Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]C1C=CC(C)=CC=1.C(N(CC)CC)C.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[C:16]1([S:22]([NH2:1])(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1ccc(N)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 132.6 %

Procedure:
To an ice cold stirred solution of p-toluidine (5.00 g, 47 mmol) and triethylamine (6.5 ml, 51 mmol) in dry THF (100 ml) under argon was slowly added benzenesulphonyl chloride (5.9 ml, 47 mmol). A white precipitate formed. The ice bath was removed and the reaction stirred at ambient temperature for four hours. THF was evaporated under reduced pressure and the resulting oil partitioned between ethyl acetate (100 ml) and 2M hydrochloric acid (100 ml). The organic layer was separated and washed with 2M hydrochloric acid (3×75 ml), water (75 mi), 5% sodium hydrogen carbonate (3×75 ml) and finally water (75 ml). 4-he solution was then dried over MgSO4, filtered and evapourated to give the crude sulphonamide, which was crystallised from ethyl acetate/hexane to give N-4-methylbenzll phenylsulphonamide (9.8 g, 85%) as a white crystalline solid.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.CN(P(N(C)C)(N(C)C)=O)C.[C:24]1([C:30]([O:32][CH3:33])=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1.CI.[NH4+].[Cl-]>C1COCC1>[CH3:33][O:32][C:30]([C:24]1([CH3:1])[CH2:29][CH2:28][CH2:27][CH:26]=[CH:25]1)=[O:31]
Reactant: COC(=O)C1=CCCCC1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C1(C)C=CCCC1
Temperature: 78 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of freshly distilled N-isopropylpropan-2-amine (4.20 mL, 29.96 mmol) in THF (150 mL) under argon was added dropwise nBuLi (12.65 mL of 2.2 M solution, 27.82 mmol). After 15 min the solution was cooled to 78° C. and dry HMPA (4.84 mL, 27.82 mmol) was added. The mixture was stirred for 30 min at 78° C. and methyl cyclohexene-1-carboxylate (3.00 g, 21.40 mmol) was then added. After stirring an additional 10 min, methyl iodide (2.00 mL, 32.10 mmol) was added. The solution was then allowed to warm to 5° C. over 2 h. An aqueous saturated solution of NH4Cl was poured into the orange mixture. After dilution with hexanes and washing with brine, the organic layer was dried over Na2SO4 and carefully evaporated to 3.3 g of generate methyl 1-methylcyclohex-2-ene-1-carboxylate, 66a, which was used without further purification.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:12]([S:15][CH2:16][CH3:17])([F:14])[F:13].[CH3:25]I.O>CN(C)C=O>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]([O:24][CH3:25])([C:12]([S:15][CH2:16][CH3:17])([F:14])[F:13])[CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: CI
Reactant: CCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSC(F)(F)C(Cn1cncn1)(OC)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a solution of 60%) sodium hydride (0.16 g, 4.0 mmol) in N,N-dimethylformamide (50 ml), 2-(2,4-difluorophenyl)-1-(ethylthio)-1,1-difluoro-3-(1H-1,2,4-triazole-1-yl)-2-propanol (1.0 g, 3.0 mmol) was added dropwise under ice cooling, followed by stirring at room temperature for 30 minutes. Methyl iodide (0.56 g, 3.9 mmol) was then added dropwise to the reaction mixture under ice cooling and the resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ether. The ether solution was washed with water and dried over sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was subjected to a silica gel column and from the chloroform eluate fraction, 1-[2-(2,4-difluorophenyl)-3-ethylthio-3,3-difluoro-2-methoxypropyl]-1H-1,2,4-triazole (0.81 g, yield: 78%) was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH:13]=O)=[C:11]([CH3:15])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:17][O:18][C:19]([C:21]1[NH:22][N:23]=[C:24]([NH2:26])[CH:25]=1)=[O:20].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:17][O:18][C:19]([C:21]1[NH:22][N:23]=[C:24]([NH:26][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH3:15])[CH:25]=1)=[O:20]
Reactant: COC(=O)c1cc(N)n[nH]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1C=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(NCc2c(-c3ccc(F)cc3)noc2C)n[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
To a solution of 3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carbaldehyde (1.75 g, 8.53 mmol) and the 5-amino-2H-pyrazole-3-carboxylic acid methyl ester hydrochloride (1.2 g, 8.53 mmol) in methanol (70 mL) at room temperature was added molecular sieves (2.5 g) and then after 1 h, acetic acid (6.8 mL, 119.4 mmol) was added. Then sodium cyanoborohydride (1.07 g, 17.1 mmol) was added portionwise and the mixture stirred at room temperature overnight. After evaporation, dichloromethane was added and the mixture washed with sodium hydrogen carbonate (saturated solution). The organic layer was then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica, heptane:ethyl acetate 7:3 to 6:4) afforded 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2H-pyrazole-3-carboxylic acid methyl ester (1.2 g, 44%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6](=O)[C:7](Cl)(Cl)Cl)[CH3:2].[NH2:13][NH2:14].Cl.[CH3:16][CH2:17][OH:18]>>[CH2:1]([O:3][C:4]([C:5]1[NH:13][N:14]=[C:7]([O:18][CH2:17][CH3:16])[CH:6]=1)=[O:12])[CH3:2]
Reactant: CCO
Reactant: NN
Reactant: CCOC(=O)CC(=O)C(Cl)(Cl)Cl
Agent: Cl
Product: CCOC(=O)c1cc(OCC)n[nH]1

Procedure:
4,4,4-Trichloro-3-oxo-butyric acid ethyl ester (Int 8, 1 eq) and H2NNH2.HCl (1.1 eq) are mixed in EtOH. The resulting mixture is refluxed overnight. The mixture is then evaporated and the obtained crude is purified by chromatography to give Int 9 and 5-ethoxy-2H-pyrazole-3-carboxylic acid ethyl ester (Int 10).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]CC)=[O:14])=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:20][CH:19]=3)[C:9]=2[N:28]([CH3:30])[CH3:29])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:26])(=[O:27])[NH2:25])=[CH:20][CH:19]=3)[C:9]=2[N:28]([CH3:30])[CH3:29])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(N(C)C)c1-c1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)c1c(-c2ccc(Cl)cc2)sc(C(=O)O)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
Ethyl 5-(4-chlorophenyl)-4-(dimethylamino)-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (compound 34e, 2.00 g, 4.30 mmol) was suspended in ethanol (30 ml) and solution of NaOH (0.86 g, 21.5 mmol) in water (4 ml) was added to it at 25° C. The reaction mixture was then heated at 75° C. under stirring for 2 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue so obtained was diluted with water (10 ml) and cooled using ice bath. To the cooled mixture was added aqueous 10% HCl to bring the pH od the solution to about 6. The mixture so obtained was extracted with ethyl acetate (3×30 ml). The combined organic layer was then dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain the title compound (1.60 g, 85.1%)
Reaction SMILES: N[C@H](C(O)=O)COC[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].C[N+](C)(C)C[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[N:31]1C(=O)CCC1=O)(C)=O.CN1CCOCC1>C(O)(=O)C>[CH2:22]1[CH2:23][CH2:24][CH:19]([NH:31][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:20][CH2:21]1
Reactant: CC(=O)ON1C(=O)CCC1=O
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: N[C@@H](COCc1ccccc1)C(=O)O
Agent: [OH-]
Solvent: CN1CCOCC1
Solvent: CC(=O)O
Product: C1CCC(NC2CCCCC2)CC1

Procedure:
H-Ser(Bzl)-OH (18.6 g, 95.4 mmol) was dissolved in 45 ml of Triton B (40% methanolic solution of Trimethylbenzylammonium Hydroxide), evaporated to dryness and the residue re-evaporated twice with DMF (250 ml each). The oily residue was taken up in DMF (250 ml) and stirred with Ac-OSu (16.5 g, 95.4 mmol) for 5 hr. A few ml (~5 ml) of NMM was added to bring the reaction to slightly basic conditions during this period of time. Acetic acid (~5 ml) was then added and the solvents removed by evaporation, leaving an oily residue which was partitioned between 5% HOAc and EtOAc. The aqueous layer was extracted once more with EtOAc and the combined EtOAc solution washed twice with small volumes of H2O, dried over Na2SO4, and evaporated to approximately 300 ml (1/3 of original volume). Crystalline product formed immediately when DCHA was added to a slightly basic condition (~35 ml). The crude material (32.5 g, mp 135°- 145°) was recrystallized from EtOH (150 ml) and ether (900 ml):
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:21][O:20]1>CN(C=O)C>[F:1][C:2]1[C:10]2[N:9]([CH2:18][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)([OH:20])[CH3:21])[C:8]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCc2[nH]c3c(F)cccc3c2C1
Reactant: CC1(c2ccncc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cccc(F)c3n2CC(C)(O)c2ccncc2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A flask was charged with 6-fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.2 g, 5.8 mmol) in DMF (10 mL) and stirred for 5 min. NaH (60% in hexane) (705 mg, 17.6 mmol) was added and the mixture stirred at RT for 10 min. Then 4-(2-methyloxiran-2-yl)pyridine (1.56 g, 11.6 mmol) was added and the mixture stirred at RT for 16 h. The progress of reaction was monitored by TLC. The reaction mixture was poured into ice water and filtered. The filtrate was washed with water and concentrated. The residue was recrystallized from ether to get pure product. 1HNMR (DMSO, HCl salt) d (ppm): 8.70 (d, 2H), 8.0 (d, 2H), 7.40 (m, 1H), 7.20 (d, 1H), 6.85 (m, 1H), 6.10 (m, 1H), 4.58 (d, 1H), 4.38 (m, 2H), 4.22 (m, 1H), 3.20 (m, 3H), 2.90 (s, 3H), 1.60 (d, 3H).
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:39][C@H:40]([C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[CH2:41][CH:42]([CH3:44])[CH3:43]>C1COCC1.C(N(CC)CC)C>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([NH:39][C@H:40]([C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[CH2:41][CH:42]([CH3:44])[CH3:43])=[O:13])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Z-Asp(OtBu)-OH (10.23 g) in THF (50 mL) was added N-methylmorpholine (3.30 mL) and isobutyl chloroformate (3.90 mL) at −20° C. After 10 min, the reaction mixture was added to the solution of H-Leu-OBzl (11.81 g in 50 mL HCl3) at −20° C., followed by addition of triethylamine (4.18 mL). The resulting mixture was allowed to warm to room temp. After filtering off the salt, the filtrate was concentrated to an oil. The oil was dissolved in 100 mL of ethyl acetate; washed with 0.2 N HCl, 5% NaHCO3 and sat. NaCl; dried over Na2SO4. After filtration, the solvent was evaporated to give Z-Asp(OtBu)-Leu-OBzl as an oil of 14.81 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:18]([O:25][C:26](=[O:32])[C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:18]([O:25][C:26](=[O:32])[C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:14](=[O:16])[C@H:9]([C@H:10]([CH2:12][CH3:13])[CH3:11])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 93.1 %

Procedure:
N-t-butyloxycarbonyl-L-isoleucine 1/2 hydrate 36.05 g, 150 mmole), L-proline benzylester hydrochloride 36.26 g, 150 mmole) and HOBT (20.26 g, 150 mmole) were dissolved in methylene chloride (500 ml), and triethylamine 18 g, 150 mmole) and WSC hydrochloride (28.76 g, 150 mmole) were added thereto at -30° C. The mixture was stirred for 2 hours at less than 0° C. and then overnight at room temperature, and the solution was washed with 5% aqueous sodium bicarbonate (500 ml, twice), 5% aqueous citric acid (500 ml, twice) and water (508 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give N-t-butyloxycarbonyl-L-isoleucyl-L-proline benzylester(yield: 58.43 g, 93.1%).
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]1.[C:16](N1C=CN=C1)(N1C=CN=C1)=[O:17].C(N(CC)C(C)C)(C)C.[NH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44]>C(#N)C>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][CH:12]([NH:15][C:16]([NH:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:17])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC1CCN(c2ccccn2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCNC(=O)NC1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
an ice-cooled solution of 1-(2-pyridinyl)-4-piperidinylamine dihydrochloride EP-A-0021973) (20.82 g, 0.0832 moles) and 1,1′-carbonyldiimidazole (14.85 g, 0.915 moles) in acetonitrile (140 ml) under an atmosphere of nitrogen was added N,N-di-iso-propylethylamine (22.0 g, 29.7 ml, 0.170 moles) over a period of 20 minutes. The resultant light brown solution was stirred at ambient temperature for 20 minutes and a solution of tert-butyl N-(2-aminoethyl)carbamate (14.0 g, 0.0874 moles) in acetonitrile (10 ml plus 5 ml rinse) was added over a period of 5 minutes. The resultant mixture was then heated under reflux for 2.5 hours. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (150 ml). This solution was washed successively with saturated aqueous sodium bicarbonate solution (70 ml) and deionised water (20 ml). The aqueous phases were extracted with ethyl acetate (2×100 ml) and the combined organic phases were washed with water. The organic phase was dried over anhydrous magnesium sulphate and the solution was concentrated to a volume of approximately 200 ml in vacuo. The resultant solution was then distilled at atmospheric pressure until the volume was approximately 75 ml. The solution was allowed to cool to ambient temperature during which time crystallisation occurred. The resultant thick slurry was diluted with ethyl acetate (60 ml) and was cooled in ice. The solid was collected by filtration and the filter cake was washed with cold ethyl acetate (2×30 ml). The resultant solid was dried in vacuo at 50° C. for 20 hours to give the crude product (24.0 g) that was recrystallised from ethyl acetate (270 ml) to give the title compound (20.7 g) as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:15][C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1>CS(C)=O.O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:20]1[CH:19]=[CH:18][N:17]=[C:16]([Cl:15])[CH:21]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cccc(Oc2ccnc(Cl)c2)c1
Reaction time: 0.17 h
Yield: 88.9 %

Procedure:
To a mixture of 3-aminophenol (3.7 g, 34.09 mmol) in DMSO (50 mL) was added Cs2CO3 (30.7 g, 94.46 mmol). The mixture stirred for 10 minutes and then 2,4-dichloropyridine (5.0 g, 33.79 mmol) was added. The mixture was stirred at 120° C. for 1.5 h. The mixture was cooled and diluted with water. The aqueous solution was extracted with EtOAc (3×100 mL). The organic extracts were combined, dried over MgSO4 and concentrated to afford a dark oil. The oil was purified via column chromatography, eluting with 30-40% EtOAc/hexanes, to afford 4-(3-Aminophenoxy)-2-chloropyridine (6.63 g, 89%) as a brown solid.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([Cl:17])[CH:12]=2)[N:3]=1.[C:18]([N:25]1[CH2:30][C@@H:29]2[CH2:31][CH:26]1[CH2:27][NH:28]2)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C([O-])([O-])=O.[K+].[K+].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:21]([O:20][C:18]([N:25]1[CH2:30][C@@H:29]2[CH2:31][C@H:26]1[CH2:27][N:28]2[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([Cl:17])[CH:12]=2)[N:3]=1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CC1CN2
Reactant: Clc1cc(-c2cc3nccn3c(Cl)n2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1nc(-c2ccnc(Cl)c2)cc2nccn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a 100 mL RBF was added 5-chloro-7-(2-chloro-pyridin-4-yl)-imidazo[1,2-c]pyrimidine (2.0 g, 7.6 mmol), 20 mL NMP, (S)—N-Boc-2,5-Diaza-bicyclo[2.2.1]heptane (1.6 g, 8.3 mmol), K2CO3 (1.05 g, 7.6 mmol) and DIEA (1.3 mL, 7.6 mmol). The mixture was stirred at rt under nitrogen for 15 h, and all starting material was converted. The reaction mixture was added to a 100 mL ice water slowly, and a white solid was precipitated out. The precipitate was filtrated and washed with 50 mL water, and further purified by flash chromatograph. The title compound was obtained. MS (ES+):427 (M+H)+.
Reaction SMILES: CC([O-])(C)C.[K+].[F:7][C:8]([F:27])([F:26])[C:9]1[CH:10]=[C:11]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[NH:12][CH:13]=[C:14]([C:17]#[N:18])[C:15]#[N:16].[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH2:32]Cl>CS(C)=O>[C:15]([C:14]([C:17]#[N:18])=[CH:13][N:12]([CH2:32][C:31]1[CH:34]=[CH:35][C:36]([Cl:37])=[C:29]([Cl:28])[CH:30]=1)[C:11]1[CH:10]=[C:9]([C:8]([F:26])([F:27])[F:7])[CH:21]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:19]=1)#[N:16]
Reactant: N#CC(C#N)=CNc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)=CN(Cc1ccc(Cl)c(Cl)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
With stirring, 16.8 g of potassium tert-butylate are added by small amounts to a solution of 45.7 g of 3,5-bis-trifluoromethyl-N-(2,2-dicyanovinyl)-aniline in 200 ml of dimethyl sulphoxide. The solution is kept for 4 hours at 40° C. With further stirring, 20.8 ml of 3,4-dichlorobenzyl chloride in 20 ml of dimethyl sulphoxide are added dropwise and the reaction mixture is then stirred for 12 hours at 40° C. The mixture is then poured onto 2 liters of ice and the precipitated product is extracted with chloroform. The chloroform solution is washed with water, dried over sodium sulphate and the chloroform is distilled off. The crude product is chromatographed over a silica gel column with methyl acetate/hexane (1:3 v/v) as eluant, yielding 15 g of the desired product in the form of yellow crystals with a melting point of 102°-103° C.
Reaction SMILES: [F:1][C:2]1([F:40])[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]3[O:13][C:14]4[C:19]([C@@:20]5([CH2:24][S:23][C:22]([NH:25]C(=O)OC(C)(C)C)=[N:21]5)[C:9]=3[CH:8]=2)=[CH:18][C:17]([C:33]2[C:34]([F:39])=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:16][CH:15]=4)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:40][C:2]1([F:1])[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]3[O:13][C:14]4[C:19]([C@@:20]5([CH2:24][S:23][C:22]([NH2:25])=[N:21]5)[C:9]=3[CH:8]=2)=[CH:18][C:17]([C:33]2[C:34]([F:39])=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:16][CH:15]=4)[CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1cnc(N3CCC(F)(F)C3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1cnc(N3CCC(F)(F)C3)cc12
Temperature: 25 °C
Reaction time: 68 h
Yield: 84.6 %

Procedure:
To a solution of (S)-tert-butyl 3-(3,3-difluoropyrrolidin-1-yl)-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazole]-2′-ylcarbamate (76.1 mg, 0.13 mmol) in DCM (1.34 mL) was added TFA (280 μL, 3.63 mmol) at ambient temperature. The reaction was stirred at ambient temperature for 68 hours. The reaction was concentrated under reduced pressure and the resulting material was purified by “catch-and release” technique using a Varian Bond ELUT SCX column. The eluate was concentrated under reduced pressure to afford (S)-3-(3,3-difluoropyrolidin-1-yl)-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazol]-2′-amine (52.14 mg, 0.11 mmol, 83% yield).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][NH:19]1.N1CCCCC1>C(O)C>[O:16]=[C:12]1[C:11](=[CH:27][C:26]2[NH:25][CH:24]=[C:23]3[C:22]=2[CH2:21][CH2:20][NH:19][C:18]3=[O:17])[C:10]2[C:14](=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[NH:13]1
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(-c3ccccc3)ccc2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C

Procedure:
A mixture of 6-phenyl-1,3-dihydro-indol-2-one (41.8 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (1 equivalent) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 3 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]1[CH2:12][C:13](N)=[O:14].Cl.[OH-:17].[Na+]>>[O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]1[CH2:12][C:13]([OH:14])=[O:17]
Reactant: [OH-]
Reactant: NC(=O)CC1Nc2ccccc2NC1=O
Agent: Cl
Agent: [Na+]
Product: O=C(O)CC1Nc2ccccc2NC1=O

Procedure:
2-(3-Oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)-acetamide (22 g, 0.11 mol) was dissolved in 10% NaOH (600 mL) and was heated under reflux for 3 hours. The mixture was cooled down via an ice-bath and was acidified with pre-cooled 10% HCl to pH -6. The solvent was concentrated and the resulting precipitate was isolated via filtration to give a gray solid as the title product: 1H NMR (DMSO-d6) δ=12.35 (bs, 1H), 10.25 (bs, 1H), 6.74–6.68 (m, 3H), 6.61–6.58 (m, 1H), 5.91 (bs, 1H), 4.08–4.04 (m, 1H), 2.69 (dd, 1H, J=5.1, 16.2 Hz), 2.51 (dd, 1H, J=6.9, 16.2 Hz)