C]=O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN1CCCC1=O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:17]([CH3:16])=[O:18]
Reactant: CCCCCON=O
Reactant: C=C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C]=O
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: CCCCCCC
Product: CCCCCOC(C)=O
Reaction time: 5 h
Yield: 18.8 %

Procedure:
To the same reaction vessel as in Example 9 were charged bistriphenylphosphinedibromopalladium (0.198 g, 0.25 mmole), stannous chloride (0.095 g, 0.5 mmole), tetra-n-butylammonium chloride (0.139 g, 0.5 mmole) and n-amyl nitrite (70 ml, 474.4 mmoles), together with n-heptane (150 ml) and N-methylpyrrolidone (50 ml). Then, ketene, carbon monooxide and nitrogen were introduced to the mixture at the rate of 10.1 ml/min (0.45 mmole/min), 300 ml/min and 100 ml/min, respectively, and the reaction was effected at 90° C. for 5 hours. The reaction product was analyzed by gas chromatography, revealing that di-n-amyl malonate (82.3 mmoles, 60.7%) and n-amyl acetate (25.5 mmoles, 18.8%) were obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=O)[CH:3]=[N:2]1.[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][NH2:17])[CH3:13].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][NH:17][CH2:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][N:2]=[CH:3]2)[CH3:13]
Reactant: O=Cc1cccc2cn[nH]c12
Reactant: CCOC(CN)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(CNCc1cccc2cn[nH]c12)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1H-indazole-7-carbaldehyde (1.75 g, 12 mmol) in MeOH (50 mL) was added aminoacetaldehyde diethyl acetal (1.74 mL, 12 mmol) and acetic acid (1.03 mL, 18 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was added to a stirred solution of sodium cyanoborohydride (816 mg, 13 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure. Then H2O and ethyl acetate were added to the reaction mixture. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was used next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[C:17]([C:18](=[O:20])[CH:19]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:6][C:7]=1[O:8]C.CC(O)=O.O>I>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[C:17]([C:18](=[O:20])[CH:19]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(-c2cc(=O)c3ccccc3o2)cc1F
Agent: I
Solvent: CC(=O)O
Solvent: O
Product: O=c1cc(-c2ccc(O)c(F)c2)oc2ccccc12
Temperature: 110 °C
Reaction time: 4 h
Yield: 72.5 %

Procedure:
To a solution of 2′-hydroxyacetophenone (1.36 g, 10 mmol) in 20 mL anhydrous pyridine was added 3-fluoro-4-methoxybenzoyl chloride (1.89 g, 10 mmol) and the reaction mixture was stirred at rt for 15 h under a nitrogen atmosphere. The reaction mixture was poured into 200 mL of 2 N HCl. The formed solid was isolated by filtration, washed with water and dried under vacuum to give a white solid (2.76 g, 95.7%). The compound (2.68 g, 9.3 mmol) was dissolved in 10 mL anhydrous pyridine. Powdered potassium hydroxide (1.57 g, 27.9 mmol) was added and the reaction mixture was stirred at rt overnight under nitrogen. Water (100 mL) was added, the solid was isolated by filtration and washed with water to give a yellow solid (1.83 g, 68%). The compound (1.78 g, 6.17 mmol) was suspended in 15 mL glacial AcOH. Five drops of conc. HCl was added and the reaction mixture was stirred at 110° C. for 2 h, then cooled to rt. Water (100 mL) was added. The formed solid was separated by filtration, washed with water and dried under vacuum to give 2-(3-fluoro-4-methoxyphenyl)chromen-4-one as a white solid (1.62 g, 97%). 2-(3-Fluoro-4-methoxyphenyl)chromen-4-one (1.6 g, 5.92 mmol) was suspended in 40 mL of HI. Glacial AcOH (15 mL) was added and the reaction mixture was stirred at 110° C. for 4 h, then cooled to rt. Water (200 mL) was added, and the solid was isolated by filtration, washed with water and dried under vacuum. The crude compound was washed with 1:1 dichloromethane and methanol (15 mL) to give 1.1 g of 2-(3-fluoro-4-hydroxyphenyl)chromen-4-one (72%) as a pale yellow solid. MS (ES) m/z: 257.91 (M+1), 256.88 (M); Mp. 275-276° C.