Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@H:15]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]([C@:23]34[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:24]3[C@@H:25]3[C@@:38]([CH3:41])([CH2:39][CH2:40]4)[C@@:37]4([CH3:42])[C@@H:28]([C@:29]5([CH3:46])[C@@H:34]([CH2:35][CH2:36]4)[C:33]([CH3:44])([CH3:43])[C@@H:32]([OH:45])[CH2:31][CH2:30]5)[CH2:27][CH2:26]3)=[O:22])[CH2:16]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:59]1(=[O:66])[O:65][C:63](=[O:64])[CH2:62][CH2:61][CH2:60]1>C(OCC)(=O)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@H:15]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]([C@:23]34[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:24]3[C@@H:25]3[C@@:38]([CH3:41])([CH2:39][CH2:40]4)[C@@:37]4([CH3:42])[C@@H:28]([C@:29]5([CH3:46])[C@@H:34]([CH2:35][CH2:36]4)[C:33]([CH3:44])([CH3:43])[C@@H:32]([O:45][C:59](=[O:66])[CH2:60][CH2:61][CH2:62][C:63]([OH:65])=[O:64])[CH2:31][CH2:30]5)[CH2:27][CH2:26]3)=[O:22])[CH2:16]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCC(Cc5ccccc5)CC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C1CCCC(=O)O1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCC(Cc5ccccc5)CC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CCCC(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-N-((1R,3S)-3-((4-benzylpiperidin-1-yl)methyl)cyclopentyl)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamide (Example 32, 0.24 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.32 g, 0.48 mmol) and glutaric anhydride (1.3 ml) were added and the contents were refluxed for about 16 hours and completion of the reaction monitored by TLC. The reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, washed with water followed by brine solution, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.1 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.82-0.95 (m, 17H) 1.13-3.01 (m, 48H); 3.05-3.12 (m, 4H), 3.13-3.54 (m, 2H), 4.18-4.21 (m, 1H), 4.45-4.17 (m, 1H), 4.58 (s, 1H), 4.72 (s, 1H); 6.28-6.30 (m, 1H), 7.11-7.13 (m, 2H), 7.14-7.22 (m, 1H), 7.24-7.29 (m, 2H); ES Mass: [M+] 825 (100%); HPLC: 90%.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11]C([O-])=O.N1CCCCC1>N1C=CC=CC=1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:11][C:10]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=Cc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCOC(=O)C=Cc1ccc(O)cc1
Yield: 80.1 %

Procedure:
To 20 g of p-hydroxybenzaldehyde and 32.5 g of monoethyl malonate were added 6 ml of pyridine and 0.2 ml of piperidine, then the mixture thus obtained was heated at 100° to 110° C. for 10 hours under stirring. The reaction mixture was then cooled, extracted with chloroform, and the chloroform layer was washed with a saturated aqueous solution of potassium hydrogen sulfite and water in this order, the chloroform extract was dried with magnesium sulfate. The solvent was removed by evaporation and the residue thus obtained was crystallized from isopropyl ether-n-hexane to yield 25.2 g of ethyl 4-hydroxycinnamate. Light yellow indefinite form crystals. Melting point: 70°-71° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=2[O:19]1>>[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH:23][C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:17]=[N:16][CH:15]=[CH:14][N:13]=4)[N:3]=3)=[CH:21][C:20]=2[O:19]1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Reactant: Nc1ccc2c(c1)OCO2
Product: FC(F)(F)c1cc(Nc2ccc3c(c2)OCO3)nc(-c2cnccn2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.192 mmol) and 3,4-methylenedioxyaniline (39 mg, 0.288 mmol) similar to Example 76 and isolated as a pink solid (21 mg, 30%). 1H NMR (CDCl3): 9.72 (d, J=1.2 Hz, 1H), 8.76 (dd, J=1.5, 2.7 Hz, 1H), 8.71 (d, J=2.7 Hz, 1H), 7.60 (s, 1H), 6.88 (s, 1H), 6.87 (d, J=8.1 Hz, 1H), 6.83 (s, 1H), 6.78 (dd, J=1.8, 8.1 Hz, 1H), 6.05 (s, 2H).
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])([CH3:3])[CH3:2]>C(O)(=O)C>[CH:1]([S:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:14]([F:17])([F:15])[F:16])([CH3:3])[CH3:2]
Reactant: CC(C)Sc1ccc([N+](=O)[O-])cc1C(F)(F)F
Solvent: CC(=O)O
Product: CC(C)Sc1ccc(N)cc1C(F)(F)F
Yield: 60 %

Procedure:
A mixture containing 132.5 g (0.5 mole) of the nitro compound prepared as in (a) above, in 800 ml of 5% aqueous acetic acid was heated to reflux with stirring. The heat mantle was removed and 150 g of powdered iron was added at such a rate as to maintain reflux. After completion of the addition, the mixture was stirred and refluxed for one hour, and filtered while hot. The filtrate was extracted with ether (3×300 ml). The combined extracts were washed with 10% sodium carbonate, and then with water. The dried solution was concentrated to dryness under reduced pressure to give 70.5 g (60%) of product as a yellow oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH2:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:13]([N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=2)[CH2:17][CH2:16]1)[CH3:14]
Reactant: CCN1CCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCN1CCN(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Temperature: 85 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
A mixture of 3.42 g (20 mmol) of 4-fluoro-2-methoxy-1-nitrobenzene, 2.67 mL (21 mmol) of 1-ethylpiperazine and 5.14 mL (30 mmol) of diisopropylethylamine in 25 mL of acetonitrile is heated for 2.5 hours at 85°C. and then for 1 hour at 95°C., and is then stirred overnight while allowing to return to room temperature. The acetonitrile is evaporated off and the residue is then taken up in 50 mL of ether and 25 mL of water. The aqueous phase is extracted with ether. The organic phases are combined, dried over Na2SO4, filtered and concentrated under vacuum. The oil obtained is triturated in an ether/cyclohexane mixture (1/1) and the precipitate is isolated by filtration, rinsed with pentane and dried in an oven. 4.1 g of the expected product are finally obtained. Yield=77%.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]1[C:12]([OH:14])=[O:13].[OH-].[Na+].Cl>>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([OH:14])=[O:13]
Reactant: O=C(O)C1C=Nc2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c[nH]c2ccccc2c1=O

Procedure:
1-Cyclopropyl-6-fluoro-8-methoxy-7-{4-amino-3-alkyl/3,3-dialkyl/3,5-dialkyl-1-piperidinyl}-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and enantiomers were prepared by hydrolysis of racemic or optically active 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-{4-benzyloxycarbonylamino/t-butyloxycarbonylamino/ethoxycarbonylamino-3-alkyl/3,3-dialkyl/3,5-dialkyl-1-piperidinyl)-4-oxo-quinoline-3-carboxylic acid with aqueous alkali preferably aqueous sodium hydroxide or inorganic acid such as hydrochloric acid at ambient temperature for 2-12 hr.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:8]>>[C:5]1(=[O:8])[C:6]2=[C:6]3[C:5](=[CH:3][CH:2]=[CH:1]2)[CH:4]=[CH:3][CH:2]=[C:1]3[CH2:7]1
Reactant: O
Reactant: Cc1ccccc1
Product: O=C1Cc2cccc3cccc1c23
Reaction time: 0.08 h

Procedure:
With respect to 1 kg of the reaction solution generated in synthesis example 1, 1 L of toluene and 2 L of water were added. These components were stirred for 5 minutes and extraction was conducted. Then, the resultant substance was kept still for 15 to 20 minutes to be separated, and the upper toluene layer was recovered. The above-extracted solution and the same amount of 4% aqueous solution of sodium hydroxide were put into a separatory funnel, shaken and kept still. Then, the lower black liquid was removed. The remaining liquid was washed with water of the same amount as that of the remaining liquid. Then, the lower layer was removed. Water was added, 2 mL of hydrochloric acid was added, and these components were shaken. The lower layer was removed, and the remaining substance was washed with water again. The oil layer was washed with an alkaline substance and concentrated to remove the solvent. The concentrate was distilled at a pressure of 1 to 2 mmHg. As a result, 16 g of acenaphthene-1-one was obtained at a distillation temperature of 120° C.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:21])[C:14]([C:16]([O:18][CH2:19]C)=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][NH:6]3.[CH3:22]OS(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:21])[C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:22]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To 9.5 g (33 mmol) of pyridocinnoline (5) obtained in Example 1, 95 ml of dimethylsulfate was added, and the mixture was heated at 100° to 120° C. for 8 hours. After air-cooled, the solution was added to 900 ml of water containing 137 g of anhydrous potassium carbonate, and the solution was stirred at room temperature for 30 minutes. The solution was extracted with 800 ml of chloroform and after drying over magnesium sulfate, the solvent was removed by distillation. The residue was purified by silica gel chromatography (250 g of silica gel, eluent solvent: chloroform), and the obtained crystal was filtered off and washed with ether to obtain 5.3 g of the subject compound (6) in a 56% yield. The result of the analysis of this compound was as follows.
Reaction SMILES: [N:1]1([C:6]2([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=O)[CH2:8][CH2:7]2)[CH:5]=[N:4][CH:3]=[N:2]1.O.[NH2:19][NH2:20]>C(O)C>[N:1]1([C:6]2([C:9](=[N:19][NH2:20])[C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH2:8][CH2:7]2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: NN
Reactant: O=C(c1ccc(Cl)cc1)C1(n2cncn2)CC1
Solvent: CCO
Solvent: O
Product: NN=C(c1ccc(Cl)cc1)C1(n2cncn2)CC1
Yield: 98 %

Procedure:
37.1 g (0.15 mol) of 4-chlorophenyl 1-(1, 2, 4-triazol-1-yl)-cyclopropyl ketone were refluxed for 6 hours with 37.5 g (0.3 mol) of 80% strength hydrazine hydrate in 150 ml of ethanol. After removing the solvent by distillation in vacuo, 38.5 g (98%) of the title compound were obtained as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][OH:20])=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:23][N:24]1[C:28]([CH3:29])=[C:27]([C:30](O)=[O:31])[C:26](=[O:33])[N:25]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.O>[OH:20][CH2:19][CH2:18][O:17][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:30]([C:27]4[C:26](=[O:33])[N:25]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:24]([CH3:23])[C:28]=4[CH3:29])=[O:31])=[CH:22][CH:21]=3)=[CH:8][CH:9]=[N:10]2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(Oc2ccnc3cc(OCCO)ccc23)cc1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: O
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCO)ccc34)cc2)c(=O)n(-c2ccccc2)n1C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of 2-((4-(4-aminophenoxy)quinolin-7-yl)oxy)ethanol (0.14 g, 0.5 mmol), 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carb oxylic acid (0.11 g, 0.51 mmol) in DCM (1.5 mL) was added HOAT (0.014 g, 0.1 mmol), and EDCI (0.11 g, 0.6 mmol). The reaction was refluxed for 3 hours. The cooled mixture was diluted with water (30 mL) and filtered. The solid was collected and stirred in a mixture of EtOAc (3 mL) and water (3 mL) overnight. The solid was collected by filtration and dried in vacuo at 50° C. for 9 hours to afford the title compound as a gray-white solid (180 mg, 74.7%).
Reaction SMILES: C(OC([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][C@@H:22]([NH:28][C@@H:29]2[C:35](=[O:36])[N:34]([CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])[C:33]3[CH:45]=[CH:46][CH:47]=[CH:48][C:32]=3[S:31][CH2:30]2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][CH2:13]1)=O)(=O)C1C=CC=CC=1.[BrH:49].C(O)(=O)C.C(OCC)C>C(O)(=O)C>[BrH:49].[BrH:49].[CH2:26]([O:25][C:23]([C@H:22]([NH:28][C@@H:29]1[C:35](=[O:36])[N:34]([CH2:37][C:38]([OH:40])=[O:39])[C:33]2[CH:45]=[CH:46][CH:47]=[CH:48][C:32]=2[S:31][CH2:30]1)[CH2:21][CH2:20][CH2:19][CH2:18][CH:15]1[CH2:14][CH2:13][NH:12][CH2:17][CH2:16]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)[C@@H](CCCCC1CCN(C(=O)OC(=O)c2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)[C@@H](CCCCC1CCNCC1)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Reaction time: 1.5 h

Procedure:
In 1 ml of acetic acid is dissolved 0.45 g of tert-butyl 3(R)-[5-(1-benzoyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and 1 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by allowing the mixture to stand at room temperature for 1.5 hours. Ethyl ether (200 ml) is added to the reaction solution, which is then allowed to stand. The supernatant liquid is decanted, and the precipitate is washed with ethyl ether and dried to give 0.3 g of 3(R)-[1(R)-ethoxycarbonyl-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-5-acetic acid.dihydrobromide as a colorless powder.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH:5]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH:21]1[O:23][CH2:22]1)(=[O:3])[CH3:2].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25].[ClH:29].C(OCC)(=O)C>C(O)C>[ClH:29].[C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH:5]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH:21]([OH:23])[CH2:22][NH:28][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CC(=O)N1c2ccccc2SC1c1ccccc1OCC1CO1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)N1c2ccccc2SC1c1ccccc1OCC(O)CNC(C)(C)C
Yield: 81 %

Procedure:
1.31 g of 3-acetyl-2-[2-(2,3-epoxypropoxy)phenyl]benzothiazoline and 4.21 ml of t-butylamine are dissolved in 10 ml of ethanol and the solution is refluxed for 1 hour. After cooling, 2 ml of 2N HCl/ethyl acetate is added to the reaction mixture and the solution is concentrated in vacuo. To the residue ether is added to produce crystals. Crystals are collected by filtration to give 1.3 g (81%) of the titled compound.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[N:16]1([C:22]([CH:24]2[CH2:26][CH:25]2[CH3:27])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:19]3[CH2:20][CH2:21][N:16]([C:22]([CH:24]4[CH2:26][CH:25]4[CH3:27])=[O:23])[CH2:17][CH2:18]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: CC1CC1C(=O)N1CCNCC1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Product: CC1CC1C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-methylcyclopropyl)methanone, the title compound was obtained as a white solid (88% yield). 13C NMR (75 MHz, CDCl3) δ 177.1, 163.5, 159.5, 144.9, 131.3, 126.4, 115.1, 49.7, 45.2, 39.5, 37.5, 37.2, 35.3, 34.6, 29.9, 28.5, 26.5, 23.4, 8.6, 4.2. MS (ES+) m/z 360 (M+3).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[C:9]([Cl:12])[CH:10]=2)[N:5]([C@@H:14]2[O:28][C@H:27]([CH2:29][O:30]C(C3C=CC(C)=CC=3)=O)[C@@H:16]([O:17]C(C3C=CC(C)=CC=3)=O)[CH2:15]2)[C:4]=1Cl)=[O:2].[CH3:41][O-:42].[Na+].CO.C(Cl)(Cl)Cl>CO>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[Cl:13])[N:5]([C@@H:14]1[O:28][C@H:27]([CH2:16][OH:17])[C@@H:29]([OH:30])[CH2:15]1)[C:4]([O:42][CH3:41])=[C:3]2[CH:1]=[O:2]
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3c(Cl)c(C=O)c4cc(Cl)c(Cl)cc43)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1c(C=O)c2cc(Cl)c(Cl)cc2n1[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
3-Formyl-2,5,6-trichloro-1-[3,5-di-O-(p-toluoyl)-2-deoxy-β-D-ribofuranosyl]indole (4.113, 198 mg, 0.33 mmol) was suspended in dry MeOH (10 mL) to which was added sodium methoxide (75 mg, 1.4 mmol). The suspension was stirred at room temperature for 16 h, after which time the solution clarified. The solvent was then removed under vacuum, and the residue was suspended in water (50 mL), and extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine (25 mL), dried over MgSO4, filtered and evaporated to yield a damp solid. The crude material was dissolved in MeOH (1 mL) and subjected to column chromatography (40×350 mm) on silica gel with 10% MeOH/CHCl3. Fractions containing product were pooled and evaporated to yield a white solid. The solid was recrystallized from warm MeOH to yield 82 mg (68%) of 4.114 as a white crystalline solid: mp 186-187° C.; Rf 0.3 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 10.21 (s, 1H), 8.29 (s, 1H), 8.22 (s, 1H), 6.32 (dd, 1H), 5.37 (b, 1H, D2O exch.), 5.15 (b, 1H, D2O exch.), 4.43 (s, 3H), 4.41 (m, 1H), 3.83 (d, 1H), 3.68 (m, 2H), 2.53 (m, 1H), 2.11 (m, 1H). 13C-NMR (125 MHz, DMSO-d6): δ 183.22, 159.16, 129.40, 125.04, 124.73, 124.66, 121.11, 114.24, 100.02, 87.29, 82.99, 70.07, 64.16, 61.03, 38.43. HRMS (EI) m/z calcd. for C15H15Cl2NO5 359.0327, found 359.0320. Anal calcd for C15H15Cl2NO5·½H2O: C, 48.80; H, 4.37; N, 3.79. Found: C, 48.48; H, 4.61; N, 3.61.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:34][C@H:35]1[N:40]([CH3:41])[C@@H:39]([CH3:42])[CH2:38][N:37]([CH2:43][CH2:44][OH:45])[CH2:36]1.[OH-].[K+]>CS(C)=O.O>[CH:30]([C:26]1[N:25]=[C:24]([CH2:23][N:18]2[C:19]3[C:15](=[C:14]([NH:13][C:11]([C:8]4[N:5]5[CH:6]=[CH:7][C:2]([O:45][CH2:44][CH2:43][N:37]6[CH2:38][C@@H:39]([CH3:42])[N:40]([CH3:41])[C@@H:35]([CH3:34])[CH2:36]6)=[CH:3][C:4]5=[N:10][CH:9]=4)=[O:12])[CH:22]=[CH:21][CH:20]=3)[C:16]([CH3:33])=[N:17]2)[CH:29]=[CH:28][CH:27]=1)([CH3:32])[CH3:31]
Reactant: C[C@@H]1CN(CCO)C[C@H](C)N1C
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(Cl)ccn34)c12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5C[C@@H](C)N(C)[C@@H](C)C5)ccn34)c12
Temperature: 95 °C
Yield: 6.5 %

Procedure:
A pressure tube was charged with 7-chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (0.500 g, 1.09 mmol), 2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)ethanol (0.375 g, 2.18 mmol), crushed potassium hydroxide (0.306 g, 5.45 mmol) in 10 mL of DMSO. The tube was sealed and heated to 95° C. for 16 hours, then allowed to cool to ambient temperature. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Column chromatography (10% MeOH/DCM/0.5% NH4OH) followed by trituration with methyl t-butyl ether afforded 42 mgs (6%) of the title compound. MS (APCI), positive scan, m/z=595.1 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=1)([O-])=O.C(O)C.O.NN>[C].[Pd].O>[NH2:1][C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCc1ccccc1-2
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)CCc1ccccc1-2
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
First, 280 g of 2-nitro-9,10-dihydrophenanthrene, 2.0 g of palladium carbon, and 2.5 L of ethanol were loaded, and then 140 mL of hydrazine monohydrate were added to the mixture. The reaction solution was stirred for 4 hours under heating reflux. After having been cooled to room temperature, the reaction solution was poured into 5 L of water. Then, the mixture was extracted with 3 L of toluene. After the water layer had been removed, the organic layer was dried with magnesium sulfate. After magnesium sulfate had been separated by filtration, the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 220 g of a pale yellow solid were obtained (in 89% yield).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([NH:5][CH2:6][C:7](=O)[CH3:8])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1C=CC=CC=1>[CH3:8][C:7]1[S:21][C:3]([C:2]([F:11])([F:10])[F:1])=[N:5][CH:6]=1
Reactant: CC(=O)CNC(=O)C(F)(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: Cc1cnc(C(F)(F)F)s1
Reaction time: 4.5 h

Procedure:
Trifluoroacetamidoacetone (8.45 g, 50 mmol) and 20.2 g (50 mmol) of Lawesson's reagent were slurried in 100 mL of benzene and the mixture heated at reflux with stirring for 4-5 hr to obtain a clear solution. This was allowed to cool and was washed with 50 mL of 10 percent aqueous sodium hydroxide solution, dried over magnesium sulfate, and filtered. The resulting solution was kugelrohr distilled at 160° C. and the distillate was distilled through a 40 cm column packed with glass helices (to remove the benzene) until the head temperature began to drop. It was then distilled through a 20 cm Vigreauz column to obtain 5.1 g (61 percent of theory) of the title compound as a pale oil boiling at 138°-141° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1.[CH:20]1(B(O)O)[CH2:22][CH2:21]1.N1C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH:20]1([N:6]2[CH2:5][CH2:4][N:3]([C@@H:7]3[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]3)[C:2]2=[O:1])[CH2:22][CH2:21]1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N2CCNC2=O)C1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](N2CCN(C3CC3)C2=O)C1
Temperature: 40 °C
Reaction time: 48 h
Yield: 27 %

Procedure:
To a solution of (R)-tert-butyl 3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (365) (10.0 g, 31.17 mmol), cyclopropylboronic acid (6.39 g, 74.35 mmol) and pyridine (8.82 g, 111.5 mmol) in anhydrous DMF (100 mL) was added Cu(OAc)2 (6.75 g, 37.17 mmol). The resulting mixture was stirred at 40° C. under O2 atmosphere (balloon) for 48 hours. After quenched with NH3.H2O (10 mL), the mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL×3). The organic layers were combined, washed with brine, dried, concentrated, and subjected to silica flash column chromatography using 0 to 70% EtOAc in PE to isolate (R)-tert-butyl 3-(3-cyclopropyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (391) (2.6 g, 23%) as a light yellow oil.