Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.C(OC([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:29][CH:30]1[CH2:34][CH2:33][N:32]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([CH3:17])[C:10]=2[F:16])[CH2:31]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(F)c(N2CCC(N)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
A mixture of 1.00 g (3.36 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.63 g (3.38 mmol) of 3-(t-butoxycarbonyl)aminopyrrolidine, 1.00 g (9.91 mmol) of triethylamine, and 35 mL of acetonitrile was refluxed for 5 hours, then stirred at room temperature overnight. The precipitate was removed by filtration and washed with acetonitrile and ether. The crude product was suspended in 20 mL of 6M hydrochloric acid and 20 mL of glacial acetic acid and was heated at 60° C. for 2 hours. The solution was concentrated to an oil which was triturated with isopropanol. The solid was collected by filtration and washed with ether to give 1.04 g of the title compound as the hydrochloride salt, mp>300° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:23]=[CH:22][C:8](/[CH:9]=[N:10]/[C:11]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]3[C:12]=2[CH2:13][O:14][C:15]3=[O:21])=[CH:7][CH:6]=1)[CH3:3].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.[O-:33][CH2:34][CH3:35].[Na+].C(O)C>C(OCC)(=O)CC>[CH3:1][N:2]([CH2:4][C:5]1[CH:23]=[CH:22][C:8]([CH:9]2[CH:29]([C:28]3[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=3)[C:34](=[O:33])[C:35]3[C:16]([C:15]([O:14][CH2:13][CH3:12])=[O:21])=[CH:17][C:18]([F:20])=[CH:19][C:11]=3[NH:10]2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: O=Cc1ccc(F)cc1
Reactant: CN(C)Cc1ccc(/C=N/c2cc(F)cc3c2COC3=O)cc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC
Solvent: CCO
Product: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ccc(F)cc1)C(c1ccc(CN(C)C)cc1)N2
Temperature: 0 °C
Reaction time: 3 h
Yield: 13 %

Procedure:
A mixture of (E)-4-(4-((dimethylamino)methyl)benzylideneamino)-6-fluoroisobenzofuran-1(3H)-one (500 mg, 1.6 mmol) and 4-fluorobenzaldehyde (218 mg, 1.76 mmol) in ethyl propionate (10 mL) was cooled to 0° C. Then a solution of sodium ethoxide in ethanol (sodium (110 mg, 4.8 mmol) in ethanol (5 mL)) was added dropwise. After the addition the mixture was stirred at room temperature for 3 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in water and then extracted with ethyl acetate (100 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product, which was purified by chromatography (silica gel, petroleum ether/ethyl acetate=1:1) to give the title compound (100 mg, yield 13%). LC-MS (ESI) m/z: 465 (M+1)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:12](Cl)(=[O:16])[C:13](Cl)=[O:14].C(Cl)Cl.[CH3:21][O-:22].[Na+].CO>C(OCC)C>[C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[C:3]2[C:12](=[O:16])[C:13]([O:22][CH3:21])=[O:14])#[N:11]
Reactant: C[O-]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(=O)c1c[nH]c2ccc(C#N)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42 %

Procedure:
To a solution of 1H-indole-5-carbonitrile (1.14 g, 8.04 mmol) in diethyl ether (12 mL) at 4° C. was added a 2.0 M solution of oxalyl chloride in methylene chloride (4.2 mL, 8.4 mmol). The resulting solution was allowed to warm to room temperature. After 90 min, the solution was cooled to −78° C. To this solution was added 25% (w/w) solution of sodium methoxide in methanol (3.83 mL, 16.8 mmol). The resulting solution was allowed to warm to room temperature. After one hour, the solution was filtered to give the title compound (768 mg, 42%) as a light brown solid. 1H NMR (DMSO-d6) δ 9.39 (s, 1H), 8.67 (m, 1H), 8.50 (s, 1H), 7.29 (m, 1H), 3.87 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7](O)=[O:8].C([O-])([O-])OC.C([O-])(=O)C.[NH4+:24].[CH3:25]O>O>[CH3:13][O:12][C:11]1[CH:10]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[N:14]=[CH:25][NH:24][C:7]2=[O:8]
Reactant: [NH4+]
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Reactant: CO
Agent: CC(=O)[O-]
Agent: COC([O-])[O-]
Solvent: O
Product: COc1cc2nc[nH]c(=O)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
In a 10-mL volume stainless steel pressure-resistant vessel were placed 1.00 g (5.1 mmol) of 4,5-dimethoxyanthranilic acid, 2.15 g (20.3 mmol) of methyl orthoformate, 1.56 g (20.3 mmol) of ammonium acetate, and 4.0 mL of methanol. The reaction was carried out at 120° C. for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and 40 mL of water was added to the reaction mixture. The resulting aqueous mixture was stirred for 15 minutes and filtered to give 0.96 g (isolated yield: 92%) of 6,7-dimethoxyquinazolin-4-one as a brown crystalline product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.CCO.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>[Cl:8][C:4]1[CH:3]=[C:2]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])[CH:7]=[CH:6][N:5]=1
Reactant: COc1ccccc1B(O)O
Reactant: Clc1cc(Br)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: COc1ccccc1-c1ccnc(Cl)c1
Temperature: 125 °C
Yield: 62.4 %

Procedure:
To a solution of 4-bromo-2-chloro-pyridine (1.5 g, 7.8 mmol) in DME/water/EtOH 5:1:1 (20 mL) was added (2-methoxyphenyl)boronic acid (1.49 g, 9.8 mmol), Pd(PPh3)2Cl2 (112 mg, 0.16 mmol), and Na2CO3 (1.65 g, 15.6 mmol). The mixture was heated at 125° C. for 90 minutes in a microwave oven. It was concentrated under reduced pressure, and the residue was purified by flash chromatography (silica gel, cHex/EtOAc 100:0 to 80:20) to give the title compound A1 (1.07 g, 62%). MS (ES) C12H10ClNO requires: 219. found: 220 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([CH3:20])[CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[O:23][C:24](=O)[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>C(O)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:24](=[O:23])[C:25]4[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:27]=[C:22]3[CH3:21])=[C:15]([CH3:20])[CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2ccccc2c(=O)o1
Reactant: Cc1cc(C#Cc2ccc(C(C)(C)C)cc2)ccc1N
Solvent: CC(=O)O
Product: Cc1cc(C#Cc2ccc(C(C)(C)C)cc2)ccc1-n1c(C)nc2ccccc2c1=O

Procedure:
4-iodo-2-methylbenzenamine 24 (233 mg, 1 mmol) on reaction with 1-tert-butyl-4-ethynylbenzene (25b, 158 mg, 1 mmol) by employing Sonagashira coupling conditions using Pd(PPh3)4 (69.3 mg, 0.06 equiv) as catalyst, CuI (22.8 mg, 0.12 equiv) as cocatalyst, butyl amine (261 mg, 3 equiv) as base and ether as solvent and kept the reaction for 6 h. After completion of the reaction as indicated by TLC and the reaction mixture is extracted into ether (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain 4-((4-tert-butylphenyl)ethynyl)-2-methyl benzene amine (26b) as pure product. Anthranilic acid (27, 137 mg, 1 mmol) on reaction with acetic anhydride at 150° C. and reflux for 30 min, after completion of reaction aqueous sodium bicarbonate solution is added and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo afforded 2-methyl 4H-benzo[d][1,3]oxazin-4-one compound (28) as pure product. To a stirred solution of 4-((4-tert-butylphenyl)ethynyl)-2-methylbenzenamine (26b, 263 mg, 1 mmol) with 2-methyl-4H-benzo[d][1,3]oxazin-4-one (28, 161 mg, 1 mmol) in acetic acid and reflux for 8 h After completion of the reaction as indicated by TLC. then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4 afforded 3-(4-((4-tert-butylphenyl)ethynyl)-2-methylphenyl)-2-methylquinazolin-4(3H)-one (29b). Reaction of 3-(4-((4-tert-butylphenyl)ethynyl)-2-methylphenyl)-2-methyl quinazolin-4(3H)-one (29b, 406 mg, 1 mmol) with 2,4-dihydroxybenzaldehyde (30d, 138 mg, 1 mmol) was taken in acetic acid Then the resulting mixture was stirred under reflux conditions for 8 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (5d) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]=[N+]=[N-])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1.N1C=CC=CC=1.O>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)=[O:30])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH2:18])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(CN=[N+]=[N-])c2)n1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Cl)cc2)n(-c2cccc(CN)c2)n1
Reaction time: 3 h
Yield: 103.2 %

Procedure:
To a solution of Example H (1.50 g, 5.55 mmol) in dry THF (10 mL) was added a THF solution (10 mL) of 4-chlorophenyl isocyanate (1.02 g, 6.66 mmol) and pyridine (5.27 g, 66.6 mmol) at RT. The reaction mixture was stirred for 3 h and then H2O (30 mL) was added. The precipitate was filtered and washed with 1N HCl and ether to give 1-{3-tert-butyl-1-[3-(aminomethyl)phenyl}-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea (2.28 g, 97%) as a white solid, which was used for next step without further purification. MS (ESI) m/z: 424 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6][CH2:5]2.[O:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18]OS(C)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[O:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6][CH2:5]2
Reactant: O=C1OCCc2cc(O)ccc21
Reactant: CS(=O)(=O)OC[C@@H]1CCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1OCCc2cc(OC[C@@H]3CCCO3)ccc21
Temperature: 70 °C

Procedure:
A mixture of 6-hydroxyisochroman-1-one (332 mg), methanesulfonic acid (S)-1-(tetrahydrofuran-2-yl)methyl ester (284 mg), cesium carbonate (1.28 g) and DMF (8 mL) was heated at 70° C. for 7 hours. The cooled reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried and concentrated. The crude product was purified by chromatography on silica gel. The product with the molecular weight of 248.28 (C14H16O4) was obtained in this way; MS (ESI): 249 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:20]3[CH:21]=[N:22][C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:9]3[N:14]([C:6]=2[N:5]=[CH:4][N:3]=1)[CH2:13][CH:12]([NH:15][C:16](=[O:19])[CH:17]=[CH2:18])[CH2:11][CH2:10]3>CCCCCC.C(O)C.C(N(CC)CC)C>[NH2:1][C:2]1[C:7]2[C:8]([C:20]3[CH:21]=[N:22][C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:9]3[N:14]([C:6]=2[N:5]=[CH:4][N:3]=1)[CH2:13][C@H:12]([NH:15][C:16](=[O:19])[CH:17]=[CH2:18])[CH2:11][CH2:10]3.[NH2:1][C:2]1[C:7]2[C:8]([C:20]3[CH:21]=[N:22][C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:9]3[N:14]([C:6]=2[N:5]=[CH:4][N:3]=1)[CH2:13][C@@H:12]([NH:15][C:16](=[O:19])[CH:17]=[CH2:18])[CH2:11][CH2:10]3
Reactant: C=CC(=O)NC1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Solvent: CCO
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: C=CC(=O)N[C@@H]1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Product: C=CC(=O)N[C@H]1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1

Procedure:
N-(4-amino-5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizin-8-yl)acrylamide (197 mg) obtained in Step 12 was subjected to optical resolution using a column for optical resolution (CHIRALPAK AD-H 20 mm×250 mm, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol/triethylamine, 50:50:0.1, flow rate: 10 ml/min) to obtain 72.4 mg of enantiomer A (retention time: 15.4 min, (R)-N-(4-amino-5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizin-8-yl)acrylamide (Compound I-1)) and 78.3 mg of enantiomer B (retention time: 32.5 min, (S)-N-(4-amino-5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizin-8-yl)acrylamide (Compound I-2)) as a light-yellow solid.
Reaction SMILES: N1C=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.BrC1[CH:17]=[N:18]C=CC=1>>[N:18]1[CH:5]=[CH:4][CH:3]=[C:2]([C:7]2[CH:8]=[CH:9][C:10]([CH:11]=[O:12])=[CH:13][CH:14]=2)[CH:17]=1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Reactant: Brc1cccnc1
Product: O=Cc1ccc(-c2cccnc2)cc1

Procedure:
This aldehyde was prepared using the procedure for 4-pyridin-2-yl-benzaldehyde in Example 126 from 3-bromopyridine and 4-formylboronic acid to give a white crystalline solid (94%): mp=53-55° C.; Rf=0.08 (30% EtOAc/hexanes); IR (KBr) 1700, 1605, 1219 cm−1; 1H NMR (CDCl3) δ 7.55-7.60 (m, 1H), 7.76-7.79 (m, 2H), 8.01-8.05 (m, 2H), 8.08-8.12 (m, 1H), 8.69-8.71 (m, 1H), 8.94-8.95 (m, 1H), 10.10 (s, 1H). LRMS 184 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:9]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:10][N:11]([CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[N:12]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1[nH]ncc1NC(=O)c1cnn2cccnc12
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nn(CCN2CCOCC2)cc1NC(=O)c1cnn2cccnc12
Temperature: 50 °C
Reaction time: 5 h
Yield: 38 %

Procedure:
To a solution of N-(5-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (39.1 mg, 0.106 mmol) in 3 mL DMF was added cesium carbonate (109.7 mg, 0.3367 mmol) and 4-(2-chloroethyl)morpholine HCl. The reaction mixture was stirred at 50° C. for 5 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The mixture of regioisomer products was separated and purified by reverse phase HPLC and lyophilized to give 19.4 mg (38%) N-(3-(5-chloro-2-methoxyphenyl)-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; LCMS (ESI) m+H=482.1; 1H NMR (400 MHz, DMSO-d6) δ: 9.50 (s, 1H), 9.31 (dd, 1H), 8.66 (d, 1H), 8.63 (s, 1H), 8.03 (s, 1H), 7.58 (dd, 1H), 7.54 (d, 1H), 7.32 (d, 1H), 7.27 (dd, 1H), 4.05 (m, 2H), 3.85 (s, 3H), 3.44 (m, 2H), 2.71 (m, 2H), 2.60 (m, 2H), 2.23 (m, 4H); and 9.3 mg (18%) of N-(5-(5-chloro-2-methoxyphenyl)-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; LCMS (ESI) m+H=482.1; 1H NMR (400 MHz, DMSO-d6) δ: 9.67 (s, 1H), 9.31 (dd, 1H), 8.76 (d, 1H), 8.65 (s, 1H), 8.34 (s, 1H), 7.48 (dd, 1H), 7.39 (d, 1H), 7.30 (d, 1H), 7.38 (t, 1H), 4.29 (t, 2H), 3.84 (s, 3H), 3.58 (t, 2H), 2.77 (t, 2H), 2.46 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1N(C2C=CC=CC=2)[C:7]2[C:12]([C:13](=[O:25])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][CH:17]=1)=[CH:11][CH:10]=[C:9]([Cl:26])[CH:8]=2)=[O:4].[NH2:33][CH2:34][CH2:35][OH:36].[CH:37]1[CH:38]=[CH:39][C:40]2[N:45](O)N=N[C:41]=2[CH:42]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:45]([C:40]2[CH:39]=[CH:38][CH:37]=[CH:42][CH:41]=2)[C:7]2[C:12]([C:13](=[O:25])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:24])[NH:33][CH2:34][CH2:35][OH:36])=[CH:18][CH:17]=1)=[CH:11][CH:10]=[C:9]([Cl:26])[CH:8]=2)=[O:4]
Reactant: NCCO
Reactant: On1nnc2ccccc21
Reactant: COC(=O)c1c(Cc2ccc(C(=O)O)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(Cc2ccc(C(=O)NCCO)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
A mixture of 3-(4-carboxybenzyl)-7-chloro-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxylic acid methyl ester (167 mg, 0.37 mmol), 2-aminoethanol (34 mg, 0.56 mmol), HOBt (50 mg), EDCI (142 mg, 0.74 mmol) and DIPEA (0.5 mL) in DCM (10 mL) and DMF (0.4 mL) was stirred at RT for 2 h. The reaction mixture was then partitioned between water and EtOAc. The organic layer was separated, washed twice with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified twice by flash chromatography to afford 7-chloro-3-[4-(2-hydroxyethylcarbamoyl)-benzyl]-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (99 mg) as an off-white powder. MS=491 [M+H]+; MP=162-163.5° C.
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][S:5]1)#[N:2].O.[NH2:10][NH2:11]>CO>[NH2:2][C:1]1[NH:11][N:10]=[C:4]([NH:8][CH2:7][CH2:6][S:5][S:5][CH2:6][CH2:7][NH:8][C:4]2[N:3]=[C:1]([NH2:2])[NH:11][N:10]=2)[N:3]=1
Reactant: N#CN=C1NCCS1
Reactant: NN
Solvent: CO
Solvent: O
Product: Nc1nc(NCCSSCCNc2n[nH]c(N)n2)n[nH]1
Temperature: 25 °C

Procedure:
To a mixture of 1.27 g of 2-cyanoiminothiazolidine well-known and 20 ml of methanol was added 0.3 ml of hydrazine monohydrate, and the mixture was stirred at room temperature for an hour. After the reaction, the solvent was evaporated under reduced pressure, and the residue was recrystallized from water to give 1.42 g of bis{2-[N-(5-amino-1,2,4-triazol-3-yl)amino]ethyl}disulfide (Compound 3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH:23]([C:25]1[NH:29][C:28]([CH3:30])=[C:27]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:26]=1[CH3:36])=O.N1CCCCC1>C(O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:25]1[NH:29][C:28]([CH3:30])=[C:27]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:26]=1[CH3:36])(=[O:12])=[O:11]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 5-(2,6-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one(1 g, 2.82 mmol), 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (548 mg, 1 eq.) and piperidine (0.416 mL, 1.5 eq.) in ethanol (5 mL) was stirred at rt for 5 days. The reaction was concentrated, acidified with 2M HCl (pH 3), stirred for 15 mins, diluted with water and filtered. The solid was washed with water and triturated with ethanol to give the titled compound as a pale orange solid.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([CH3:12])[CH2:9][CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>[Ni].C(O)(C)C>[CH:1]1([CH2:7][CH:8]([CH3:12])[CH2:9][CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(CCO)CC1=CCCCC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(C)O
Product: CC(CCO)CC1CCCCC1
Yield: 93 %

Procedure:
A solution of 4-(cyclohex-1-en-1-yl)-3-methylbutan-1-ol (1.68 kg, 10.0 mols), isopropyl alcohol (100 ml) and Raney nickel (100 g) or other suitable sponge-metal catalyst was hydrogenated at 400 psi, at 140° C. for 10-12 h until the theoretical amount of hydrogen was taken up. The mixture was cooled and filtrated. The isopropyl alcohol was evaporated and the residue obtained was distilled under reduced pressure to provide 4-(Cyclohex-1-yl)-3-methylbutan-1-ol (1.58 kg, yield: 93%, purity: 99% sum of the isomers).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[Br:12][C:13]1[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([CH:20]=1)[CH:18]=O.[C:25]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])#[N:26].N1CCCCC1>C(O)C.O>[CH2:31]([O:30][C:28]([C:27]1[CH:18]([C:17]2[CH:16]=[C:15]([O:21][CH3:22])[C:14]([O:23][CH3:24])=[C:13]([Br:12])[CH:20]=2)[C:3]2[C:2](=[CH:1][C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[CH:4]=2)[O:11][C:25]=1[NH2:26])=[O:29])[CH3:32]
Reactant: CCOC(=O)CC#N
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: Oc1ccc2ccccc2c1
Solvent: O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(N)Oc2cc3ccccc3cc2C1c1cc(Br)c(OC)c(OC)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
2-Naphthol (170 mg, 1.2 mmol), 5-bromo-3,4-dimethoxy-benzaldehyde (245 mg, 1 mmol) and ethyl cyanoacetate (113 mg, 1 mmol) were taken in 5 ml ethanol at room temperature, charged with piperidine (50 μl) and then stirred at 80° C. for 18 h. Reaction was complete and clean. The reaction mixture was then cooled down to room temperature, diluted with water to 20 ml, solids were separated by filtration, washed with methanol and dried under high vacuum (360 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([NH:15][CH3:16])[CH:13]=[CH2:14]>C(#N)C>[CH2:12]([N:15]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])[CH3:16])[CH:13]=[CH2:14]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Reactant: C=CCNC
Solvent: CC#N
Product: C=CCN(C)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 93.4 %

Procedure:
4-chloro-1-fluoro-2-nitro-benzene (2.53 g, 14.41 mmol) was dissolved in anhydrous acetonitrile (80 mL). Allyl methyl amine (1.64 mL, 17.29 mmol) was added dropwise while the solution was stirred. The mixture was heated at 80° C. overnight, concentrated with silica gel powder (18 g), and purified by flash chromatography eluting with 10% ethyl acetate in hexanes (1 L) to give the title compound (3.05 g, 93%). MS (DCI) m/z 227.09 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 2.80 (s, 3 H) 3.76 (d, J=5.43 Hz, 2 H) 5.16–5.29 (m, 2 H) 5.85 (m, 1 H) 7.00 (d, J=9.16 Hz, 1 H) 7.33 (dd, J=8.99, 2.54 Hz, 1 H) 7.74 (d, J=2.71 Hz, 1 H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:21][CH2:20][C:19]2[C:22]([S:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[NH:36][C:35](=[O:40])[C:34]4([CH3:42])[CH3:41])=[C:23]([Cl:26])[CH:24]=[CH:25][C:18]=2[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[Cl:26][C:23]1[CH:24]=[CH:25][C:18]2[CH2:17][CH2:16][NH:15][CH2:21][CH2:20][C:19]=2[C:22]=1[S:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35](=[O:40])[C:34]2([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCCCc3ccc4c(c3)C(C)(C)C(=O)N4)c2CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)C(=O)Nc2ccc(CCCSc3c(Cl)ccc4c3CCNCC4)cc21
Temperature: 25 °C

Procedure:
Add trifluoroacetic acid (0.2 mL, 2.6 mmol) to a solution of 3-tert-butoxycarbonyl-7-chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (257 mg, 0.5 mmol) in dichloromethane (5 mL) then stir at ambient temperature over the weekend. Concentrate in vacuo. Dissolve the residue in methanol and load onto an SCX column. Elute with methanol followed by 7M ammonia in methanol. Collect the basic fraction and concentrate in vacuo. Purify the residue by prep-LCMS [Supelco Discovery C18 column (21.2×100 mm, 5 μm packing), 25 mL/min flow rate, eluting with a water/acetonitrile gradient containing acetic acid as modifier over 12 min, fraction collection triggered by Electrospray MS] to give 7-chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a white solid (101 mg, 25% over 2 steps). MS (ES+) m/z: 415 (M+H)+.