Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH3:32][C:33]1[S:34][C:35]([S:39]([NH2:42])(=[O:41])=[O:40])=[C:36]([CH3:38])[N:37]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:35]3[S:34][C:33]([CH3:32])=[N:37][C:36]=3[CH3:38])(=[O:40])=[O:41])=[O:31])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: Cc1nc(C)c(S(N)(=O)=O)s1
Product: Cc1nc(C)c(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4ccccc4)c3C)cc2)s1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 2,4-dimethyl-1,3-thiazole-5-sulfonamide: 1H-NMR [CDCl3/CD3OD(10:1)] δ 7.46-7.22 (9H, m), 6.20 (1H, br.s), 3.48-3.45 (2H, m), 2.88-2.82 (2H, m), 2.64 (3H, s), 2.59 (3H, s), 2.30 (3H, s), 2.20 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][N:5]2[C:11]=1[C:12]([O:14]CC)=[O:13].[Li+].[OH-]>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][N:5]2[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)c1c(C)nc2cc(C)ccn12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccn2c(C(=O)O)c(C)nc2c1
Yield: 82.5 %

Procedure:
The ethyl 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxylate (6.4 g, 29.3 mmol) was dissolved in 75 mL of ethanol (95%), 1 M LiOH (60 mL, 60 mmol) was added and reaction was heated to reflux for 36 hours. The resulting solution was concentrated to dryness and then made acidic (pH˜2-3) with the addition of 4 N HCl; resulting solids were collected by filtration and rigorously dried to give 4.6 grams (82%) of 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid, an off-white solid. mp 180-183° C.; 1H NMR (300 MHz, CD3OD) δ 9.52 (d, J=7.1 Hz, 1H), 7.73 (td, J=1.8, 0.9, 0.9 Hz, 1H), 7.48 (dd, J=7.1, 1.3 Hz, 1H), 2.81 (s, 3H), 2.63 (s, 3H). HRMS (EI), M+1 calcd. for C10H11N2O2, 191.0815; found 191.0837. Retention time=0.6-0.7 minutes (mobile phase: 60% water:acetonitrile).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22]>>[OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH:14]=[C:20]3[S:16][C:17](=[O:22])[NH:18][C:19]3=[O:21])=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(-c2cccc(O)c2)cc1
Product: O=C1NC(=O)C(=Cc2ccc(-c3cccc(O)c3)cc2)S1
Yield: 100 %

Procedure:
In a manner similar to that of Example 1(f), starting with 15 g (75.7 mmol) of 3′-hydroxybiphenyl-4-carbaldehyde and 8.85 g (75.7 mmol) of 2,4-thiazolidine dione, 22.5 g (100%) of the expected product are obtained.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1ccncc1
Reactant: NCCc1ccc(Cl)cc1
Solvent: CO
Product: N#CNC(=NCCc1ccc(Cl)cc1)c1ccncc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 57.7 %

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.5 g, 2.6 mmol) was dissolved in methanol (5 ml), and 2-(4 chlorophenyl)ethylamine (0.46 g, 3.0 mmol) having been diluted with methanol (5 ml) was added. The mixture was stirred at room temperature for 40 minutes. After the reaction was completed, the reaction solution was then concentrated under reduced pressure. The residual concentrate was further crystallized from methanol-diethyl ether to give the title compound (0.44 g, 1.5 mmol, yield: 58%) as colorless needles.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5](=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[CH:16]([C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=1[O:26][CH3:27])=O.C(O)(=O)C.N1CCCCC1>ClCCl>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([CH:16]=[C:6]([C:5](=[O:12])[CH:4]([O:3][CH2:1][CH3:2])[O:13][CH2:14][CH3:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:19]([O:26][CH3:27])[CH:20]=1)#[N:23]
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Reactant: COc1cc(C#N)ccc1C=O
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1ccc(C#N)cc1OC)C(=O)C(OCC)OCC

Procedure:
618.2 mg (2.83 mmol) of ethyl 4,4-diethoxy-3-oxobutanoate [Johnson et al., J. Am. Chem. Soc. 41, 812 (1919)], 500.0 mg (2.58 mmol) of 4-formyl-3-methoxybenzonitrile, 232.0 mg (3.86 mmol) of acetic acid and 43.9 mg (0.51 mmol) of piperidine are dissolved in 20 ml of dichloromethane and heated under reflux with an inverse water trap ovemight. Cooling is followed by washing twice with water, and the organic phase is dried with magnesium sulfate. The solvent is removed in a rotary evaporator, and the residue is purified by column chromatography (silica gel, mobile phase:cyclohexane/ethyl acetate 4:1). 824 mg (77.0% of theory) of the title compound are obtained as a mixture of the E/Z isomers.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([NH:17][C:18]1[S:19][C:20]([C:24](O)=[O:25])=[C:21]([Cl:23])[N:22]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:1]([NH:8][C:24]([C:20]1[S:19][C:18]([NH:17][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:22][C:21]=1[Cl:23])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1nc(Cl)c(C(=O)O)s1)c1ccccc1
Reactant: NCc1ccccc1
Product: O=C(Nc1nc(Cl)c(C(=O)NCc2ccccc2)s1)c1ccccc1
Yield: 20 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use benzylamine in place of α-ethylbenzylamine to react with 2-benzoylamino-4-chlorothiazole-5-carboxylic acid, the title compound was obtained as a white solid in 20% yield; m. p. 247-249° C.; 1H NMR (DMSO-d6, 300 MHz) δ 12.5 (s, 1H), 8.11-7.93 (m, 2H), 7.72 (t, J=5.7 Hz, 1H), 7.58-6.95 (m, 8H), 4.48 (d, J=5.7 Hz, 2H); 13C NMR (DMSO-d6, 75 MHz) δ 166.1, 160.0, 138.5, 134.2, 133.0, 131.4, 128.6, 128.5, 128.4, 127.5, 127.2, 119.6, 43.4; MS (ES+) m/z 372.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[I-].[K+].[OH:13][CH2:14][C:15]1[CH:27]=[C:26]2[N:17]([C:18](=[O:28])[NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=32)[N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:13][CH2:14][C:15]1[CH:27]=[C:26]2[N:17]([C:18](=[O:28])[N:19]([CH2:7][C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=32)[N:16]=1
Reactant: O=c1[nH]c2ccccc2c2cc(CO)nn12
Reactant: COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(Cn2c(=O)n3nc(CO)cc3c3ccccc32)cc1

Procedure:
210 g of p-methoxybenzyl bromide and 40 g of potassium iodide are added to 114 g of 2-(hydroxymethyl)pyrazolo[1,5-c]quinazolin-5(6H)-one and 276 g of potassium carbonate in 2 l. of methanol. After refluxing for 5 hours, the reaction is cooled, poured into 6 l. of water and the title compound is filtered off and dried.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]([CH2:29][C@@H:30]([OH:35])[C@@H:31]([OH:34])[CH2:32][OH:33])[CH2:22][C@@H:23]([OH:28])[C@@H:24]([OH:27])[CH2:25][OH:26])=[CH:14][CH:13]=1)(C)(C)C.Cl>C(O)C>[OH:35][C@@H:30]([C@@H:31]([OH:34])[CH2:32][OH:33])[CH2:29][N:21]([CH2:22][C@@H:23]([OH:28])[C@@H:24]([OH:27])[CH2:25][OH:26])[CH2:20][CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH2:7])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(OCCN(C[C@@H](O)[C@@H](O)CO)C[C@@H](O)[C@@H](O)CO)cc1
Agent: Cl
Solvent: CCO
Product: NCCCCc1ccc(OCCN(C[C@@H](O)[C@@H](O)CO)C[C@@H](O)[C@@H](O)CO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
To a solution containing the compound 18 (0.502 g, 0.972 mmol) in ethanol (10 mL) was slowly added concentrated hydrochloric acid (12N, 2 mL). The clear solution was stirred at room temperature for 4 hours. The reaction mixture was concentrated under vacuum. The residue was taken into ethanol (3 mL) and the resulting solution was concentrated again under vacuum. The procedure was repeated two more times to ensure no aqueous solvent remained. The residue was chromatographed over silica gel, eluting with a mixture of concentrated ammonium hydroxide (0-10%), methane (0-30%), and methylene chloride (100-60%), to afford 0.396 g (98%) of the product 19 as a low melting white solid. [α]D25=+24.2° (c 0.265, MeOH). 1H NMR (300 MHz, DMSO-d6): δ 1.32-1.52 (m, 4H), 2.46-2.55 (m, 4H), 2.74-2.79 (m, 2H), 2.84-2.96 (m, 2H), 3.31-3.99 (m, 16H), 4.01 (t, J=5.9 Hz, 2H), 6.40 (br s, 2H), 6.82 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H). m/z (APCI)=417 [C20H36N2O7+H]+.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:15][C:14]2[CH:16]=[C:17]([O:20][CH2:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])[CH:18]=[CH:19][C:13]=2[CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:36][C:37]1[CH:47]=[CH:46][C:40]([O:41][CH2:42][C@H:43]2[O:45][CH2:44]2)=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([N:8]([CH:9]1[CH2:15][C:14]2[CH:16]=[C:17]([O:20][CH2:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])[CH:18]=[CH:19][C:13]=2[CH2:12][CH2:11][CH2:10]1)[CH2:44][C@H:43]([OH:45])[CH2:42][O:41][C:40]1[CH:46]=[CH:47][C:37]([O:36][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:38][CH:39]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc(OC[C@@H]3CO3)cc2)cc1
Reactant: CCCCNC(=O)COc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: CCCCNC(=O)COc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccc(OCc3ccccc3)cc1)CCC2
Reaction time: 3 h
Yield: 46.2 %

Procedure:
under nitrogen, to a solution of 2-(8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)-N-butylacetamide (388 mg) and (2S)-1-(4-benzyloxyphenoxy)-2,3-epoxypropane (340 mg) in dichloromethane (10 ml) was added ytterbium(III) trifluoromethanesulfonate (63 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford 2-[8-[N-benzyl-N-[(2S)-3-(4-benzyloxyphenoxy)-2-hydroxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N-butylacetamide (300 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:23])[NH:10][C:11]3[C:16]([C:17]=2[OH:18])=[CH:15][C:14]([N+:19]([O-:21])=[O:20])=[C:13]([Cl:22])[CH:12]=3)[CH:5]=[CH:6][CH:7]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[CH2:37][CH2:38]O)=[O:30])([CH3:27])([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[CH2:37][CH2:38][O:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([Cl:22])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=2)[NH:10][C:9](=[O:23])[C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2c(O)c1-c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCCCC1CCOc1c(-c2cccc(Br)c2)c(=O)[nH]c2cc(Cl)c([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
To a solution of 3-(3-bromophenyl)-7-chloro-4-hydroxy-6-nitro-1H-quinolin-2-one (100 mg in 4.0 mL of tetrahydrofuran) at 0° C. was added 64 mg of 2-(2-hydroxyethyl)-piperidine-1-carboxylic acid tert-butyl ester and 93 mg of triphenylphosphine followed by 0.050 mL of diethyl azodicarboxylate and the mixture warmed to room temperature. After 20 hours, the solvents were removed in vacuo and the residue purified by flash chromatography on silica gel (hexane:ethylacetate, 2:1) to give the title compound (92 mg).
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]([C:10]1[C:11]([Cl:30])=[C:12]([C:26]([Cl:29])=[CH:27][CH:28]=1)[CH2:13][O:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[C:22]([CH3:25])[CH:21]=[CH:20]2)[CH3:9])=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl.O>CO>[Cl:30][C:11]1[C:10]([N:8]([C:6](=[O:7])[CH2:5][OH:4])[CH3:9])=[CH:28][CH:27]=[C:26]([Cl:29])[C:12]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[C:22]([CH3:25])[CH:21]=[CH:20]2
Reactant: CC(=O)OCC(=O)N(C)c1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CO)c3Cl)c2n1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 8-[3-(N-acetoxyacetyl-n-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (640 mg) in methanol (6.4 ml) was added potassium carbonate (395 mg), and the mixture was stireed for 2 hours at ambient temperature. To the mixture was added chloroform and water, the organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (chloroform:ethyl acetate=3.1, V/V) to give 8-[2,6-dichloro-3-(N-hydroxyacetyl-N-methylamino)benzyloxy]-2-methylquinoline (580 mg) as colorless amorphous.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Brc1ccc(Br)nc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)cn2)CC1
Temperature: 80 °C
Yield: 10.1 %

Procedure:
A tube was charged with 2,5-dibromopyridine (0.24 g, 1.0 mmol), 4-Amino-piperidine-1-carboxylic acid tert-butyl ester (0.22 g, 1.1 mmol), di-isopropylethylamine (0.19 mL, 1.1 mmol) and N-methylpyrrolidinone (1.0 mL). The tube was sealed and the mixture was heated at 80° C. overnight. The temperature was increased to 120° C. and heated overnight. The reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by rotary evaporation. The residue was purified by silica gel chromatography using gradient elution of ethyl acetate and hexanes to afford 4-(5-bromo-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (36 mg, 10%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][C:13]([N:15]1[C@H:22]([CH3:23])[CH2:21][CH2:20][C@H:19]2[C@H:17]([O:18]2)[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+]>CO.O>[CH2:5]([O:12][C:13]([N:15]1[CH2:16][C@@H:17]([OH:18])[C@H:19]([N:1]=[N+:2]=[N-:3])[CH2:20][CH2:21][C@H:22]1[CH3:23])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H]1CC[C@@H]2O[C@@H]2CN1C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@@H]1CC[C@@H](N=[N+]=[N-])[C@H](O)CN1C(=O)OCc1ccccc1
Yield: 62.9 %

Procedure:
Sodium azide (1.8 g, 27.7 mmol) was added to a (1R,4R,7S)-4-Methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester (2.4 g, 9.2 mmol, Example 1e) and ammonium chloride (1.48 g, 27.7 mmol) in MeOH (16 ml) and H2O (1.6 ml), then was refluxed overnight. The reaction mixture was concentrated in vacuo by rotary evaporation, then was diluted with water (5 ml) and extracted with EtOAc (10 ml). The organic layer was then extracted with water, brine, dried with MgSO4, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 25% EtOAc/hexanes) to yield the title compound (1.76 g, 63%); Liquid chromatgraphy/Electrospray mass spec: M+H+=305.2.
Reaction SMILES: [I:1]Cl.[N:3]1[C:4](=[O:12])[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12>C(O)(=O)C>[I:1][C:10]1[CH:9]=[CH:8][C:7]2=[N:3][C:4](=[O:12])[N:5]=[C:6]2[CH:11]=1
Reactant: O=C1N=c2ccccc2=N1
Reactant: ClI
Solvent: CC(=O)O
Product: O=C1N=c2ccc(I)cc2=N1
Temperature: 80 °C

Procedure:
A mixture of iodine monochloride and 2H-benzimidazole-2-one (0.67 g) (Method 59) in glacial acetic acid (8 ml) was heated to 80° C. for 1 hour then cooled. The mixture was partitioned between saturated aqueous sodium sulphite solution and DCM. The organic layer was evaporated to dryness then redissolved in ethyl acetate. The aqueous layer was extracted with ethyl acetate then all ethyl acetate extracts were combined and washed with saturated aqueous sodium hydrogencarbonate solution, water and brine. The organic extracts were passed through a Varian Chem Elut column and washed through with ethyl acetate. Volatile material was removed by evaporation to give the title compound (0.36 g) as a solid which was used without further purification. MS (ESP−): 261 (M+H)+.
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[NH:7][CH:6]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=2[O:20][CH3:21])[C:5]1=[O:22])(=O)C.O.NN>O1CCCC1>[CH3:21][O:20][C:13]1[C:14]([O:18][CH3:19])=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH:6]1[NH:7][C:8](=[O:10])[CH2:9][NH:4][C:5]1=[O:22]
Reactant: COc1cccc(CC2NC(=O)CN(C(C)=O)C2=O)c1OC
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(CC2NC(=O)CNC2=O)c1OC
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
To a suspension of 1-acetyl-3-(2,3-dimethoxybenzyl)-2,5-piperazinedione (2.49 g) in tetrahydrofuran (38 ml) was added hydrazine monohydrate (0.43 ml) at room temperature and the mixture was stirred at the same temperature for 30 minutes. The resulting precipitates were collected by filtration and washed with tetrahydrofuran to give powders of 3-(2,3-dimethoxybenzyl)-2,5-piperazinedione (1.40 g)
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[C:12]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH2:34][CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)=[C:13]2[O:19][CH2:18][O:17][C:14]2=[N:15][CH:16]=1.[CH3:41][N:42]([CH3:47])[CH2:43][C:44](O)=[O:45].CN(C=O)C>C(OCC)(=O)C>[Cl:10][C:11]1[C:12]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH2:34][CH:35]4[CH2:40][CH2:39][N:38]([C:44](=[O:45])[CH2:43][N:42]([CH3:47])[CH3:41])[CH2:37][CH2:36]4)=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)=[C:13]2[O:19][CH2:18][O:17][C:14]2=[N:15][CH:16]=1
Reactant: CN(C)CC(=O)O
Reactant: COc1cc2c(Nc3c(Cl)cnc4c3OCO4)ncnc2cc1OCC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Nc3c(Cl)cnc4c3OCO4)ncnc2cc1OCC1CCN(C(=O)CN(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.5 %

Procedure:
Diisopropylethylamine (0.118 ml) was added to a mixture of 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (0.15 g), N,N-dimethylglycine (0.042 g), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.154 g) and DMF (3 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with ethyl acetate and washed with brine. The organic solution was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 100:3 mixture of methylene chloride and a 7M methanolic ammonia solution as eluent. There was thus obtained the title compound as a solid (0.051 g); NMR Spectrum: (DMSOd6) 1.11-1.36 (m, 2H), 1.83 (d, 2H), 2.11 (m, 1H), 2.19 (s, 6H), 2.61 (t, 1H), 3.03 (m, 2H), 3.12 (d, 1H), 3.93 (s, 3H), 4.06 (m, 3H), 4.4 (d, 1H), 6.19 (br s, 2H), 7.19 (brs, 1H), 7.78 (m, 2H), 8.39 (br s, 1H), 9.71 (br s, 1H); Mass Spectrum: M+H+ 529 and 531.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[N:15]=2)[N:10]=[CH:9][CH:8]=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].CO[CH2:29][CH2:30]OC>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:29]([C:7]1[CH:8]=[CH:9][N:10]=[C:11]2[C:16]=1[N:15]=[C:14]([O:17][CH3:18])[CH:13]=[CH:12]2)=[CH2:30]
Reactant: COc1ccc2nccc(OS(=O)(=O)C(F)(F)F)c2n1
Reactant: COCCOC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1ccnc2ccc(OC)nc12
Reaction time: 3 h
Yield: 81 %

Procedure:
To a solution of 6-(methyloxy)-1,5-naphthyridin-4-yl trifluoromethanesulfonate (from Prep. 2b) (5.0 g, 16.23 mmol) in DME (80 mL) and H2O (40 mL) was added trivinyl boronate (1.96 g, 8.1 mmol), K2CO3 (2.23 g, 16.23 mmol) and Pd(PPh3)4 (0.19 g, 0.16 mmol). After 3 h at 90° C. under N2, the reaction solution was concentrated under vacuum and purified on silica (hexane/EtOAc, 4:1) to give the title compound as a yellow oil (2.44 g, 81%): LC/MS (m/z) (ES) 187 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc(C(F)(F)F)cc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2cc(C(F)(F)F)ccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1
Yield: 16 %

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-])=O.Cl.[NH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(CC)C(C)C)(C)C>C(#N)C.[Zn]>[NH2:1][CH2:4][CH:5]([NH:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])C=Cc1ccccc1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: [Zn]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CCNC(CN)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 148.3 %

Procedure:
Trans-□-Nitrostyrene (4.04 g, 27.1 mmol) was added to a solution of ethyl 3-aminopropanoate hydrochloride (4.16 g, 27.1 mmol), and N,N-diisopropylethylamine (9.43 mL, 54.2 mmol) in acetonitrile (70 mL). After 15 min, anhydrous hydrochloric acid gas was bubbled into the solution until acidic. The mixture was concentrated, redissolved in ethanol (60 mL) and aqueous hydrochloric acid (12 M; 30 mL), and cooled to 0° C. Zinc dust (8.80 g, 134 mmol) was added in portions over 5 min. After 0.5 h, the mixture was concentrated to remove ethanol and saturated aqueous sodium carbonate was added. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated to give the title compound (9.5 g). MS 237 (M+1).